Platinum-based Chemotherapy In Triple-negative Breast Cancer Research Articles

BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

Abstract P1-15-05: Is absolute lymphocyte count associated with platinum-sensitivity? A phase II single arm study evaluating the efficacy of neoadjuvant carboplatin and docetaxel in triple negative breast cancer

Abstract Background: Platinum-based chemotherapy is still considered investigational for the treatment of sporadic triple negative breast cancer (TNBC). Since patients with TNBC have a high rate of chemotherapy resistance, it is critical to identify platinum-sensitive individuals prior to initiating therapy. Higher absolute lymphocyte count (ALC) is associated with improved clinical response to anthracycline-based chemotherapy, the current standard of care in TNBC. We report the initial results of a phase II single arm study evaluating the efficacy of neoadjuvant carboplatin and docetaxel in TNBC. We also report results of an exploratory analysis assessing whether ALC can be used to predict pathologic complete response (pCR) after treatment with platinum-based chemotherapy. Patients and Methods: 78 patients with clinical stage II or III TNBC have been enrolled in this ongoing study evaluating the efficacy of neoadjuvant carboplatin and docetaxel (NCT201404107). Patients received docetaxel 75 mg/m2 and carboplatin AUC 6 every three weeks for a total of 6 cycles. Blood samples were collected prior to each cycle, and a posttreatment sample was collected > 3 weeks after completing cycle 6. pCR was defined as no residual invasive disease in the breast, with or without ductal carcinoma in situ, and no tumor deposits in sampled lymph nodes. Baseline characteristics of patients were summarized with descriptive statistics. Univariate and multivariate logistic regression analyses were used to identify factors associated with pCR. Results: Out of the 78 enrolled patients, 60 have completed all 6 treatment cycles and surgery. The preliminary pCR rate is 46.7%. Age, race, clinical stage, and tumor grade determined at time of diagnosis were not significantly different between pCR patients and non-pCR patients. In univariate analyses, patients with higher ALCs at the posttreatment time point were more likely to have pCR than those who had lower ALCs (OR 5.5, 95% CI 1.5-20.7, p=0.011). Additionally, patients who had higher minimum ALCs were also more likely to have pCR (OR 9.1, 95% CI 1.5-54.9, p=0.016). Baseline ALC values were not associated with pCR. The associations of posttreatment and minimum ALCs to pCR remained statistically significant even after controlling for age and clinical stage at time of diagnosis (posttreatment ALC OR 7.6, 95% CI 1.7-34.8, p=0.009; minimum ALC OR 9.0, 95% CI 1.5-55.2, p=0.018). Conclusion: The pCR rate of our cohort is similar to that of other trials evaluating neoadjuvant platinum-based chemotherapy in TNBC. Baseline ALC did not predict which patients would achieve pCR. However, the associations of posttreatment and minimum ALCs with pCR indicate patients who are able to maintain a robust population of circulating lymphocytes throughout treatment with platinum-based chemotherapy are more likely to respond favorably. The link between patient immunity and platinum-based chemotherapy suggests addition of immunotherapy agents to neoadjuvant chemotherapy may improve patient outcomes. Citation Format: Chen I, Guo F, Summa T, Luo J, Ellis MJ, Ma CX, Weilbaecher KN, Naughton MJ, Suresh R, Peterson LL, Cherian MA, Bose R, Frith AE, Hernandez-Aya LF, Gillanders WE, Ademuyiwa FO. Is absolute lymphocyte count associated with platinum-sensitivity? A phase II single arm study evaluating the efficacy of neoadjuvant carboplatin and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-05.

P5-19-14: Platinum-Based Chemotherapy in Triple-Negative Breast Cancer.

Abstract Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center and the Ottawa Hospital Cancer Centre. This cohort was compared to a control group that included metastatic TNBC treated with conventional agents that included anthracyclines, taxanes, capecitabine, and vinorelbine. Results: A total of 166 metastatic TNBC patients were analyzed: 60 treated with PBC and 106 managed with conventional treatment. Median age at diagnosis was 48 years and distant disease-free interval was 26 months (m) for both groups. Patients on both groups had multiple sites of metastases at diagnosis of recurrence than a single site of metastasis (69% for both groups). Of the 60 patients treated with PBC, 90% received a combination regimen, most commonly weekly cisplatin plus gemcitabine in 37% of patients and cisplatin plus vinorelbine in 17% of patients. The median number of cycles delivered was 4 (1-24). 33% received the PBC as first-line treatment, 38% as second-line, 18% as third-line, 7% as fourth line, and 3% as fifth-line. Only 8 patients (5%) discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group compared to the conventional group (5 vs. 2 m, p=0.108; 5 vs. 2 m, p=0.01; and 4 vs. 1 m, p=0.026). Patients treated with PBC had a longer OS compared to those managed conventionally (16 vs. 10 m, p=0.039). Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm its benefit in order to integrate it as part of the routine management of these patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-14.

Platinum-based chemotherapy in triple-negative breast cancer.

1090 Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center. A case-control study was designed, with 3 controls per case matched by age, comprising metastatic TNBC treated with conventional agents. Results: A total of 116 patients were analyzed: 29 treated with PBC and 87 managed with conventional treatment. Median age at diagnosis was 47 years and distant disease-free interval was 27 months (m) for both groups. Patients treated with PBC had more sites of disease (100% vs. 70%, p<0.0001) and a worse performance status (ECOG 2 21% vs. 6%, p=0.034), respectively. Of the 29 patients treated with PBC, 79% received a combination regimen, most commonly weekly cisplatin and gemcitabine in 62% of patients. The median number of cycles delivered was 4 (2-11). 31% received PBC as first-line treatment, 35% as second-line, 28% as third-line and 7% as fifth-line. Only 2 patients discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group (5 vs. 2 m, p=0.225; 3 vs. 2 m, p=0.063; and 4 vs. 1 m, p=0.009). Patients treated with PBC had a longer OS compared to those managed conventionally (18 vs. 13 m, p=0.025). Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm this benefit.