Does Germline Variant Status Influence Treatment Outcome?

A primary analysis of data from the multicenter prospective randomized clinical GeparOcto trial, conducted between December 2014 and June 2016, showed no difference in pathologic complete response (pCR) among patients with early-stage breast cancer enrolled in 2 neoadjuvant treatment arms: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC; 451) and weekly paclitaxel and nonpegylated liposomal doxorubicin (Myocet) (PM; 463). In addition, patients with triple-negative breast cancer (TNBC) in the PM arm received carboplatin (PMCb) and all patients with ERBB2-positive disease got trastuzumab and pertuzumab.

Through a secondary analysis of GeparOcto data for patients screened between August 2017 and December 2018, and especially because “TNBC is associated with a hereditary cause,” the investigators from Germany sought to answer an additional question: Do germline BRCA1/2 (gBRCA1/2) status and BC predisposition genes influence treatment outcome? Their results were published yesterday in JAMA Oncology.

The 914 women recruited for this analysis were screened for variants in BRCA1/2 and 16 additional BC predisposition genes at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany. Their mean (range) age was 48 (21-76) years, and the treatment arms remained the same. There were 403 patients with TNBC, 382 with ERBB2-positive disease, and 160 with ERBB2-negative, hormone receptor—positive disease.

“Irrespective of the treatment arm and subtype, patients with gBRCA1/2 variants had higher pCR rates compared with patients without gBRCA1/2 variants,” the authors noted. “Variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response.”

The overall pCR rate was 60.4% in patients with BRCA1/2 variations compared with 46.7% in those without (odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01). Among this patient subgroup, patients with TNBC in both treatment arms were shown to have the highest pCR rates versus those without a BRCA1/2 variation:

• PMCb arm: 74.3% versus 47.0% (OR, 3.26; 95% CI, 1.44-7.39; P .005)
• iddEPC arm: 64.7% versus 45.0% (OR, 2.24; 95% CI, 1.04-4.84; P = .04)

Having BRCA1/2-positive status correlated, too, with a higher rate of pCR for patients who had ERBB2-negative, hormone receptor—positive disease: 31.8% versus 11.9% (OR, 3.44; 95% CI, 1.22-9.72; P = .02).

“We demonstrate that iddEPC appears to be also effective in these patients and may be considered in future prospective studies. The elevated pCR rate in gBRCA1/2-mutated ERBB2-negative, HR-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start,” the authors concluded.

Reference

Pohl-Rescigno E, Jauke J, Loibl S, et al. Association of germline variant status with therapy response in high-risk early-stage breast cancer: a secondary analysis of the GeparOcto randomized clinical trial [published online March 12, 2020]. JAMA Oncol. doi: 10.1001/jamaoncol.2020.0007.