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Rethinking breast cancer follow-up based on individual risk and recurrence management

Open AccessPublished:June 30, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102434

      Highlights

      • Review of current recommendations for breast cancer follow-up.
      • Summary of recent advances in recurrent breast cancer management.
      • Description of new diagnostic modalities, predictive models of recurrence and circulating biomarkers as a tool for early detection of relapse.
      • Proposal of a research and development agenda towards implementing risk-based breast cancer follow-up in routine clinical practice.
      • Focus on the role of multidisciplinary teams in breast cancer surveillance.

      Abstract

      Current follow-up policies for early breast cancer aim to detect loco-regional recurrences and manage treatment-related adverse effects. Their “one size fits all” approach does not take into account differences in subtypes at initial diagnosis, individual prognosis and treatments received. They are derived from clinical trials conducted when early detection means - other than mammography - and treatment options were limited. Herein, we address the arguments for re-evaluating current breast cancer follow-up strategies starting from recent advances in breast cancer local and systemic treatments and discussing individual risk of recurrence prediction models, time-adapted imaging and biomarker assessment for disease diagnostic anticipation. This change in perspective would transform breast cancer follow-up into an integrated, multidisciplinary team medical practice. Hence we discuss the important role of patient-centered approaches, but also of general practitioners and other health professionals, in the final promotion of personalized surveillance programs and patient education.

      Keywords

      Introduction

      Breast cancer is the most common cancer in women in the world and remains a major public health burden with 25% of all cancer cases and 15% of all cancer deaths among females [

      International Agency for Research on Cancer. Latest global cancer data: Cancer burden rises to 19.3 million new cases and 10.0 million cancer deaths in 2020. Press release 292. 15 December 2020. Available from: https://www.iarc.who.int/news-events/latest-global-cancer-data-cancer-burden-rises-to-19-3-million-new-cases-and-10-0-million-cancer-deaths-in-2020/.

      ]. Incidence increased with the introduction of mammography screening and continues to grow, mainly due to population ageing; meanwhile, breast cancer survival has significantly improved over the past decades [
      • Ferlay J.
      • Ervik M.
      • Lam F.
      • Colombet M.
      • Mery L.
      • Piñeros M.
      • et al.
      Global Cancer Observatory: Cancer Today.
      ]. Ten-year cancer specific survival exceeds 70%, with 89% survival for local and 62% for regional disease [
      • Ferlay J.
      • Ervik M.
      • Lam F.
      • Colombet M.
      • Mery L.
      • Piñeros M.
      • et al.
      Global Cancer Observatory: Cancer Today.
      ]. The risk of recurrence of patients diagnosed with hormonal receptor (HR)-negative breast cancer is high during the first two years after the initial diagnosis, but rapidly drops thereafter below that of HR-positive tumors [
      • Park S.
      • Koo J.S.
      • Kim M.S.
      • Park H.S.
      • Lee J.S.
      • Lee J.S.
      • et al.
      Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry.
      ]. In patients with HR-positive disease, the annual risk of relapse remains constant at long term, and relapse may occur as late as a decade after the initial diagnosis [
      • Park S.
      • Koo J.S.
      • Kim M.S.
      • Park H.S.
      • Lee J.S.
      • Lee J.S.
      • et al.
      Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry.
      ]. Early relapses have a worse prognosis than late ones [

      Pedersen RN, Mellemkjær L, Ejlertsen B, Nørgaard M, Cronin-Fenton DP. Mortality After Late Breast Cancer Recurrence in Denmark. J Clin Oncol. 2022 Feb 16:JCO2102062. doi: 10.1200/JCO.21.02062. Epub ahead of print. PMID: 35171656.

      ].
      Previous data from randomized trials failed to demonstrate any benefit from screening for metastatic recurrences [
      • Palli D.
      • Russo A.
      • Saieva C.
      • Ciatto S.
      • Rosselli Del Turco M.
      • et al.
      Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up.
      ,
      • Rosselli Del Turco M.
      • Palli D.
      • Cariddi A.
      • Ciatto S.
      • Pacini P.
      • Distante V.
      Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up.
      ,
      • The GIVIO Investigators
      Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicentre randomized controlled trial.
      ]. However, all these studies were rather underpowered, and date back to when metastatic work-up used diagnostic tests with limited sensitivity and accuracy, and few treatments were available for recurrent cases. These considerations are even more important in oligometastatic disease, a state between localized and disseminated spreading.
      Starting from current breast cancer follow-up recommendations, this critical review aims to report the arguments for re-evaluating surveillance strategies to provide an early diagnosis of recurrent breast cancer, taking into account individual risk of recurrence based on time-adapted imaging, prediction models, and biomarker assessment, with a focus on oligometastatic disease and recent advances in both local and systemic treatments.

      Current recommendations for early breast cancer follow-up

      Surveillance after treatment of localized breast cancer aims at early detection of loco-regional recurrences or contralateral breast cancer, management of treatment-related complications, and psychological support to enable a return to normal life. Detection of asymptomatic disseminated metastases is not part of current follow-up measures because the use of imaging, i.e., chest X-ray, abdominal ultrasound, bone scan [
      • Palli D.
      • Russo A.
      • Saieva C.
      • Ciatto S.
      • Rosselli Del Turco M.
      • et al.
      Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up.
      ,
      • Rosselli Del Turco M.
      • Palli D.
      • Cariddi A.
      • Ciatto S.
      • Pacini P.
      • Distante V.
      Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up.
      ,
      • The GIVIO Investigators
      Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicentre randomized controlled trial.
      ], and circulating tumor markers, i.e., Carcinoembryonic antigen 15.3 (CA 15.3), and Carcinoembryonic antigen (CEA) [
      • Kokko R.
      • Holli K.
      • Hakama M.
      Ca 15–3 in the follow-up of localised breast cancer: a prospective study.
      ,

      Nicolini A, Tartarelli G, Carpi A, Metelli MR, Ferrari P, Anselmi L, Conte M, Berti P, Miccoli P. Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA-CA15.3 panel in the early detection of distant metastases. BMC Cancer. 2006 Nov 20;6:269. doi: 10.1186/1471-2407-6-269. PMID: 17116247; PMCID: PMC1684262.

      ], for diagnostic anticipation failed to demonstrate any benefit on overall survival (OS) or quality of life. Although the goals of breast cancer follow-up are widely shared, the pattern of care for breast cancer survivors shows some level of variability across international guidelines (Table 1) [

      Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, RubioIT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Committee. Electronic address: [email protected] Ann Oncol. 2019 Aug 1;30(8):1194-1220. doi: 10.1093/annonc/mdz173.

      ,
      • Gradishar W.J.
      • Anderson B.O.
      • Abraham J.
      • Aft R.
      • Agnese D.
      • Allison K.H.
      • et al.
      Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology 8.
      ,

      Ditsch N, Kolberg-Liedtke C, Friedrich M, Jackisch C, Albert US, Banys-Paluchowski M, et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2021. Breast Care (Basel, Switzerland), 01 Jun 2021, 16(3):214-227 doi: 10.1159/000516419.

      ,
      • Runowicz C.D.
      • Leach C.R.
      • Henry N.L.
      • et al.
      American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline.
      ].
      Table 1Current guidelines in breast cancer follow-up.
      ASCOESMONCCNAGO
      Hystory and physical examEvery 3–6 months years 1 to 3, every 6 months years 4 to 5, yearly thereafterEvery 3–6 months years 1 to 3, every 6 months years 4 to 5, yearly thereafterEvery 3–12 months years 1 to 5Every 3 months years 1 to 3, every 6 months years 4 to 5, yearly thereafter
      Self examNoNoNoYes
      MammographyYearlyYearlyYearlyYearly
      Breast USNoYearlyNoYearly
      Breast MRIOnly in selected patientsOnly in young patients < 35, with dense breast, very strong family history, and genetic predispositionNoIf conventional imaging are inconclusive
      Chest XrayNoNoNoNo
      CT scanNoNoNoNo
      Pelvic examNoYearly in patients on tamoxifenYearly in patients on tamoxifenNo
      Blood testNoLimited to patients on endocrine therapy

      Frequency is not specified
      NoNo
      Tumor markersNoNoNoNo
      DXALimited to cases on AIs, tamoxifen or with secondary ovarian failure

      Frequency is not specified
      Limited to cases on AIs







      Frequency is not specified
      Limited to cases on AIs, or with secondary ovarian failure

      Frequency is not specified
      Limited to cases on AIs, or with secondary ovarian failure

      Every 2 years
      Abdominal USNoNoNoNo
      Bone scanNoNoNoNo
      PET/CTNoNoNoNo
      whole body MRI*NoNoNoNo
      AIs: Aromatase Inhibitors; DXA: dual-energy x-ray absorptiometry (bone densitometry); *except for TP53 germline mutation carriers, where it is recommended for all patients.
      In general, follow-up is more frequent (2–4 times/year) during the first 2–3 years after treatment completion, and becomes less regular thereafter. All national and international guidelines agree on the need to obtain a detailed history and clinical examination at each scheduled visit.
      Mammography is unanimously recommended, while breast ultrasound and magnetic resonance imaging (MRI) is recommended in specific patient groups, i.e., those with familiar history and genetic predisposition, or in selected cases of inconclusive conventional imaging. In asymptomatic patients other examinations are not recommended, except for laboratory tests during adjuvant hormonal therapy endorsed by the European Society of Medical Oncology (ESMO) guidelines [

      Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, RubioIT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Committee. Electronic address: [email protected] Ann Oncol. 2019 Aug 1;30(8):1194-1220. doi: 10.1093/annonc/mdz173.

