Advertisement

Risk-based decision-making in the treatment of HER2-positive early breast cancer: Recommendations based on the current state of knowledge

Open AccessPublished:May 19, 2021DOI:https://doi.org/10.1016/j.ctrv.2021.102229

      Highlights

      • Risk of relapse must be evaluated to optimise treatment for HER2-positive early breast cancer.
      • Decision about whether to offer neoadjuvant chemotherapy plus pertuzumab–trastuzumab.
      • Patients with a pathological complete response continue HER2-targeted therapy to complete 18 cycles (before and after surgery).
      • Patients with residual disease after standard-of-care neoadjuvant chemotherapy plus HER2-targeted therapy should receive post-neoadjuvant trastuzumab emtansine to complete 14 cycles (after surgery).
      • For patients who undergo surgery first, treatment with adjuvant chemotherapy plus pertuzumab–trastuzumab is the standard of care for those patients with a higher risk of relapse.
      • For patients with node-negative disease and tumours <2 cm at presentation, paclitaxel for 12 weeks plus 18 cycles of trastuzumab might be a good option for the post-operative adjuvant therapy.

      Abstract

      Treatment of HER2-positive early breast cancer (EBC) continues to evolve with neoadjuvant (pre-operative) and adjuvant (post-operative) HER2-targeted therapies as standard of care. There are two important decision points. The first involves deciding between neoadjuvant therapy or proceeding directly to surgery. Neoadjuvant chemotherapy (NACT) plus pertuzumab–trastuzumab is appropriate for patients with high-risk HER2-positive EBC (tumour diameter ≥2 cm, and/or node-positive disease). Patients with node-negative disease and tumour diameter <2 cm are candidates for upfront surgery followed by paclitaxel for 12 weeks plus 18 cycles of trastuzumab, with the option to add pertuzumab (if pN+). The second decision point involves the pathohistological result at surgery after neoadjuvant therapy. Total pathological complete response (tpCR: ypT0/is, ypN0) is associated with improved survival endpoints. Patients with tumours ≥2 cm and/or node-positive disease at diagnosis who have a tpCR after dual blockade should continue pertuzumab–trastuzumab in the adjuvant setting to complete 1 year (18 cycles) of treatment. For patients with invasive residual disease, 14 cycles of post-neoadjuvant trastuzumab emtansine (T-DM1) therapy significantly increases invasive-DFS compared with trastuzumab. Extended adjuvant therapy with neratinib is an option in selected patients (HER2-positive and oestrogen receptor [ER]-positive) who have completed adjuvant trastuzumab-based therapy. Less aggressive chemotherapy regimens are recommended in populations with a lower risk of recurrence (patients with small tumours without axillary involvement; patients unlikely to tolerate anthracycline-taxane or taxane-carboplatin regimens). Ultimately, treatment recommendations should be consistent with local and international guidelines. Further studies will guide optimisation of treatment for patients with HER2-positive EBC according to the risk of disease recurrence.

      Keywords

      Introduction

      The HER2-positive early breast cancer (EBC) treatment landscape evolved steadily over two decades [
      • Loibl S.
      • Gianni L.
      HER2-positive breast cancer.
      ]. Pivotal adjuvant trials [
      • Piccart-Gebhart M.J.
      • Procter M.
      • Leyland-Jones B.
      • Goldhirsch A.
      • Untch M.
      • Smith I.
      • et al.
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
      ,
      • Romond E.H.
      • Perez E.A.
      • Bryant J.
      • Suman V.J.
      • Geyer C.E.
      • Davidson N.E.
      • et al.
      Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
      ,
      • Joensuu H.
      • Kellokumpu-Lehtinen P.-L.
      • Bono P.
      • Alanko T.
      • Kataja V.
      • Asola R.
      • et al.
      Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.
      ,
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • Pienkowski T.
      • Martin M.
      • Press M.
      • et al.
      Adjuvant trastuzumab in HER2-positive breast cancer.
      ,
      • Perez E.A.
      • Romond E.H.
      • Suman V.J.
      • Jeong J.-H.
      • Davidson N.E.
      • Geyer C.E.
      • et al.
      Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31.
      ] transformed standards of care, catalysing transition from chemotherapy to chemotherapy-plus-trastuzumab (significantly improving disease-free/overall survival [DFS/OS]). Neoadjuvant treatment opened two major avenues: increased pathological complete response (pCR; therefore, increased DFS and potentially OS) [
      • Cortazar P.
      • Zhang L.
      • Untch M.
      • Mehta K.
      • Costantino J.P.
      • Wolmark N.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis.
      ], and a new therapy selection window: “post-neoadjuvant treatment [
      • Gianni L.
      • Pienkowski T.
      • Im Y.-H.
      • Roman L.
      • Tseng L.-M.
      • Liu M.-C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial.
      ,
      • Robidoux A.
      • Tang G.
      • Rastogi P.
      • Geyer C.E.
      • Azar C.A.
      • Atkins J.N.
      • et al.
      Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP Protocol B-41): An open-label, randomised phase 3 trial.
      ,
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA).
      ,
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • Delaloge S.
      • Moy B.
      • Iwata H.
      • et al.
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ,
      • Swain S.M.
      • Ewer M.S.
      • Viale G.
      • Delaloge S.
      • Ferrero J.-M.
      • Verrill M.
      • et al.
      Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): A phase II, open-label, multicenter, multinational cardiac safety study.
      ,
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ].” Recently, post-neoadjuvant trastuzumab emtansine (T-DM1) was evaluated for invasive residual disease at surgery after neoadjuvant chemotherapy (NACT) plus anti-HER2 therapy [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ]. Extended adjuvant neratinib has been evaluated post-adjuvant trastuzumab [
      • Chan A.
      • Delaloge S.
      • Holmes F.A.
      • Moy B.
      • Iwata H.
      • Harvey V.J.
      • et al.
      Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Chan A.
      • Moy B.
      • Mansi J.
      • Ejlertsen B.
      • Holmes F.A.
      • Chia S.
      • et al.
      Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial.
      ].
      Chemotherapy de-escalation with trastuzumab has been evaluated in selected subgroups with low relapse risk (mainly phase II trials), to reduce toxicity without compromising outcomes [

      Cortes J, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Escrivá S, et al. Chemotherapy (CT) de-escalation using an FDG-PET/CT (F-PET) and pathological response-adapted strategy in HER2[+] early breast cancer (EBC): PHERGain Trial. J Clin Oncol 2020;38:Abstract 503.

      ,
      • van Ramshorst M.S.
      • van der Voort A.
      • van Werkhoven E.D.
      • Mandjes I.A.
      • Kemper I.
      • Dezentjé V.O.
      • et al.
      Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial.
      ,
      • Harbeck N.
      • Gluz O.
      • Christgen M.
      • Kates R.E.
      • Braun M.
      • Küemmel S.
      • et al.
      De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the west german study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET.
      ]. However, there is no clinical consensus for such strategies; optimal treatment is still standard-of-care chemotherapy plus anti-HER2 therapy.
      We discuss evolving clinical risk-based decision-making approaches for HER2-targeted therapy; integrating recent data including those generated by clinical trials.

      Methods

      Journal publications (last 5 years) and congress abstracts (last 2 years: ASCO/ESMO/SABCS/EBCC/St. Gallen) were reviewed.
      Journal publications were identified by a PubMed search of English language publications over a 5-year period (June 2013–June 2018) using the following search terms:
      “HER2-positive” OR “ERBB2-positive” OR “neu-positive” AND (“early breast cancer” OR “localised breast cancer” OR “localized breast cancer”) AND
      • 1.
        (”trastuzumab” OR “pertuzumab” OR “anti-HER2 treatment” OR “anti-HER2 therapy”);
      • 2.
        (“optimisation” OR “optimization” OR “optimal” OR “dose reduction” OR “escalation” OR “timing” OR “risk”).
      Results were screened manually to identify clinical trials (identified through the title or abstract stating clinical trial and/or phase I, II, II or IV number, or having a ClinicalTrials.gov or EUDRACT identifier code in the abstract).

      Discussion

      Clinical risk-based decision-making

      In the changing paradigm, initial treatment selection should be underpinned by assessing recurrence risk by multidisciplinary teams at diagnosis to define an optimal treatment pathway that encompasses neoadjuvant, adjuvant (including post-neoadjuvant) or extended adjuvant therapy >1 year.
      To optimise treatment selection, we need to identify subgroups at increased relapse risk that would benefit from dual blockade, and subgroups at relatively low risk, in which chemotherapy may be de-escalated. Defining risk involves evaluating tumour stage and clinical nodal status, patient-related (comorbidity/histology/tumour type/tumour grade/proliferation) and biological characteristics (HER2/hormone receptor [HR] status), which all affect therapy choice and influence response.
      The treatment algorithm continues to evolve (Fig. 1). Patients with low recurrence risk are currently defined as having small (<2cm diameter), node-negative tumours; patients with higher risk, with tumours ≥2 cm and/or node-positive disease [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ]. There are two important clinical trial-supported decision points for managing patients at high risk. 1) To initiate neoadjuvant systemic therapy or primary surgery. Patients with ≥2 cm tumours or node-positive disease at presentation (by palpation, sonography or biopsy) should be treated with standard NACT plus dual HER2 blockade (pertuzumab–trastuzumab). 2) Presence/absence of invasive residual disease after NACT plus anti-HER2 therapy treatment; patients with residual invasive cancer after standard neoadjuvant therapy should receive T-DM1 for 14 cycles. Evidence suggests that those with pCR should continue HER2-targeted therapy to complete 1 year (18 cycles) with pertuzumab–trastuzumab [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ]. Some uncertainty remains in cases of pCR for patients with node-negative disease and ≥2 cm tumours at diagnosis; post-neoadjuvant trastuzumab may be sufficient [

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ]. However, if the initial risk was such that the use of NACT plus dual blockade was justified, achieving pCR while receiving pertuzumab plus trastuzumab should not trigger treatment de-escalation to trastuzumab alone.
      Figure thumbnail gr1
      Fig. 1Current treatment algorithm for HER2-positive EBC [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ,

      Genentech Inc. Herceptin® (trastuzumab). Prescribing Information. February ed.

      ,

      Genentech Inc. PERJETA® (pertuzumab). Prescribing Information. May ed.

      ,

      Puma Biotechnology. NERLYNX™ (neratinib). Prescribing Information.

      ] and planned/ongoing studies. EBC: early breast cancer; ET: endocrine therapy; H: trastuzumab; HR: hormone-receptor; N: lymph node status; NACT: neoadjuvant chemotherapy; p: pathological staging; P: pertuzumab; pac: paclitaxel; pCR: pathological complete response; SC: subcutaneous; T: tumour diameter; T-DM1: trastuzumab emtansine.
      a. NCT03726879.
      b. NCT03595592.
      c. NCT04675827 (a sub-study of DecreSCendo will investigate the use of PH FDC SC for the treatment of patients who achieve a pCR following neoadjuvant therapy).
      d. NCT04266249.
      e. SC formulations improve patient and HCP convenience (see HannaH78 and FeDeriCa79 study results for data on H SC and PH FDC SC, respectively).
      f. Recommended for patients with tumours ≥2cm and/or node-positive disease at diagnosis.
      g. Guideline recommendations (NCCN, AGO, ESMO, St. Gallen) for the adjuvant use of trastuzumab with paclitaxel alone represent off-label use in this setting.
      h. Neratinib has not been approved for use after PH or T-DM1.
      i. NCT04622319.
      j. NCT04457596.
      k. Study not yet published on ClinicalTrials.gov.

      Trastuzumab: The core adjuvant therapy component

      Trastuzumab, a recombinant HER2-targeting humanised monoclonal antibody, inhibits HER2 signalling (inhibiting proliferation), triggers antibody-dependent cellular cytotoxicity and may contribute to adaptive immunity development [
      • Loibl S.
      • Gianni L.
      HER2-positive breast cancer.
      ,
      • Norton N.
      • Fox N.
      • McCarl C.-A.
      • Tenner K.S.
      • Ballman K.
      • Erskine C.L.
      • et al.
      Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.
      ,

      Genentech Inc. Herceptin® (trastuzumab). Prescribing Information. February ed.

      ]. Several landmark studies demonstrated its inclusion in adjuvant regimens significantly improved outcomes versus chemotherapy-only [
      • Piccart-Gebhart M.J.
      • Procter M.
      • Leyland-Jones B.
      • Goldhirsch A.
      • Untch M.
      • Smith I.
      • et al.
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
      ,
      • Romond E.H.
      • Perez E.A.
      • Bryant J.
      • Suman V.J.
      • Geyer C.E.
      • Davidson N.E.
      • et al.
      Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
      ,
      • Joensuu H.
      • Kellokumpu-Lehtinen P.-L.
      • Bono P.
      • Alanko T.
      • Kataja V.
      • Asola R.
      • et al.
      Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.
      ,
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • Pienkowski T.
      • Martin M.
      • Press M.
      • et al.
      Adjuvant trastuzumab in HER2-positive breast cancer.
      ,
      • Perez E.A.
      • Romond E.H.
      • Suman V.J.
      • Jeong J.-H.
      • Davidson N.E.
      • Geyer C.E.
      • et al.
      Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31.
      ]. Long-term follow-up confirmed that improvements were durable, leading to significant OS improvements regardless of chemotherapy partner (±anthracyclines) [
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • de Azambuja E.
      • Procter M.
      • Suter T.M.
      • et al.
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial.
      ,
      • Perez E.A.
      • Romond E.H.
      • Suman V.J.
      • Jeong J.-H.
      • Sledge G.
      • Geyer C.E.
      • et al.
      Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
      ,
      • Cameron D.
      • Piccart-Gebhart M.J.
      • Gelber R.D.
      • Procter M.
      • Goldhirsch A.
      • de Azambuja E.
      • et al.
      11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: Final analysis of the HERceptin Adjuvant (HERA) trial.
      ]. Meta-analyses showed the benefit extended to women with tumours ≤2 cm in diameter ± axillary involvement [
      • O'Sullivan C.C.
      • Bradbury I.
      • Campbell C.
      • Spielmann M.
      • Perez E.A.
      • Joensuu H.
      • et al.
      Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤2 cm: A meta-analysis of the randomized trastuzumab trials.
      ]. In early trials, trastuzumab was typically administered for 1 year [
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • de Azambuja E.
      • Procter M.
      • Suter T.M.
      • et al.
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial.
      ].

