Journal
CANCER CELL
Volume 40, Issue 6, Pages 609-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2022.05.005
Keywords
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Categories
Funding
- Quantum Leap Healthcare Collaborative, FNIH, NIH/NCI I-SPY2+ [PO1-CA210961]
- NIH/NCI [28XS197 P-0518835]
- NIH/NCI CCMI [U54CA209891]
- NIH/NCI CCSG [P30-CA82103]
- NIH/NHGRI Big Data [U54-HG007990]
- Breast Cancer Research Foundation [BCRF-20-165]
- UCSF, GMU, Gateway for Cancer Research [G-16-900, G-20-600]
- SideOut Foundation
- Safeway (an Al-bertsons Company)
- William K. Bowes, Jr. Foundation
- Biomarkers Consortium
- Salesforce
- OpenClinica
- Formedix
- Hologic
- TGen
- CCS Associates
- Berry Consultants
- Breast Cancer Research - Atwater Trust
- Stand Up To Cancer
- California Breast Cancer Research Program
- Give Breast Cancer the Boot
- Angela and Shu Kai Chan Chair in Cancer Research (LvtV)
- IQVIA
- Genentech
- Amgen
- Pfizer
- Merck
- Seattle Genetics
- Daiichi Sankyo
- AstraZeneca
- Dynavax Technologies
- Puma Biotechnology
- AbbVie
- Madrigal Pharmaceuticals
- Plexxikon
- Regeneron
- Agendia
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By incorporating gene expression, protein/phosphoprotein, and clinical data, we have created new breast cancer subtypes that can better predict drug responses. The best performing subtypes include Immune, DNA repair, and HER2/Luminal phenotypes. Treatment allocation based on these subtypes significantly increases the overall pathologic complete response rate. This study is important for guiding future breast cancer treatment.
Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from similar to 990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
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