      ]. Regular bone density evaluation is recommended for patients undergoing ovarian function suppression and/or aromatase inhibitors. Pelvic examination is included in the ESMO and National Comprehensive Cancer Network (NCCN) guidelines for women on tamoxifen [

      Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, RubioIT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Committee. Electronic address: [email protected] Ann Oncol. 2019 Aug 1;30(8):1194-1220. doi: 10.1093/annonc/mdz173.

      ,
      • Gradishar W.J.
      • Anderson B.O.
      • Abraham J.
      • Aft R.
      • Agnese D.
      • Allison K.H.
      • et al.
      Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology 8.
      ] but not in the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) [

      Ditsch N, Kolberg-Liedtke C, Friedrich M, Jackisch C, Albert US, Banys-Paluchowski M, et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2021. Breast Care (Basel, Switzerland), 01 Jun 2021, 16(3):214-227 doi: 10.1159/000516419.

      ], and American Society of Clinical Oncology (ASCO) [
      • Runowicz C.D.
      • Leach C.R.
      • Henry N.L.
      • et al.
      American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline.
      ] guidelines. Patients are encouraged by all towards adopting a healthy lifestyle, including diet modification and exercise. Hormone replacement therapy is generally discouraged. Long-term survivorship problems including psychological needs and issues related to work, family and sexuality are advised to be addressed in specialized rehabilitation facilities and services. Notably, follow-up continues to be variable in real practice and most often inconsistent with international guidelines even in shared recommendations [
      • Hahn E.E.
      • Hays R.D.
      • Kahn K.L.
      • Litwin M.S.
      • Ganz P.A.
      Use of imaging and biomarker tests for posttreatment care of early-stage breast cancer survivors.
      ,
      • Natoli C.
      • Brocco D.
      • Sperduti I.
      • et al.
      Breast cancer “tailored follow-up” in Italian oncology units: a web-based survey.
      ].

      Risk and time-adapted imaging

      Surveillance should include anamnesis, symptoms reporting, physical examination and annual mammography, regardless of age, stage of disease, and biological features at initial diagnosis. This strategy aims to early detect local, regional or contralateral recurrences and is based on the results of prospective studies evaluating the clinical value of mammography [
      • Lash T.L.
      • Fox M.P.
      • Silliman R.A.
      Reduced mortality rate associated with annual mammograms after breast cancer therapy.
      ]. In contrast, screening for metastatic disease in breast cancer patients treated with curative intent was unsuccessful, as shown by studies that reported no significant differences in terms of OS between patients undergoing or not intensive follow-up to detect metastases in advance [
      • Palli D.
      • Russo A.
      • Saieva C.
      • Ciatto S.
      • Rosselli Del Turco M.
      • et al.
      Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up.
      ,
      • Rosselli Del Turco M.
      • Palli D.
      • Cariddi A.
      • Ciatto S.
      • Pacini P.
      • Distante V.
      Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up.
      ,
      • The GIVIO Investigators
      Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicentre randomized controlled trial.
      ]. Notably, all these studies were published in the nineties when therapeutic options for recurrent patients were limited. In the same years, Hellman and Weichselbaum developed and announced the concept of oligometastatic disease (OM) as a potentially curable state of disease associated with a favorable prognosis [
      • Hellman S.
      • Weichselbaum R.R.
      Oligometastases.
      ]. Since then, several studies reported the activity of ablative loco-regional therapies and their potential to improve OS [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.
      ,
      • Chalkidou A.
      • Macmillan T.
      • Grzeda M.T.
      • Peacock J.
      • Summers J.
      • Eddy S.
      • et al.
      Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study.
      ,
      • Lievens Y.
      • Guckenberger M.
      • Gomez D.
      • Hoyer M.
      • Iyengar P.
      • Kindts I.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
      ]. Hence, not surprisingly the ESTRO-ASTRO consensus recently endorsed the use of imaging modalities, including positron emission tomography (PET/CT), contrast-enhanced chest/abdominal and pelvis CT, and/or brain or spine MRI, that adequately detect small lesions in common metastatic sites [
      • Lievens Y.
      • Guckenberger M.
      • Gomez D.
      • Hoyer M.
      • Iyengar P.
      • Kindts I.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
      ], as imaging remains the cornerstone to identify OM [
      • Pirasteh A.
      • Lovrec P.
      • Pedrosa I.
      Imaging and its Impact on Defining the Oligometastatic State.
      ].
      There is a lot of controversy about the use of circulating tumor markers during follow-up. The European Group on Tumour Markers (EGTM) recommends serial serum measurements of CA 15.3 and CEA every 2–4 months during the initial five years after diagnosis, and less frequently thereafter. Nevertheless, EGTM acknowledges that the impact of this practice on clinical outcome is unclear [
      • Molina R.
      • Barak V.
      • van Dalen A.
      • Duffy M.J.
      • Einarsson R.
      • Gion M.
      • et al.
      Tumor markers in breast cancer- European Group on Tumor Markers recommendations.
      ]. More recently, the use of PET/CT has been proposed to resolve any suspicious lesions on surveillance imaging [

      deSouza NM, Liu Y, Chiti A, Oprea-Lager D, Gebhart G, Van Beers BE, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. European Journal of Cancer (Oxford, England: 1990) 2018 Mar;91:153-163. doi: 10.1016/j.ejca.2017.12.012.

      ] or diagnose asymptomatic disease [
      • Paydary K.
      • Seraj S.M.
      • Zadeh M.Z.
      • Emamzadehfard S.
      • Shamchi S.P.
      • Gholami S.
      • et al.
      The evolving role of FDG- PET/CT in the diagnosis, staging, and treatment of breast cancer.
      ] in breast cancer survivors with rising circulating tumor markers.
      A risk-based approach to order imaging was recently proposed by deSouza and Tempany [
      • deSouza N.M.
      • Tempany C.M.
      A risk-based approach to identifying oligometastatic disease on imaging.
      ]. The authors assessed the metastatic risk by evaluating primary tumor histological and molecular features, together with morphological/functional imaging, and response to chemotherapy. Finally, they propose an imaging workflow depending on the characteristics of the primary tumor and its potential to spread, and suggest intensifying follow-up visits and examinations between 2 and 4 years after the end of treatment, when most OM cases are expected to occur. Several studies are currently evaluating imaging for different follow-up strategies, including the Japanese study UMIN000012429 which randomizes high-risk patients to physical examination, mammography and tumor marker evaluation yearly ± chest and abdominal CT, bone scan (or alternatively PET/CT), and brain MRI/CT twice a year for the first 3 years and every year for the next 2 years [
      • Hojo T.
      • Masuda N.
      • Mizutani T.
      • Shibata T.
      • Kinoshita T.
      • Tamura K.
      • et al.
      Intensive vs. standard post-operative surveillance in high- risk breast cancer patients (INSPIRE): Japan Clinical Oncology Group Study JCOG1204.
      ].

      Management of recurrent breast cancer

      Loco-regional recurrence (LRR)

      LRR occurs in 5–15% of cases treated with breast conservative surgery (BCS) plus adjuvant radiotherapy (RT) or mastectomy [
      Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
      Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials..
      ,
      • Christiansen P.
      • Al Suliman N.
      • Bjerre K.
      • Moller S.
      Recurrence pattern and prognosis in low-risk breast cancer patients – data from the DBCG 89-A programme.
      ,

      Bartelink H, Maingon P, Poortmans P, Weltens C, Fourquet A, Jager J, et al. European organisation for research and treatment of cancer radiation oncology and breast cancer groups. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol 2015 Jan;16(1):47-56. doi: 10.1016/S1470-2045(14)71156-8.

      ], and represents an independent poor prognostic factor [

      Pedersen RN, Mellemkjær L, Ejlertsen B, Nørgaard M, Cronin-Fenton DP. Mortality After Late Breast Cancer Recurrence in Denmark. J Clin Oncol. 2022 Feb 16:JCO2102062. doi: 10.1200/JCO.21.02062. Epub ahead of print. PMID: 35171656.