      Dual anti-HER2 therapy

      The next step in adjuvant therapy’s evolution was adding a second anti-HER2 therapy with trastuzumab-complementary activity. Pertuzumab, a HER2 dimerisation domain-directed monoclonal antibody, inhibits ligand-initiated intracellular signalling through MAP kinase and PI3K [

      Genentech Inc. PERJETA® (pertuzumab). Prescribing Information. May ed.

      ]. Lapatinib [

      GlaxoSmithKline. TYKERB® (lapatinib). Prescribing Information. January ed.

      ], neratinib [

      Puma Biotechnology. NERLYNX™ (neratinib). Prescribing Information.

      ] and tucatinib [

      Seattle Genetics Inc. TUKYSA™ (tucatenib). Prescribing Information. 2020.

      ] are tyrosine kinase inhibitors (TKIs) that inhibit HER2′s intracellular TK domains [
      • Loibl S.
      • Gianni L.
      HER2-positive breast cancer.
      ].
      In ALTTO [
      • Piccart-Gebhart M.
      • Holmes E.
      • Baselga J.
      • de Azambuja E.
      • Dueck A.C.
      • Viale G.
      • et al.
      Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
      ], patients with HER2-positive EBC were randomised to 1 year’s trastuzumab, lapatinib, or trastuzumab plus lapatinib, or 12–18 weeks’ trastuzumab then 28–34 weeks’ lapatinib concurrent/sequential with chemotherapy per physician’s choice. The lapatinib-alone arm was terminated early for futility. The remaining comparisons showed, although there were fewer events in the dual therapy arms, neither concurrent trastuzumab plus lapatinib nor sequential trastuzumab → lapatinib produced pre-specified statistically significant improvements in DFS versus trastuzumab. Adding lapatinib was also associated with more adverse events (AEs; Grade 3/4 diarrhoea/rash/hepatotoxicity) [
      • Piccart-Gebhart M.
      • Holmes E.
      • Baselga J.
      • de Azambuja E.
      • Dueck A.C.
      • Viale G.
      • et al.
      Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
      ].
      Based on NeoSphere, adjuvant pertuzumab–trastuzumab was evaluated in APHINITY (Table 1) [
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]. Patients with node-positive or high-risk (tumour diameter >1 cm) node-negative operable BC who had not received neoadjuvant therapy were eligible. Patients with node-negative tumours 0.5–1.0 cm with high-risk features (histological/nuclear Grade 3/HR-negative/<35 years) were initially eligible; enrolment of patients with node-negative disease was subsequently capped. Patients were randomised to receive, with standard chemotherapy, 1 year’s pertuzumab–trastuzumab or placebo–trastuzumab. Pertuzumab–trastuzumab and chemotherapy significantly improved 3-year invasive DFS (IDFS; primary endpoint) versus placebo (hazard ratio [HRa] 0.81; 95% CI 0.66–1.00; p = 0.045), reducing relative recurrence risk by 19% [
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]. The effect was driven by patients at higher relapse risk due to lymph-node involvement/HR-negative disease. Safety was consistent with previous studies, there were no new safety issues noted, but low-grade diarrhoea was more common in the pertuzumab group than the placebo group.
      Table 1Optimising adjuvant therapy in patients with invasive non-metastatic HER2-positive early breast cancer (APHINITY
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ,
      • Piccart M.
      • Procter M.
      • Fumagalli D.
      • de Azambuja E.
      • Clark E.
      • Ewer M.S.
      • et al.
      Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.
      ).
      Patient characteristicsAdjuvant regimen



      (No. of patients)
      IDFSOS
      3-year6-year6-year
      %HRa



      (95% CI)
      %HRa



      (95% CI)
      %HRa



      (95% CI)
      Node-positive or node-negative disease with tumour >1cmaChemotherapyb + PH (2,400)94.10.81

      (0.66–1.00)
      90.60.76

      (0.64–0.91)
      94.80.85

      (0.67–1.07)
      Chemotherapyb + Placebo/H (2,404)93.287.893.9
      CI, confidence interval; H, trastuzumab; HRa, hazard ratio; IDFS, invasive disease-free survival; OS, overall survival; PH, pertuzumab–trastuzumab.
      a. Patients with node-negative tumours 0.5–1.0 cm in diameter were initially eligible if ≥1 high-risk feature was present: histological or nuclear grade 3, negativity for oestrogen and progesterone receptors, or age younger than 35 years. Under a protocol amendment that was added after 3655 patients had undergone randomisation, patients with node-negative disease were no longer eligible for enrolment.
      b. Chemotherapy consisted of 3 or 4 cycles (q3w) of 5-fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide, followed by 3 or 4 cycles (q3w) of docetaxel or 12 weekly cycles of paclitaxel; 4 cycles (q3w or q2w) of cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles (q3w) of docetaxel or 12 qw cycles of paclitaxel; or 6 cycles (q3w) of docetaxel plus carboplatin.
      The 6-year update was recently reported [
      • Piccart M.
      • Procter M.
      • Fumagalli D.
      • de Azambuja E.
      • Clark E.
      • Ewer M.S.
      • et al.
      Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.
      ]. Between-arm IDFS differences remained consistent, with a 24% relative reduction in recurrence risk after 6 years’ median follow-up (HRa 0.76; 95% CI 0.64–0.91). In node-positive disease, 6-year IDFS was 87.9% with pertuzumab–trastuzumab and 83.4% with placebo–trastuzumab (absolute difference 4.5%; HRa 0.72; 95% CI 0.59–0.87). Adding pertuzumab had no statistically significant effect in node-negative disease (HRa 1.02; 95% CI 0.69–1.53). With longer follow-up, pertuzumab’s effect was apparent regardless of HR status. In HR-positive disease, pertuzumab–trastuzumab was associated with better 6-year IDFS than placebo–trastuzumab (HRa 0.73; 95% CI 0.59–0.92), whereas inHR-negative disease the between-group difference non-significantly favoured pertuzumab–trastuzumab (HRa 0.83; 95% CI 0.63–1.10). There were fewer deaths in the pertuzumab–trastuzumab arm (125 [5.2%] versus 147 [6.1%]), although OS differences were non-significant (HRa 0.85; 95% CI 0.67–1.07, p = 0.170). However, data remain immature (43% of events required for final analysis). Follow-up is ongoing; final OS will be assessed at 640 events. No new cardiac concerns emerged.
      Based on the APHINITY 6-year data, the ESMO Magnitude of Clinical Benefit Score (ESMO-MCBS) for adjuvantpertuzumab–trastuzumab in HER2-positive EBC has recently been upgraded to an ‘A’, which is the highest score possible for a regimen in the curative setting.[

      European Society for Medical Oncology (ESMO). ESMO-MCBS scorecards: Pertuzumab. 2021.

      ]

      Anti-HER2 adjuvant therapy duration

      Standard adjuvant anti-HER2 therapy lasts 1 year (18 q3w cycles), including patients who start in the neoadjuvant setting [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ]. HERA compared safety and efficacy of 1 and 2 years’ trastuzumab; 2 years did not provide additional benefits [
      • Piccart-Gebhart M.J.
      • Procter M.
      • Leyland-Jones B.
      • Goldhirsch A.
      • Untch M.
      • Smith I.
      • et al.
      Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
      ,
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • de Azambuja E.
      • Procter M.
      • Suter T.M.
      • et al.
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial.
      ]. Other trials examined shorter durations [
      • Pivot X.
      • Romieu G.
      • Debled M.
      • Pierga J.-Y.
      • Kerbrat P.
      • Bachelot T.
      • et al.
      6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial.
      ,
      • Mavroudis D.
      • Saloustros E.
      • Malamos N.
      • Kakolyris S.
      • Boukovinas I.
      • Papakotoulas P.
      • et al.
      Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).
      ,
      • Conte P.
      • Frassoldati A.
      • Bisagni G.
      • Brandes A.A.
      • Donadio M.
      • Garrone O.
      • et al.
      Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: Final results of the phase III randomized Short-HER study‡.
      ,
      • Joensuu H.
      • Fraser J.
      • Wildiers H.
      • Huovinen R.
      • Auvinen P.
      • Utriainen M.
      • et al.
      Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial.
      ]. Recent meta-analyses demonstrated that 1 year remains optimal [
      • Inno A.
      • Barni S.
      • Ghidini A.
      • Zaniboni A.
      • Petrelli F.
      One year versus a shorter duration of adjuvant trastuzumab for HER2-positive early breast cancer: A systematic review and meta-analysis.
      ,
      • Niraula S.
      • Gyawali B.
      Optimal duration of adjuvant trastuzumab in treatment of early breast cancer: A meta-analysis of randomized controlled trials.
      ]. However, PERSEPHONE [
      • Earl H.M.
      • Hiller L.
      • Vallier A.-L.
      • Loi S.
      • McAdam K.
      • Hughes-Davies L.
      • et al.
      6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.
      ] demonstrated non-inferiority of 0.5 versus 1 year’s adjuvant trastuzumab for DFS (89.4% [6 months]; 89.8% [1 year]; non-inferiority margin 3%; HRa 1.07; 90% CI 0.93–1.24) and OS (93.8% and 94.8%; 1.14; 0.95–1.37) [
      • Earl H.M.
      • Hiller L.
      • Vallier A.-L.
      • Loi S.
      • McAdam K.
      • Hughes-Davies L.
      • et al.
      6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.
      ]. Subgroups in which 1 year might be superior included ER-negative disease (HRa 1.26; 95% CI 0.96–1.65), patients who received: taxane without an anthracycline (2.46; 1.27–4.77), NACT (1.50; 1.03–2.17) and trastuzumab concurrently with chemotherapy (1.45; 1.10–1.92). Further work is required to identify subgroups potentially suited to an abbreviated regimen. Thus, 1 year remains standard of care [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ].

      Extending adjuvant therapy with TKIs

      Although 2 years’ adjuvant trastuzumab proved no more effective than 1 in HERA [
      • Goldhirsch A.
      • Gelber R.D.
      • Piccart-Gebhart M.J.
      • de Azambuja E.
      • Procter M.
      • Suter T.M.
      • et al.
      2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial.
      ], ExteNET demonstrated that a longer duration could be effective by changing to a TKI. ExteNET investigated one additional year of neratinib after standard neoadjuvant and adjuvant chemotherapy plus trastuzumab [
      • Martin M.
      • Holmes F.A.
      • Ejlertsen B.
      • Delaloge S.
      • Moy B.
      • Iwata H.
      • et al.
      Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Chan A.
      • Moy B.
      • Mansi J.
      • Ejlertsen B.
      • Holmes F.A.
      • Chia S.
      • et al.
      Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial.
      ]. This resulted in improved 5-year DFS versus placebo (HRa 0.73; 95% CI 0.57–0.92). Subgroup analyses showed only patients with HR-positive disease receiving concurrent endocrine therapy (ET) benefitted from neratinib (IDFS HRa 0.60; 95% CI 0.43–0.83 versus 0.95; 0.66–1.35 in HR-negative disease). Benefits appeared greater in patients who started neratinib ≤1 year post-trastuzumab completion (HRa 0.70; 95% CI 0.54–0.90) versus >1 year post-completion (1.00; 0.51–1.94). Benefits came at the cost of more AEs, particularly diarrhoea; however, no long-term effects from neratinib-associated diarrhoea were observed. During neratinib treatment, 55% experienced Grade 1/2 and 40% experienced Grade 3 diarrhoea without prophylaxis; much higher than reported with prophylaxis subsequently [
      • Barcenas C.H.
      • Hurvitz S.A.
      • Di Palma J.A.
      • Bose R.
      • Chien A.J.
      • Iannotti N.
      • et al.
      Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: The CONTROL trial.
      ].

      Neoadjuvant therapy

      Neoadjuvant therapy is standard of care for most patients with high-risk disease [

      Curigliano G, Burstein HJ, P Winer E, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-12.

