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Multicenter Study
. 2023 Jun 1;9(6):835-840.
doi: 10.1001/jamaoncol.2023.0181.

Assessment of the HER2DX Assay in Patients With ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab

Adrienne G Waks  1   2   3 , Esther R Ogayo  1   3   4 , Laia Paré  5 , Mercedes Marín-Aguilera  5 , Fara Brasó-Maristany  6 , Patricia Galván  6 , Oleguer Castillo  6 , Olga Martínez-Sáez  6 , Ana Vivancos  7 , Patricia Villagrasa  5 , Guillermo Villacampa  5 , Paolo Tarantino  1   2   3 , Neelam Desai  2   8 , Jennifer Guerriero  2   3   4 , Otto Metzger  1   2   3 , Nadine M Tung  2   8 , Ian E Krop  1   2   3   9 , Joel S Parker  10 , Charles M Perou  10 , Aleix Prat  6   11   12   13   14 , Eric P Winer  1   2   3   9 , Sara M Tolaney  1   2   3 , Elizabeth A Mittendorf  2   3   4
Affiliations
Multicenter Study

Assessment of the HER2DX Assay in Patients With ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab

Adrienne G Waks et al. JAMA Oncol. .

Abstract

Importance: Patients with early-stage ERBB2 (formerly HER2)-positive breast cancer (ERBB2+ BC) who experience a pathologic complete response (pCR) after receiving neoadjuvant therapy have favorable survival outcomes. Predicting the likelihood of pCR may help optimize neoadjuvant therapy.

Objective: To test the ability of the HER2DX assay to predict the likelihood of pCR in patients with early-stage ERBB2+ BC who are receiving deescalated neoadjuvant therapy.

Design, setting, and participants: In this diagnostic/prognostic study, the HER2DX assay was administered on pretreatment tumor biopsy samples from patients enrolled in the single-arm, multicenter, prospective phase 2 DAPHNe clinical trial who had newly diagnosed stage II to III ERBB2+ BC that was treated with neoadjuvant paclitaxel weekly for 12 weeks plus trastuzumab and pertuzumab every 3 weeks for 4 cycles.

Interventions and exposures: The HER2DX assay is a classifier derived from gene expression and limited clinical features that provides 2 independent scores to predict prognosis and likelihood of pCR in patients with early-stage ERBB2+ BC. The assay was administered on baseline tumor samples from 80 of 97 patients (82.5%) in the DAPHNe trial.

Main outcomes and measures: The primary aim was to test the ability of the HER2DX pCR likelihood score (as a continuous variable from 0-100) to predict pCR (ypT0/isN0).

Results: Of 80 participants, 79 (98.8%) were women and there were 4 African American (5.0%), 6 Asian (7.5%), 4 Hispanic (5.0%), and 66 White individuals (82.5%); the mean (range) age was 50.3 (26.0-78.0) years. The HER2DX pCR score was significantly associated with pCR (odds ratio, 1.05; 95% CI, 1.03-1.08; P < .001). The pCR rates in the HER2DX high, medium, and low pCR score groups were 92.6%, 63.6%, and 29.0%, respectively (high vs low odds ratio, 30.6; P < .001). The HER2DX pCR score was significantly associated with pCR independently of hormone receptor status, ERBB2 immunohistochemistry score, HER2DX ERBB2 expression score, and prediction analysis of microarray 50 ERBB2-enriched subtype. The correlation between the HER2DX pCR score and prognostic risk score was weak (Pearson coefficient, -0.12). Performance of the risk score could not be assessed due to lack of recurrence events.

Conclusions and relevance: The results of this diagnostic/prognostic study suggest that the HER2DX pCR score assay could predict pCR following treatment with deescalated neoadjuvant paclitaxel with trastuzumab and pertuzumab in patients with early-stage ERBB2+ BC. The HER2DX pCR score might guide therapeutic decisions by identifying patients who are candidates for deescalated or escalated approaches.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Waks reported nonfinancial support from Reveal Genomics during the conduct of the study as well as research support from Genentech, Macrogenics, and Merck and personal fees from AstraZeneca outside the submitted work. Dr Paré reported a patent pending (906 439) and being an employee of Reveal Genomics. Dr Marín-Aguilera reported being an employee of Reveal Genomics. Dr Brasó-Maristany reported a patent for a HER2DX assay pending. Dr Villagrasa reported a patent for EP21383165 issued as well as being a cofounder of Reveal Genomics. Dr Villacampa reported personal fees from MSD, AstraZeneca, Pierre Fabrer, and GSK outside the submitted work. Dr Tarantino reported personal fees from AstraZeneca, Daiichi Sankyo, and Lilly outside the submitted work. Dr Guerriero reported personal fees from Array BioPharma, AstraZeneca, BD Biosciences, Carisma, Codagenix, Duke Street Bio, GlaxoSmithKline, and OncoOne and grants from Array BioPharma, Eli Lilly, Merck, and GlaxoSmithKline outside the submitted work. Dr Metzger-Filho reported grants from Roche/Genentech during the conduct of the study as well as personal fees from Astra Zeneca, Alliance Foundation Trials, Resilience, Oncoclinicas, and Merck and grants from Pfizer outside the submitted work. Dr Tung reported research support and consulting fees from AstraZeneca outside the submitted work. Dr Krop reported grants from Roche during the conduct of the study as well as personal fees from AstraZeneca, Daiichi Sankyo, Genentech/Roche, Macrogenics, Seattle Genetics, Novartis, and Merck and grants from Pfizer outside the submitted work. Dr Parker reported being an equity holder in and consultant for Reveal Genomics during the conduct of the study as well as personal fees from GeneCentric and BMS and a patent with Veracyte outside the submitted work. Dr Perou reported being an equity stockholder in and consultant for Reveal Genomics as well as holding a patent with Bioclassifier outside the submitted work. Dr Prat reported personal fees from Reveal Genomics and Roche during the conduct of the study as well as personal fees from Novartis, AstraZeneca, Daiichi-Sankyo, and Oncolytics Biotech and patents licensed to Reveal Genomics outside the submitted work. Dr Tolaney reported personal fees from Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Chugai Pharmaceuticals, Zetagen, Myovant, Umoja Biopharma, Menarini/Stemline, Bayer, and Aadi Bio as well as grants from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Sanofi, and Seattle Genetics outside the submitted work. Dr Mittendorf reported service on scientific advisory boards for Astra Zeneca, Exact Sciences, Roche/Genentech, and Merck; steering committee service for BMS, Lilly, and Roche/Genentech; and research support from Roche/Genentech and Gilead during the conduct of the study as well as research funding from Susan Komen for the Cure and participation as a member of the American Society of Clinical Oncology board of directors outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Performance and Genomic Features of the HER2DX Pathologic Complete Response (pCR) Score for Predicting pCR Following Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab (THP) Therapy
Receiver operating characteristic curve analysis of the HER2DX pCR score among all patients (A), hormone receptor (HR)–negative patients (B), and HR-positive patients (C). D, Expression of the 4 HER2DX gene expression signatures (immune, proliferation, luminal, and ERBB2 [formerly HER2] amplicon) across the HER2DX pCR score high, medium, and low groups. AUC indicates area under the curve; IGG immunoglobulin G; IHC, immunohistochemistry.
See this image and copyright information in PMC

References

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