CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer

Abstract

Purpose: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points.

Patients and methods: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing.

Results: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS.

Conclusion: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

FIG 1.

CONSORT diagram (Alliance CALGB 40603 trial). Bev, bevacizumab; Carbo, carboplatin; ddAC, dose-dense doxorubicin and cyclophosphamide; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ITT, intent-to-treat; NA, not available; PD, progressive disease; PgR, progesterone receptor; TNBC, triple-negative breast cancer; Tx, treatment; wP, weekly paclitaxel.

FIG 2.

Effect of the pretreatment clinical stage and response on EFS. (A) EFS in the mITT population. EFS stratified by (B) pCR versus RD, (C) pCR versus RD and stage, and (D) RCB. EFS, event-free survival; HR, hazard ratio; mITT, modified intent-to-treat; pCR, pathologic complete response; RCB, residual cancer burden; RD, residual disease.

FIG 3.

Effect of addition of bevacizumab and carboplatin to LTO in CALGB 40603. EFS stratified by (A and C) bevacizumab and (B and D) carboplatin treatment within the (A and B) mITT and (C and D) basal-like patient populations. pCR rate within the basal-like and non–basal-like subsets stratified by (E) bevacizumab and (F) carboplatin treatment. Bev, bevacizumab; Carbo, carboplatin; EFS, event-free survival; HR, hazard ratio; LTO, long-term outcome; mITT, modified intent-to-treat; pCR, pathologic complete response; RD, residual disease.

FIG 4.

Genomic correlates with response and survival in TNBC. (A) Clinical and genomic feature association with likelihood of pCR and EFS outcomes. Nonsignificant (P > .05) associations are given in gray, features associated with both pCR and EFS are given in red, features associated with just EFS are given in blue, and features associated with only pCR are given in light blue. A few selected significant features are labeled. (B) EFS Kaplan-Meier plots for patients with TNBC stratified by (left-to-right) TIL quantification (20% cutoff), NK_cells_MCP_PMID.31942075_PMID.31942077 signature tertiles, TCGA.BRCA.1198_IMMUNE1_JCI.2020_PMID.32573490 signature tertiles, and IgG evenness groups. (C) Features significantly associated with EFS in patients with residual disease (n = 191); negative log₂ HR indicates lower risk of event. (D) Correlation of TILs with immune effector and checkpoint signatures: (left-to-right, top-first) CD4+ memory T cells, CD8+ T cells, NK cells, PD-1 expression, IgG cluster, and IgG evenness. (E) Spearman correlation matrix for continuous TIL quantification and top 20 most correlated signatures, ordered by correlation with TILs. (F) Comparison of multivariable Cox proportional hazards models for EFS within the set of TNBC with TIL quantification (n = 178). Features that are significant in the multivariate Cox model are in blue bold text, HR and 95% CI, AIC. AIC, Akaike information criteria; EFS, event-free survival; HR, hazard ratio; IgG, immunoglobulin G; MCP, Microenvironment Cell Populations-counter; NK, natural killer; ns, not significant; pCR, pathologic complete response; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCGA, The Cancer Genome Atlas; TIL, tumor-infiltrating lymphocyte; TIL, tumor-infiltrating lymphocyte; TNBC, triple-negative breast cancer.