      ]. Originally used to render tumours operable/to avoid mastectomy, NACT did not improve long-term outcomes versus adjuvant chemotherapy in patients with operable disease [
      • Fisher B.
      • Brown A.
      • Mamounas E.
      • Wieand S.
      • Robidoux A.
      • Margolese R.G.
      • et al.
      Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18.
      ]. Today, it provides a better understanding of disease biology and is useful in tailoring treatment. It is integral to multidisciplinary treatment; pCR status provides additional important prognostic information at the patient level that reflects tumour biology. With pCR, a treatment can be continued in the post-neoadjuvant setting, whereas with residual disease, the plan may be modified to improve outcomes [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ].

      Neoadjuvant pertuzumab–trastuzumab

      Neoadjuvant pertuzumab–trastuzumab with chemotherapy [
      • Gianni L.
      • Pienkowski T.
      • Im Y.-H.
      • Roman L.
      • Tseng L.-M.
      • Liu M.-C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial.
      ,
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA).
      ] significantly improves pCR versus single anti-HER2 therapy plus chemotherapy, and is widely considered standard of care. NeoSphere demonstrated breast pCR superiority of pertuzumab–trastuzumab plus docetaxel versus other combinations of anti-HER2 therapies ± docetaxel [
      • Gianni L.
      • Pienkowski T.
      • Im Y.-H.
      • Roman L.
      • Tseng L.-M.
      • Liu M.-C.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial.
      ]. All patients received 3 adjuvant 5-fluorouracil/epirubicin/cyclophosphamide (FEC) cycles post-surgery and those receiving antibodies alone also received adjuvant docetaxel. NeoSphere was not powered to demonstrate progression-free survival (PFS; equivalent to EFS as noted by the authors) significance; 5-year rates were 86% (pertuzumab–trastuzumab plus docetaxel), 81% (trastuzumab plus docetaxel) and 73% (pertuzumab plus docetaxel or pertuzumab–trastuzumab) [
      • Gianni L.
      • Pienkowski T.
      • Im Y.-H.
      • Tseng L.-M.
      • Liu M.-C.
      • Lluch A.
      • et al.
      5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.
      ].
      The cardiac safety TRYPHAENA study demonstrated low overall rates of symptomatic left ventricular (LV) systolic dysfunction with total pCR (tpCR; ypT0/is, ypN0) rates of 54.7–63.6% with pertuzumab–trastuzumab plus anthracycline-containing and non-anthracycline containing regimens [
      • Schneeweiss A.
      • Chia S.
      • Hickish T.
      • Harvey V.
      • Eniu A.
      • Hegg R.
      • et al.
      Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA).
      ].

      From NACT to post-neoadjuvant therapy: Individualising therapy on the basis of outcome

      The landmark pooled analysis (CTNeoBC) of ~ 12,000 patients with neoadjuvant treatment demonstrated pCR after NACT was associated with improved outcomes [
      • Cortazar P.
      • Zhang L.
      • Untch M.
      • Mehta K.
      • Costantino J.P.
      • Wolmark N.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis.
      ], i.e., significantly better event-free survival (HRa 0.48; 95% CI 0.43–0.54) and OS (0.36; 0.31–0.42). It should be noted that CTNeoBC included patients from the full BC spectrum; pCR–outcome association was strongest for triple-negative and HER2-positive BC [
      • Cortazar P.
      • Zhang L.
      • Untch M.
      • Mehta K.
      • Costantino J.P.
      • Wolmark N.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis.
      ].
      A recently completed pooled analysis confirmed pCR (ypT0/is, ypN0)–long-term outcome associations [

      Loibl S, Untch M, Buyse M, Robidoux A, Gianni L, Schneeweiss A, et al. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC). Cancer Res 2020;80:Abstract P5-06-2.

      ]. 3,710 patients were included; 1,499 achieved pCR (median follow-up: 61 months). Results demonstrate that baseline tumour size and nodal status (traditional poor-prognostic factors), remain important even post-pCR [

      Loibl S, Untch M, Buyse M, Robidoux A, Gianni L, Schneeweiss A, et al. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC). Cancer Res 2020;80:Abstract P5-06-2.

      ].
      A pooled analysis of 1,764 patients who received trastuzumab, pertuzumab, or both as part of a systemic neoadjuvant regimen showed that pCR-attaining patients had better long-term outcomes than those with residual disease, regardless of HR status/clinical stage. However, it is important to be aware that some pCR-achieving patients still experienced recurrence; therefore, the best possible therapy should be continued after surgery and further efforts should be made to define prognostic factors for recurrence [

      Swain SM, Macharia H, Cortes J, Dang C, Gianni L, Hurvitz S, et al. Risk of recurrence and death in patients with early HER2-positive breast cancer who achieve a pathological complete response (pCR) after different types of HER2-targeted therapy: A retrospective exploratory analysis. Cancer Res 2020;80:Abstract P1-18-01.

      ].

      Post-neoadjuvant therapy to optimise outcomes in women with residual disease

      Given that patients with residual disease post-neoadjuvant therapy have worse prognosis, strategies are needed to optimise therapy. KATHERINE was designed to address this unmet need by optimising anti-HER2 therapy and evaluating the potential for adapting treatment post-neoadjuvant therapy. KATHERINE enrolled patients with residual invasive disease at surgery after completing ≥6 cycles (16 weeks) of chemotherapy containing ≥9 weeks’ taxane-based therapy and 9 weeks’ trastuzumab. Anthracyclines, alkylating agents and a second anti-HER2 agent were permitted. Patients were randomised to 14 cycles of T-DM1 or trastuzumab [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ]. ~18% per arm previously received pertuzumab plus trastuzumab. After ~41 months’ median follow-up, T-DM1 significantly improved IDFS versus trastuzumab (HRa 0.50; 95% CI 0.39–0.64; p < 0.001). Three-year IDFS improved 11.3% by switching to T-DM1. Benefits were apparent in all subgroups regardless of extent of residual disease, including those with node-negative disease and residual tumours <1 cm [

      Geyer CE, Jr., Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE. Cancer Res 2019;79 (Suppl):Abstract GS1-10.

      ].
      Safety was consistent with the known T-DM1 safety profile, including liver enzyme elevations and thrombocytopenia. T-DM1-treated patients experienced more AEs than trastuzumab-treated. Discontinuation rates due to AEs were higher with T-DM1 (18.0% versus 2.1%) as were serious AEs (12.7% versus 8.1%) [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ].
      Exploratory analyses have examined the extent of T-DM1 benefit in subgroups. IDFS benefit was consistent regardless of HR status and previous anti-HER2 therapy [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ]. Comparing pre-neoadjuvant tumour and surgical samples showed evidence of a change from HER2-positive to HER2-negative in 70/845 patients. Among these, no IDFS events occurred in those randomised to T-DM1 versus 11 in those randomised to trastuzumab [
      • Loibl S.
      • Huang C.
      • Mano M.S.
      • Mamounas E.P.
      • Geyer C.E.J.
      • Untch M.
      • et al.
      Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (T) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: Subgroup analysis from KATHERINE.
      ]. Based on these findings, it is not currently recommended to re-examine HR and/or HER2 status in the breast and/or axilla in cases of residual disease, as systemic therapy choice is based on HR and HER2 status at presentation. Exploratory analyses of surgical tissue samples indicated that PIK3CA status did not influence outcomes. High versus low HER2 gene expression was associated with worse IDFS with trastuzumab, but not T-DM1 [

      Denkert C, Lambertini C, Fasching PA, Pogue-Geile KL, Mano MS, Untch M, et al. Biomarker data from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine vs. trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. J Clin Oncol 2020;38:Abstract 502.

      ].
      T-DM1 reduced incidence of distant recurrence as a first event (10.5% versus 15.9%) with trastuzumab (HRa 0.60; 95% CI, 0.45–0.79) [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ]. A subset of these patients experienced central nervous system (CNS) recurrence as a first event: 5.9% randomised to T-DM1; 4.3%, to trastuzumab [
      • von Minckwitz G.
      • Huang C.-S.
      • Mano M.S.
      • Loibl S.
      • Mamounas E.P.
      • Untch M.
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      ]. In patients who only had CNS recurrence, time to detection of CNS metastases was longer with T-DM1 (17.5 months) versus trastuzumab (11.9 months) [

      Untch M, Geyer CE, Huang CS, Loibl S, Wolmark N, Mano MS, et al. Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC). Ann Oncol 2019;30:Abstract LBA19.

      ]. Results suggest that T-DM1 provides good control of visceral disease while highlighting an unmet medical need for effective post-neoadjuvant treatment to prevent recurrence in the CNS.
      KATHERINE established a new standard of care for patients with residual disease post-neoadjuvant therapy [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ]. It must be emphasised that the only way to identify patients who benefit from post-neoadjuvant T-DM-1 is through routine neoadjuvant therapy use.

      De-escalation of NACT

      De-escalation studies are shown in Table 2.
      Table 2De-escalation of neoadjuvant chemotherapy in patients with HER2-positive early breast cancer.
      Trial (n)Patient characteristicsNeoadjuvant regimenpCR,

      % (95% CI)

      (ypT0/is, ypN0)
      3-year EFS, % (95% CI)3-year OS, % (95% CI)
      TRAIN-2
      • van Ramshorst M.S.
      • van der Voort A.
      • van Werkhoven E.D.
      • Mandjes I.A.
      • Kemper I.
      • Dezentjé V.O.
      • et al.
      Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial.
      ,

      van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol 2020;38:Abstract 501.



      mc, ol, r, ph3 (438)
      Stage II–IIIPac/Cb/PH × 968 (61–74)93.5

      (90.4–96.6)
      98.2

      (96.4–100)
      FEC/PH × 3 → Pac/Cb/PH × 667 (60–73)92.7

      (88.3–96.2)
      97.7

      (95.7–99.7)
      KRISTINE
      • Hurvitz S.A.
      • Martin M.
      • Symmans W.F.
      • Jung K.H.
      • Huang C.-S.
      • Thompson A.M.
      • et al.
      Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial.
      ,
      • Hurvitz S.A.
      • Martin M.
      • Jung K.H.
      • Huang C.-S.
      • Harbeck N.
      • Valero V.
      • et al.
      Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: Three-year outcomes from the phase III KRISTINE study.


      mc, ol, r, ph3 (444)
      Stage II–III

      cT2–4 (>2cm)/ cN0–3 /cM0 (>2cm)
      TDM-1/P × 644.485.3

      (80.5–90.1)
      97.0

      (94.6–99.4)
      Doc/Cb/PH × 655.7

      94.2

      (91.0–97.4)
      97.6

      (95.5–99.7)
      WSG-TP-II

      Gluz O, Nitz U, Christgen M, Kuemmel S, Holtschmidt J, Priel J, et al. De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study. J Clin Oncol. 2020;38:Abstract 515.



      mc, ol, r, ph2 (207)
      Hormone receptor-positive

      cT1c-T4a–c
      ET/PH × 12 wks24 (16–34)
      Pac/PH × 12 wks57 (47–67)
      Cb, carboplatin; CI, confidence interval; Doc, docetaxel; EFS, event-free survival; ET, endocrine therapy; FEC, 5-fluorouracil, epirubicin and cyclophosphamide; HR+, hormone receptor-positive; mc, multicentre; ol, open-label; OS, overall survival; P, pertuzumab; ph, phase; Pac, paclitaxel; pCR, pathological complete response; PH, pertuzumab-trastuzumab; r, randomised.
      KRISTINE assessed de-escalation in patients with stage II/III BC to determine whether tolerability could be improved without compromising efficacy by forgoing conventional chemotherapy [
      • Hurvitz S.A.
      • Martin M.
      • Symmans W.F.
      • Jung K.H.
      • Huang C.-S.
      • Thompson A.M.
      • et al.
      Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial.
      ]. Patients were randomised to neoadjuvant T-DM1 plus pertuzumab or chemotherapy (docetaxel and carboplatin) plus pertuzumab–trastuzumab q3w for 6 cycles. Patients continued treatment with T-DM1 plus pertuzumab or pertuzumab–trastuzumab after surgery, respectively, to complete 18 cycles (1 year). At primary analysis, the T-DM1-based regimen produced significantly lower tpCR (ypT0/is, ypN0) than conventional chemotherapy (44.4% versus 55.7%, p = 0.016) [
      • Hurvitz S.A.
      • Martin M.
      • Symmans W.F.
      • Jung K.H.
      • Huang C.-S.
      • Thompson A.M.
      • et al.
      Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial.
      ]. After 3 years’ follow-up, EFS event risk was higher with T-DM1 plus pertuzumab (HRa 2.61; 95% CI 1.36–4.98), driven by locoregional progression events pre-surgery (15 versus 0) and more non-invasive recurrence events post-surgery (3 versus 0) [
      • Hurvitz S.A.
      • Martin M.
      • Jung K.H.
      • Huang C.-S.
      • Harbeck N.
      • Valero V.
      • et al.
      Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: Three-year outcomes from the phase III KRISTINE study.
      ]. IDFS event risk post-surgery was similar between arms (HRa 1.11; 95% CI 0.52–2.40]). However, as IDFS does not capture events prior to surgery (including locoregional progressions observed in 6.7% of patients in the T-DM1 plus pertuzumab arm) and event rates were low overall, IDFS data should be interpreted with caution. The T-DM1-based regimen had a favourable safety profile overall. Patients receiving neoadjuvant T-DM1 plus pertuzumab had fewer Grade ≥3 AEs and serious AEs versus conventional chemotherapy plus pertuzumab–trastuzumab [
      • Hurvitz S.A.
      • Martin M.
      • Symmans W.F.
      • Jung K.H.
      • Huang C.-S.
      • Thompson A.M.
      • et al.
      Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial.
      ]. During adjuvant treatment Grade ≥3 AEs and AEs leading to treatment discontinuation were more common in the T-DM1 plus pertuzumab arm. In summary, KRISTINE did not meet its primary endpoint of improved pCR with the T-DM1-based regimen; consequently, these data did not change the standard-of-care neoadjuvant treatment.
      WSG-TP-II evaluated chemotherapy de-escalation in patients with HR-positive/HER2-positive EBC [

      Gluz O, Nitz U, Christgen M, Kuemmel S, Holtschmidt J, Priel J, et al. De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study. J Clin Oncol. 2020;38:Abstract 515.

