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
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.
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.
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.
ClinicalTrials.gov Identifier: NCT02032277.