Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer

Abstract

IntroductionThe purpose of this investigation was to evaluate the efficacy of cisplatin chemotherapy in BRCA1 mutation carriers with metastatic breast cancer.MethodsIn a phase II, open-label study, 20 patients with metastatic breast cancer who carried a mutation in BRCA1 were treated with cisplatin 75 mg/m2 intravenously every 3 weeks as part of a 21-day cycle for 6 cycles. Restaging studies to assess response were performed after cycles 2 and 6, and every three months thereafter.ResultsBetween July 2007 and January 2009, 20 patients were enrolled. Baseline characteristics were as follows: 65% had prior adjuvant chemotherapy, 55% had prior chemotherapy for metastatic breast cancer; mean age was 48 years (ranges 32 to 70); 30% estrogen receptor (ER) or progesterone receptor (PR)+, 70% ER/PR/Human Epidermal Growth Factor Receptor 2 (HER2)- and 0% HER2+. Overall response rate was 80%; nine patients experienced a complete clinical response (45%) and seven experienced a partial response (35%). Overall survival was 80% at one year, 60% at two years and 25% at three years. Four of the 20 patients are alive four years after initiating treatment. The median time to progression was 12 months. The median survival from the start of cisplatinum treatment was 30 months. Cisplatin-related adverse events, including nausea (50%), anemia (5%) and neutropenia (35%) were mostly mild to moderate in severity.ConclusionsThis phase II study demonstrates that cisplatin chemotherapy has high activity in women with a BRCA1 mutation and metastatic breast cancer and is generally well tolerated.Trial registrationThis trial is registered retrospectively on the clinical trials website ClinicalTrials.gov. The identifier is NCT01611727.

Have We Given up on a Cure for Ovarian Cancer?

“…How is it that the information from other laboratories is good enough to be used to decide on the use of other drugs, such as platinum agents-or to decide whether a woman should remove her breasts-but is not good enough to support a decision to give olaparib? At the 2014 San Antonio Breast Cancer Symposium, Dr. Andrew Tutt presented data (which extend our group's previous report from Poland 10 ) showing that carboplatin is a better drug than doxorubicin for the treatment of metastatic breast cancer in BRCA carriers 11 . Will Myriad claim that carboplatin can be given only if the genetic test is BRAC Analysis cdx?…”

ATM Mutations in Cancer: Therapeutic Implications

“…This has been demonstrated in the context of BRCA1-or BRCA2-mutated cancer, particularly breast and ovarian cancer. Cisplatin chemotherapy had a high response rate in patients with BRCA1 mutations and breast cancer, both in the metastatic and neoadjuvant settings (3,66). This principle also has been extended to other mutations that affect double-strand DNA repair.…”

“…Cancers with mutations in genes encoding proteins involved in DNA repair may be more sensitive to treatments that induce synthetic lethality by inducing DNA damage or inhibiting complementary DNA repair mechanisms. For example, BRCA1-mutated tumors may be sensitive to platinum therapy; indeed, 80% response rates, including 45% complete responses in BRCA1-mutated breast cancer, have been reported with cisplatin (3). Interrupting DNA damage repair with mitomycin C also may also be effective; a patient with PALB2-(a partner and localizer of BRCA2) mutated pancreatic cancer achieved a 36þ-month response on mitomycin C therapy (4).…”

Mainstreaming genetic testing of cancer predisposition genes

“…For example, platinum-based therapies are not standard treatment for breast cancer but can have utility in BRCA1/2 carriers, who are particularly sensitive to platinum-based drugs. 8,9 Newer, personalised therapies that either target the CPG mutation directly or pathways that become vulnerable because of the CPG mutation, are increasingly being developed. For example, some gastrointestinal tumours result from germline gain-offunction mutations in KIT or PDGFRA that could be inhibited by imantinib.…”