      ]. Patients received 12 weeks’ ET (tamoxifen/aromatase inhibitor)/paclitaxel plus pertuzumab–trastuzumab. Adjuvant chemotherapy omission was allowed in patients achieving pCR after 12 weeks. Pertuzumab–trastuzumab was continued post-surgery to complete 1 year. pCR (ypT0/is, ypN0) was achieved in 24% in the ET arm and 57% in the paclitaxel arm. Survival results are awaited. This strategy is, at present, hypothesis-generating and may be the basis for further evaluation.
      WSG-ADAPT used predictive information from early response to de-escalate therapy [
      • Harbeck N.
      • Gluz O.
      • Christgen M.
      • Kates R.E.
      • Braun M.
      • Küemmel S.
      • et al.
      De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the west german study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET.
      ]. It enrolled patients with HER2-negative or HER2-positive disease; the latter received HER2-targeted therapy. Patients with HER2-positive and HR-positive EBC received 12 weeks’ neoadjuvant T-DM1 ± ET, or trastuzumab with ET. tpCR (ypT0, ypN0) was similar in patients who received T-DM1 (41.0%) and T-DM1 plus ET (41.5%); both were higher than trastuzumab with ET (15.1%). Early response was defined as proliferation decrease ≥30% of Ki-67 from baseline or low cellularity (<500 invasive tumour cells) in a biopsy obtained at 3 weeks. tpCR was significantly higher in early responders (35.7%, 71/199) than non-responders (19.8%, 20/101) (odds ratio 2.2; 95% CI 1.24–4.19, p = 0.005). AEs were higher with T-DM1 (most common: fatigue, nausea, headache, elevations in ALT and AST, and thrombocytopenia); although there were relatively few therapy-related severe AEs (5.3% versus 3.1% with trastuzumab) [
      • Harbeck N.
      • Gluz O.
      • Christgen M.
      • Kates R.E.
      • Braun M.
      • Küemmel S.
      • et al.
      De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the west german study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET.
      ]. Importantly, there was no alopecia, peripheral polyneuropathy or febrile neutropenia reported.
      Long-term efficacy results were recently reported and showed no differences in DFS/OS despite higher pCR rates [

      Harbeck N, Nitz U, Christgen M, Kuemmel S, Braun M, Schumacher C, et al. De-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs trastuzumab+ET in early HR+/HER2+ breast cancer (BC): ADAPT-TP survival results. Ann Oncol 2020;31:Abstract LBA14.

      ]; likely due to standard chemotherapy, which was administered to all patients with residual disease and most with pCR. 5-year DFS results in patients who achieved pCR after 12 weeks of T-DM1 ± ET or without further chemotherapy may allow prospective de-escalation trials in certain patients.
      These strategies should be evaluated in a phase III randomised controlled trial, to further assess the promising effect summarised here.

      De-escalation of NACT using biomarkers

      Several studies used Ki-67 to identify patients suitable for de-escalation, with mixed results. In PerELISA, postmenopausal women with HER2-positive, HR-positive EBC received letrozole for 2 weeks, then underwent biopsy for Ki-67 re-evaluation. Patients with responses (>20% Ki-67 reduction from baseline) continued letrozole and received 5 pertuzumab–trastuzumab cycles [
      • Guarneri V.
      • Dieci M.V.
      • Bisagni G.
      • Frassoldati A.
      • Bianchi G.V.
      • De Salvo G.L.
      • et al.
      De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: Results of the PerELISA neoadjuvant study.
      ]. Non-responders received paclitaxel plus pertuzumab–trastuzumab. tpCR (ypT0/is, ypN0) was achieved in 9/44 responders (20.5%) and 13/16 non-responders (81.3%). Results suggest that Ki-67 may identify a subset of patients with HR-positive disease who might achieve tpCR without chemotherapy, and alternatively, that lack of response might identify patients who may derive a particular benefit from neoadjuvant paclitaxel plus trastuzumab-pertuzumab [
      • Guarneri V.
      • Dieci M.V.
      • Bisagni G.
      • Frassoldati A.
      • Bianchi G.V.
      • De Salvo G.L.
      • et al.
      De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: Results of the PerELISA neoadjuvant study.
      ]. Larger studies must be performed before reaching definite conclusions.
      Patients with HER2-positive/HR-negative EBC in WSG-ADAPT received 12 weeks’ pertuzumab–trastuzumab ± paclitaxel. tpCR (ypT0/is ypN0) was higher with pertuzumab–trastuzumab plus paclitaxel (90.5%) versus pertuzumab–trastuzumab (34.4%) [
      • Nitz U.A.
      • Gluz O.
      • Christgen M.
      • Grischke E.M.
      • Augustin D.
      • Kuemmel S.
      • et al.
      De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab +/- weekly paclitaxel.
      ]. In the pertuzumab–trastuzumab arm (N = 92), 38, 30 and 24 patients were classified as responders, unclassifiable or non-responders, respectively; pCR rates were 44.7%, 42.9% and 8.3%. Thus, although failing to show non-inferiority of the chemotherapy-free and chemotherapy-containing regimens, WSG-ADAPT showed that change in proliferation correlates with pCR [
      • Nitz U.A.
      • Gluz O.
      • Christgen M.
      • Grischke E.M.
      • Augustin D.
      • Kuemmel S.
      • et al.
      De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab +/- weekly paclitaxel.
      ].
      PerELISA and WSG-ADAPT suggest that biomarkers like Ki-67 could provide useful information for tailoring treatment beyond “tumour burden” alone, and possibly reduce exposure to ineffective therapies in patients unlikely to achieve pCR. However, the clinical utility of proliferation markers obtained 3 weeks after initiating treatment is questionable given a significant proportion of patients were unclassifiable in WSG-ADAPT. Nonetheless, early biomarkers should continue to be pursued, perhaps combined with functional imaging.
      In a collaborative translational research effort, a set of four “baseline” biomarkers were found to be correlated with probability of achieving pCR with a chemotherapy-free regimen of trastuzumab and lapatinib. These included a PAM50 HER2-enriched subtype, strong IHC expression of HER2 (97.5% IHC 3+), lack of PIK3CA mutations and a HER2 FISH ratio of ≥4.6 [

      Veeraraghavan J, Gutierrez C, Angelis CD, Wang T, Pascual T, Weigelt B, et al. A multiparameter classifier to predict response to lapatinib plus trastuzumab (LT) without chemotherapy in HER2+ breast cancer (BC). J Clin Oncol 2020;38:Abstract 1011.

      ]. Whether this multiparameter classifier would also apply to dual blockade with pertuzumab–trastuzumab remains to be seen.
      In any event, more emphasis on RNA-based biomarkers such as the PAM50 subclassification is warranted, as they may indicate varying degrees of HER2 “oncogene addiction” [
      • Brasó-Maristany F.
      • Griguolo G.
      • Pascual T.
      • Paré L.
      • Nuciforo P.
      • Llombart-Cussac A.
      • et al.
      Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.
      ].
      Evidence for the use of tumour-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers for response to therapy in HER2-positive EBC is conflicting; further data from prospectively planned analyses of treatment response by TILs levels is needed [
      • Ingold Heppner B.
      • Untch M.
      • Denkert C.
      • Pfitzner B.M.
      • Lederer B.
      • Schmitt W.
      • et al.
      Tumor-infiltrating lymphocytes: A predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer.
      ,
      • Perez E.A.
      • Ballman K.V.
      • Tenner K.S.
      • Thompson E.A.
      • Badve S.S.
      • Bailey H.
      • et al.
      Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the N9831 adjuvant trial in patients with early-stage HER2-positive breast cancer.
      ].
      A strong correlation was observed between early changes in tumour standardised uptake values corrected for lean body mass (SULmax) on FDG-PET and tpCR (ypT0/is, ypN0) after 4 cycles of neoadjuvant pertuzumab–trastuzumab for stage II/III HER2-positive ER-negative BC in TBCRC026 (median reduction in SULmax for tpCR versus no pCR: 63.8% versus 33.5%, p < 0.001) [

      Connolly RM, Leal JP, Solnes L, Huang C-Y, Carpenter A, Gaffney K, et al. Phase II clinical trial assessing the correlation of standardized uptake value (SUV) on positron emission tomography (PET) with pathological complete response (pCR) to pertuzumab and trastuzumab in patients with primary operable HER2-positive breast cancer. J Clin Oncol 2018;36:Abstract TBCRC026.

      ]. A major challenge with generalised Ki-67 use is lack of concordance among pathologists; thus, further work in this important area will be very relevant.
      PHERGain also uses FDG-PET as a biomarker to tailor neoadjuvant therapy (NCT03161353). Patients are randomised to NACT plus pertuzumab–trastuzumab (A) or pertuzumab–trastuzumab ± ET (B); adapted by FDG-PET outcome after 2 cycles (responders continue regimen B, non-responders switch to regimen A). All patients will receive 18 pertuzumab–trastuzumab cycles. pCR (ypT0/is, N0) was achieved in 57.7% of patients in group A and 35.4% in group B (37.9% of PET-responders, i.e. without any chemotherapy, and 25.9% of PET non-responders after chemotherapy plus pertuzumab–trastuzumab) [

      Cortes J, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Escrivá S, et al. Chemotherapy (CT) de-escalation using an FDG-PET/CT (F-PET) and pathological response-adapted strategy in HER2[+] early breast cancer (EBC): PHERGain Trial. J Clin Oncol 2020;38:Abstract 503.

      ]. Proportions of patients with AEs, serious AEs and a ≥10% decline in global health status was greater in group A versus B. Group B responders without pCR will receive chemotherapy post-surgery. Follow-up is ongoing to determine 3-year IDFS.

      Adjuvant chemotherapy de-escalation

      Less aggressive chemotherapy regimens are recommended in lower-risk populations, e.g., patients with smaller tumours without axillary involvement or frail patients less likely to tolerate anthracyclines-taxanes/taxanes-carboplatin.
      APT is a phase II trial that evaluated adjuvant chemotherapy de-escalation in patients with small, node-negative HER2-positive tumours (T ≤ 3 cm) (Table 3) [
      • Tolaney S.M.
      • Barry W.T.
      • Dang C.T.
      • Yardley D.A.
      • Moy B.
      • Marcom P.K.
      • et al.
      Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.
      ]. Treatment comprised 12 weeks’ paclitaxel plus 18 trastuzumab cycles. Primary endpoint was DFS. In 3–7-year follow-up analyses, patients were at minimal risk of recurrence and distant recurrence (98.7% survival without invasive disease at 3 years [
      • Tolaney S.M.
      • Barry W.T.
      • Dang C.T.
      • Yardley D.A.
      • Moy B.
      • Marcom P.K.
      • et al.
      Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.
      ]; 93% DFS at 7 years [
      • Tolaney S.M.
      • Guo H.
      • Pernas S.
      • Barry W.T.
      • Dillon D.A.
      • Ritterhouse L.
      • et al.
      Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.
      ]). Among 410 patients, 23 DFS events occurred during 6.5 years’ follow-up; only four were distant recurrences. Most patients had HR-positive disease (67%). Based on these data, patients at lower risk of relapse (T1 tumours, no axillary involvement) are considered candidates for paclitaxel-trastuzumab as standard adjuvant therapy.
      Table 3De-escalation of adjuvant chemotherapy in patients with HER2-positive early breast cancer.
      TrialPatient characteristicsAdjuvant regimen

      (No. of patients)
      3-year DFS, % (95% CI)7-year DFS,

      % (95% CI)
      7-year OS

      % (95% CI)
      APT
      • Tolaney S.M.
      • Barry W.T.
      • Dang C.T.
      • Yardley D.A.
      • Moy B.
      • Marcom P.K.
      • et al.
      Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.
      ,
      • Tolaney S.M.
      • Guo H.
      • Pernas S.
      • Barry W.T.
      • Dillon D.A.
      • Ritterhouse L.
      • et al.
      Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.


      uc, mc, ph2
      Stage I, tumour diameter ≤3 cmPac/H × 12 wks → H × 40 wks (406)98.7 (97.6–99.8)93 (90.4–96.2)95 (92.4–97.7)
      ATEMPT
      • Tolaney S.M.
      • Trippa L.
      • Barry W.
      • Hu J.
      • Dang C.
      • Yardley D.
      • et al.
      A randomized phase II study of adjuvant trastuzumab emtansine (TDM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT).


