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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

Otto Metzger Filho, Daniel G Stover, Sarah Asad, Peter J Ansell, Mark Watson, Sibylle Loibl, Charles E Geyer, Junu Bae, Katharine Collier, Mathew Cherian, Joyce O'Shaughnessy, Michael Untch, Hope S Rugo, Jens Huober, Mehra Golshan, William M Sikov, Gunter Von Minckwitz, Priya Rastogi, David Maag, Norman Wolmark, Carsten Denkert & W Fraser Symmans

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.
   
citation Filho O M, Stover D G, Asad S, Ansell P J, Watson M, Loibl S, Geyer C E, Bae J, Collier K, Cherian M, O'Shaughnessy J, Untch M, Rugo H S, Huober J, Golshan M, Sikov W M, von Minckwitz G, Rastogi P, Maag D, Wolmark N, Denkert C, Symmans W F. 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. JAMA Oncol 2021; 7:603-608.
   
type journal paper/review (English)
date of publishing 01-4-2021
journal title JAMA Oncol (7/4)
ISSN electronic 2374-2445
pages 603-608
PubMed 33599688
DOI 10.1001/jamaoncol.2020.7310