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. 2023 Sep;34(9):783-795.
doi: 10.1016/j.annonc.2023.05.012. Epub 2023 Jun 9.

Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer

G Villacampa  1 , N M Tung  2 , S Pernas  3 , L Paré  4 , C Bueno-Muiño  5 , I Echavarría  6 , S López-Tarruella  6 , M Roche-Molina  6 , M Del Monte-Millán  6 , M Marín-Aguilera  4 , F Brasó-Maristany  7 , A G Waks  8 , T Pascual  9 , O Martínez-Sáez  7 , A Vivancos  10 , P F Conte  11 , V Guarneri  11 , M Vittoria Dieci  11 , G Griguolo  11 , J Cortés  12 , A Llombart-Cussac  13 , M Muñoz  7 , M Vidal  7 , B Adamo  7 , A C Wolff  14 , A DeMichele  15 , P Villagrasa  4 , J S Parker  16 , C M Perou  16 , A Fernandez-Martinez  16 , L A Carey  16 , E A Mittendorf  17 , M Martín  6 , A Prat  18 , S M Tolaney  19
Affiliations

Association of HER2DX with pathological complete response and survival outcomes in HER2-positive breast cancer

G Villacampa et al. Ann Oncol. 2023 Sep.

Abstract

Background: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status.

Materials and methods: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status.

Results: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. 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 = 2.36 (1.09-5.42). 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 = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk.

Conclusions: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.

Keywords: HER2; HER2DX; breast cancer; neoadjuvant; pathological complete response; pertuzumab.

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Conflict of interest statement

Conflicts of Interest Disclosure

G.V has received a speaker’s fee from MSD, Pfizer, GSK and Pierre Fabrer, has held an advisory role with AstraZeneca and received consultant fees from Reveal Genomics. C. B-M received honoraria as speakers’ honoraria from Roche, Novartis, Lilly, M.S.D and AstraZeneca and G.S.K and Travel Grant from Roche, Novartis and Pfizer. I.E. reports Speaker fees from Roche, Teva, Novartis, Pfizer, Lily and advisory role from Lilly and Astrazeneca. S.L-T reports consulting or advisory role fees from AstraZeneca, Novartis, Roche, Pfizer, Pierre Fabre, Lilly, Seagen, Daichii-Sankyo Europe GmbH, Gilead Sciences, MDS, GlaxoSmithKline, Veracyte and speakers Bureau fees from Lilly. T.M. reports consulting or advisory boards fees from AstraZeneca, Novartis, Roche, GSK and travel grants from Novartis and Astra Zeneca. Y.J. reports consultant or advisory role fees from Novartis, Pfizer, Roche, and AstraZeneca, she received speaker honoraria from Roche, Novartis, Lilly and AstraZeneca, travel and trainnig grants from Roche, Novartis, Pfizer, and Lilly. JA.G-S reports consulting and advisory services fees for Seagen, Gilead, Sanofi. Consultancy/speaker fees from Novartis, Celgene, Eli Lilly, EISAI, AstraZeneca, Daiichi Sankyo, MSD, Pierre Fabre. Institution research funding from AstraZeneca and travel support from Novartis, Roche, Pfizer. F.M. reports consulting or advisory role fees from Roche/Genentech, Novartis, Pfizer, AstraZeneca, MSD, Daiichi Sankyo/Astrazeneca and speakers' bureau fees from Pfizer. Travel, Accommodations, Expenses from Roche/Genentech, Daiichi Sankyo/Astra Zeneca. A.R-L reports consultant Fees from Roche, AstraZeneca, Pfizer, Seagen, Novartis, Lilly, AstraZeneca and Pierre-Fabré and Speaker Bureau fees from Daiichi-Sankyo, Msd and Gilead. AI.B. reports consulting or advisory fees from Pfizer, Novartis, Seagen, Roche, Pierre Fabre. Travel and accommodations fees from Pfizer. A.P. reports advisory and consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo, institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas and Pfizer; stockholder and consultant of Reveal Genomics, SL; A.P. is also listed as an inventor on patent applications for the HER2DX assay. C.M.P is an equity stockholder and consultant of BioClassifier LLC, and for Reveal Genomics. C.M.P is also listed as an inventor on patent applications for the Breast PAM50 assay. J.S.P is an equity stockholder and consultant for Reveal Genomics and is also listed as an inventor on patent applications for the Breast PAM50 assay. F.B-M. has a patent application EP21383165. L.P is listed as an inventor on patent PCT/EP2021/070788. F.S. has no competing financial and non-financial interests. EAM reports compensated service on scientific advisory boards for AstraZeneca, Exact sciences (formerly Genomic Health), Merck, Roche/Genentech; uncompensated service on steering committees for Bristol Myers Squibb, Lilly, and Roche/Genentech; and institutional research support from Roche/Genentech (via SU2C grant) and Gilead. She receives research funding from Susan Komen for the Cure for which she serves as a Scientific Advisor. She also reports uncompensated participation as a member of the American Society of Clinical Oncology Board of Directors. SMT has served as a consultant for: Novartis, Pfizer, Merck, Lilly, Nektar, NanoString Technologies, AstraZeneca, Puma Biotechnology, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, Odonate Therapeutics, OncoPep, Kyowa Hakko Kirin, Samsung Bioepis, CytomX Therapeutics, Daiichi Sankyo, Athenex, Gilead, Mersana, Certara, Chugai Pharma, Ellipses Pharma, Infinity, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics; SMT has received institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Cyclacel, Nektar, Gilead, Odonate Therapeutics, Sanofi, Seattle Genetics. M.M. reports Research grants from PUMA; consulting/advisory fees from Roche, Novartis, AstraZeneca, Daiichi-Sankyo, Seagen, Lilly, Sanofi; speakers’ honoraria from Seagen, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, Roche. Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid: Chairman, GEICAM Member of Board of Directors, TRIO. The rest of authors declare no conflict of interest. AGW receives institutional research funding from Genentech/Roche, Macrogenics, and Merck.