      r, mc, ph2
      Stage ITDM-1 q3w × 17 (383)97.7 (96.2–99.3)
      Pac/H × 12 wks → H × 39 wks (114)92.8 (87.8–98.1)
      CI, confidence interval; DFS, disease-free survival; H, trastuzumab; mc, multicentre; Pac, paclitaxel; r, randomised; uc, uncontrolled.
      ATEMPT investigated efficacy of 1 year of adjuvant T-DM1 and whether T-DM1 was associated with less toxicity than paclitaxel-trastuzumab [
      • Tolaney S.M.
      • Trippa L.
      • Barry W.
      • Hu J.
      • Dang C.
      • Yardley D.
      • et al.
      A randomized phase II study of adjuvant trastuzumab emtansine (TDM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT).
      ]. Patients with stage I HER2-positive EBC were allocated to receive 17 T-DM1 cycles q3w, or qw paclitaxel plus trastuzumab for 12 weeks followed by trastuzumab q3w for 39 weeks (Table 3). Co-primary endpoints were DFS in the T-DM1 arm (pre-defined acceptable threshold at 3 years), and differences in clinically relevant toxicity (CRT) rates between the arms. After 3.1 years’ median follow-up, DFS was 97.7% (95% CI 96.2–99.3) in the TDM1 arm; in line with the threshold [
      • Tolaney S.M.
      • Trippa L.
      • Barry W.
      • Hu J.
      • Dang C.
      • Yardley D.
      • et al.
      A randomized phase II study of adjuvant trastuzumab emtansine (TDM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT).
      ]. However, longer follow-up is desirable, as relapses can occur beyond 3 years, particularly in a patient population enriched with the HER2-positive/HR-positive subtype.
      CRT incidence was the same in both arms (46%; p = 0.91). Despite not meeting the pre-specified difference criterion, there were important differences between the safety profiles. Thrombocytopenia and elevated ALT and bilirubin were more common with T-DM1 versus paclitaxel-trastuzumab. Additionally, 17% of T-DM1 patients discontinued therapy early due to AEs. However, serially collected patient-reported outcomes indicated that these patients had better QoL and better work productivity versus those receiving paclitaxel-trastuzumab [

      Partridge A, Zheng Y, Rosenberg S, Gelber R, Gelber S, Barry W, et al. Patient reported outcomes from the adjuvant trastuzumab emtansine (T-DM1) vs. paclitaxel + trastuzumab (TH) (ATEMPT) trial (TBCRC 033). Cancer Res 2020;80:Abstract PD10-02.

      ]. Cost differential and the lack of regulatory approval for T-DM1 in this setting should also be considered for this decision.

      Replacing adjuvant taxanes and trastuzumab with TDM-1 in high-risk patients

      KAITLIN evaluated replacing taxanes and trastuzumab with T-DM1 in adjuvant regimens for patients with high-risk disease; indicated by node-positive disease or node-negative, HR-negative disease and tumours >2 cm [

      Harbeck N, Im S-A, Barrios CH, Bonnefoi HR, Gralow J, Toi M, et al. Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol 2020;38:Abstract 500.

      ]. Patients were randomly allocated within 9 weeks of surgery to 3 or 4 anthracycline-based chemotherapy cycles followed by T-DM1 plus pertuzumab or pertuzumab–trastuzumab plus a taxane. KAITLIN did not meet one of the co-primary endpoints: 3-year IDFS in the ITT population was similar between groups (93.1% versus 94.2%, respectively; HRa 0.98; 95% CI 0.72–1.32). Grade ≥3 AE (51.8% versus 55.4%) and SAE (21.4% versus 23.3%) rates were similar, but more patients discontinued T-DM1 (26.8%) than trastuzumab (4.0%). T-DM1-pertuzumab does not provide an efficacy advantage over pertuzumab–trastuzumab plus taxane-based adjuvant therapy in patients with high-risk EBC [

      Harbeck N, Im S-A, Barrios CH, Bonnefoi HR, Gralow J, Toi M, et al. Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol 2020;38:Abstract 500.

      ].

      Tailoring treatment regimens to minimise cardiotoxicity risks

      This remains at the forefront of adjuvant and neoadjuvant therapy goals. Cardiotoxicity is a significant adverse effect associated with conventional chemotherapy (particularly high-dose anthracyclines) and HER2-targeted therapy, where much of the data are from adjuvant trials. Trastuzumab-related cardiac dysfunction does not appear to be dose-dependent and is often manageable and reversible. Long-term follow-up shows that most cardiac events occur on-treatment, with few additional events occurring post-anti-HER2 treatment [
      • de Azambuja E.
      • Ponde N.
      • Procter M.
      • Rastogi P.
      • Cecchini R.S.
      • Lambertini M.
      • et al.
      A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.
      ,
      • Ganz P.A.
      • Romond E.H.
      • Cecchini R.S.
      • Rastogi P.
      • Geyer C.E.
      • Swain S.M.
      • et al.
      Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG oncology: A randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with ac followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2.
      ]. Baseline risk factors associated with cardiac event development in key trials included baseline LVEF <60%, hypertension, body mass index >25, age ≥60 and non-Caucasian ethnicity [
      • de Azambuja E.
      • Ponde N.
      • Procter M.
      • Rastogi P.
      • Cecchini R.S.
      • Lambertini M.
      • et al.
      A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.
      ]. SAFE-HEaRt showed that HER2-targeted therapy can be administered to patients with reduced LVEF (40–49%) under close monitoring while receiving cardioprotective medications [
      • Lynce F.
      • Barac A.
      • Geng X.
      • Dang C.
      • Yu A.F.
      • Smith K.L.
      • et al.
      Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.
      ].
      To date, anthracycline plus taxane-based chemotherapy is the most used NACT regimen across subtypes [
      • Cain H.
      • Macpherson I.R.
      • Beresford M.
      • Pinder S.E.
      • Pong J.
      • Dixon J.M.
      Neoadjuvant therapy in early breast cancer: Treatment considerations and common debates in practice.
      ]. However, an anthracycline-free regimen (docetaxel and carboplatin) plus 1 year’s trastuzumab was associated with less congestive heart failure (CHF) and cardiac dysfunction compared with an anthracycline-containing regimen (doxorubicin and cyclophosphamide followed by docetaxel, AC-T) plus 1 year’s trastuzumab in BCIRG006 [
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • Pienkowski T.
      • Martin M.
      • Press M.
      • et al.
      Adjuvant trastuzumab in HER2-positive breast cancer.
      ]. CHF incidence was 0.7% with AC-T, 2.0% with AC-T plus trastuzumab, and 0.4% with docetaxel/carboplatin plus trastuzumab. Proportions of patients with >10% reductions in LVEF were 11.2%, 18.6% and 9.4%, respectively [
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • Pienkowski T.
      • Martin M.
      • Press M.
      • et al.
      Adjuvant trastuzumab in HER2-positive breast cancer.
      ].
      Five-year DFS rates were 84% with the anthracycline-containing and 81% with the anthracycline-free regimen at the cost of more CHF episodes [
      • Slamon D.
      • Eiermann W.
      • Robert N.
      • Pienkowski T.
      • Martin M.
      • Press M.
      • et al.
      Adjuvant trastuzumab in HER2-positive breast cancer.
      ]. There was no difference in OS. For this reason the anthracycline-free regimen is recommended for patients at higher cardiotoxicity risk [
      • Denduluri N.
      • Somerfield M.R.
      • Eisen A.
      • Holloway J.N.
      • Hurria A.
      • King T.A.
      • et al.
      Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) -negative and adjuvant targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
      ].
      It is important to note that cardiotoxicity observed in trials after the initial pivotal trials is reassuring even in those with anthracycline use (ALTTO [
      • Piccart-Gebhart M.
      • Holmes E.
      • Baselga J.
      • de Azambuja E.
      • Dueck A.C.
      • Viale G.
      • et al.
      Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
      ], APHINITY [
      • von Minckwitz G.
      • Procter M.
      • de Azambuja E.
      • Zardavas D.
      • Benyunes M.
      • Viale G.
      • et al.
      Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
      ]), with rates of cardiac events being lower that in initially reported HER2 adjuvant trials.
      TRAIN-2 showed that some patients do well without anthracyclines [
      • van Ramshorst M.S.
      • van der Voort A.
      • van Werkhoven E.D.
      • Mandjes I.A.
      • Kemper I.
      • Dezentjé V.O.
      • et al.
      Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial.
      ,

      van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol 2020;38:Abstract 501.

      ]. Patients were randomised to 9 neoadjuvant paclitaxel/carboplatin cycles or 3 of FEC followed by 6 of paclitaxel/carboplatin. All received concurrent pertuzumab–trastuzumab. 68% achieved pCR (ypT0/is, ypN0) with the anthracycline-free regimen (67% in the anthracycline-containing regimen); 3-year EFS rates were 93.5% and 92.7%, respectively; and 3-year OS rates were 98.2% and 97.7%. Although these outcome numbers appear very similar, the trial was not designed or powered to demonstrate non-inferiority of the non-anthracycline regimen, as shown by the broad 95% confidence interval of the EFS hazard ratios (Table 2).
      Significant decreases in LV function occurred in 3% in the anthracycline-free and 8% in the anthracycline-containing arm. New malignancies occurred more often following anthracycline-containing than anthracycline-free treatment (5% versus 2%). Potential long-term impacts of these findings on clinical symptomatology requires further evaluation [

      van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol 2020;38:Abstract 501.

      ].

      Subcutaneous pertuzumab–trastuzumab

      Trastuzumab is available in a subcutaneous formulation, co-formulated with recombinant human hyaluronidase. Subcutaneous administration is preferred by patients over intravenous [
      • Gligorov J.
      • Ataseven B.
      • Verrill M.
      • De Laurentiis M.
      • Jung K.H.
      • Azim H.A.
      • et al.
      Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients.
      ,
      • Pivot X.
      • Gligorov J.
      • Müller V.
      • Curigliano G.
      • Knoop A.
      • Verma S.
      • et al.
      Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: Final analysis of 488 patients in the international, randomized, two-cohort PrefHer study.
      ,
      • Pivot X.
      • Spano J.P.
      • Espie M.
      • Cottu P.
      • Jouannaud C.
      • Pottier V.
      • et al.
      Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study.
      ], with no difference in 6-year EFS/OS [
      • Jackisch C.
      • Stroyakovskiy D.
      • Pivot X.
      • Ahn J.S.
      • Melichar B.
      • Chen S.-C.
      • et al.
      Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: Final analysis of the HannaH phase 3 randomized clinical trial.
      ]. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection has recently been approved by the FDA and EMA, and provides non-inferior serum trough concentrations and nearly identical tpCR rates to separate intravenous infusions [
      • Tan A.R.
      • Im S.-A.
      • Mattar A.
      • Colomer R.
      • Stroyakovskii D.
      • Nowecki Z.
      • et al.
      Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): A randomised, open-label, multicentre, non-inferiority, phase 3 study.
      ]. Patients prefer subcutaneous over IV administration (85% versus 14%) [
      • O'Shaughnessy J.
      • Sousa S.
      • Cruz J.
      • Fallowfield L.
      • Auvinen P.
      • Pulido C.
      • et al.
      Patient (pt) preference for the pertuzumab–trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study.
      ]. Recently completed trials [
      • Denys H.
      • Martinez-Mena C.L.
      • Martens M.T.
      • D’Hondt R.G.
      • Graas M.-P.
      • Evron E.
      • et al.
      Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer.
      ,
      • ten Tije A.J.
      • van Steenis S.
      • Briers J.
      • Elsten E.M.P.
      Safety and tolerability of subcutaneous trastuzumab (H SC) self-administered at home via single-use injection device (SID) in patients (pts) with HER2-positive early breast cancer (EBC): Primary and final analysis of the open-label, phase IIIB HOMERUS study.
      ] show that subcutaneous trastuzumab home administration is feasible and preferred by patients. An expanded access study (NCT04395508) is evaluating the safety of home-administered subcutaneous pertuzumab–trastuzumab by home health nurses. A sub-study of a planned chemotherapy de-escalation trial (DECRESCENDO; NCT04675827) will include secondary evaluation of the fixed-dose combination in patients with EBC that allows for treatment outside oncology centres.

