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. 2024 May 1;10(5):603-611.
doi: 10.1001/jamaoncol.2023.7304.

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials

Aranzazu Fernandez-Martinez  1   2 , Mattia Rediti  3 , Gong Tang  4   5 , Tomás Pascual  1   6   7   8 , Katherine A Hoadley  1   2 , David Venet  3 , Naim U Rashid  9 , Patricia A Spears  1 , Md N Islam  10 , Sarra El-Abed  11 , Judith Bliss  12 , Matteo Lambertini  13   14 , Serena Di Cosimo  15 , Jens Huobe  16 , David Goerlitz  17 , Rong Hu  10 , Peter C Lucas  4   18 , Sandra M Swain  4   17 , Christos Sotiriou  3 , Charles M Perou  1   2 , Lisa A Carey  1   19
Affiliations

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials

Aranzazu Fernandez-Martinez et al. JAMA Oncol. .

Abstract

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC).

Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41.

Design, setting, and participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023.

Main outcomes and measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses.

Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94.

Conclusions and relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pascual reported personal fees from Pfizer, Veracyte, AstraZeneca, Novartis, and Pfizer outside the submitted work. Dr El-abed reported grants from Novartis, Roche/Genentech, Pfizer, AstraZeneca, and BCRF via institution outside the submitted work. Dr Bliss reported grants from AstraZeneca and Merck Sharp & Dohme to ICR-CTSU, grants from Puma Technology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Eli Lilly, and Roche to ICR-CTSU outside the submitted work. Dr Lambertini reported advisory roles and speaker honoraria from Roche, Lilly, Novartis, Pfizer, and AstraZeneca, an advisory role at Seagen, an advisory role, travel expenses, and research funding (to the institution) from Gilead, advisory roles at MSD, Exact Sciences, speaker honoraria from Takeda, speaker honoraria and travel support from Daiichi Sankyo, speaker honoraria from Knight, Ipsen, Sandoz Speaker, and Libbs outside the submitted work. Dr Huober reported personal fees from Roche, Lilly, Pfizer, Novartis, MSD, AstraZeneca, Gilead, Seagen, and Daiichi outside the submitted work. Dr Lucas reported equity interest from Amgen outside the submitted work; in addition, Dr Lucas had a patent for “Small Molecules and their use as MALT1 Inhibitors” issued (WO 2022/204386). Dr Swain reported grants from BCRF, Alexander Savchuk Foundation, and NSABP Foundation during the conduct of the study; grants from Genentech/Roche to institution for other trials, personal fees from Genentech/Roche (nonpromotional speaking and consulting honoraria), nonfinancial support from Genentech/Roche for in-kind travel, fees from Genentech/Roche for in-kind third party writing, and board of directors nonfinancial support from NSABP outside the submitted work. Dr Perou reported grants from NCI Breast SPORE program P50-CA58223 during the conduct of the study; personal fees from Bioclassifier LLC as an equity stockholder and royalties and personal fees from Reveal Genomics equity stockholder and consultant outside the submitted work; in addition, Dr Perou had a patent for US Patent No. 12 995 459 with royalties paid from Bioclassifier. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curves of the Association of Pathologic Complete Response (pCR) With Event-Free Survival by Tumor Intrinsic Subtype
Kaplan-Meier event-free survival (EFS) proportions at 5 years are provided. Cox regression models were stratified by clinical trial. Patients with normal-like tumors were removed from the analysis. RD indicates residual disease.
Figure 2.
Figure 2.. Kaplan-Meier Curves of the Association of the Treatment Arm With Event-Free Survival by Tumor Intrinsic Subtype
Kaplan-Meier event-free survival (EFS) proportions at 5 years are provided. Cox regression models were stratified by clinical trial. Patients with normal-like tumors and treated with lapatinib only were removed from the analysis.
Figure 3.
Figure 3.. Forest Plots Showing the Association of Gene Expression Biomarker Levels at Baseline With Pathologic Complete Response (PCR) and Event-Free Survival (EFS)
A selection of the most interesting and consistent biomarkers across the 3 studies and the combined cohort is shown. All the models have been stratified by clinical trial and adjusted by tumor size, hormone receptor status, and clinical node involvement. The whiskers indicate the 95% CIs. HR indicates hazard ratio; IgG, immunoglobulin G; OR, odds ratio; PD-L1, programmed death-ligand 1.
See this image and copyright information in PMC

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