Talazoparib Toxicities Manageable in gBRCA-Mutated HER2-Negative Advanced Breast Cancer
April 20, 2020 04:00am
By Darcy Lewis
Despite evidence from previous studies that showed that platinum-based chemotherapy agents are active in patients with breast cancer, platinum-based chemotherapy was not found to be superior to standard chemotherapy in terms of eliciting pathologic complete responses in patients with HER2-negative breast cancer carrying a BRCA mutation, according to data from the INFORM trial published in the Journal of Clinical Oncology.
Nadine Tung, MD
Despite evidence from previous studies that showed that platinum-based chemotherapy agents are active in patients with breast cancer1, platinum-based chemotherapy was not found to be superior to standard chemotherapy in terms of eliciting pathologic complete responses (pCR) in patients with HER2-negative breast cancer carrying aBRCAmutation, according to data from the INFORM trial published in the Journal of Clinical Oncology.2
“Given the previously reported impressive activity of platinum agents inBRCA-associated breast cancer, these results were surprising,” said Nadine Tung, MD, director of the Cancer Risk and Prevention Program, head of Medical Oncology at Beth Israel Deaconess Medical Center and lead author of the INFORM trial, in a statement. “The INFORM trial underscores the importance of confirming results from single-arm trials with randomized trials.”
The patient population in the study included 118 individuals with a mean age of 42 years (range, 24-73), most of whom hadBRCA-mutated disease (69%) and T2 or T3 (75%). Nodal involvement was seen in almost half of the patients at baseline and 81% had clinical stage II or III disease. About 30% to 36% of patients had hormone receptor-positive, HER2-negative breast cancer. Ninety-two percent of cancers were invasive ductal, and 77% were high-grade. Between the platinum-based chemotherapy arm and the standard chemotherapy clinical and tumor, characteristics were similar.3
A total of 117 patients were evaluable for response and toxicity, and of those patients, 60 received a platinum chemotherapy of single-agent cisplatin and 57 received a standard chemotherapy combination of doxorubicin plus cyclophosphamide. The pCR rate observed in the platinum group was 18% compared with 26% in the standard group (risk ratio [RR] 0.70; 90% CI, 0.39-1.2). A 10% cutoff was used to determine the pCR rate among patients with triple-negative breast cancer. In patients with triple-negative breast cancer (TNBC), the RR observed for the platinum group versus the standard group was (0.30; 90% CI, 0.05-1.7).
The investigators also assessed pCR among patients who had nodal involvement at the time of their sentinel lymph node biopsy (SLNB). There was 1 patient with a positive preoperative node at SLNB who had a significant residual disease in the breast following chemotherapy at the time of definitive surgery.
In terms of residual cancer burden scores (RCB), patients who were treated with platinum had a 33% RCB 0/1 compared with 46% among patient who were given standard chemotherapy. Patients with TNBC who received platinum had an RCB 0/1 of 36% and the standard group had an RCB 0/1 of 47%. In patients with ER-positive, HER2-negative breast cancer, the rate of RCB 0/1 was 25% in the platinum group and 42% in the standard group. For 11 patients, the RCB score could not be assigned because they received fewer than 4 cycles of chemotherapy as required based on the study protocol, however, these patients were evaluated as having RCB > 1.
The presence of tumor mutation did affect response. Patients who were treated with platinum-based chemotherapy had a lower pCR rate than patients who were treated with standard chemotherapy. Additionally, participants who were BRCA carriers who were diagnosed prior to age 40 and those with large T size, nodal involvement, ER or progesterone receptor expression, lower histologic grade or less lymphocytic infiltration had a lower pathologic response to neoadjuvant chemotherapy.
In terms of treatment delivery, at least one dose reduction occurred in 5% of patients in the platinum arm and 2% of those in the standard arm. In the platinum and standard arm respectively, at least one dose delay was experienced in 10% and 9% of patients. In the standard group, 89% of patients were treated on a 2-week schedule. Across arms, 93% of patients who received platinum and 35% of patients who received standard chemotherapy received growth factor support.
Five patients received fewer than 4 cycles of chemotherapy either because of toxicity or due to insufficient response to treatment, and 7 patients received additional chemotherapy before surgery. Additional presurgery chemotherapy was administered to 1 of the 5 patients who received fewer than 4 cycles of chemotherapy and was counted among the 7 patients. Residual cancer was demonstrated for 4 out of 7 patients with 3 patients not demonstrated. The 11 patients who did not receive the number of cycles required by protocol were evaluated as not attaining a pCR or RBC 1.
The toxicity profile showed that few grade 3 or higher adverse events (AEs) occurred in either arm. Of the 60 patients who received platinum-based chemotherapy, 11 experienced hematologic grade ≥ 3 AEs, which were nausea/vomiting (n = 3), increased creatinine (n = 2), thromboembolic event (n = 2), fatigue (n = 1) tinnitus (n = 1), pulmonary hypertension (n = 1), and hyperglycemia (n = 1). Of the 57 patients who received standard chemotherapy, 4 experienced nonhematologic grade ≥ 3 AEs, which included fatigue (n = 1), nausea (n = 1), diarrhea (n = 1), and headache (n = 1).
Patients in both the platinum arm and the standard arm experienced grade 3/4 neutropenia (7% and 5%), and 3% of those in the platinum arm as well as 10% of those in the standard arm had at least 1 episode of febrile neutropenia. Grade 1 alopecia was observed in 7% of the patients in the platinum group but could not be assessed among patients in the standard group due to expected chemotherapy-related hair loss. Nausea and vomiting occurred more frequently in patients who were treated with platinum-based chemotherapy and myelosuppression was more common among those who were treated with standard chemotherapy.
Patients in the INFORM trial were randomized 1:1 to receive either cisplatin 75 mg/m2intravenously (IV) for 4 cycles or to doxorubicin-cyclophosphamide (AC) 60 mg/m2IV and cyclophosphamide 600 mg/m2IV for 4 cycles every 2 (dose-dense [dd]) or 3 weeks. Randomization was stratified by ER status and by treatment site. Patients with TNBC followed a mandatory dd schedule and growth factor was mandatory for patients who received dd standard chemotherapy, but was optional for other patients. Before starting chemotherapy all patients required tumor biopsies.
Following 4 cycles of chemotherapy as indicated in the protocol, patients underwent definitive breast surgery.
To be eligible for INFORM, individuals required a pathologic confirmation of invasive breast cancer that was HER2-negative and known ER/PR status. Patients were also required to have a life expectancy of six months or more.
Although these study data differ from previously reported data on the activity of platinum-based chemotherapy in patients withBRCA-associated breast cancer, Tung noted that the INFORM trial does not discount prior research.2
In a statement, Tung said “We demonstrated that both regimens can be effective and treatment choice may need to incorporate an individual’s other health concerns and anticipated side effects with each regimen,” Tung said.