      Future perspectives

      Much progress has been made in optimising treatment, but many avenues remain open to exploration. There is a need to better match patients with available therapies based on individual characteristics, including biomarkers. This can be achieved by generating new trial evidence and examining long-term outcomes in pre-existing studies to optimise biomarker use (tumour-infiltrating lymphocytes, subtyping of immune cells, early response as measured by PET-FDG, circulating tumour DNA). Although biomarker work over the last 15 years has only yielded prognostic factors, it is hoped further work will identify biomarkers that can identify patients with early response and, alternatively, early recurrence. Patients with HER2-enriched subtypes have higher pCR rates after neoadjuvant therapy, including anti-HER2 agents, after accounting for HR status and chemotherapy [
      • Schettini F.
      • Pascual T.
      • Conte B.
      • Chic N.
      • Brasó-Maristany F.
      • Galván P.
      • et al.
      HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis.
      ]. It remains to be determined whether therapy can be de-escalated using this marker; further dedicated clinical trials are needed in this area.
      The HER2DX-combined prognostic score, developed using clinical–pathological data on TILs, PAM50 subtypes and expression of 55 genes in a retrospective analysis of the Short-HER phase III trial, has been used to identify patients with HER2-positive EBC who may be candidates for escalated or de-escalated systemic treatment [
      • Prat A.
      • Guarneri V.
      • Paré L.
      • Griguolo G.
      • Pascual T.
      • Dieci M.V.
      • et al.
      A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: A retrospective study with an external evaluation.
      ]. Further clinical validation of this tool is needed.
      There is a need to understand better the significance of biomarker status alteration. Tumour heterogeneity occurs with respect to HR and HER2 status [
      • Brasó-Maristany F.
      • Griguolo G.
      • Pascual T.
      • Paré L.
      • Nuciforo P.
      • Llombart-Cussac A.
      • et al.
      Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.
      ,
      • Wang R.-X.
      • Chen S.
      • Jin X.
      • Chen C.-M.
      • Shao Z.-M.
      Weekly paclitaxel plus carboplatin with or without trastuzumab as neoadjuvant chemotherapy for HER2-positive breast cancer: Loss of HER2 amplification and its impact on response and prognosis.
      ,
      • Robertson S.
      • Rönnlund C.
      • de Boniface J.
      • Hartman J.
      Re-testing of predictive biomarkers on surgical breast cancer specimens is clinically relevant.
      ,
      • Jeong Y.S.
      • Kang J.
      • Lee J.
      • Yoo T.-K.
      • Kim S.H.
      • Lee A.
      Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer.
      ]. Re-evaluation of biomarkers in patients with residual disease is of interest to researchers; there are no guidelines on how to manage patients with altered tumour biomarker status [
      • Ahn S.
      • Woo J.W.
      • Lee K.
      • Park S.Y.
      HER2 status in breast cancer: Changes in guidelines and complicating factors for interpretation.
      ]. An association between HER2 heterogeneity and pCR rate for patients with HER2-positive EBC treated with neoadjuvant TDM-1 plus pertuzumab has been described; however, this has not yet been validated for clinical use [

      Filho OM, Viale G, Trippa L, Li T, Yardley DA, Mayer IA, et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. J Clin Oncol 2019;37:Abstract 502.

      ].
      Future clinical trials should be designed to further optimise therapy in patients on the basis of pCR. In patients who achieve pCR after 12–16 weeks of pertuzumab–trastuzumab plus a taxane, it remains to be determined whether anthracycline chemotherapy can be avoided, at least in some subsets.
      CompassHER2-pCR (NCT04266249), HER2-RADiCAL (ClinicalTrials.gov pending) and DECRESCENDO will enrol patients who have been given neoadjuvant taxane plus trastuzumab-pertuzumab (no anthracycline).
      Combining cancer immunotherapies and chemotherapy is playing an important role in treatment of many patients and is effective in patients with triple-negative BC [
      • Schmid P.
      • Adams S.
      • Rugo H.S.
      • Schneeweiss A.
      • Barrios C.H.
      • Iwata H.
      • et al.
      Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
      ,
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kümmel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. Pembrolizumab plus trastuzumab produced objective responses in patients with PD-L1-positive tumours with advanced trastuzumab-resistant HER2-positive BC [
      • Loi S.
      • Giobbie-Hurder A.
      • Gombos A.
      • Bachelot T.
      • Hui R.
      • Curigliano G.
      • et al.
      Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b–2 trial.
      ]. Atezolizumab plus T-DM1 did not improve overall PFS in KATE2, but subgroup analyses suggested improved PFS in patients with HER2-positive advanced BC with PD-L1 expression [
      • Emens L.A.
      • Esteva F.J.
      • Beresford M.
      • Saura C.
      • De Laurentiis M.
      • Kim S.-B.
      • et al.
      Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): A phase 2, multicentre, randomised, double-blind trial.
      ]. KATE3 will assess atezolizumab and T-DM1 in this subgroup (ClinicalTrials.gov pending). The potential role of cancer immunotherapies is currently being evaluated in patients with HER2-positive EBC in the neoadjuvant (atezolizumab: IMpassion050, NCT03726879; APTneo, NCT03595592 ; pembrolizumab: Keyriched-1, NCT03988036; neoHIP, NCT03747120; durvalumab: Pro00020917, NCT03820141) and post-neoadjuvant settings (atezolizumab: ASTEFANIA, NCT04873362).
      There is growing interest in potential combinations of HER2-targeted therapies and existing treatment modalities/agents. CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) and ETs are often used as first-line therapies for metastatic, HR-positive, HER2-negative BC [
      • Turner N.C.
      • Slamon D.J.
      • Ro J.
      • Bondarenko I.
      • Im S.-A.
      • Masuda N.
      • et al.
      Overall survival with palbociclib and fulvestrant in advanced breast cancer.
      ,
      • Im S.-A.
      • Lu Y.-S.
      • Bardia A.
      • Harbeck N.
      • Colleoni M.
      • Franke F.
      • et al.
      Overall survival with ribociclib plus endocrine therapy in breast cancer.
      ,
      • Sledge G.W.
      • Toi M.
      • Neven P.
      • Sohn J.
      • Inoue K.
      • Pivot X.
      • et al.
      The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: A randomized clinical trial.
      ,
      • Li J.
      • Huo X.
      • Zhao F.
      • Ren D.
      • Ahmad R.
      • Yuan X.
      • et al.
      Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis.
      ]. PATINA (NCT02947685) is evaluating palbociclib, ET and trastuzumab-pertuzumab in ER-positive, HER2-positive disease.
      There are several novel HER2-targeted conjugates, e.g., fam-trastuzumab deruxtecan-nxki (recently granted accelerated approval metastatic BC after DESTINY-Breast01) [

      Krop IE, Saura C, Yamashita T, Park YH, Kim S-B, Tamura K, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Cancer Res 2020;80:Abstract GS1-03.

      ,

      Food and Drug Administration (FDA). FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. 2019.

      ]; trastuzumabduocarmazine (being evaluated for metastatic BC) [
      • Banerji U.
      • van Herpen C.M.L.
      • Saura C.
      • Thistlethwaite F.
      • Lord S.
      • Moreno V.
      • et al.
      Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: A phase 1 dose-escalation and dose-expansion study.
      ]. Fam-trastuzumab deruxtecan-nxki will be compared with T-DM1 in DESTINY Breast-05 (NCT04622319: EBC with residual invasive BC following neoadjuvant therapy).
      Tucatinib increases 1-year PFS/OS with capecitabine and trastuzumab in heavily pre-treated patients with metastatic BC and CNS involvement (HER2CLIMB) [
      • Murthy R.K.
      • Loi S.
      • Okines A.
      • Paplomata E.
      • Hamilton E.
      • Hurvitz S.A.
      • et al.
      Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
      ]. An exploratory analysis in patients with intracranial involvement showed that objective response and duration of response were significantly longer with tucatinib [
      • Lin N.U.
      • Borges V.
      • Anders C.
      • Murthy R.K.
      • Paplomata E.
      • Hamilton E.
      • et al.
      Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial.
      ]. The potential of the tucatinib-T-DM1 combination to further improve outcomes and address the unmet medical need of CNS metastases will be evaluated in CompassHER2-RD (NCT04457596) [
      • File D.
      • Curigliano G.
      • Carey L.A.
      Escalating and de-escalating therapy for early-stage HER2-positive breast cancer.
      ].

      Authors’ recommendations

      At present, the most important characteristics to be considered in risk-based clinical decision-making for the initial treatment of patients with HER2-positive disease include, in order of importance, tumour size, nodal status, HR status, histological grade, patient age, menopausal status and comorbidities.

      Conclusions

      The past decades have witnessed major advances in therapeutic options for patients with HER2-positive EBC, with HER2-targeted therapies as the well-established standard of care. Neoadjuvant pertuzumab–trastuzumab plus chemotherapy is standard of care for most patients with high-risk disease, in whom such therapy can eradicate the disease in the breast and axillary nodes. tpCR (ypT0/is, ypN0) is associated with improved long-term outcomes; however, traditional poor-prognostic factors, e.g., tumour size and baseline nodal status, remain important after pCR. Patients with tumours ≥2 cm and/or node-positive disease at diagnosis who achieve pCR should continue pertuzumab–trastuzumab to complete a full 1-year course [
      • Burstein H.J.
      • Curigliano G.
      • Loibl S.
      • Dubsky P.
      • Gnant M.
      • Poortmans P.
      • et al.
      Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
      ,
      • Cardoso F.
      • Kyriakides S.
      • Ohno S.
      • Penault-Llorca F.
      • Poortmans P.
      • Rubio I.T.
      • et al.
      Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,

      AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      ,

      National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

      ]. Residual invasive disease at surgery is a major decision point. KATHERINE’s results provide direction for the treatment of women with residual invasive disease after surgery by showing that T-DM1 significantly increases IDFS and decreases risk of recurrence by 50%. Patients at lower risk of relapse (i.e., T1 tumours; no axillary involvement) should be considered candidates for de-escalated adjuvant chemotherapy (paclitaxel-trastuzumab per APT, or perhaps T-DM1 per ATEMPT in the future). Ultimately, treatment recommendations should be consistent with local and international guidelines [
      • Cain H.
      • Macpherson I.R.
      • Beresford M.
      • Pinder S.E.
      • Pong J.
      • Dixon J.M.
      Neoadjuvant therapy in early breast cancer: Treatment considerations and common debates in practice.
      ]. Further studies will continue to guide improvements in therapeutic efficacy and the optimisation of treatment for patients with HER2-positive EBC according to their risk of disease recurrence.

      Role of the funding source

      This article was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Employees of the sponsor were involved in the writing and reviewing of the review; and in the decision to submit the article for publication in conjunction with the academic authors.

      Declaration of Competing Interest

      All authors received medical writing support from Roche for this article. CJ reports personal fees from Roche, Novartis, Celgene, Exact Sciences, AstraZeneca, and Pfizer; and grants from Exact Sciences, during the conduct of the study. PC is an employee of Genentech, Inc. CEG reports non-financial support (unpaid advisory boards), grants and travel support from Genentech/Roche, Daiichi Sankyo, and AstraZeneca, during the conduct of the study; personal fees from Exact Sciences (paid advisory board) and Athenex (paid consultant); and research funding and non-financial support (writing support) from AbbVie, outside the submitted work. LG reports personal fees (advisory board meetings) from Amgen, ADC Therapeutics, AstraZeneca, Celgene, Eli Lilly, G1 Therapeutics, Genentech, Inc., Genomic Health, MSD, Oncolytics Biotech, Odonate Therapeutics, Onkaido Therapeutics, Roche, Pfizer, Taiho Pharmaceutical, Sandoz, Seattle Genetics, Synthon and Zymeworks; grants from Pfizer, Zymeworks and Revolution Medicines; free consultancy for Forty Seven and Metis Precision Medicine; and paid consultancy for Menarini Ricerche, Synaffix, Novartis and Revolution Medicines, during the conduct of the study. In addition, LG has a patent, EPA 12195182.6 12196177.5-ROCHE, pending (co-inventor). JG reports grants, personal fees and non-financial support for clinical trials, travel support, advisory boards and speakers’ bureaus from Roche-Genentech, Eisai, Genomic Health and Pfizer; personal fees and non-financial support for clinical trials, travel support, advisory boards and speakers’ bureaus from Novartis and Lilly; personal fees and non-financial support for clinical trials and advisory boards from Daiichi Sankyo and MSD; grants and personal fees for travel support, advisory boards and speakers’ bureaus from Mylan; personal fees and non-financial support for travel support, advisory boards and speakers’ bureaus from Pierre Fabre; and personal fees for advisory boards and speakers’ bureaus from AstraZeneca, outside the submitted work. ZM is an employee of Roche and owns stock in Roche Holding, Ltd. EAP reports no other conflicts of interest pertinent to this work outside of the above-mentioned medical writing support. AS reports research grants from AbbVie, Celgene and Roche; expert testimony for Roche and AstraZeneca; travel expenses from Celgene, Pfizer and Roche; honoraria from AstraZeneca, Celgene, Lilly, MSD, Novartis, Pfizer, Roche and Tesaro; and grants for medical writing from Roche, outside the submitted work. SMT reports grants to her institute as principal investigator on studies from AstraZeneca, Eli Lilly, Merck, Nektar Therapeutics, Novartis, Pfizer, Genentech/Roche, Immunomedics, Exelixis, BMS, Eisai, NanoString, Cyclacel, Sanofi and Odonate Therapeutics; personal fees (honorarium for consultancy and/or advisory boards) from AstraZeneca, Eli Lilly, Merck, Nektar Therapeutics, Pfizer, Genentech/Roche, Immunomedics, BMS, Eisai, NanoString, Puma, Sanofi, Celldex, Odonate, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, AbbVie, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi-Sankyo, CytomX and Samsung Bioepis, Inc.; personal fees from Exelixis; and travel expense reimbursement for advisory boards from Nektar Therapeutics, outside the submitted work. MU reports compensation for his role as an advisor/consultant and for travel expenses to his institute from AbbVie, Amgen GmbH, AstraZeneca, BMS, Celgene GmbH, Daiichi Sankyo, Eisai GmbH, Lilly Deutschland, Lilly Int., MSD Merck, Mundipharma, Myriad Genetics, Odonate Therapeutics, Pfizer Germany, PUMA Biotechnology, Roche Pharma AG, Sanofi Aventis Deutschland GmbH, Teva Pharmaceuticals Ind. Ltd., Novartis, Pierre Fabre and Clovis Oncology. AW has received personal fees from Pierre Fabre, Roche, Amgen, MSD, Boehringer-Ingelheim, Novartis, Pfizer, AstraZeneca, Athenex, Gerson Lehmann Group, Coleman Expert Network Group, Guidepoint global, Helios Medical, Simon-Kucher and Partners, Lilly and Daiichi Sankyo. After completion of this work AW is employed by AstraZeneca. MP reports grants to her institute from Radius, AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon and Servier; personal fees from AstraZeneca, Lilly, MSD, Novartis, Odonate Therapeutics, Pfizer, Roche-Genentech, Camel-IDS, Debiopharm, Menarini, Seattle Genetics, Immunomedics, Oncolytics (for being on the Scientific Board) and Immutep, outside the submitted work.

