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.

Moment of truth-adding carboplatin to neoadjuvant/adjuvant chemotherapy in triple negative breast cancer improves overall survival: An individual participant data and trial-level Meta-analysis

“…A total of 863 studies were identified in the literature search, of which 23 studies were selected for full text review after screening the titles and abstracts. Of these, eight studies [ 8 , 9 , [15] , [16] , [17] , [18] , [23] , [24] , [25] , [26] , [27] , [28] , [29] ] fulfilled the eligibility criteria and were included for qualitative synthesis and meta-analysis, with a total of 2425 patients. ( Fig.…”

“…Disease progression under therapy was not considered as an event for DFS. 3 year DFS 85.8% vs 76.1%, HR 0.56 [95%CI 0.34–0.93]; p = 0.024 3 yr OS 91.9% vs 86.0%, HR 0.6, [95%CI 0.32–1.12], p = 0.109 84/158 (53·2%, 54·4–60·9) vs 58/157 (36·9%, 29·4–44·5) OR: 1·94 (1·24–3·04) p = 0.005 Sikov (2016, 2022) CALGB 40603 [ 9 , 29 ] EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause RFS in protocol From definitive surgery to first instance of ipsilateral invasive breast tumour recurrence, local/regional invasive breast cancer recurrence, distant recurrence, or death from any cause. Number of Participants who Died Due to Any Cause or had a recurrence.…”

Integration of multi-omics data shows downregulation of mismatch repair, purin, and tublin pathways in AR-negative triple-negative chemotherapy-resistant breast tumors

“…Survival association analysis for the selected biomarkers were independently investigated using the online tool Kaplan-Meier (KM) plotter 44 . In addition, 1) TCGA paired tumor and normal-adjacent TNBC samples 14 , 2) non-LAR vs. LAR TNBC gene expression cohorts 3) non-LAR gene expression cohorts with respect to pathologic complete response phenotype were also surveyed using publically available gene expression data 3,[45][46][47][48][49] .…”

Chemotherapy coupled to macrophage inhibition leads to enhanced T and B cell infiltration and durable triple negative breast cancer regression

“…To determine if there was any clinical correlation with these immune cell subsets, we derived a signature using differentially expressed genes (log Fc>0.03) from the T12 and T11 tams, which are included in Supplemental Table S1. We applied T12 TAM and T11 TAM signatures to two data obtained from stage II-III TNBC patients from the CALGB 40603 trial (35) and the SCAN-B dataset (36).The T12 TAM signature was significantly upregulated in human claudin-low tumors from TNBC patients, while the T11 TAM signature was not specifically associated with these human claudin-low tumors (Fig 7a, 7b, 7c, 7d). Additionally, high expression of the T12 TAM signature was associated with a decreased overall survival in TNBC patients from the SCAN-B dataset (Fig 7e).…”