Highlights
- •We correlated the breast cancer intrinsic subtypes with pCR in HER2+ disease.
- •The HER2-E subtype was significantly and consistently associated with pCR after anti-HER2-based therapy.
- •The HER2-E subtype was associated with pCR irrespective of hormone receptor status.
- •The HER2-E subtype was associated with pCR also with chemo-free neoadjuvant schemes.
Abstract
Background
HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes.
Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological
complete response (pCR) rates following anti-HER2-based regimens. Here, we present
a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based
neoadjuvant treatments with or without chemotherapy (CT).
Methods
A systematic literature search was performed in February 2019. The primary objective
was to compare the association between HER2-E subtype (versus others) and pCR. Selected
secondary objectives were to compare the association between 1) HER2-E subtype and
pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and
HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within
HER2-E subtype. A random-effect model was applied. The Higgins’ I2 was used to quantify heterogeneity.
Results
Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype
was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001,
I2 = 33%), in HR+ (OR = 3.61, p < 0.001, I2 = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I2 = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients
(OR = 5.52, p < 0.001, I2 = 0%) and in HR + disease (OR = 4.08, p = 0.001, I2 = 0%). HR-negative status was significantly associated with pCR compared to HR + status
in all patients (OR = 2.41, p < 0.001, I2 = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I2 = 0%).
Conclusions
The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR
following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future
trial designs to escalate or de-escalate systemic therapy in HER2+ disease should
consider this genomic biomarker.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer Treatment ReviewsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US.Cancer Invest. 2010; 28: 963-968https://doi.org/10.3109/07357907.2010.496759
- Human Epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline focused update.J Clin Oncol Off J Am Soc Clin Oncol. 2018; 36: 2105-2122https://doi.org/10.1200/JCO.2018.77.8738
- Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med. 2001; 344: 783-792https://doi.org/10.1056/NEJM200103153441101
- Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Oncol. 2013; 14: 461-471https://doi.org/10.1016/S1470-2045(13)70130-X
- 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: 1688-1700https://doi.org/10.1016/S1470-2045(17)30717-9
- Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med. 2006; 355: 2733-2743https://doi.org/10.1056/NEJMoa064320
- Trastuzumab emtansine for HER2-positive advanced breast cancer.N Engl J Med. 2012; 367: 1783-1791https://doi.org/10.1056/NEJMoa1209124
- Changing natural history of HER2-positive breast cancer metastatic to the brain in the era of new targeted therapies.Clin Breast Cancer. 2018; 18: 29-37https://doi.org/10.1016/j.clbc.2017.07.017
- Clinical implications of the intrinsic molecular subtypes of breast cancer.Breast Edinb Scotl. 2015; 24: S26-S35https://doi.org/10.1016/j.breast.2015.07.008
- Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.J Natl Cancer Inst. 2014; 106https://doi.org/10.1093/jnci/dju152
- HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade.J Natl Cancer Inst. 2019; 30https://doi.org/10.1093/jnci/djz042
- Comprehensive molecular portraits of human breast tumors.Nature. 2012; 490: 61-70https://doi.org/10.1038/nature11412
- Deconstructing the molecular portraits of breast cancer.Mol Oncol. 2011; 5: 5-23https://doi.org/10.1016/j.molonc.2010.11.003
- HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial.Lancet Oncol. 2017; 18: 545-554https://doi.org/10.1016/S1470-2045(17)30021-9
- Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III Trial of paclitaxel plus trastuzumab with or without lapatinib.J Clin Oncol Off J Am Soc Clin Oncol. 2016; 34: 542-549https://doi.org/10.1200/JCO.2015.62.1268
- Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study.Clin Cancer Res Off J Am Assoc Cancer Res. 2014; 20: 511-521https://doi.org/10.1158/1078-0432.CCR-13-0239
Swain SM, Tang G, Lucas PC, et al. Intrinsic subtypes of HER2-positive breast cancer and their associations with pathologic complete response (pCR) and outcomes: Findings from NSABP B-41, a randomized neoadjuvant trial. J Clin Oncol. 2018;36(15_suppl):580-580. doi:10.1200/JCO.2018.36.15_suppl.580.
