Peter A. Fasching, MD
In an analysis from the GeparQuinto trial reported in the Journal of Clinical Oncology, Peter A. Fasching, MD, of Erlangen University Hospital, Comprehensive Cancer Center Erlangen-EMN, and colleagues found that the addition of bevacizumab (Avastin) to neoadjuvant chemotherapy increased the likelihood of pathologic complete response in patients with BRCA1/2-mutant triple-negative breast cancer.1 However, pathologic complete response was not significantly predictive of improved disease-free survival in BRCA1/2-mutation carriers.
In the GeparQuinto trial, 1,948 HER2-negative patients were enrolled to test the efficacy of adding bevacizumab to neoadjuvant chemotherapy. Treatment of these HER2-negative patients consisted of epirubicin and cyclophosphamide on day 1 and every 3 weeks, for a total of 4 cycles, followed by docetaxel on day 1 and every 3 weeks, for a total of 4 cycles. Patients were randomized to receive either bevacizumab from the beginning of chemotherapy until surgery or no additional treatment.
The current analysis included outcomes in patients from the GeparQuinto trial with triple-negative breast cancer in the HER2-negative arm (n = 663); among them, 493 patients who received anthracycline and taxane-containing neoadjuvant therapy with (n = 233) or without (n = 260) bevacizumab underwent successful germline DNA sequencing. BRCA1/2 mutations were detected in 90 patients (18.3%), including BRCA1 mutations in 74 and BRCA2 mutations in 16 (none with both mutations); among these patients, 49% received bevacizumab and 57% received chemotherapy alone.
Pathologic Complete Response and Disease-Free Survival
Among all patients, pathologic complete response rate was 50% in patients with BRCA1/2 mutations vs 31.5% in patients without mutations (odds ratio [OR] = 2.17, P = .001). Pathologic complete response rates were 48.6% among BRCA1-mutation carriers (overall response [OR] = 1.97, P = .008, vs wild-type) and 56.3% among BRCA2-mutation carriers (OR = 2.48, P = .106, vs wild-type).
Among patients receiving bevacizumab, pathologic complete response rate was 61.5% among 39 patients with BRCA1/2 mutations vs 35.6% among 194 patients without mutations (OR = 2.90, P = .004). Among patients receiving chemotherapy alone, pathologic complete response rates were 41.2% among 51 patients with mutations and 27.8% among 212 patients without mutations (OR = 1.82, P = .088).
Additional studies and analyses need to be conducted to clarify the population in which BRCA1/2 mutation status uncouples [pathologic complete response] from a favorable prognosis.— Peter A. Fasching, MD, and colleagues
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Disease-free survival was better in patients with vs without BRCA1/2 mutations (hazard ratio [HR] = 0.644, P = .047). Among patients without BRCA1/2 mutations, pathologic complete response was a significant predictor of improved disease-free survival (HR = 0.18, P < .001). However, among patients without mutations, pathologic complete response was not associated with a significant improvement in disease-free survival (HR = 0.74, P = .472). Hazard ratios for disease-free survival for bevacizumab treatment vs chemotherapy alone were 1.39 (95% confidence interval [CI] = 0.61–3.15) in patients with BRCA1/2 mutations and 1.02 (95% CI = 0.74–1.40) in those without mutations.
The investigators concluded: “The addition of bevacizumab may increase the [pathologic complete response] after standard neoadjuvant chemotherapy for patients with triple-negative breast cancer with BRCA1/2 mutations. In patients treated with anthracycline and taxane-based chemotherapy (with or without bevacizumab), the [pathologic complete response] was a weaker predictor of disease-free survival for BRCA1/2 mutation carriers than for patients without mutations.”
They noted: “This study is the largest so far that has examined the effect of BRCA1/2 mutations in the neoadjuvant treatment of triple-negative breast cancer. [Pathologic complete response] rates are clearly higher in patients with BRCA1/2 mutations. High pathologic complete response rates in patients treated with chemotherapy and bevacizumab imply a role of antiangiogenic-induced hypoxia in the synthetic lethality of tumor cells with BRCA1/2 mutations. In this study, with standard treatment with anthracyclines, cyclophosphamide, and taxanes (with or without bevacizumab), the data suggest that BRCA1/2 mutation carriers do not benefit as much from a [pathologic complete response] in comparison with patients with a BRCA1/2 wild-type genotype. Additional studies and analyses need to be conducted to clarify the population in which BRCA1/2 mutation status uncouples [pathologic complete response] from a favorable prognosis.”
The GeparQuinto Clinical Trial was a collaborative project of the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie Breast Study Group. The presented work was a collaboration between those study groups and the Mayo Clinic, Rochester, Minnesota. ■
DISCLOSURE: The study was supported by a National Cancer Institute Specialized Program of Research Excellence grant in breast cancer to the Mayo Clinic, a National Institutes of Health grant, and the Breast Cancer Research Foundation. For full disclosures of the study authors, visit JCO.org.
1. Fasching PA, Loibl S, Hu C, et al: BRCA1/2 mutations and bevacizumab in the neoadjuvant treatment of breast cancer: Response and prognosis results in patients with triple-negative breast cancer from the GeparQuinto study. J Clin Oncol 36:2281-2287, 2018.
The treatment of triple-negative breast cancer remains a clinical challenge with no single validated target, though numerous pathways are druggable and are being investigated. In the subset of BRCA-mutated triple-negative breast cancer, the approval of the first poly (ADP-ribose) polymerase (PARP)...