126MO - HER2DX and pathological complete response in HER2-positive breast cancer: a combined analysis of 4 neoadjuvant studies

Background

The optimal neoadjuvant therapy for HER2-positive breast cancer patients is subject to ongoing debate and the use of biomarkers can help to personalise treatment decision. The 27-gene HER2DX test predicts pathological complete response (pCR) following neoadjuvant trastuzumab-based chemotherapy. Here, we evaluated the value of HER2DX to predict increases in pCR rate when 1) a second anti-HER2 agent is added to trastuzumab and chemotherapy, and 2) multi-agent chemotherapy is used instead of a single agent taxane in the context of dual HER2 blockade.

Methods

We conducted a combined analysis of four neoadjuvant cohorts with HER2DX and clinical data (i.e., DAPHNe, GOM-HGUGM-2018-05, CALGB-40601 and ISPY-2). All patients were treated with neoadjuvant trastuzumab (n=568) in combination with multi-agent chemotherapy (n=282), a single taxane (n=286), pertuzumab (n=264), lapatinib (n=103) or without a second anti-HER2 drug (n=201). Interaction tests were performed to evaluate the predictive capacity of HER2DX to identify patients who benefit most from each treatment approach.

Results

HER2DX pCR as continuous score was significantly associated with pCR in all patients (odds-ratio [OR]=1.62, 95% CI 1.43-1.85; AUC=0.75), in patients treated with trastuzumab and chemotherapy (OR=1.48, 1.18-1.86) and in patients treated with dual HER2 blockade and chemotherapy (OR=1.69, 1.50-1.91). A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR=4.10, 1.85-9.07; interaction test p=0.03). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR=2.52, 1.18-5.52; interaction test p=0.01). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of type of treatment.

Conclusions

HER2DX might help identify patients with HER2-positive breast cancer who benefit from neoadjuvant dual HER2 blockade in combination with a single taxane.

Legal entity responsible for the study

The authors.

Funding

Reveal Genomics.

Disclosure

A.G. Waks: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech, Macrogenics, Merck. G. Villacampa: Financial Interests, Personal, Invited Speaker: GSK, Pierre Fabre, Pfizer, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. C. Bueno Muiño: Financial Interests, Speaker’s Bureau: Roche/Novartis/Lilly/M.S.D/AstraZeneca; Financial Interests, Research Grant: Roche/Novartis/Pfizer. I. Echavarria Diaz-Guardamino: Financial Interests, Invited Speaker: Roche/Teva/Novartis/Pfizer/Lily; Financial Interests, Advisory Board: Lilly/AstraZeneca. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Gilead, GSK, Roche, Pierre Fabre, Seagen, Menarini, Stemline, Gebro Pharma; Non-Financial Interests, Invited Speaker: GEICAM, SEOM. M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. A.C. Wolff: Financial Interests, Institutional, Invited Speaker, Became site PI upon departure of a previous Hopkins faculty member who was site PI for this study.: Roche; Other, Co-chair of ASCO/CAP Panel on HER2 Testing in Breast Cancer: American Society of Clinical Oncology. C.M. Perou: Financial Interests, Personal, Invited Speaker: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. L.A. Carey: Financial Interests, Personal, Royalties, immediate family member-royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme.: Falcon Therapeutics; Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.