- RNA Sequencing to predict response to neoadjuvant anti-HER2 therapy: a secondary analysis of the NeoALTTO randomized clinical trial.JAMA Oncol. 2017; 3: 227-234https://doi.org/10.1001/jamaoncol.2016.3824
Bianchini G, Parker JS, Carey LA, et al. Research-based PAM50 predicts risk of relapse in residual disease after anti-HER2 therapies. Ann Oncol. 2018; 29(8_suppl):viii58–viii86.
- Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.Ann Oncol Off J Eur Soc Med Oncol. 2015; 26: 2429-2436https://doi.org/10.1093/annonc/mdv395
- Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial.Ann Oncol. 2016; 27: 1867-1873https://doi.org/10.1093/annonc/mdw262
- Tumor-infiltrating lymphocytes in patients receiving trastuzumab/pertuzumab-based chemotherapy: a TRYPHAENA substudy.J Natl Cancer Inst. 2019; 111: 69-77https://doi.org/10.1093/jnci/djy076
- Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling.BMC Res Notes. 2013; 6: 507https://doi.org/10.1186/1756-0500-6-507
- 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 Off J Eur Soc Med Oncol. 2018; 29: 646-653https://doi.org/10.1093/annonc/mdx773
- Safety, activity, and molecular heterogeneity following neoadjuvant non-pegylated liposomal doxorubicin, paclitaxel, trastuzumab, and pertuzumab in HER2-positive breast cancer (Opti-HER HEART): an open-label, single-group, multicenter, phase 2 trial.BMC Med. 2019; 17: 8https://doi.org/10.1186/s12916-018-1233-1
Pernas S, Petit A, Climent F, et al. Abstract P2-09-11: PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer. Cancer Res. 2018;78(4 Supplement):P2-09-11. doi:10.1158/1538-7445.SABCS17-P2-09-11.
Prat A, Slamon D, Hurvitz S, et al. Abstract PD3-06: Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC). Cancer Res. 2018; 78 (4 Supplement):PD3-06. doi:10.1158/1538-7445.SABCS17-PD3-06.
- De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2 weeks letrozole: results of the PerELISA neoadjuvant study.Ann Oncol. 2019; 30: 921-926https://doi.org/10.1093/annonc/mdz055
- Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006.J Clin Oncol Off J Am Soc Clin Oncol. 2013; 31: 1726-1731https://doi.org/10.1200/JCO.2012.44.8027
Prat A, De Angelis C, Pascual T, et al. Abstract P2-09-12: Independent validation of the HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer. Cancer Res. 2018; 78(4 Supplement):P2-09-12. doi:10.1158/1538-7445.SABCS17-P2-09-12.
Prat A, De Angelis C, Pascual T, et al. HER2-enriched subtype and ERBB2 mRNA as predictors of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer: A combined analysis of TBCRC006/023 and PAMELA trials. J Clin Oncol. 2018; 36(15_suppl):509–509. doi:10.1200/JCO.2018.36.15_suppl.509.
- Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer.Cancer Treat Rev. 2018; 67: 63-70https://doi.org/10.1016/j.ctrv.2018.04.015
- 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: 1700-1712https://doi.org/10.1093/annonc/mdx308
- Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial.JAMA Oncol. 2015; 1: 448-454https://doi.org/10.1001/jamaoncol.2015.0830
- Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers.J Clin Oncol Off J Am Soc Clin Oncol. 2015; 33: 983-991https://doi.org/10.1200/JCO.2014.58.1967
- PAM50 HER2-enriched subtype as an independent prognostic factor in early-stage HER2+ breast cancer following adjuvant chemotherapy plus trastuzumab in the ShortHER trial.J Clin Oncol. 2019; 37: 544
- Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.Ann Oncol Off J Eur Soc Med Oncol. 2014; 25: 1544-1550https://doi.org/10.1093/annonc/mdu112
- Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer.J ImmunoTher Cancer. 2019; 7https://doi.org/10.1186/s40425-019-0548-6
- PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab.Ann Oncol Off J Eur Soc Med Oncol. 2016; 27: 1519-1525https://doi.org/10.1093/annonc/mdw197
- Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer.J Clin Oncol Off J Am Soc Clin Oncol. 2014; 32: 3753-3761https://doi.org/10.1200/JCO.2013.54.5384
- Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer.Int J Cancer. 2016; 139: 2336-2342https://doi.org/10.1002/ijc.30276
- Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.Breast Cancer Res Treat. 2018; 167: 731-740https://doi.org/10.1007/s10549-017-4533-9
- A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.Ann Oncol Off J Eur Soc Med Oncol. 2019; https://doi.org/10.1093/annonc/mdz076
Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011]. The Cochrane Collaboration http://handbook.cochrane.org.
