Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

Abstract

IMPORTANCE The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome.OBJECTIVE To determine treatment outcome for BC according to germline variant status. DESIGN, SETTING, AND PARTICIPANTSThis retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018.MAIN OUTCOMES AND MEASURES Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. RESULTSIn the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02). CONCLUSIONS AND RELEVANCEEffective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.

Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes

“…Another chemotherapeutic drugs that have biological background for efficacy in BRCA mutated tumors are topo-isomerase II inhibitors like anthracyclines 31,32 . Sensitivity to anthracylines and alkylating agents in BRCA carriers with breast cancer are emphasized by recent reports from INFORM and GeparOcto clinical trials 15,23 .…”

“…Currently, there are conflicting data regarding the predictive and prognostic values of BRCA mutations on the survival of non-metastatic breast cancer patients [6][7][8] . BRCA carriers with TNBC have been shown to be more sensitive to DNA-damaging agents [9][10][11][12][13][14][15] but this did not translate into a survival benefit 6,9,12,16,17 .…”

Update Mammakarzinom 2020 Teil 4 – fortgeschrittenes Mammakarzinom

“…10 % der Fälle bei TNBC und in ca. 4-5 % bei HER2-negativen HR-positiven Patientinnen der Fall ist [18][19][20][21][22]. Für Veliparib, das mit einer Chemotherapie in fast regulärer Dosis kombiniert werden kann, konnte nachgewiesen werden, dass seine Hinzunahme zu einer Chemotherapie mit Carboplatin und Paclitaxel die Prognose von Patientinnen mit HER2-negativem, fortgeschrittenem Mammakarzinom verbessern kann, wenn eine BRCA1/2-Mutation der Keimbahn nachgewiesen worden war [23] (BROCADE-Studie).…”

Update Breast Cancer 2020 Part 4 – Advanced Breast Cancer

“…10% of cases of TNBC and in ca. 4 – 5% of HER2-negative HR-positive patients 18 , 19 , 20 , 21 , 22 . For veliparib, which can be combined with chemotherapy in a nearly regular dose, it was shown that the addition of veliparib to chemotherapy with carboplatin and paclitaxel can improve the prognosis of patients with HER2-negative advanced breast cancer if a BRCA1/2 germline mutation had been found 23 (BROCADE study).…”

“…10% der Fälle bei TNBC und in ca. 4 – 5% bei HER2-negativen HR-positiven Patientinnen der Fall ist 18 , 19 , 20 , 21 , 22 . Für Veliparib, das mit einer Chemotherapie in fast regulärer Dosis kombiniert werden kann, konnte nachgewiesen werden, dass die Hinzunahme von Veliparib zu einer Chemotherapie mit Carboplatin und Paclitaxel die Prognose von Patientinnen mit HER2-negativem, fortgeschrittenem Mammakarzinom verbessern kann, wenn eine BRCA1/2-Mutation der Keimbahn nachgewiesen worden war 23 (BROCADE-Studie).…”