      ]. The management of LRR requires a multidisciplinary approach [

      Thomas A Buchholz, Sonia Ali , Kelly K Hunt. Multidisciplinary Management of Locoregional Recurrent Breast Cancer. J Clin Oncol 2020 Jul 10;38(20):2321-2328. doi: 10.1200/JCO.19.02806.

      ]. Total mastectomy represents the standard of care for isolated LRR after BCS. However, secondary BCS ± RT is an alternative approach that could be discussed case by case [

      Thomas A Buchholz, Sonia Ali , Kelly K Hunt. Multidisciplinary Management of Locoregional Recurrent Breast Cancer. J Clin Oncol 2020 Jul 10;38(20):2321-2328. doi: 10.1200/JCO.19.02806.

      ].
      Recent publications showed that re-irradiation is safe [
      • Hannoun-Levi J.
      • Resch A.
      • Gal J.
      • Kauer-dorner D.
      • Strnad V.
      • Niehoff P.
      • et al.
      Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group.
      ], including secondary fractionated external beam whole breast [
      • Janssen S.
      • Rades D.
      • Meyer A.
      • Fahlbusch F.B.
      • Wildfang I.
      • Meier A.
      • et al.
      Local recurrence of breast cancer: conventionally fractionated partial external beam re-irradiation with curative intention.
      ], intraoperative or accelerated partial breast irradiation by intrabeam [
      • Kraus-Tiefenbacher U.
      • Bauer L.
      • Scheda A.
      • Schoeber C.
      • Schaefer J.
      • Steil V.
      • et al.
      Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy.
      ], interstitial multi-catheter brachytherapy (MCB) or external beam partial breast irradiation [
      • Hannoun-Levi J.
      • Resch A.
      • Gal J.
      • Kauer-dorner D.
      • Strnad V.
      • Niehoff P.
      • et al.
      Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group.
      ,

      Arthur DW, Winter KA, Kuerer HM, Haffty B, Cuttino L, Todor DA, et al. Effectiveness of Breast-Conserving Surgery and 3-Dimensional Conformal Partial Breast Reirradiation for Recurrence of Breast Cancer in the Ipsilateral Breast.The NRG Oncology/RTOG 1014 Phase 2 Clinical Trial. JAMA Oncol. 2020 Jan 1;6(1):75-82. doi: 10.1001/jamaoncol.2019.4320.

      ]. In the series by Kurtz et al. [
      • Kurtz J.M.
      • Jacquemier J.
      • Amalric R.
      • Brandone H.
      • Aymes Y.
      • Hans D.
      • et al.
      Is breast conservation after local recurrence feasible?.
      ], subsequent LRR were observed in 36% and 31% of patients receiving salvage BCS with or without re-irradiation, respectively. In another series, the rate of subsequent recurrence was just 20.5% [
      • Deutsch M.
      Repeat high-dose external beam irradiation for in-breast tumor recurrence after previous lumpectomy and whole breast irradiation.
      ]. Experiences including salvage brachytherapy are associated with a high rate of relapse preferentially located away from the initial tumor bed [
      • Maulard C.
      • Housset M.
      • Brunel P.
      • Delanian S.
      • Taurelle R.
      • Baillet F.
      Use of perioperative or split course interstitial brachytherapy techniques for salvage irradiation of isolated local recurrences after conservative management of breast cancer.
      ]. The GEC-ESTRO multicentric study reported 10-year actuarial secondary LRR and OS rates of 7.2% and 76.4%, respectively, after secondary BCS with re-irradiation of the tumor bed using MCB [
      • Hannoun-Levi J.
      • Resch A.
      • Gal J.
      • Kauer-dorner D.
      • Strnad V.
      • Niehoff P.
      • et al.
      Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group.
      ]. Re-irradiation following chest wall recurrence has also been employed with disease control range between 62% and 89% [
      • Maulard C.
      • Housset M.
      • Brunel P.
      • Delanian S.
      • Taurelle R.
      • Baillet F.
      Use of perioperative or split course interstitial brachytherapy techniques for salvage irradiation of isolated local recurrences after conservative management of breast cancer.
      ,
      • Datta N.R.
      • Puric E.
      • Klingbiel D.
      • Gomez S.
      • Bodis S.
      Hyperthermia and Radiation Therapy in Locoregional Recurrent Breast Cancers: A Systematic Review and Meta-analysis.
      ]. One of the other possible options is to combine RT and hyperthermia to enhance the effects of re-irradiation with higher rate of complete response over re-irradiation alone (60.2% vs 38.1%) [
      • Datta N.R.
      • Puric E.
      • Klingbiel D.
      • Gomez S.
      • Bodis S.
      Hyperthermia and Radiation Therapy in Locoregional Recurrent Breast Cancers: A Systematic Review and Meta-analysis.
      ,
      • Thomsen A.R.
      • Vaupel P.
      • Grosu A.L.
      • Notter M.
      Hyperthermia Plus Re-Irradiation in the Management of Unresectable Locoregional Recurrence of Breast Cancer in Previously Irradiated Sites.
      ]. There is currently limited literature describing proton beam radiation therapy (PRBT) for re-treatment of breast cancer. Re-irradiation with PBRT has acceptable toxicities and offers great short term clinical outcomes without the additional risk of pulmonary or cardiac toxicity [
      • Gabani P.
      • Patel H.
      • Thomas M.A.
      • Bottani B.
      • Goddu S.M.
      • Straube W.
      • et al.
      Clinical outcomes and toxicity of proton beam radiation therapy for re-irradiation of locally recurrent breast cancer.
      ,
      • Choi J.I.
      • Khan A.J.
      • Powell S.N.
      • McCormick B.
      • Lozano A.J.
      • Del Rosario G.
      • et al.
      Proton reirradiation for recurrent or new primary breast cancer in the setting of prior breast irradiation.
      ].
      Systemic therapy is indicated for inoperable LRR at presentation, as supraclavicular or internal mammary recurrences and chest wall inoperable recurrences. If the disease responds favorably, some of these patients become candidates for surgical resection and/or consolidation with comprehensive radiation, meanwhile that systemic therapy reduces the risk of distant disease [
      • Pedersen A.N.
      • Møller S.
      • Steffensen K.D.
      • Haahr V.
      • Jensen M.
      • Kempel M.M.
      • et al.
      Supraclavicular recurrence after early breast cancer: A curable condition?.
      ].
      For HER2-overepressing (HER2-positive) breast cancer, chemotherapy in combination with HER2-targeted therapy is a reasonable option, since inoperable LRR patients were included in the Cleopatra trial [
      • Swain S.M.
      • Baselga J.
      • Kim S.B.
      • Ro J.
      • Semiglazov V.
      • Campone M.
      • et al.
      CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.
      ]. Over the last three decades, only two prospective randomized trials provided information on the benefits of adjuvant systemic therapies after LRR excision. The SAKK23/82 trial evaluated the benefit of tamoxifen compared to (vs) placebo after excision and radiation in postmastectomy LRR patients (5-year Disease Free Survival [DFS] 61% vs 40%) [
      • Waeber M.
      • Castiglione-Gertsch M.
      • Dietrich D.
      • Thürlimann B.
      • Goldhirsch A.
      • Brunner K.W.
      • et al.
      Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation.
      ].
      The CALOR trial at 9 years of median follow-up demonstrated a significant benefit in term DFS for postoperative chemotherapy in patients with radically excised Estrogen Receptor (ER)-negative LRR but not in patients with ER-positive LRR as summarized in Table 2 [
      • Wapnir I.L.
      • Price K.N.
      • Anderson S.J.
      • Robidoux A.
      • Martín M.
      • Nortier J.W.R.
      • et al.
      Efficacy of chemotherapy for ER-negative and ER-positive isolated locoregional recurrence of breast cancer: final analysis of the CALOR trial.
      ].
      Table 2Nine-year results of CALOR: disease-free and overall survival according to estrogen receptor status.
      CT (%)No CT (%)HR95 %CIp-int
      10y-DFS rateER+50591.070.57–2.000.013
      ER-70340.290.13–0.66
      10y-OS rateER+76660.700.32–1.550.53
      ER-73530.480.19–1.20
      CT: adjuvant chemotherapy; DFS: disease free survival; OS: overall survival: ER: estrogen receptor; HR: hazard ratio; p-int: test for interaction statistical significance.

