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 non-anthracycline 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 (AUC 6) every 28 days x 4 plus nab-paclitaxel (100 mg/m 2) 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 (AEs), 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 32/67 (48%) pCR (RCB 0), 10/67 (15%) RCB I, 19/67 (28%) RCB II, 5/67 (7%) RCB III, and 1/67 (2%) progressed and had no surgery. Univariate analysis showed GSIS "immune-hot" and DNA repair defect (DRD) were associated with higher pCR with odds ratio of 4.62 (P=0.005) and 4.76 (P=0.03) respectively, and with RCB 0/I vs. RCB II/III with odds ratio 4.80 (P=0.01). "Immune-hot" GSIS was highly correlated with DRD status (P=0.03), TILs level (P<0.001), and TNBC molecular subtype (P<0.001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I vs. II/III with odds ratio 7.19 (95% CI 2.01-25.68, P=0.002) and 8.95 (95%. CI 2.09-38.23, P=0.003), respectively. Conclusions. The combination of carboplatin and nabpaclitaxel for early stage high risk TNBC showed manageable toxicity and encouraging anti-tumor activity. GSIS "immune-hot" signature is associated with higher pCR rate and RCB class 0/1. This study provides additional rationale for using non-anthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. The Oncologist 2020;9999:• • 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 were associated with higher pCR and residual cancer burden class 0/1. The association of GSIS "immune-hot" signature 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.

Automated Quantification of sTIL Density with H&E-Based Digital Image Analysis Has Prognostic Potential in Triple-Negative Breast Cancers

“…Three pathologists (ES, AR, and EB) evaluated 204 cases, and the remaining cases were evaluated by a single pathologist (ES) with a consensus reached with the other two pathologists in difficult cases. We used the manual sTIL status as a continuous variable when possible and with a cutpoint of >10% [ 21 , 39 , 40 , 41 ].…”

Approaching Neoadjuvant Therapy in the Management of Early-Stage Breast Cancer

“…In BrighTNess, the addition of carboplatin increased the pCR rate in BRCAwildtype patients from 29 to 59%, versus an increase from 41 to 50% in BRCA carriers. 51 Additionally, in GeparSixto, there was an absolute improvement in DFS at 35 months with the addition of carboplatin, which was greater in BRCA-wildtype patients (85 versus 74%; HR 0.53; 95% CI 0.29-0.96), versus in BRCA-mutated patients (86 versus 82%). 53,54 Although the addition of platinum to a NACT regimen leads to higher pCR rates, the associated toxicities often necessitating dose reductions or cycle eliminations and the contradictory longterm survival results make it a controversial choice.…”

“…In contrast, the GeparSixto trial demonstrated that the addition of carboplatin significantly improved pCR (53% vs 43%, p=0.005) which resulted in higher rates of 3-year EFS (86% vs 76%, HR of 0.60, 95% CI 0.34-0.93). 51 In the BrighTNess study, patients with stage II to III TNBC were randomized to weekly paclitaxel with or without carboplatin and veliparib (an oral PARP inhibitor) followed by doxorubicin and cyclophosphamide. The addition of carboplatin improved the pCR rate from 31% to 58% while the addition of veliparib had no effect on pCR rates.…”

Refining patient selection for breast cancer immunotherapy: beyond PD-L1

“…Figure1. An overview of the main biomarkers for immunotherapy in breast cancer 18. F-FDG,18 F-fluorodeoxyglucose; HRD, homologous recombination deficiency; LDH, lactate dehydrogenase; MMR, mismatch repair; NLR, neutrophil-to-lymphocyte ratio; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PET, positron emission tomography; PLR, platelet-to-lymphocyte ratio; TILs, tumour infiltrating lymphocytes; TLSs, tertiary lymphoid structures; TMB, tumour mutational burden.…”

“…CyTOF, cytometry by time of flight; F-FDG,18 F-fluorodeoxyglucose; H&E, haematoxylin and eosin; HRD, homologous recombination deficiency; ICIs, immune checkpoint inhibitors; IF, immunofluorescence; IHC, immunohistochemistry; LDH, lactate dehydrogenase; MSI/dMMR, microsatellite instability/mismatch repair deficiency; NLR, neutrophil-tolymphocyte ratio; OS, overall survival; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PET, positron emission tomography; PFS, progression free survival; PLR, platelet-to-lymphocyte ratio; POLE, polymerase epsilon; TILs, tumour-infiltrating lymphocytes; TLS, tertiary lymphoid structure; TMB, tumour mutational burden; TME, tumour microenvironment.…”