Figures

Figure 1.
Figure 1.. Association of HER2DX pCR score with pCR in the combined neoadjuvant cohort of 765 patients.
(A) Univariable and multivariable logistic models to predict pCR (n=765). (B) Pooled results in patients treated with chemotherapy and dual HER2 blockade (n=431), with chemotherapy and trastuzumab (n=250) or dual HER2 blockade alone (n=84). (C) Pooled results in patients with HR-positive (n=486) or HR-negative (n=277) disease. (D) Calibration plots for the pCR endpoint. X-axis shows average predicted probability values for each decile, and y-axis shows corresponding observed probability in each decile. Error bars represent 95% confidence intervals of mean predicted probabilities. The diagonal line represents the perfect calibration, the dotted curve represents the estimated calibration, and the solid curve the corrected estimation after correction for overfitting (bootstrap validation with resampling of 1000 interactions) (E) Area under the ROC curve with 95% confidence interval of HER2DX pCR score to predict pCR in all patients (n=765). OR: odds ratio; 95% CI: 95% confidence interval; pCR: pathological complete response; AUC: area under the ROC curve; TH: Paclitaxel and trastuzumab; AC-TDM1-P: Doxorubicin, cyclophosphamide, ado-trastuzumab emtansine and pertuzumab; AC-TH: Doxorubicin, cyclophosphamide, paclitaxel and trastuzumab; AC-THP: Doxorubicin, cyclophosphamide, paclitaxel, trastuzumab and pertuzumab; HL: Trastuzumab and lapatinib; TCH: Docetaxel, carboplatin and trastuzumab; TCHP: Docetaxel, carboplatin, trastuzumab and pertuzumab; THL: Paclitaxel, trastuzumab and lapatinib; THP: Paclitaxel, trastuzumab and pertuzumab. *A separate multivariable model has been performed using HER2DX pCR groups instead of HER2DX pCR score. To avoid multicollinearity, HER2DX pCR groups and HER2DX pCR score cannot be included in the same model.
Figure 2.
Figure 2.. Association of HER2DX pCR groups with response to dual HER2 blockade and with response to multi-agent chemotherapy in the combined neoadjuvant cohort.
(A) Bar plots showing the pCR rates across the HER2DX pCR groups based on single versus dual HER2 blockade. (B) Forest plots evaluating the association of HER2DX pCR groups with pCR according to dual HER2 blockade administration in cohorts that compared dual blockade vs. single anti-HER2 (DAPHNe, BiOnHER and PAMELA cohorts were not included). (C) Bar plots showing the pCR rates across the HER2DX pCR groups based on single taxane versus multi-agent chemotherapy in the cohort of 367 patients treated with dual HER2 blockade. OR: odds ratio; 95% CI: 95% confidence interval; pCR: pathological complete response.
Figure 3:
Figure 3:. HER2DX pCR groups association with clinical-pathological variables and with genomic and proteomic data from The Cancer Genome Atlas (TCGA) breast cancer project.
(A) HER2DX pCR groups ranking and association with clinical-pathological variables, type of treatment and therapy response in the combined cohort (n=765). Each column represents the information for a patient. (B) HER2DX pCR score was evaluated in 161 HER2+ tumor samples from TCGA breast cancer dataset using the cbioportal data portal. Tumor samples were rank ordered based on their HER2DX pCR score (from low [left] to high [right]). Below the tumor samples with HER2DX pCR score data, DNA somatic mutation status in TP53 and PIK3CA, gene expression patterns of 1,283 genes, and the expression of HER2 and ER proteins (from reverse-phase protein array data) are shown. The heatmap reveals the expression patterns of the top 1,283 genes whose expression was found differentially expressed across the HER2DX pCR groups (false discovery rate<1%). T: Clinical tumor stage; N: Clinical nodal stage, pCR: pathological complete response. ICH: Immunohistochemistry, IGG: Immunoglobulin G signature, ER: Estrogen receptor.
Figure 4.
Figure 4.. Event-free survival (EFS) by pCR status and HER2DX risk group in the NEOHER and PAMELA combined cohorts (n=268).
(A) EFS in the overall population by pCR status (n=268), (B) EFS in the overall population by HER2DX risk group (n=268), (C) EFS in the pCR population by HER2DX risk group (n=118), (D) EFS in the non-pCR population by HER2DX risk group (n=150). EFS: event-free survival; HR: hazard ratio; 95% CI: 95% confidence interval.
See this image and copyright information in PMC

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