      References

        • Loibl S.
        • Gianni L.
        HER2-positive breast cancer.
        Lancet. 2017; 389: 2415-2429
        • Piccart-Gebhart M.J.
        • Procter M.
        • Leyland-Jones B.
        • Goldhirsch A.
        • Untch M.
        • Smith I.
        • et al.
        Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
        N Engl J Med. 2005; 353: 1659-1672
        • Romond E.H.
        • Perez E.A.
        • Bryant J.
        • Suman V.J.
        • Geyer C.E.
        • Davidson N.E.
        • et al.
        Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
        N Engl J Med. 2005; 353: 1673-1684
        • Joensuu H.
        • Kellokumpu-Lehtinen P.-L.
        • Bono P.
        • Alanko T.
        • Kataja V.
        • Asola R.
        • et al.
        Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.
        N Engl J Med. 2006; 354: 809-820
        • Slamon D.
        • Eiermann W.
        • Robert N.
        • Pienkowski T.
        • Martin M.
        • Press M.
        • et al.
        Adjuvant trastuzumab in HER2-positive breast cancer.
        N Engl J Med. 2011; 365: 1273-1283
        • Perez E.A.
        • Romond E.H.
        • Suman V.J.
        • Jeong J.-H.
        • Davidson N.E.
        • Geyer C.E.
        • et al.
        Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31.
        J Clin Oncol. 2011; 29: 3366-3373
        • Cortazar P.
        • Zhang L.
        • Untch M.
        • Mehta K.
        • Costantino J.P.
        • Wolmark N.
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis.
        Lancet. 2014; 384: 164-172
        • Gianni L.
        • Pienkowski T.
        • Im Y.-H.
        • Roman L.
        • Tseng L.-M.
        • Liu M.-C.
        • et al.
        Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2012; 13: 25-32
        • Robidoux A.
        • Tang G.
        • Rastogi P.
        • Geyer C.E.
        • Azar C.A.
        • Atkins J.N.
        • et al.
        Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP Protocol B-41): An open-label, randomised phase 3 trial.
        Lancet Oncol. 2013; 14: 1183-1192
        • Schneeweiss A.
        • Chia S.
        • Hickish T.
        • Harvey V.
        • Eniu A.
        • Hegg R.
        • et al.
        Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA).
        Ann Oncol. 2013; 24: 2278-2284
        • Martin M.
        • Holmes F.A.
        • Ejlertsen B.
        • Delaloge S.
        • Moy B.
        • Iwata H.
        • et al.
        Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1688-1700
        • von Minckwitz G.
        • Procter M.
        • de Azambuja E.
        • Zardavas D.
        • Benyunes M.
        • Viale G.
        • et al.
        Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
        N Engl J Med. 2017; 377: 122-131
        • Swain S.M.
        • Ewer M.S.
        • Viale G.
        • Delaloge S.
        • Ferrero J.-M.
        • Verrill M.
        • et al.
        Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): A phase II, open-label, multicenter, multinational cardiac safety study.
        Ann Oncol. 2018; 29: 646-653
        • von Minckwitz G.
        • Huang C.-S.
        • Mano M.S.
        • Loibl S.
        • Mamounas E.P.
        • Untch M.
        • et al.
        Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
        N Engl J Med. 2019; 380: 617-628
        • Chan A.
        • Delaloge S.
        • Holmes F.A.
        • Moy B.
        • Iwata H.
        • Harvey V.J.
        • et al.
        Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2016; 17: 367-377
        • Chan A.
        • Moy B.
        • Mansi J.
        • Ejlertsen B.
        • Holmes F.A.
        • Chia S.
        • et al.
        Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial.
        Clin Breast Cancer. 2021; 21: 80-91.e7
      1. Cortes J, Gebhart G, Ruiz Borrego M, Stradella A, Bermejo B, Escrivá S, et al. Chemotherapy (CT) de-escalation using an FDG-PET/CT (F-PET) and pathological response-adapted strategy in HER2[+] early breast cancer (EBC): PHERGain Trial. J Clin Oncol 2020;38:Abstract 503.

        • van Ramshorst M.S.
        • van der Voort A.
        • van Werkhoven E.D.
        • Mandjes I.A.
        • Kemper I.
        • Dezentjé V.O.
        • et al.
        Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial.
        Lancet Oncol. 2018; 19: 1630-1640
        • Harbeck N.
        • Gluz O.
        • Christgen M.
        • Kates R.E.
        • Braun M.
        • Küemmel S.
        • et al.
        De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the west german study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET.
        J Clin Oncol. 2017; 35: 3046-3054
        • Burstein H.J.
        • Curigliano G.
        • Loibl S.
        • Dubsky P.
        • Gnant M.
        • Poortmans P.
        • et al.
        Estimating the benefits of therapy for early stage breast cancer the St Gallen International Consensus Guidelines for the Primary Therapy of Early Breast Cancer 2019.
        Ann Oncol. 2019; 30: 1541-1557
        • Cardoso F.
        • Kyriakides S.
        • Ohno S.
        • Penault-Llorca F.
        • Poortmans P.
        • Rubio I.T.
        • et al.
        Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2019; 30: 1194-1220
      2. AGO (German Gynecological Oncology Group). AGO Breast Cancer guidelines v1. 2021.

      3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1. 2021.

        • Norton N.
        • Fox N.
        • McCarl C.-A.
        • Tenner K.S.
        • Ballman K.
        • Erskine C.L.
        • et al.
        Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.
        Breast Cancer Res. 2018; 20https://doi.org/10.1186/s13058-018-0989-8
      4. Genentech Inc. Herceptin® (trastuzumab). Prescribing Information. February ed.

        • Goldhirsch A.
        • Gelber R.D.
        • Piccart-Gebhart M.J.
        • de Azambuja E.
        • Procter M.
        • Suter T.M.
        • et al.
        2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial.
        Lancet. 2013; 382: 1021-1028
        • Perez E.A.
        • Romond E.H.
        • Suman V.J.
        • Jeong J.-H.
        • Sledge G.
        • Geyer C.E.
        • et al.
        Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2–positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
        J Clin Oncol. 2014; 32: 3744-3752
        • Cameron D.
        • Piccart-Gebhart M.J.
        • Gelber R.D.
        • Procter M.
        • Goldhirsch A.
        • de Azambuja E.
        • et al.
        11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: Final analysis of the HERceptin Adjuvant (HERA) trial.
        Lancet. 2017; 389: 1195-1205
        • O'Sullivan C.C.
        • Bradbury I.
        • Campbell C.
        • Spielmann M.
        • Perez E.A.
        • Joensuu H.
        • et al.
        Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤2 cm: A meta-analysis of the randomized trastuzumab trials.
        J Clin Oncol. 2015; 33: 2600-2608
      5. Genentech Inc. PERJETA® (pertuzumab). Prescribing Information. May ed.

      6. GlaxoSmithKline. TYKERB® (lapatinib). Prescribing Information. January ed.

      7. Puma Biotechnology. NERLYNX™ (neratinib). Prescribing Information.

      8. Seattle Genetics Inc. TUKYSA™ (tucatenib). Prescribing Information. 2020.

        • Piccart-Gebhart M.
        • Holmes E.
        • Baselga J.
        • de Azambuja E.
        • Dueck A.C.
        • Viale G.
        • et al.
        Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: Results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
        J Clin Oncol. 2016; 34: 1034-1042
        • Piccart M.
        • Procter M.
        • Fumagalli D.
        • de Azambuja E.
        • Clark E.
        • Ewer M.S.
        • et al.
        Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up.
        J Clin Oncol. 2021; 39: 1448-1457
      9. European Society for Medical Oncology (ESMO). ESMO-MCBS scorecards: Pertuzumab. 2021.

        • Pivot X.
        • Romieu G.
        • Debled M.
        • Pierga J.-Y.
        • Kerbrat P.
        • Bachelot T.
        • et al.
        6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial.
        Lancet Oncol. 2013; 14: 741-748
        • Mavroudis D.
        • Saloustros E.
        • Malamos N.
        • Kakolyris S.
        • Boukovinas I.
        • Papakotoulas P.
        • et al.
        Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG).
        Ann Oncol. 2015; 26: 1333-1340
        • Conte P.
        • Frassoldati A.
        • Bisagni G.
        • Brandes A.A.
        • Donadio M.
        • Garrone O.
        • et al.
        Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: Final results of the phase III randomized Short-HER study‡.
        Ann Oncol. 2018; 29: 2328-2333
        • Joensuu H.
        • Fraser J.
        • Wildiers H.
        • Huovinen R.
        • Auvinen P.
        • Utriainen M.
        • et al.
        Effect of adjuvant trastuzumab for a duration of 9 weeks vs 1 year with concomitant chemotherapy for early human epidermal growth factor receptor 2-positive breast cancer: the SOLD randomized clinical trial.
        JAMA Oncol. 2018; 4: 1199https://doi.org/10.1001/jamaoncol.2018.1380
        • Inno A.
        • Barni S.
        • Ghidini A.
        • Zaniboni A.
        • Petrelli F.
        One year versus a shorter duration of adjuvant trastuzumab for HER2-positive early breast cancer: A systematic review and meta-analysis.
        Breast Cancer Res Treat. 2019; 173: 247-254
        • Niraula S.
        • Gyawali B.
        Optimal duration of adjuvant trastuzumab in treatment of early breast cancer: A meta-analysis of randomized controlled trials.
        Breast Cancer Res Treat. 2019; 173: 103-109
        • Earl H.M.
        • Hiller L.
        • Vallier A.-L.
        • Loi S.
        • McAdam K.
        • Hughes-Davies L.
        • et al.
        6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.
        Lancet. 2019; 393: 2599-2612
        • Barcenas C.H.
        • Hurvitz S.A.
        • Di Palma J.A.
        • Bose R.
        • Chien A.J.
        • Iannotti N.
        • et al.
        Improved tolerability of neratinib in patients with HER2-positive early-stage breast cancer: The CONTROL trial.
        Ann Oncol. 2020; 31: 1223-1230
      10. Curigliano G, Burstein HJ, P Winer E, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-12.

        • Fisher B.
        • Brown A.
        • Mamounas E.
        • Wieand S.
        • Robidoux A.
        • Margolese R.G.
        • et al.
        Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18.
        J Clin Oncol. 1997; 15: 2483-2493
        • Gianni L.
        • Pienkowski T.
        • Im Y.-H.
        • Tseng L.-M.
        • Liu M.-C.
        • Lluch A.
        • et al.
        5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.
        Lancet Oncol. 2016; 17: 791-800
      11. Loibl S, Untch M, Buyse M, Robidoux A, Gianni L, Schneeweiss A, et al. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC). Cancer Res 2020;80:Abstract P5-06-2.

      12. Swain SM, Macharia H, Cortes J, Dang C, Gianni L, Hurvitz S, et al. Risk of recurrence and death in patients with early HER2-positive breast cancer who achieve a pathological complete response (pCR) after different types of HER2-targeted therapy: A retrospective exploratory analysis. Cancer Res 2020;80:Abstract P1-18-01.

      13. Geyer CE, Jr., Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE. Cancer Res 2019;79 (Suppl):Abstract GS1-10.

        • Loibl S.
        • Huang C.
        • Mano M.S.
        • Mamounas E.P.
        • Geyer C.E.J.
        • Untch M.
        • et al.
        Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (T) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: Subgroup analysis from KATHERINE.
        Ann Oncol. 2020; 31 (Abstract 96O)
      14. Denkert C, Lambertini C, Fasching PA, Pogue-Geile KL, Mano MS, Untch M, et al. Biomarker data from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine vs. trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. J Clin Oncol 2020;38:Abstract 502.

      15. Untch M, Geyer CE, Huang CS, Loibl S, Wolmark N, Mano MS, et al. Peripheral neuropathy (PN), thrombocytopenia (TCP) and central nervous system (CNS) recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine (T-DM1) or trastuzumab (H) in patients (pts) with residual invasive HER2-positive breast cancer (BC). Ann Oncol 2019;30:Abstract LBA19.

        • Hurvitz S.A.
        • Martin M.
        • Symmans W.F.
        • Jung K.H.
        • Huang C.-S.
        • Thompson A.M.
        • et al.
        Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial.
        Lancet Oncol. 2018; 19: 115-126
        • Hurvitz S.A.
        • Martin M.
        • Jung K.H.
        • Huang C.-S.
        • Harbeck N.
        • Valero V.
        • et al.
        Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive breast cancer: Three-year outcomes from the phase III KRISTINE study.
        J Clin Oncol. 2019; 37: 2206-2216
      16. Gluz O, Nitz U, Christgen M, Kuemmel S, Holtschmidt J, Priel J, et al. De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study. J Clin Oncol. 2020;38:Abstract 515.