      Oligometastatic disease

      The initial definition of oligometastatic disease (OM) in 1995 has been changing over the years [
      • Hellman S.
      • Weichselbaum R.R.
      Oligometastases.
      ]. To date OM refers to 1–5 metastatic lesions all amenable of ablative intent [
      • Lievens Y.
      • Guckenberger M.
      • Gomez D.
      • Hoyer M.
      • Iyengar P.
      • Kindts I.
      • et al.
      Defining oligometastatic disease from a radiation oncology perspective: An ESTRO-ASTRO consensus document.
      ] not only by loco-regional treatments but also through a multimodal approach including systemic therapies [
      • Gutiontov S.I.
      • Pitroda S.P.
      • Tran P.T.
      • Weichselbaum R.R.
      (Oligo)metastasis as a Spectrum of Disease.
      ].
      In a review published by Salama et al. complete resection of liver metastases was associated with a median progression free survival (PFS) and an OS of 14–34 months and 24–63 months respectively; after lung metastasectomy, median OS was 32–97 months, and 5-year OS 27–80% [
      • Salama J.K.
      • Chmura S.J.
      Surgery or ablative radiotherapy for breast cancer oligometastases.
      ].
      Stereotactic Body Radiation Therapy (SBRT) is emerging as a valid alternative approach when surgery is not feasible [
      • Milano M.T.
      • Katz A.W.
      • Zhang H.
      • Huggins C.F.
      • Aujla K.S.
      • Okunieff P.
      Oligometastatic breast cancer treated with hypofractionated stereotactic radiotherapy: Some patients survive longer than a decade.
      ] (Table 3).
      Table 3Major outcomes of SBRT for oligometastatic breast cancer.
      ReferenceNumber of PatientsNumber of lesionsSite of SBRT (lesions)Outcomes
      Milano et al
      • Milano M.T.
      • Zhang H.
      • Metcalfe S.K.
      • Muhs A.G.
      • Okunieff P.
      Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy.
      4085Liver (33)Lung

      (19)Bone

      (17)Lymph nodes

      (16)
      4-year OS: 59%

      4-year PFS: 38%

      4-year LC: 89%
      Trovo et al
      • Trovò M.
      • Furlan C.
      • Polesel J.
      • Fiorica F.
      • Arcangeli S.
      • Giaj-Levra N.
      • et al.
      Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial.
      5492Bones (60)Nodes

      (23)Lung

      (4)Liver

      (5)
      1-year PFS: 75%

      2-year PFS: 53%

      2-year LC: 97%

      2-year OS 95%
      David et al
      • David S.
      • Tan J.
      • Savas P.
      • Bressel M.
      • Kelly D.
      • Foroudi F.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: A prospective clinical trial.
      1519Bone (19)2-year LC: 100%

      2-year DFS: 67%
      Scorsetti et al
      • Scorsetti M.
      • Franceschini D.
      • De Rose F.
      • Comito T.
      • Villa E.
      • Iftode C.
      • et al.
      Stereotactic body radiation therapy: A promising chance for oligometastatic breast cancer.
      3343Liver (36)Lung

      (7)
      1-year LC: 98%

      2-year LC: 90%

      3-year LC: 90%

      1-year OS: 93%

      2-year OS: 66%

      1-year PFS: 48%

      2-year PFS: 27%
      Wilson et al
      • Wilson T.G.
      • Robinson T.
      • MacFarlane C.
      • Spencer T.
      • Herbert C.
      • Wade L.
      • et al.
      Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.
      91>150BrainMedian OS: 15.7 months
      SBRT: Stereotactic Body Radiation Therapy; OS: Overall Survival; DFS Disease Free Survival; LC: Local Control.
      In the pilot study by Milano et al. 40 patients reported a 4-year actuarial OS, PFS and LRR of 59%, 38%, and 89%, respectively [
      • Milano M.T.
      • Zhang H.
      • Metcalfe S.K.
      • Muhs A.G.
      • Okunieff P.
      Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy.
      ]. Trovò et al. conducted a prospective phase II trial to evaluate SBRT to all metastatic sites [
      • Trovò M.
      • Furlan C.
      • Polesel J.
      • Fiorica F.
      • Arcangeli S.
      • Giaj-Levra N.
      • et al.
      Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial.
      ], and after a median follow-up of 30 months, 1- and 2-year PFS was 75% and 53%, respectively; 2-year Local Control (LC) and OS were 97% and 95%, respectively. Considering bone metastases only, David et al. treated prospectively 15 patients [
      • David S.
      • Tan J.
      • Savas P.
      • Bressel M.
      • Kelly D.
      • Foroudi F.
      • et al.
      Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: A prospective clinical trial.
      ], and at a median follow-up time of 24 months, 2-year LC was 100% and distant-PFS was 67%. Scorsetti et al. focused their attention on patients with 1–3 lung and liver inoperable lesions [
      • Scorsetti M.
      • Franceschini D.
      • De Rose F.
      • Comito T.
      • Villa E.
      • Iftode C.
      • et al.
      Stereotactic body radiation therapy: A promising chance for oligometastatic breast cancer.
      ], and at a median follow-up of 24 months reported LC rates of 98% at 1 year and 90% at 2 and 3 years, median PFS was 11 months, with a PFS rate at 1 and 2 years of 48% and 27%, respectively. Finally, Wilson et al. retrospectively analyzed 91 patients who received SBRT for brain metastases [
      • Wilson T.G.
      • Robinson T.
      • MacFarlane C.
      • Spencer T.
      • Herbert C.
      • Wade L.
      • et al.
      Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.
      ] and showed a median OS of 15.7 months. None of these studies reported major toxicities. More recently, Palma and colleagues published the long-term results of the SABR-COMET, the first phase II randomized trial including oligometastatic patients; of note, breast cancer was one of the most commonly evaluated primary tumor (18 cases). Patients were randomized between standard-of-care alore or plus SBRT on all metastatic sites. With a median follow-up of 51 months, the results confirmed a significant improvement of OS in the SBRT group (42.3% vs 17.7%) [
      • Palma D.A.
      • Olson R.
      • Harrow S.
      • Gaede S.
      • Louie A.V.
      • Haasbeek C.
      • et al.
      Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.
      ]. Based on these data and awaiting for the results of the ongoing randomized trial NRG BR002 [

      Chmura SJ, Winter KA, Al-Hallaq HA, Borges VF, Jaskowiak NT, Matuszak M, et al. NRGBR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical ablation for newly oligometastatic breast cancer (nct02364557). j clin oncol 2019;37:TPS1117. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.TPS1117.

      ], the use of radical RT to all metastatic sites in breast cancer patients with OM should be considered a valuable option, and its recommendation should be individualized.
      Other local ablative approaches could be considered, such as percutaneous thermal ablation, radionuclide therapy, trans-arterial chemoembolization and percutaneous ethanol injection, all showing promising results with rates of LC ranging from 37.5% to 92 % in different series [
      • Barral M.
      • Auperin A.
      • Hakime A.
      • Cartier V.
      • Tacher V.
      • Otmezguine Y.
      • et al.
      Percutaneous Thermal Ablation of Breast Cancer Metastases in Oligometastatic Patients.
      ,
      • Serafini A.N.
      Therapy of metastatic bone pain.
      ,
      • Bale R.
      • Putzer D.
      • Schullian P.
      Local Treatment of Breast Cancer Liver Metastasis.
      ,

      Swierz MJ, Storman D, Riemsma RP, Wol R, Mitus JW, Pedziwiatr M, et al. Percutaneous ethanol injection for liver metastases. Cochrane Database of Systematic Reviews 2020, Issue 2. Art. No.: CD008717. DOI: 10.1002/14651858.CD008717.pub3.

      ].
      Very few randomized trials were published about these techniques and, despite of radiofrequency ablation (RFA) for small liver metastases (<2 cm) [
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ], they appear less active compared to SBRT [

      Saeed H, Kirby A. Local therapies for managing oligometastatic breast cancer: a review 2021. https://doi.org/10.21037/abs-20-145.

      ].

      Metastatic disease

      The introduction of innovative treatments has resulted in significant survival improvement in metastatic breast cancer, especially in HER2-positive and HR-positive/HER2-negative, hereinafter luminal-like, cases. Real-world evidence in metastatic breast cancer population collected from 2008 to 2017 confirmed the year of metastatic diagnosis as a strong independent prognostic factor, particularly among HER2-positive patients with a median OS of 39.1 months in 2008 vs 58 months in 2013 [
      • Grinda T.
      • Antoine A.
      • Jacot W.
      • Blaye C.
      • Cottu P.H.
      • Diéras V.
      • et al.
      Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008–2017 ESME cohort.
      ]. More recently, data from randomized trials confirmed an OS benefit also in patients with luminal-like disease due to the combination of CDK4/6 inhibitors with standard endocrine therapy (reviewed in [
      • Schettini F.
      • Giudici F.
      • Giuliano M.
      • Cristofanilli M.
      • Arpino G.
      • Del Mastro L.
      • et al.
      Overall Survival of CDK4/6-Inhibitor-Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis.
      ]). Table 4 reports the use of CDK4/6 inhibitors in different settings. Notably, the added value of these novel agents was demonstrated irrespective of endocrine partner, patient age, visceral or bone metastases, number of metastatic sites, lobular or ductal subtypes, length of treatment free interval, or line of therapy [

      Gao JJ, Cheng J. Bloomquist E, Sanchez J, Wedam SB, Singh H, et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis Lancet Oncol. 2020 Feb;21(2):250-260. doi: 10.1016/S1470-2045(19)30804-6.

