Phase II Trial of Neoadjuvant Carboplatin and Nab-Paclitaxel in Patients with Triple-Negative Breast Cancer

Abstract

Background: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).

Patients and methods: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m² ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).

Results: Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively.

Conclusion: The combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.

Keywords: Carboplatin; Nab-paclitaxel; Neoadjuvant; Triple-negative breast cancer.

Figure 1

Kaplan‐Meier survival curves (n = 67): Survival analysis showed 3‐year DFS of 87.3% (95% CI, 74.9%–93.8%; n = 67, events = 9) (A), 3‐year OS of 90.2% (95% CI, 77.8%–95.8%; n = 67, events = 6) (B), and for the 35 patients with residual disease, 3‐year DFS of 79.0% (95% CI, 58.5%–90.2%; n = 35, events = 8) (C).Abbreviations: CI, confidence interval; DFS, disease‐free survival; NR, not reached; OS, overall survival.

Figure 2

Association of GeparSixto immune signature with triple‐negative breast cancer molecular subtype, pCR status, and biomarkers (n = 63). Of 67 patients enrolled, 63 pretreatment tumor specimens were available for analysis. Hierarchical clustering of 12 immunologically relevant genes in 63 tumors showed two distinct immune groups with different expression levels, including immune‐cold tumors with low expression of immune genes, and immune‐hot tumors with high expression of immune genes. Gray blocks on DRD, BRCA, and TILs indicate no results (not analyzed because of limited specimen availability).Abbreviations: BL1, basal‐like 1; BL2, basal‐like 2; DRD, DNA repair defect; IM, immunomodulatory; LAR, luminal androgen receptor; M, mesenchymal; MSL, mesenchymal stem‐like; MUT, mutation; pCR, pathological complete response; TIL, tumor‐infiltrating lymphocyte; UNS, unspecified, WT, wild type.