Abstract
Background: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). Patients and methods: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) breast cancer received neoadjuvant taxane–anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. Results: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. Conclusions: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2− disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 642-651 |
| Number of pages | 10 |
| Journal | Annals of Oncology |
| Volume | 32 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2021 |
Bibliographical note
Funding Information:This publication is partly based on research using information obtained from www.projectdatasphere.org, which is maintained by Project Data Sphere, LLC. Neither Project Data Sphere, LLC nor the owner(s) of any information from the web site have contributed to, approved, or are in any way responsible for the contents of this publication. The authors thank Dr Bastiaan van der Baan for supporting this analysis of Agendia test results from the I-SPY2 trial. Additional acknowledgements that relate to the overall I-SPY2 TRIAL have been included in the Supplementary Appendix, available at https://doi.org/10.1016/j.annonc.2021.02.011. This work was supported in part by grant funding from the Breast Cancer Research Foundation (to WFS); National Institutes of Health [grant number P0513149] (to LE, LV, WFS); Cancer Prevention and Research Institute of Texas (CPRIT) [grant number RP180712] (to WFS, DT); and Safeway Foundation (I-SPY2). The I-SPY2 TRIAL is supported by Quantum Leap Healthcare Collaborative (2013 to present) and the Foundation for the National Institutes of Health (2010-2012) and by a grant [grant number 28XS197] from the National Cancer Institute Center for Biomedical Informatics and Information Technology. WFS is a co-inventor of a pending patent application for the sensitivity to endocrine therapy and co-founder with equity in Delphi Diagnostics that licensed the intellectual property. LP and WFS are co-inventors of an issued patent for the algorithm to calculate residual cancer burden that is freely available on the internet. LvV is a co-inventor of an issued patent for the MammaPrint test and holds equity in Agendia that licensed the intellectual property. The remaining authors have declared no conflicts of interest.
Publisher Copyright:
© 2021 European Society for Medical Oncology
Keywords
- chemo-endocrine
- hormonal
- prediction
- prognosis
- response
- treatments