      ].
      Table 4CDK4/6 inhibitors phase III trials according to sensitivity/resistance to aromatase inhibitors, patients representation and outcome results.
      StudyPALOMA-2MONALEESA-2MONARCH-3MONALEESA-7PALOMA-3MONALEESA-3MONARCH-2
      Setting1st line1st line1st line1st and 2nd line2nd line1st and 2nd line2nd line
      Endocrine therapyLetrozoleLetrozoleLetrozole

      or anastrozole
      Tamoxifen, letrozole, or anastrozole

      Fulvestrant



      Fulvestrant



      Fulvestrant

      CDK4/6 inhibitorPalbociclibRibociclibAbemaciclibRibociclibPalbociclibRibociclibAbemaciclib
      No. patients666668493672521669726
      Endocrine status*AI-sensitiveAI-sensitiveAI-sensitiveMixedAI-resistant*MixedAI-resistant
      PFS, mos27.6 vs 14.525.3 vs 1628.18 vs 14.7623.8 vs 13.011.2 vs 4.6

      20.5 vs 12.8

      16.4 vs 9.3

      HR0.563 (0.46–0.69; p < 0.01)0.56 (0.45–0.70; p < 0.01)0.54 (0.44–0.69; p < 0.01)0.55 (0.44–0.69; p < 0.01))0.50 (0.40–0.62; p < 0.01)0.59 (0.48–0.73; p < 0.01)0.55 (0.44–0.68; p < 0.01)
      OS, mosImmature63.9 vs 51.4 (0.004)Immature34.9 vs 28.0NR vs 40.346.7 vs 37.3
      HRImmature0.75 (0.52–1.08)Immature0.81 (0.64–1.03; p = 0.09)0.72 (0.56–0.92; p = 0.004)0.75 (0.60–0.94; p = 0.01)
      “AI-sensitive” status is defined as patients who have never received aromatase inhibitors, or who have received previous AIs but relapse > 12 months from the end of the AI.
      “AI-resistant” status is defined as patients whose relapsed occurred under aromatase inhibitor treatment or<12 months from previous AI’s completion.
      In HER2-positive breast cancer patients previously untreated or relapsing>12 months after the end of adjuvant anti-HER2 therapy, adding pertuzumab (P) to trastuzumab (H) and docetaxel improved outcomes in Cleopatra trial (median OS: 57·1 months vs 40·8 months; HR: 0·69, 95% CI 0·58–0·82) [
      • Swain S.M.
      • Miles D.
      • Sung-Bae Kim S.B.
      • Im Y.H.
      • Im S.A.
      • Semiglazov V.
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      ]. Given this OS advantage, induction approach with 6–8 courses and then H plus (+) P maintenance (±endocrine therapy depending on hormone receptor status) is frequently used. After progression, trastuzumab deruxtecan (TDx) [
      • Modi S.
      • Saura C.
      • Yamashita T.
      • Park Y.H.
      • Kim S.B.
      • Tamura K.
      • et al.
      Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.
      ], tucatinib [
      • 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.
      ], neratinib [
      • Saura C.
      • Oliveira M.
      • Yin-Hsun Feng Y.-H.
      • Dai M.S.
      • Chen S.W.
      • Hurvitz S.A.
      • et al.
      Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ‡ 2 HER2-Directed Regimens: Phase III NALA Trial.
      ] and margetuximab [
      • Rugo H.S.
      • Im S.A.
      • Cardoso F.
      • Cortes J.
      • Curigliano G.
      • Musolino A.
      • et al.
      Efficacy of Margetuximab vs Trastuzumab in Patients with Pretreated ERBB2-Positive Advanced Breast Cancer A Phase 3 Randomized Clinical Trial.
      ] are emerging as effective therapies. Recently TDx (DESTINY 03 Trial) showed improved PFS by 72% over standard second line treatment and encouraging not yet estimable OS trend [
      • Cortés J.
      • Kim S.
      • Chung W.
      • Im S.
      • Park Y.H.
      • Hegg R.
      • et al.
      Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.
      ], while tucatinib in the third or more line ensured a 4.5 month OS gain [
      • 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.
      ].
      Immunotherapy (IT) associated to chemotherapy has emerged as a good first-line option in triple negative breast cancer (TNBC) patients whose tumor expresses PD-L1. The addition of atezolizumab to nab-paclitaxel improved PFS, and potentially (only descriptive analysis) OS in previously untreated patients, based on data from the phase III Impassion 130 trial (Table 5) [
      • Schmid P.
      • Rugo H.S.
      • Adams S.
      • Schneeweiss A.
      • Barrios C.H.
      • Iwata H.
      • et al.
      Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. However, atezolizumab combined with paclitaxel did not significantly improve PFS or OS compared with placebo in the phase III IMpassion131 [
      • Miles D.
      • Gligorov J.
      • André F.
      • Cameron D.
      • Schneeweiss A.
      • Barrios C.
      • et al.
      Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of firstline paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.
      ]. More recently, an improvement in both PFS and OS in the combined positive score (CPS) > 10 PD-L1 subset of patients with advanced TNBC was reported by the KEYNOTE-355 phase III trial with pembrolizumab combined to investigators’ choice of chemotherapy [
      • Cortes J.
      • Cescon D.W.
      • Rugo H.S.
      • Nowecki Z.
      • Im S.A.
      • Yusof M.
      • et al.
      KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab þ chemotherapy versus placebo þ chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer.
      ,
      • Rugo H.S.
      • Cortés J.
      • Cescon D.W.
      • Im S.
      • Yusof M.
      • Gallardo C.
      • et al.
      LBA16 KEYNOTE-355: final results from a randomized, double-blind phase III study of first-line pembrolizumab þ chemotherapy vs placebo þ chemotherapy for metastatic TNBC.
      ]. In patients with germline BRCA mutation, the PARP inhibitors olaparib and talazoparib showed an advantage in PFS in two trials (OlympiAD, EMBRACA) [
      • Robson M.E.
      • Tung N.
      • Conte P.
      • Im S.A.
      • Senkus E.
      • Xu B.
      • et al.
      OlympiAD final overall survival and tolerability results: olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.
      ]. Veliparib added to first line carboplatin-paclitaxel combination slightly improved PFS as well [
      • Diéras V.
      • Han H.S.
      • Kaufman B.
      • Wildiers H.
      • Friedlander M.
      • Ayoub J.P.
      • et al.
      Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ]. A Cochrane meta-analysis of the randomized trials showed a small OS benefit associated with the use of these drugs [

      Taylor AM., Chan DLH. Tio M., Patil SM., Traina TA., Robson ME., et al. PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer. Cochrane Database Syst Rev. 2021 Apr 22;4(4):CD011395. doi: 10.1002/14651858.CD011395.pub2. PMID: 33886122; PMCID: PMC8092476.

      ]. In advanced lines, sacituzumab govitecan has demonstrated promising activity in a phase I/II study and in the first report of the phase III ASCENT study [
      • Bardia A.
      • Messersmith W.A.
      • Kio E.A.
      • Berlin J.D.
      • Vahdat L.
      • Masters G.A.
      • et al.
      Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132- 01 basket trial.
      ,

      Hurvitz SA, Tolaney SM, Punie K, et al. GS3-06. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Presented at the San Antonio Breast Cancer Symposium, December 8-11 2020. Virtual Meeting. Available from: https://www.hematologyandoncology.net/supplements/highlights-in-metastatic-breast-cancer-from-the-2020-san-antonio-breast-cancer-symposium/.

      ].
      Table 5PD-1/PD-L1 inhibitors for metastatic TNBC.
      Clinical TrialPopulationTreatments armPatientsORR (%)pPFS (m)pOS (m)p
      IMpassion 130Unselected first-line mTNBCAtezolizumab + Nab-paclitaxel45156.00.0027.20.00221.00.08
      Nab-paclitaxel45145.95.518.7
      PD-L1 + mTNBCAtezolizumab + Nab-paclitaxel18558.90.0027.50.000125.4not tested
      Nab-paclitaxel18442.65.017.9
      IMpassion 131Unselected first-line mTNBCAtezolizumab + Paclitaxel43153.6

      not tested
      5.7

      not formally tested
      19.2not tested
      Paclitaxel22047.55.622.8
      mTNBC PD-L1+Atezolizumab + Paclitaxel19163.4

      not tested
      6.00.222.1not tested
      Paclitaxel10155.45.728.3
      Keynote 355Unselected first-line mTNBCPembrolizumab + Chemotherapy56640.87.5not formally tested17.2not tested
      Chemotherapy28137.05.615.5
      mTNBC PD-L1+ (CPS ≥ 10)Pembrolizumab + Chemotherapy22052.79.70.001223.00.0093

      Chemotherapy10340.85.616.1
      “AI-resistant” status is defined as patients whose relapsed occurred under aromatase inhibitor treatment or <12 months from previous AI’s completion.

