Abstract
This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and ≥1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy ± carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (BRCA1 + n = 10; BRCA2 + n = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25–55) and clinical stage included I (n = 2), II (n = 9), and III (n = 2). Most tumors (n = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30–98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4–6 months of single-agent talazoparib.
Highlights
The BRCA genes were first described in families with breast and ovarian cancers through genetic linkage analysis.[1,2,3] A metaanalysis of 10 studies estimated the lifetime risk of breast cancer in BRCA1 carriers to be ~47–66 and 40–57% in BRCA2 carriers
The ovarian cancer risk was estimated at 35–46% in BRCA1 carriers and 13–23% in BRCA2 carriers.[4]
The trial was subsequently amended to allow for longer single-agent treatment of talazoparib prior to surgery to assess pathologic response
Summary
The BRCA genes were first described in families with breast and ovarian cancers through genetic linkage analysis.[1,2,3] A metaanalysis of 10 studies estimated the lifetime risk of breast cancer in BRCA1 carriers to be ~47–66 and 40–57% in BRCA2 carriers. The ovarian cancer risk was estimated at 35–46% in BRCA1 carriers and 13–23% in BRCA2 carriers.[4] Other studies have estimated these risks to be even higher.[5] Given these risks, targeting BRCA pathogenic mutations in breast cancer patients is an attractive strategy for systemic therapy. A previous analysis from The University of Texas MD Anderson Cancer Center evaluated response to NAC in women with a known BRCA mutation.[6] Of the BRCA1 carriers, 26/57 (46%) achieved a pathologic complete response (pCR). Both BRCA1 and triple receptor-negative breast cancer (TNBC) were independent predictors of pCR. In this reported cohort, >80% of the patients received an anthracycline and taxane-based therapy. Sikov et al described an increase in pCR from 41 to 54% in patients with TNBC, unselected for BRCA status, with the addition of carboplatin to standard anthracycline and taxane-based chemotherapy.[8]
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