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Brief Report
February 18, 2021

Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 2Department of Medicine, The Ohio State University College of Medicine, Columbus
  • 3Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus
  • 4AbbVie, Inc, North Chicago, Illinois
  • 5Washington University, St Louis, Missouri
  • 6German Breast Group, Neu-Isenburg, Germany
  • 7Massey Cancer Center, Virginia Commonwealth University, Richmond
  • 8Now with Houston Methodist Cancer Center, Houston, Texas
  • 9Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas
  • 10Helios Klinikum Berlin-Buch, Berlin, Germany
  • 11University of California, San Francisco
  • 12University Medical Center Ulm, Ulm, Germany
  • 13Now with Department of Interdisciplinary Medical Services, Breast Center, Cantonal Hospital St Gallen, St Gallen, Switzerland.
  • 14Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
  • 15Breast Oncology Program, Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts
  • 16Now with Yale Cancer Center, New Haven, Connecticut
  • 17Women and Infants Hospital of Rhode Island, Providence
  • 18University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania
  • 19Allegheny General Hospital, Pittsburgh, Pennsylvania
  • 20Institute of Physiology and Pathophysiology, Department of Medicine, Philipps-University Marburg and University Hospital of Giessen and Marburg, Marburg, Germany
  • 21The University of Texas MD Anderson Cancer Center, Houston
JAMA Oncol. 2021;7(4):603-608. doi:10.1001/jamaoncol.2020.7310
Key Points

Question  Does triple-negative breast cancer (TNBC) subtyping inform on chances of achieving a pathologic complete response (pCR) and on the potential benefits of adding carboplatin to standard neoadjuvant chemotherapy?

Findings  This prespecified secondary analysis of a randomized clinical trial of 634 patients with stages II to III TNBC found that in 482 women with evaluable RNA sequencing, basal-like and immunomodulatory subtypes were associated with higher pCR rates. After analyzing important biological processes related to these phenotypes, tumor cell proliferation and immune scores were identified as independent factors informing on chances of achieving pCR; TNBC subtyping was not informative for treatment decision.

Meaning  With further validation and long-term survival data, RNA-based proliferation and immune scores may inform the development of novel therapies for patients with TNBC.

Abstract

Importance  Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood.

Objective  To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC.

Design, Setting, and Participants  This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression–based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019.

Interventions  Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib.

Main Outcomes and Measures  Association of gene expression–based molecular subtype (PAM50 and TNBC subtypes) with pCR.

Results  Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin.

Conclusions and Relevance  In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC.

Trial Registration  ClinicalTrials.gov Identifier: NCT02032277

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