      Towards a tailored breast cancer follow-up

      Prognostication through patient and primary tumor-related characteristics

      Risk stratification has traditionally relied on clinic-pathological features, such as age, tumor stage, and HR status. Patients at the extremes of age, i.e., either very young or very old, have poor prognosis [
      • Adami H.O.
      • Malker B.
      • Holmberg L.
      • Persson I.
      • Stone B.
      The relation between survival and age at diagnosis in breast cancer.
      ,
      • Billena C.
      • Wilgucki M.
      • Flynn J.
      • Modlin L.
      • Tadros A.
      • Razavi P.
      • et al.
      10-Year Breast Cancer Outcomes in Women </=35 Years of Age.
      ]. The impact of age on outcome varies according to breast cancer subtypes. In a study of 17,500 stage I-III breast cancer patients, those aged ≤ 40 years had a poorer survival than others (hazard ratio 1.4, 95% CI 1.2–1.7) when diagnosed with luminal A and B breast cancer, but not when diagnosed with HER2-positive breast cancer [
      • Partridge A.H.
      • Hughes M.E.
      • Warner E.T.
      • Ottesen R.A.
      • Wong Y.N.
      • Edge S.B.
      • et al.
      Subtype-Dependent Relationship Between Young Age at Diagnosis and Breast Cancer Survival.
      ]. Some population-based and randomized trials have also reported increased breast cancer mortality in elderly (>65 years), which has been attributed to an advanced stage at diagnosis, increased comorbidity and differences in treatment [

      Bastiaannet E, Liefers GJ, de Craen AJ, Kuppen PJ, van de Water W, Portielje JE, et al. Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast cancer research and treatment. 2010;124:801-7. DOI: 10.1007/s10549-010-0898-8.

      ,

      van de Water W, Markopoulos C, van de Velde CJ, Seynaeve C, Hasenburg A, Rea D, et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA 2012;307:590-7. DOI: 10.1001/jama.2012.84.

      ,
      • Eaker S.
      • Dickman P.W.
      • Bergkvist L.
      • Holmberg L.
      Uppsala/Orebro Breast Cancer G. Differences in management of older women influence breast cancer survival: results from a population-based database in Sweden.
      ]. It is well known that nodal involvement is an independent prognostic factor, the 5-year survival rate being 99% vs 85% for those with localized or regional disease, respectively [
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer Statistics, 2017.
      ]. Historically, both ER and Progesterone Receptor expression have been associated with improved breast cancer outcomes, including time to treatment failure, DFS and OS [
      • Bartlett J.M.
      • Brookes C.L.
      • Robson T.
      • van de Velde C.J.
      • Billingham L.J.
      • Campbell F.M.
      • et al.
      Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.
      ].
      The information derived from patient and primary tumor features, specifically tumor size, nodal status, tumor grade, ER status and modality of detection (clinical/screening) was used to build prognostic models such as PREDICT [
      • Wishart G.C.
      • Azzato E.M.
      • Greenberg D.C.
      • Rashbass J.
      • Kearins O.
      • Lawrence G.
      • et al.
      PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer.
      ,
      • Candido Dos Reis F.J.
      • Wishart G.C.
      • Dicks E.M.
      • Greenberg D.
      • Rashbass J.
      • Schmidt M.K.
      • et al.
      An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation.
      ] to estimate both breast cancer-specific mortality and overall survival at 5 and 10 years.

      Gene expression profiles to unveil breast cancer subtypes and prognosis

      Besides these established clinicopathological factors, advances over the last decade have dramatically increased both our understanding of breast cancer biology and our ability to obtain molecular information from primary tissue. Genomic studies have identified various distinct breast cancer subtypes that differ significantly in prognosis and therapeutic targets [

      Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70. DOI: 10.1038/nature11412.

      ,
      • Perou C.M.
      • Sorlie T.
      • Eisen M.B.
      • van de Rijn M.
      • Jeffrey S.S.
      • Rees C.A.
      • et al.
      Molecular portraits of human breast tumours.
      ]. The genes that distinguish breast cancer intrinsic subtypes involve ER (the luminal cluster), HER2 expression (HER2–enriched), and a group of genes called the basal cluster. Data from the Surveillance, Epidemiology, and End Results Program (SEER) program shows that the 5-year relative survival rate is 90.4% for luminal, 83.6% for HER2-enriched, and 76.7% for basal subtypes, respectively [

      Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.

      ]. Of note, LRR rates were 12%, 8%, 4% and 2% in TNBC, HER2-overexpressing, luminal B and A, respectively; corresponding rates of distance metastasis were 27.4%, 19.2%, 12.1%, and 6.4 % (p < 0.001). Similar results were reported by van Maaren et al. that analysed the pattern of recurrence overtime among 8062 patients from the Dutch population-based registry [
      • van Maaren M.C.
      • de Munck L.
      • Strobbe L.J.A.
      • Sonke G.S.
      • Westenend P.J.
      • Smidt M.L.
      • et al.
      Ten-year recurrence rates for breast cancer subtypes in the Netherlands: A large population-based study.
      ]. Notably, the 2-year peak was most evident in HER2-positive and TNBC patients; whereas, luminal cases showed a trend to recur later during follow-up at a slow steady rate.

      Genomic classifiers enter clinical practice

      The application of genomics to breast cancer diagnostics has generated different tools (Table 6). To quantify the likelihood of distant recurrence (DR) in node-negative, ER-positive, HER2-negative breast cancer patients treated with adjuvant tamoxifen, Paik et al. developed a 21-gene recurrence score (RS) assay (OncotypeDx) [
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ]. According to the explorative analysis of the NSABP B-14 trial, the 10 years-DR rate was significantly lower in the low- than in the high-risk group (6.8% vs 30.5%; p < 0.001). The RS was prospectively validated by the PlanB [
      • Gluz O.
      • Nitz U.A.
      • Christgen M.
      • Kates R.E.
      • Shak S.
      • Clemens M.
      • et al.
      West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment.
      ], the TAILORx [
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • Pritchard K.I.
      • Albain K.S.
      • Hayes D.F.
      • et al.
      Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.
      ], the Young Women’s Breast Cancer Study [
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • Pritchard K.I.
      • Albain K.S.
      • Hayes D.F.
      • et al.
      Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
      ], and the RxPonder trials [
      • Poorvu P.D.
      • Gelber S.I.
      • Rosenberg S.M.
      • Ruddy K.J.
      • Tamimi R.M.
      • Collins L.C.
      • et al.
      Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer.
      ]. OncotypeDx is the only genomic test included in 8th AJCC TNM classification [

      Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:290-303. DOI: 10.3322/caac.21393.

      ] and is recommended by ASCO [
      • Andre F.
      • Ismaila N.
      • Henry N.L.
      • Somerfield M.R.
      • Bast R.C.
      • Barlow W.
      • et al.
      Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update-Integration of Results From TAILORx.
      ] and ESMO [

      Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, RubioIT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO Guidelines Committee. Electronic address: [email protected] Ann Oncol. 2019 Aug 1;30(8):1194-1220. doi: 10.1093/annonc/mdz173.

      ] to assist adjuvant therapy choice. In parallel with the development of the OncotypeDx, the original Amsterdam 70-gene prognostic signature [

      van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. The New England journal of medicine. 2002;347:1999-2009. DOI: 10.1056/NEJMoa021967.

      ] was prospectively evaluated in the MINDACT trial [

      Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New Engl J Med. 2016;375:717-29. DOI: 10.1056/NEJMoa1602253.

      ], showing a 5-year distant metastasis-free survival of 94.7%. in patients classified as high risk by clinical features and low risk by genomics [

      Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. New Engl J Med. 2016;375:717-29. DOI: 10.1056/NEJMoa1602253.

