Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer

Abstract

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 PARTICIPANTSThis 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. RESULTSOf 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 RELEVANCEIn 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-...

Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics

“…Unfortunately, no clinical trial data are available using volasertib in combination with chemotherapy in TNBC patients. Nonetheless, by analyzing the recently published BrighTNess phase 3 neoadjuvant clinical trial in which carboplatin was added to standard neoadjuvant chemotherapy for TNBC patients (48), we observed a negative correlation between PLK1 and PLK2 expression in those patients whose tumors achieved a pathological complete response as compared to those with residual disease (Supplemental Figure S12). This provides additional support for the potential clinical relevance of PLK2 loss and carboplatin response.…”

Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions

“…The most predictive transcripts were PD-L1 and CCL5. Subsequent studies confirmed the predictive value of immunophenotyping and TILs, suggesting a role of the immune system in clearing tumor cells during chemotherapy [92]. Another gene signature consisting of HLF, CXCL13, SULT1E1, and GBP1 in pre-treatment samples predicted the extent of lymphocytic infiltration after NACT [93].…”

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study

“…New technologies such as multiplex immunofluorescent profiling of the immune microenvironment and whole transcriptome RNA sequencing may also aid the future fine-tuning of sTILs as a predictive marker for pCR. Immunomodulatory mRNA signatures and the PAM50 basal-like profile are associated with significantly higher pCR rates in TNBC [ 42 ]. Immune-associated mRNA signatures were associated with pCR after NAC in the GeparNuevo trial, although they were of limited use to predict the response to additional immune-checkpoint blockade by durvalumab [ 43 ].…”