pCR Not a surrogate for relapse-free survival in TNBC BRCA1/2 mutation carriers

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Carboplatin Associated with Better Outcomes than Docetaxel in Advanced BRCA1/2-mutation Breast Cance
Carboplatin Associated with Better Outcomes than Docetaxel in Advanced BRCA1/2-mutation Breast Cance

CHICAGO—In patients with triple-negative breast cancer (TNBC) who are BRCA1/2 mutation carriers, pathologic complete response (pCR) is not a surrogate for relapse-free survival, in contrast to those with non-BRCA mutations, the first study to demonstrate this difference concluded at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting. 

Although pCR has been demonstrated to serve as a surrogate for outcome in patients receiving neoadjuvant systemic therapy for TNBC, to date, no data have determined if this is also true for BRCA1/BRCA2 mutation carriers with TNBC, said Shani Paluch-Shimon, MD, of the Sheba Breast Collaborative Group, Tel-Hashomer, Israel. 

The study's objectives were to assess, in a cohort of patients with TNBC, if treatment response and/or outcome differed between patients with and without a BRCA mutation and if pCR is a surrogate for outcome among BRCA mutation carriers.

The investigators identified 80 cases of TNBC from a prospective database of 588 patients, 354 of whom had undergone BRCA1/2 genotyping. All had received neoadjuvant dose-dense chemotherapy with an anthracycline and a taxane. “Triple negative” was defined as HER2 0/+1 on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) less than 2.0 if IHC +2; estrogen and progesterone receptor negativity and 1% or fewer cells positive on IHC; pCR was defined as no residual invasive tumor in the breast and lymph nodes. 

Median follow-up was 44 months.

The found that overall survival for those with BRCA versus BRCA wild type was not statistically significant (P = 0.68). The BRCA1/2 carriers (n=37) had a pCR response of 67%, whereas for noncarriers (n=43), it was 37% (P = 0.007). However, despite this higher response rate, “there was no difference in relapse-free survival between the BRCA1/2 carriers and noncarriers,” she reported. All of the recurrences were locally advanced or distant.

Among those achieving pCR (n = 41), noncarriers had a superior relapse-free response compared with BRCA1/2 carriers (Log-rank P = .043). Conversely, for those who did not achieve a pCR (n = 39), relapse-free survival was superior among BRCA1/2 carriers (Log-rank P = .024).

No difference in relapse-free survival was noted among BRCA1/2 carriers with or without pCR (Log-rank P = .712), while in the noncarrier group, relapse-free survival was superior for those achieving pCR compared with those did not (Log-rank P < .0001).

“Preliminary translational data demonstrate ALDH1 over-expression in the BRCA1/2 carriers pretreatment biopsies but not in the noncarriers,” Paluch-Shimon said. “The chemosensitivity in BRCA-associated TNBC may increase the mutational spectrum in these tumors due to predisposition to DNA breaks, resulting in selection of more aggressive, metastases prone clones; in addition, BRCA1/2 tumors may be enriched for breast cancer stem cells.”

She concluded by noting that median survival is not yet reached; other caveats are the limited sample size, no central laboratory assessment of pathological specimens, and that genotyping was only performed for founder ethnic mutations.



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