      17. Harbeck N, Nitz U, Christgen M, Kuemmel S, Braun M, Schumacher C, et al. De-escalated neoadjuvant T-DM1 with or without endocrine therapy (ET) vs trastuzumab+ET in early HR+/HER2+ breast cancer (BC): ADAPT-TP survival results. Ann Oncol 2020;31:Abstract LBA14.

        • Guarneri V.
        • Dieci M.V.
        • Bisagni G.
        • Frassoldati A.
        • Bianchi G.V.
        • De Salvo G.L.
        • et al.
        De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: Results of the PerELISA neoadjuvant study.
        Ann Oncol. 2019; 30: 921-926
        • Nitz U.A.
        • Gluz O.
        • Christgen M.
        • Grischke E.M.
        • Augustin D.
        • Kuemmel S.
        • et al.
        De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab +/- weekly paclitaxel.
        Ann Oncol. 2017; 28: 2768-2772
      18. Veeraraghavan J, Gutierrez C, Angelis CD, Wang T, Pascual T, Weigelt B, et al. A multiparameter classifier to predict response to lapatinib plus trastuzumab (LT) without chemotherapy in HER2+ breast cancer (BC). J Clin Oncol 2020;38:Abstract 1011.

        • Brasó-Maristany F.
        • Griguolo G.
        • Pascual T.
        • Paré L.
        • Nuciforo P.
        • Llombart-Cussac A.
        • et al.
        Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade.
        Nat Commun. 2020; 11https://doi.org/10.1038/s41467-019-14111-3
        • Ingold Heppner B.
        • Untch M.
        • Denkert C.
        • Pfitzner B.M.
        • Lederer B.
        • Schmitt W.
        • et al.
        Tumor-infiltrating lymphocytes: A predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer.
        Clin Cancer Res. 2016; 22: 5747-5754
        • Perez E.A.
        • Ballman K.V.
        • Tenner K.S.
        • Thompson E.A.
        • Badve S.S.
        • Bailey H.
        • et al.
        Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the N9831 adjuvant trial in patients with early-stage HER2-positive breast cancer.
        JAMA Oncol. 2016; 2: 56https://doi.org/10.1001/jamaoncol.2015.3239
      19. Connolly RM, Leal JP, Solnes L, Huang C-Y, Carpenter A, Gaffney K, et al. Phase II clinical trial assessing the correlation of standardized uptake value (SUV) on positron emission tomography (PET) with pathological complete response (pCR) to pertuzumab and trastuzumab in patients with primary operable HER2-positive breast cancer. J Clin Oncol 2018;36:Abstract TBCRC026.

        • Tolaney S.M.
        • Barry W.T.
        • Dang C.T.
        • Yardley D.A.
        • Moy B.
        • Marcom P.K.
        • et al.
        Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer.
        N Engl J Med. 2015; 372: 134-141
        • Tolaney S.M.
        • Guo H.
        • Pernas S.
        • Barry W.T.
        • Dillon D.A.
        • Ritterhouse L.
        • et al.
        Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer.
        J Clin Oncol. 2019; 37: 1868-1875
        • Tolaney S.M.
        • Trippa L.
        • Barry W.
        • Hu J.
        • Dang C.
        • Yardley D.
        • et al.
        A randomized phase II study of adjuvant trastuzumab emtansine (TDM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT).
        Cancer Res. 2020; 80 (Abstract TBCRC 033)
      20. Partridge A, Zheng Y, Rosenberg S, Gelber R, Gelber S, Barry W, et al. Patient reported outcomes from the adjuvant trastuzumab emtansine (T-DM1) vs. paclitaxel + trastuzumab (TH) (ATEMPT) trial (TBCRC 033). Cancer Res 2020;80:Abstract PD10-02.

      21. Harbeck N, Im S-A, Barrios CH, Bonnefoi HR, Gralow J, Toi M, et al. Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine (T-DM1) + pertuzumab versus trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer (EBC). J Clin Oncol 2020;38:Abstract 500.

        • de Azambuja E.
        • Ponde N.
        • Procter M.
        • Rastogi P.
        • Cecchini R.S.
        • Lambertini M.
        • et al.
        A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.
        Breast Cancer Res Treat. 2020; 179: 161-171
        • Ganz P.A.
        • Romond E.H.
        • Cecchini R.S.
        • Rastogi P.
        • Geyer C.E.
        • Swain S.M.
        • et al.
        Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG oncology: A randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with ac followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2.
        J Clin Oncol. 2017; 35: 3942-3948
        • Lynce F.
        • Barac A.
        • Geng X.
        • Dang C.
        • Yu A.F.
        • Smith K.L.
        • et al.
        Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.
        Breast Cancer Res Treat. 2019; 175: 595-603
        • Cain H.
        • Macpherson I.R.
        • Beresford M.
        • Pinder S.E.
        • Pong J.
        • Dixon J.M.
        Neoadjuvant therapy in early breast cancer: Treatment considerations and common debates in practice.
        Clin Oncol (R Coll Radiol). 2017; 29: 642-652
        • Denduluri N.
        • Somerfield M.R.
        • Eisen A.
        • Holloway J.N.
        • Hurria A.
        • King T.A.
        • et al.
        Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) -negative and adjuvant targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline.
        J Clin Oncol. 2016; 34: 2416-2427
      22. van der Voort A, van Ramshorst MS, van Werkhoven ED, Mandjes IA, Kemper I, Vulink AJ, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. J Clin Oncol 2020;38:Abstract 501.

        • Gligorov J.
        • Ataseven B.
        • Verrill M.
        • De Laurentiis M.
        • Jung K.H.
        • Azim H.A.
        • et al.
        Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients.
        Eur J Cancer. 2017; 82: 237-246
        • Pivot X.
        • Gligorov J.
        • Müller V.
        • Curigliano G.
        • Knoop A.
        • Verma S.
        • et al.
        Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: Final analysis of 488 patients in the international, randomized, two-cohort PrefHer study.
        Ann Oncol. 2014; 25: 1979-1987
        • Pivot X.
        • Spano J.P.
        • Espie M.
        • Cottu P.
        • Jouannaud C.
        • Pottier V.
        • et al.
        Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study.
        Eur J Cancer. 2017; 82: 230-236
        • Jackisch C.
        • Stroyakovskiy D.
        • Pivot X.
        • Ahn J.S.
        • Melichar B.
        • Chen S.-C.
        • et al.
        Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: Final analysis of the HannaH phase 3 randomized clinical trial.
        JAMA Oncol. 2019; 5: e190339https://doi.org/10.1001/jamaoncol.2019.0339
        • Tan A.R.
        • Im S.-A.
        • Mattar A.
        • Colomer R.
        • Stroyakovskii D.
        • Nowecki Z.
        • et al.
        Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): A randomised, open-label, multicentre, non-inferiority, phase 3 study.
        Lancet Oncol. 2021; 22: 85-97
        • O'Shaughnessy J.
        • Sousa S.
        • Cruz J.
        • Fallowfield L.
        • Auvinen P.
        • Pulido C.
        • et al.
        Patient (pt) preference for the pertuzumab–trastuzumab fixed-dose combination for subcutaneous use (PH FDC SC) in HER2-positive early breast cancer (EBC): Primary analysis of the open-label, randomised crossover PHranceSCa study.
        Ann Oncol. 2020; 31 (Abstract 165MO)
        • Denys H.
        • Martinez-Mena C.L.
        • Martens M.T.
        • D’Hondt R.G.
        • Graas M.-P.
        • Evron E.
        • et al.
        Safety and tolerability of subcutaneous trastuzumab at home administration, results of the phase IIIb open-label BELIS study in HER2-positive early breast cancer.
        Breast Cancer Res Treat. 2020; 181: 97-105
        • ten Tije A.J.
        • van Steenis S.
        • Briers J.
        • Elsten E.M.P.
        Safety and tolerability of subcutaneous trastuzumab (H SC) self-administered at home via single-use injection device (SID) in patients (pts) with HER2-positive early breast cancer (EBC): Primary and final analysis of the open-label, phase IIIB HOMERUS study.
        Ann Oncol. 2020; 31 (Abstract 223P)
        • Schettini F.
        • Pascual T.
        • Conte B.
        • Chic N.
        • Brasó-Maristany F.
        • Galván P.
        • et al.
        HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis.
        Cancer Treat Rev. 2020; 84: 101965https://doi.org/10.1016/j.ctrv.2020.101965
        • Prat A.
        • Guarneri V.
        • Paré L.
        • Griguolo G.
        • Pascual T.
        • Dieci M.V.
        • et al.
        A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: A retrospective study with an external evaluation.
        Lancet Oncol. 2020; 21: 1455-1464
        • Wang R.-X.
        • Chen S.
        • Jin X.
        • Chen C.-M.
        • Shao Z.-M.
        Weekly paclitaxel plus carboplatin with or without trastuzumab as neoadjuvant chemotherapy for HER2-positive breast cancer: Loss of HER2 amplification and its impact on response and prognosis.
        Breast Cancer Res Treat. 2017; 161: 259-267
        • Robertson S.
        • Rönnlund C.
        • de Boniface J.
        • Hartman J.
        Re-testing of predictive biomarkers on surgical breast cancer specimens is clinically relevant.
        Breast Cancer Res Treat. 2019; 174: 795-805
        • Jeong Y.S.
        • Kang J.
        • Lee J.
        • Yoo T.-K.
        • Kim S.H.
        • Lee A.
        Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer.
        J Pathol Transl Med. 2020; 54: 87-94
        • Ahn S.
        • Woo J.W.
        • Lee K.
        • Park S.Y.
        HER2 status in breast cancer: Changes in guidelines and complicating factors for interpretation.
        J Pathol Transl Med. 2020; 54: 34-44
      23. Filho OM, Viale G, Trippa L, Li T, Yardley DA, Mayer IA, et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. J Clin Oncol 2019;37:Abstract 502.

        • Schmid P.
        • Adams S.
        • Rugo H.S.
        • Schneeweiss A.
        • Barrios C.H.
        • Iwata H.
        • et al.
        Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
        N Engl J Med. 2018; 379: 2108-2121
        • Schmid P.
        • Cortes J.
        • Pusztai L.
        • McArthur H.
        • Kümmel S.
        • Bergh J.
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 810-821
        • Loi S.
        • Giobbie-Hurder A.
        • Gombos A.
        • Bachelot T.
        • Hui R.
        • Curigliano G.
        • et al.
        Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b–2 trial.
        Lancet Oncol. 2019; 20: 371-382
        • Emens L.A.
        • Esteva F.J.
        • Beresford M.
        • Saura C.
        • De Laurentiis M.
        • Kim S.-B.
        • et al.
        Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): A phase 2, multicentre, randomised, double-blind trial.
        Lancet Oncol. 2020; 21: 1283-1295
        • Turner N.C.
        • Slamon D.J.
        • Ro J.
        • Bondarenko I.
        • Im S.-A.
        • Masuda N.
        • et al.
        Overall survival with palbociclib and fulvestrant in advanced breast cancer.
        N Engl J Med. 2018; 379: 1926-1936
        • Im S.-A.
        • Lu Y.-S.
        • Bardia A.
        • Harbeck N.
        • Colleoni M.
        • Franke F.
        • et al.
        Overall survival with ribociclib plus endocrine therapy in breast cancer.
        N Engl J Med. 2019; 381: 307-316
        • Sledge G.W.
        • Toi M.
        • Neven P.
        • Sohn J.
        • Inoue K.
        • Pivot X.
        • et al.
        The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: A randomized clinical trial.
        JAMA Oncol. 2020; 6: 116https://doi.org/10.1001/jamaoncol.2019.4782
        • Li J.
        • Huo X.
        • Zhao F.
        • Ren D.
        • Ahmad R.
        • Yuan X.
        • et al.
        Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis.
        JAMA Netw Open. 2020; 3: e2020312https://doi.org/10.1001/jamanetworkopen.2020.20312
      24. Krop IE, Saura C, Yamashita T, Park YH, Kim S-B, Tamura K, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Cancer Res 2020;80:Abstract GS1-03.

      25. Food and Drug Administration (FDA). FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. 2019.

        • Banerji U.
        • van Herpen C.M.L.
        • Saura C.
        • Thistlethwaite F.
        • Lord S.
        • Moreno V.
        • et al.
        Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: A phase 1 dose-escalation and dose-expansion study.
        Lancet Oncol. 2019; 20: 1124-1135
        • Murthy R.K.
        • Loi S.
        • Okines A.
        • Paplomata E.
        • Hamilton E.
        • Hurvitz S.A.
        • et al.
        Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.
        N Engl J Med. 2020; 382: 597-609
        • Lin N.U.
        • Borges V.
        • Anders C.
        • Murthy R.K.
        • Paplomata E.
        • Hamilton E.
        • et al.
        Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial.
        J Clin Oncol. 2020; 38: 2610-2619
        • File D.
        • Curigliano G.
        • Carey L.A.
        Escalating and de-escalating therapy for early-stage HER2-positive breast cancer.
        Am Soc Clin Oncol Educ Book. 2020; 40: 1-11