      ]. Others genomic classifiers include the Predictor Analysis of Microarray 50 (PAM50) which defines the intrinsic subtype of breast cancer according to 50 prespecified genes [
      • Wallden B.
      • Storhoff J.
      • Nielsen T.
      • Dowidar N.
      • Schaper C.
      • Ferree S.
      • et al.
      Development and verification of the pam50-based prosigna breast cancer gene signature assay.
      ]; EndoPredict (EP) integrating clinicopathological factors to generate a comprehensive risk score (EPclin) [
      • Filipits M.
      • Rudas M.
      • Jakesz R.
      • Dubsky P.
      • Fitzal F.
      • Singer C.F.
      • et al.
      A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.
      ], and the Breast Cancer Index, comprising the molecular grade index (MGI) and the two-gene ratio HOXB13/IL17BR (H/I), which evaluate tumor proliferation and estrogen signaling [
      • Ma X.J.
      • Hilsenbeck S.G.
      • Wang W.
      • Ding L.
      • Sgroi D.C.
      • Bender R.A.
      • et al.
      The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer.
      ], respectively, have all the potential to identify patients at low risk for a late recurrence [
      • Noordhoek I.
      • Treuner K.
      • Putter H.
      • Zhang Y.
      • Wong J.
      • Meershoek-Klein Kranenbarg E.
      • et al.
      Breast Cancer Index Predicts Extended Endocrine Benefit to Individualize Selection of Patients with HR+ Early-stage Breast Cancer for 10 Years of Endocrine Therapy.
      ].
      Table 6Genomic tools to assess the risk of breast cancer recurrence.
      OncotypeDxMammaPrintProsigna

      PAM 50
      EndoPredictBreast Cancer Index
      Type of assay21 genes70 genes50 genes12 genesHOXB13/IL17BR ratio and molecular grade index
      Prognostic stratificationLow risk

      RS < 11



      Intermediate risk RS 11–25



      High risk

      RS > 25
      High genomic risk



      Low genomic risk
      Node negative

      Low risk

      ROR 0–40



      Intermediate risk ROR 41–60



      High risk

      ROR 61–100
      Low risk

      EP < 5

      EPclin score < 3.3



      High risk

      EP ≥ 5

      EPclin score ≥ 3.3

      Low risk – BCI < 5.0825



      Intermediate risk 5.0825 < BCI < 6.5025



      High risk – BCI ≥ 6.5025
      Clinical applicabilityPrognostic

      (Early recurrence)
      Prognostic (Early recurrence)Prognostic (Early and late recurrence)Prognostic (Early and late recurrence)Prognostic (Early and late recurrence)
      Studies of prospective-retrospective validationNSABP B-14

      NSABP B-20

      ATAC
      RASTERATAC

      ABCSG8
      ATAC

      ABCSG6

      ABCSG8
      ATAC

      Ma.17

      Trans-ATTom
      Prospective randomized phase III trialsPlan B

      TAILORx

      RxPONDER
      MINDACT
      NCCN Level of evidenceIIIIAIIAIIA
      ESMO Level of evidenceIAIAIBIB

      Liquid biopsy as a prognostic and early detection tool

      The generic term liquid biopsy refers to the collection of body fluids, often blood, and associated biological material, i.e., proteins, DNA, RNA and/or cells. Liquid biopsies have the potential to monitor disease progression allowing earlier intervention and dynamic treatment management of breast cancer [
      • Pantel K.
      • Alix-Panabières C.
      Liquid biopsy: potential and challenges.
      ]. In the context of breast cancer follow-up, the most explored circulating tumor markers CEA and Ca 15.3, demonstrated limited potential to anticipate early detection of recurrence, while they can be used for treatment monitoring of overt metastases. Hence, the majority of research on liquid biopsy centered on more accurate biomarkers, such as circulating tumor cells (CTCs), and circulating cell-free tumor DNA (ctDNA).
      In the neoadjuvant setting CTC enumeration by CellsSearch™ was predictive of clinical outcome both in unselected patients [

      Bidard FC, Weigelt B, Reis-Filho JS. Going with the flow: from circulating tumor cells to DNA. Sci Transl Med. 2013 Oct 16;5(207):207ps14. doi: 10.1126/scitranslmed.3006305.

      ] as well as in TNBC [

      Hall CS, Karhade M, Laubacher BA, Kuerer HM, Krishnamurthy S, DeSnyder S, et al. Circulating tumor cells and recurrence after primary systemic therapy in stage III inflammatory breast cancer. J Natl Cancer Inst. 2015 Sep 14;107(11):djv250. doi: 10.1093/jnci/djv250.

      ], even independently of other clinico-pathological relevant information [
      • Bidard F.C.
      • Michiels S.
      • Mueller V.
      • Riethdorf S.
      • Esserman L.J.
      • Lucci A.
      • et al.
      Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.
      ]. In the adjuvant setting, presence and number of CTCs detected before chemotherapy have shown to be independent predictors of DFS and OS [
      • Rack B.
      • Schindlbeck C.
      • Juckstock J.
      • Andergassen U.
      • Hepp P.
      • Zwingers T.
      • et al.
      Circulating tumor cells predict survival in early average-to-high risk breast cancer patients.
      ].
      Besides, ctDNA is influenced by tumor burden [
      • Zhang E.W.
      • Dagogo-Jack I.
      • Kuo A.
      • Rooney M.M.
      • Shaw A.T.
      • Digumarthy S.R.
      Association between circulating tumor DNA burden and disease burden in patients with ALK-positive lung cancer.
      ,
      • Zhou Y.
      • Xu Y.
      • Gong Y.
      • Zhang Y.
      • Lu Y.
      • Wang C.
      • et al.
      Clinical factors associated with circulating tumor DNA (ctDNA) in primary breast cancer.
      ], so serial assessment of ctDNA has the potential to provide early recurrence detection; moreover, longitudinal ctDNA analysis can capture tumor heterogeneity and clonal evolution during disease progression [
      • Yeh P.
      • Hunter T.
      • Sinha D.
      • Ftouni S.
      • Wallach E.
      • Jiang D.
      • et al.
      Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia.
      ]. The first variant detected in the blood of women with breast cancer was PIK3CA. The study by Beaver et al. was pioneer in demonstrating the feasibility and prognostic potential of ctDNA [
      • Beaver J.A.
      • Jelovac D.
      • Balukrishna S.
      • Cochran R.
      • Croessmann S.
      • Zabransky D.J.
      • et al.
      Detection of cancer DNA in plasma of patients with early-stage breast cancer.
      ]. Since then, several research groups have worked on the clinical development of ctDNA in early-stage BC. In an exploratory analysis of the phase III NeoALTTO trial, which randomized patients with HER2-positive breast cancer to neoadjuvant trastuzumab, lapatinib, or their combination, Rothé and colleagues found that basal circulating PIK3CA and TP53 variants were associated with decreased pathological complete response (pCR) [
      • Rothè F.
      • Silva M.J.
      • Venet D.
      • Campbell C.
      • Bradburry I.
      • Rouas G.
      • et al.
      Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial.
      ]. Similarly, a post-hoc analysis of the phase II I-SPY 2 study found that ctDNA at baseline is associated with high tumor burden, aggressive disease, and poor likelihood of pCR in patients with HER2-negative breast treated with neoadjuvant pembrolizumab [
      • Magbanua M.J.M.
      • Swigart L.B.
      • Wu H.T.
      • Hirst G.L.
      • Yau C.
      • Wolf D.M.
      • et al.
      Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.
      ]. Apart from being a predictive marker, the advantage of ctDNA is that it works on an individual patient level. In their prospective multicentre study Garcia-Murillas et al. monitored patients with early-stage BC, regardless of HR or HER2 status [
      • Garcia-Murillas I.
      • Chopra N.
      • Comino-Méndez I.
      • Beaney M.
      • Tovey H.
      • Cutts R.J.
      • et al.
      Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer.
      ]. Primary tumors were sequenced to identify somatic variants and tumor-specific customized assays were used to track these mutations in the blood during follow-up at each scheduled visit. The study showed that the occurrence of ctDNA in blood samples predicted patient relapse before the development of clinical symptoms up to 1 year of anticipation. ctDNA could represent surrogates of microscopic traces of malignancy. Ongoing clinical studies, including the PREDICT DNA prospective study in which the absence of ctDNA is being correlated with pCR (NCT02743910); the French clinical trial assessing the prognostic value of ctDNA in patients undergoing neoadjuvant chemotherapy (NCT03357120); the observational Chinese study focusing on the detection of ctDNA soon after surgery with curative intent (NCT04353557) will allow to better define the validity of ctDNA and to finally assess its clinical utility.

