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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Metzger Filho reported research funding from AbbVie and personal compensation for consulting to AbbVie-sponsored advisory board outside of the submitted work. Dr Watson reported grants from Alliance Foundation Trials during the conduct of the study. Dr Loibl reported grants from AbbVie during the conduct of the study; grants from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics, Novartis, Pfizer, and Roche outside of the submitted work; and honorarium for lectures and advisory boards paid to the institution by AstraZeneca, Bristol Myers Squibb, Celgene, Chugai, Immunomedics, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, prIME/Medscape, Pierre Fabre, Puma, Roche, Samsung, and Seagen outside the submitted work. In addition, Dr Loibl reported having a patent to EP14153692.0 pending. Dr Geyer reported grants from AbbVie and the NSABP Foundation during the conduct of the study and grants from Genentech/Roche, NSABP Foundation, and AstraZeneca for NRG Oncology; travel and personal fees from Daiichi Sankyo and Exact Sciences; and personal and consulting fees from Athenex outside the submitted work. In addition, Dr Geyer reported serving without compensation on the advisory boards of Daiichi Sankyo and Exact Sciences. Dr O'Shaughnessy reported personal fees from AstraZeneca, Immunomedics, Lilly, Merck, Novartis, Pfizer, Roche, and Seattle Genetics outside the submitted work. Dr Untch reported personal fees paid to the institution by AbbVie, Agendia, Amgen, Celgene, Clovis, Daiichi Sankyo, Eisai, Lilly, Merck, Merck Sharp & Dohme, Molecular Health, Mundipharma, Myriad Genetics, Novartis, Pfizer, Pierre Fabre, Roche Pharma, and Sanofi Aventis outside the submitted work. Dr Rugo reported grants for clinical trial support to the UC Regents from Daiichi Sankyo, Immunomedics, Lilly, Macrogenics, Merck, Novartis, Odonate, Pfizer, Polyphor, Roche, Seattle Genetics, and Sermonix; consulting fees from Samsung; and honoraria from Puma outside the submitted work. Dr Huober reported personal fees from AstraZeneca, Celgene, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche; grants from Celgene, Hexal, and Novartis; and travel costs from Daiichi Sankyo, Pfizer, and Roche outside the submitted work. Dr Golshan reported personal fees from AbbVie during the conduct of the study. Dr Sikov reported travel costs from AbbVie during the conduct of the study, and patient payments for study participation paid to the institution by AbbVie outside the submitted work. Dr von Minckwitz reported equity in Cara GmbH. Dr Rastogi reported travel and lodging from AstraZeneca, Genentech/Roche, and Lilly outside the submitted work. Dr Denkert reported being founder and shareholder of Sividon Diagnostics (now Myriad); personal fees from Daiichi Sankyo, Merck Sharp & Dohme Oncology, Molecular Health, Novartis, and Roche; and grants from Myriad outside the submitted work. In addition, Dr Denkert reported having a patent to EP18209672 issued and a patent to EP20150702464 pending; and is involved in the development of VMScope digital pathology software. Dr Symmans reported being founder of Delphi Diagnostics and being a scientific advisor, shareholder, and having intellectual property in the company, as well as equity in IONIS Pharmaceuticals outside the submitted work. In addition, Dr Symmans reported having a patent issued for a method to measure residual cancer burden. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

Figure 2.. Expression-Based Subtypes, Proliferation, and Immune Signatures and Response to Neoadjuvant Chemotherapy

Treatment for arms A and B was paclitaxel followed by doxorubicin and cyclophosphamide (T-AC) plus carboplatin with or without veliparib, and for arm C was T-AC alone. A, Percent pathologic complete response (pCR) of basal-like vs nonbasal-like PAM50 subtypes; P value for interaction test of basal-like vs nonbasal-like with arm (A and B vs C) is nonsignificant (P = .80), as indicated. B, Error bars denote 95% CIs based on normal approximation. Number of individual subtypes was too small to warrant statistical comparison. Triple-negative breast cancer (TNBC) subtypes are denoted as BL1, basal-like 1; BL2, basal-like 2; IM, immunomodulatory; LAR, luminal androgen receptor; M, mesenchymal; MSL, mesenchymal stem–like; and UNS, unselected TNBC type. C and D, Proliferation signature was calculated from a subset of PAM50-related genes as part of PAM50 classification. GeparSixto immune signature was calculated as the median expression of 7 genes (CXCL9, CD8A, CCL5, CXCL13, CD21, FOXP3, CD80) positively associated with tumor-infiltrating lymphocytes in that trial. Distribution of tumors by proliferation signature score and immune signature score, with pCR and residual disease (RD) indicated for patients who received T-AC plus carboplatin and/or veliparib (arms A and B) or T-AC alone (arm C). Dashed lines indicate median for each signature score, and proportions of pCR for each quartile above/below median are indicated in each corner.