- Meta-analysis in clinical trials.Control Clin Trials. 1986; 7: 177-188
- Quantifying heterogeneity in a meta-analysis.Stat Med. 2002; 21: 1539-1558https://doi.org/10.1002/sim.1186
- Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis.J Clin Epidemiol. 2001; 54: 1046-1055
- Bias in meta-analysis detected by a simple, graphical test.BMJ. 1997; 315: 629-634https://doi.org/10.1136/bmj.315.7109.629
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. https://www.R-project.org/.
The Cochrane Collaboration. Review Manager (RevMan). Copenhagen: The Nordic Cochrane Centre; 2014.
PROSPERO International prospective register of systematic reviews. https://www.crd.york.ac.uk/prospero/.
- PAM50 subtypes in baseline and residual tumors following neoadjuvant trastuzumab-based chemotherapy in HER2-positive breast cancer: a consecutive-series from a single institution.Front Oncol. 2019; 9https://doi.org/10.3389/fonc.2019.00707
- 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: 25-32https://doi.org/10.1016/S1470-2045(11)70336-9
- Why do we need systematic overviews of randomized trials?.Stat Med. 1987; 6: 233-244
- Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science. 1987; 235: 177-182https://doi.org/10.1126/science.3798106
- Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet Lond Engl. 2014; 384: 164-172https://doi.org/10.1016/S0140-6736(13)62422-8
- Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.J Clin Oncol. 2012; 30: 1796-1804
- Trial-level prediction of long-term outcome based on pathologic complete response (pCR) after neoadjuvant chemotherapy for early-stage breast cancer (EBC).Contemp Clin Trials. 2018; 71: 194-198
- Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes: a meta-analysis.JAMA Oncol. 2016; 2: 751-776
Spring LM, Fell G, Arfe A, et al. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Individual patient-level meta-analyses of over 27,000 patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-03.
FDA Guidance for Industry. Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Available at: https://www.fda.gov/media/83507/download. Last accessed: 02/12/2020.
Rimawi MF, Niravath P, Wang T, et al. TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 vs. 24 Weeks in Patients with HER2-positive Breast Cancer. Clin Cancer Res. 2019; doi: 10.1158/1078-0432.CCR-19-0851 [Epub ahead of print].
- Escalation and de-escalation in HER2 positive early breast cancer.Curr Opin Oncol. 2019; 31: 35-42https://doi.org/10.1097/CCO.0000000000000492
- De-escalation of treatment in HER2-positive breast cancer: determinants of response and mechanisms of resistance.Breast Edinb Scotl. 2017; 34: S19-S26https://doi.org/10.1016/j.breast.2017.06.022
- PERSEPHONE.NPJ Breast Cancer. 2019; 5: 1https://doi.org/10.1038/s41523-018-0098-y
- 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 Off J Am Soc Clin Oncol. 2019; 37: 1868-1875https://doi.org/10.1200/JCO.19.00066
Metzger Filho O, Viale G, Trippa L, 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(15_suppl):502-502. doi:10.1200/JCO.2019.37.15_suppl.502.
- Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies.J Clin Oncol. 2014; 32: 3883-3891https://doi.org/10.1200/JCO.2014.55.2836
- Statistical controversies in clinical research: assessing pathologic complete response as a trial-level surrogate end point for early-stage breast cancer.Ann Oncol. 2016; 27: 10-15https://doi.org/10.1093/annonc/mdv507
Article Info
Publication History
Published online: January 17, 2020
Accepted:
January 10,
2020
Received in revised form:
January 9,
2020
Received:
October 2,
2019
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
