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SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

ABSTRACT: SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

SUBMITTER: Nahleh ZA

PROVIDER: S-EPMC4963434 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

Nahleh Z A ZA Barlow W E WE Hayes D F DF Schott A F AF Gralow J R JR Sikov W M WM Perez E A EA Chennuru S S Mirshahidi H R HR Corso S W SW Lew D L DL Pusztai L L Livingston R B RB Hortobagyi G N GN

Breast cancer research and treatment 20160708 3

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) ...[more]

PMID: 27393622

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Project description:Background: We examined changes in the tumor immune microenvironment during neoadjuvant chemotherapy by comparing immune gene mRNA expression, tumor infiltrating lymphocyte (TIL) count and PD-L1 protein expression in pre- and post-treatment tissues. Methods: Paired pre- and post- treatment tumor samples from 60 patients were profiled using the Nanostring Immune Oncology 360 platform to measure the expression of 770 immune-related genes that also allowed us to test 14 immune cell type and 27 previously published prognostic and immuno therapy response predictive gene signatures. All samples were also assessed for TIL counts and PD-L1 protein expression by immunohistochemistry. Gene expression levels were compared by paired t-test with Bonferroni correction. TIL count, PD-L1 protein expression and immune gene signatures were compared using Wilcoxon signed-rank test. Baseline immune markers were correlated with pathologic complete response (pCR) using estrogen receptor (ER) and treatment adjusted logistic regression. Results: TIL counts were significantly lower in post- compared to pre-treatment samples (17% vs 7%, p=0.013) but stromal PD-L1 protein expression was not significantly different. At baseline, higher TIL count and PD-L1 expression were associated with pCR. High expression of a mast cell metagene was associated with residual disease (RD). No individual genes or VEGF gene signature were associated with benefit from bevacizumab. In patients with RD (n=31), genes involved with tissue repair and inflammation (DUSP1, EGR1, IL6, ATF3, CD36, CXCL2, CD69, NGFR, KLF2, THBD, DAB2) showed significantly higher expression after therapy while most other immune markers decreased. The T effector, T-reg, MHC-I, MHC-II, IFNgamma, STAT-1 and M1 macrophage gene signatures were all significantly lower in post- versus pre-treatment samples and only the IL8/VEGFR and T-helper gene signatures showed higher expression after therapy. Conclusions: High mast cell gene expression is associated with lower pCR rate. TIL counts and most immune parameters decrease after neoadjuvant chemotherapy.

Project description:PurposeOne third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab.Patients and methodsPatients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed.ResultsPatients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated.ConclusionIn stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

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Dataset Information

SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

Publications

SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

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