Genomic-based predictive biomarkers to anti-HER2 therapies: A combined analysis of CALGB 40601 (Alliance) and PAMELA clinical trials.

Authors

Aranzazu Fernandez-Martinez

Aranzazu Fernandez-Martinez

Lineberger Comprehensive Center. Department of Genetics. University of North Carolina, Chapel Hill, NC

Aranzazu Fernandez-Martinez , Maki Tanioka , Cheng Fan , Joel S. Parker , Katherine A. Hoadley , Ian E. Krop , Javier Cortes , Antonio Llombart Cussac , Paolo Nuciforo , Patricia Galván , Tomas Pascual , Ann H. Partridge , Aleix Prat , Lisa A. Carey , Charles M. Perou

Organizations

Lineberger Comprehensive Center. Department of Genetics. University of North Carolina, Chapel Hill, NC, Dana-Farber Cancer Institute, Boston, MA, IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Hospital Arnau de Vilanova Valencia, Servicio de Oncología Médica, Valencia, Spain, Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, Department of Medical Oncology, Hospital Clínic de Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain, Department of Medical Oncology, Hospital Clínic de Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), SOLTI Breast Cancer Cooperative Group, Barcelona, Spain, Department of Medical Oncology, Hospital Clínic de Barcelona. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS). SOLTI Breast Cancer Cooperative Group, Barcelona, Spain, Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC

Research Funding

U.S. National Institutes of Health
Other Foundation

Background: In HER2-positive breast cancer, new biomarkers of response are needed in order to direct multi-agent anti-HER2 combinations towards patients in whom they are truly needed. CALGB 40601 and PAMELA trials tested neoadjuvant dual HER2 blockade and included gene expression analysis aimed to evaluate different genomic biomarkers of trastuzumab and/or lapatinib benefit. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 265 and 142 pre-treatment tumors of the CALGB 40601 and the PAMELA clinical trials respectively. Intrinsic subtypes were determined by nCounter PAM50-predictor on the PAMELA samples. A new HER2-positive specific gene-centering method was trained on the PAMELA RNAseq data, and showed a higher concordance with PAM50 predictions obtained from nCounter platform. This method was then applied to CALGB 40601 samples. Results: In the combined cohort, the subtype distribution was 10% Luminal A, 8% Luminal B, 62% HER2-enriched (HER2-E), 10% Basal and 10% Normal-like. The pCR rate was significantly higher in HER2-E vs. not HER2-E subtypes (48.6% vs. 20.7%; P < 0.001). HER2-E subtype correlation, ERBB2 amplicon and B-cell genomic signatures were associated with pCR, while luminal signatures were associated with non-responders. In multivariate analysis HER2-E subtype, ERBB2 mRNA and IgG signature expression were independent predictors of response to paclitaxel + trastuzumab +/-lapatinib (OR = 1.98, OR = 1.51, OR = 1.48, respectively, P <0.05). The event free survival analysis at 5 years in the CALGB 40601 cohort showed a benefit of dual vs single anti-HER2-blockade (HR 0.35, P <0.05). Within the HER2-E, ERBB2-high and IgG–high subpopulations, there were also a benefit of dual vs. single anti-HER2 treatment (HR = 0.32, HR = 0.15, HR =0.15, respectively, P <0.05). Conclusions: Intrinsic subtype, ERBB2 mRNA levels, and IgG genomic signature are independent predictive biomarkers of response in the combined cohort. The clinical implementation of these biomarkers could help to design future escalation/de-escalation clinical trials in the HER2-positive neoadjuvant setting. Support: U10CA180821, U10CA180882, U24CA196171, P50-CA58223, GSK, SPORE, BCRF and SEOM. https://acknowledgments.alliancefound.org.

Disclaimer

This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org

Abstract Details

Meeting

2019 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Breast Cancer—Local/Regional/Adjuvant

Track

Breast Cancer

Sub Track

Neoadjuvant Therapy

Citation

J Clin Oncol 37, 2019 (suppl; abstr 571)

DOI

10.1200/JCO.2019.37.15_suppl.571

Abstract #

571

Poster Bd #

63

Abstract Disclosures

Similar Abstracts

First Author: Christian F. Singer

First Author: David H Aggen

First Author: Jan Paredes Mogica