      Potential for a refined, tailored, risk-based follow-up model

      As we have learned from studies on the use of imaging and biomarkers for the diagnosis of asymptomatic recurrence and data on oligometastatic disease, early diagnosis is now possible and a harbinger of a fruitful integration of local and systemic therapies. In particular, the development of multidisciplinary treatments, with selective and increasingly less toxic drugs, may improve the long-term outcome and cure rate of selected patients with recurrent breast cancer.
      In particular, serial biomarker monitoring after adjuvant therapy has the potential to anticipate the diagnosis of recurrence at a minimal asymptomatic stage and to prescribe 'salvage' adjuvant therapy with the aim of eliminating minimal residual disease. Such a strategy assumes that there is a curative window of minimal disease burden in breast cancer patients, prior to the development and detection of clinically manifest metastatic disease, or that early treatment of subclinical metastatic disease can lead to significantly longer disease control. Due to the complexity of breast cancer, the option of maintaining the “single disease” approach appears untenable, as does the individualization of single patient’s care, obliging us to conceptualize breast cancer less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Hence, we propose a rethinking of current follow-up practices based on patient risk of recurrence according to clinicopathological features and predictive patterns, as well as age, co-morbidities, emotions, diet, and habits; an intensive follow-up program in high-risk selected population should take into account liquid biopsy (ctDNA), imaging, and an additional diagnostic procedure (such as PET-CT if not already used, when circulating biomarkers (positive) and follow-up imaging are discordant (negative), as shown in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Schema of hypothetical breast cancer follow-up model including patient risk stratification, liquid biopsy and imaging to early detect and promptly treat oligometastases and minimal residual disease.
      We recognize that the development of risk-based breast cancer follow-up needs clinical evidence, which is currently lacking. The first challenge is the definition of the optimal biomarker for breast cancer relapse with high specificity and adequate sensitivity (CTCs vs ctDNA). Secondly, a cost-effectiveness analysis should include imaging to compare conventional tests (US, CT and bone scan) and advanced imaging (PET-PET/CT and whole-body MRI). We also need to establish the timing of biomarker(s) and imaging during surveillance. In addition, radiation risks and false-positive results represent potential adverse effects of the intensive follow-up programme and could cause psychological distress and anxiety resulting in a worsening of patients' quality of life (QoL). Prospective studies should include appropriate tools for personal monitoring; Patient-Reported Outcomes (PROs) and QoL assessment could be very useful to collect information on late effects of cancer diagnosis and treatment.

      Multidisciplinary team to address breast cancer survivor needs

      Survival planning has the potential to improve the quality of life (QoL) by allowing patients access to resources to manage the physical, emotional, and social consequences of cancer treatment and reducing the morbidity and mortality associated with a history of cancer [
      • O'Hea E.L.
      • Creamer S.
      • Flahive J.M.
      • Keating B.A.
      • Crocker C.R.
      • Williamson S.R.
      • et al.
      Survivorship care planning, quality of life, and confidence to transition to survivorship: a randomized controlled trial with women ending treatment for breast cancer.
      ]. The survival care model rather than cancer-focused should be patient-centered to include their expectations and needs. Several studies are promoted on the development of “patient-centered medical homes” whose philosophy is based on primary care patient-centered, complete, team-based, coordinated, accessible and focused on quality and safety [
      • Hudson S.V.
      • Ohman-Strickland P.A.
      • Bator A.
      • O'Malley D.
      • Gundersen D.
      • Lee H.S.
      • et al.
      Breast and prostate cancer survivors' experiences of patient-centered cancer follow-up care from primary care physicians and oncologists.
      ]. Different players should be involved and considered, including in first place general practitioners (GPs), psychologists and specialists in oncological field (i.e., medical and radiation oncologists, nurse, case manager) [
      • Santiá P.
      • Jansana A.
      • Del Cura I.
      • Padilla-Ruiz M.
      • Domingo L.
      • Louro J.
      • et al.
      Adherence of long-term breast cancer survivors to follow-up care guidelines: a study based on real-world data from the SURBCAN cohort.
      ,
      • Haq R.
      • Kong A.
      • Gulasingam P.
      A Multidisciplinary Approach to Implement Personalized Breast Cancer Treatment and Care Plans.
      ]. The approach to the patient should be multidimensional to take into consideration not only the survivor as a patient within programs aimed at the early diagnosis of disease recurrence but above the person, as entirety, and his family network. An educational intervention should include information on self-management strategies for the main symptoms that the patient may develop during follow up [
      • Van de Poll-Franse L.V.
      • Nicolaije K.A.
      • Vos M.C.
      • Pijnenborg J.M.A.
      • Boll D.
      • Husson O.
      • et al.
      The impact of a cancer survivorship care plan on gynecological cancer patient and health care provider reported outcomes (ROGY Care): study protocol for a pragmatic cluster randomized controlled trial.
      ,
      • Fillion L.
      • Gagnon P.
      • Leblond F.
      • Gélinas S.J.
      • Dupuis R.
      • et al.
      A brief intervention for fatigue management in breast cancer survivors.
      ]. Recently, the use of technology for digital medicine is being promoted to communicate health problems, manage chronic diseases, and seek health information [
      • Davis S.N.
      • O'Malley D.M.
      • Bator A.
      • Ohman-Strickland P.
      • Clemow L.
      • Ferrante J.M.
      • et al.
      Rationale and design of extended cancer education for longer term survivors (EXCELS): a randomized control trial of 'high touch' vs. 'high tech' cancer survivorship self-management tools in primary care.
      ,

      O'Hea E, Wu J, Dietzen L, Harralson T, Boudreaux ED. The Polaris Oncology Survivorship Transition (POST) System: A Patient- and Provider-Driven Cancer Survivorship Planning Program. J Oncol Navig Surviv. 2016 Nov;7(10):11-24. PMCID: PMC5568840.

      ], thus, digital tools may be extremely valuable for follow-up purposes. Nevertheless, it is understandable that tools based on artificial intelligence can help in the planning and monitoring of survival care programs, but they cannot make up for the role of human resources. Multidisciplinary teams are essential for approaching survival research and assistance from a comprehensive perspective [
      • Schnipper L.E.
      • Bastian A.
      New frameworks to assess value of cancer care: strengths and limitations.
      ,
      • Elf M.
      • Flink M.
      • Nilsson M.
      • Tistad M.
      • von Koch L.
      • Ytterberg C.
      The case of value-based healthcare for people living with complex long-term conditions.
      ].

      Conclusions

      Follow-up of breast cancer is currently based on a minimalist policy to detect local and contralateral recurrences. However, management varies widely from centre to centre regardless of the recommendations of official guidelines. Predictive models, new diagnostic modalities and biomarker assessment could play a crucial role in selecting breast cancer patients at higher risk of developing locoregional or distant recurrence. Recent data show that identifying patients with oligometastatic disease and asymptomatic recurrence offers the possibility to use effective systemic therapies and local ablative treatments earlier and possibly improve long-term outcome. The challenge of personalizing follow-up cannot be separated from surveillance programs shared with the multidisciplinary team to address not only patient individual risk but also patient individual needs at any time after breast cancer treatment with curative intent.

      Role of the funding source

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      CRediT authorship contribution statement

      Fiorenza De Rose: Conceptualization, Investigation, Supervision. Bruno Meduri: Conceptualization, Investigation, Supervision. Maria Carmen De Santis: Conceptualization, Investigation, Supervision. Antonella Ferro: Writing – review & editing. Lorenza Marino: Writing – review & editing. Riccardo Ray Colciago: Investigation, Writing – review & editing. Fabiana Gregucci: Writing – review & editing. Valentina Vanoni: Supervision, Writing – review & editing. Giovanni Apolone: Writing – review & editing. Serena Di Cosimo: Conceptualization, Investigation, Supervision, Validation. Suzette Delaloge: Supervision, Writing – review & editing. Javier Cortes: Supervision, Writing – review & editing. Giuseppe Curigliano: Supervision, Writing – review & editing.

      Declaration of Competing Interest

      Dr. S. Delaloge: Research funding to the Institution: Pfizer, Novartis, AstraZeneca, g Roche Genentech, Lilly, Puma, Myriad, Orion, Amgen, Sanofi, Genomic Health, GE, Servier, MSD, BMS, Pierre Fabre, Seagen, Exact Sciences, Rappta, Besins, European Commission, French government, Fondation ARC; all the competing interests were outside the submitted work. Dr. J. Cortes: Consulting/Advisor: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin. Honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo. Research funding to the Institution: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London. Stock, patents and intellectual property: MedSIR. Travel, accommodation, expenses: Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo; all the competing interests were outside the submitted work. Dr G. Curigliano: Consulting/Advisor and speakers’ bureau: Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung and Daiichi Sankyo; Honoraria: Ellipses Pharma; Travel and accommodations: Roche/Genentech and Pfizer; all the competing interests were outside the submitted work. Dr. S. Di Cosimo: Consulting/Advisor: Pierre-Fabre, MedSIR; Honoraria: Ellipses Pharma; IQVIA; Research funding to the Institution: Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC); all the competing interests were outside the submitted work.

      Acknowledgement

      GA is Principal Investigator (PI) and SDC is co-PI of the project granted by Regione Lombardia “I controlli periodici (follow-up) dopo la diagnosi e le terapie in pazienti liberi da malattia e asintomatici: verso una personalizzazione delle strategie di follow-up” within the “Progetti di innovazione in ambito sanitario e sociosanitario” frame work (decreto n. 2713/20189).

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