Introduction
Among women with a
BRCA1 mutation and breast cancer, choice of chemotherapy is a critical issue. There are emerging data which suggest that mutation carriers may respond differently than non-carriers to particular agents [
1‐
3].
BRCA1-associated cancers differ from non-hereditary cancers for a range of pathologic and molecular factors, including tumor grade and histologic appearance [
4‐
7]. Several studies have shown that the response to treatment for women with a
BRCA1-associated breast cancer reflects the underlying tumor biology, in particular, the impairment of the DNA damage response and repair pathways, and that it is possible to exploit the sensitivity of
BRCA1-associated cancers to DNA damage [
8,
9].
This study was performed as a component of a large, multi-center research program conducted in Poland at the Pomeranian Medical University, which is designed to characterize the hereditary burden of breast cancer in the country and to identify and evaluate means of prevention, screening and treatment for women with
BRCA1 mutations. There are three
BRCA1 founder mutations in Poland (5382insC, C61G and 4153delA), which account for the great majority of all
BRCA1 mutations in Polish families [
10‐
12].
We have previously reported, in a small study of
BRCA1-positive women with early breast cancer, that a high rate of complete pathologic response was achieved using cisplatin chemotherapy as a single agent in the neo-adjuvant setting [
13]. It is equally important that we evaluate the benefit of cisplatin in women with disseminated breast cancer, including those who have previously been treated with one or more chemotherapy regimens. This study was undertaken to evaluate the efficacy of cisplatin chemotherapy in
BRCA1 carriers with metastatic breast cancer. The primary objective was to determine the objective response rate of cisplatin in
BRCA1 carriers with metastatic breast cancer. The secondary objectives were to determine three-year survival and to evaluate the toxicities of cisplatin in
BRCA1 carriers with metastatic breast cancer.
Materials and methods
Patient eligibility
Female patients age ≥18 years, with measurable (defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria [
14]) metastatic (stage IV) breast cancer, and who were known to carry a
BRCA1 mutation, were eligible. In addition, the following were required: adequate hematologic, renal and hepatic function; adequate recovery from recent surgery and/or radiation therapy; recovery from all prior treatment-related toxicities (to grade <2 according to National Cancer Institute Common Toxicity Criteria, Version 3.0, except alopecia); life expectancy of at least 12 weeks; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients could have received up to four prior chemotherapies for metastatic disease. Patients with known brain metastases were not eligible. Patients previously treated with a platinum-based chemotherapy were not eligible.
The protocol was approved by the Ethics Committee of the Pomeranian Medical University with jurisdiction over the specific sites that registered patients on the study. The study was approved by Ethics Committee of the Pomeranian Medical University BN-001/83/07
Patients were recruited from three academic hospitals in Poland. All patients provided written informed consent before enrollment.
Study design and treatment
This was a Phase II, open-label, non-randomized, multi-center study. Cisplatin (Ebewe, Austria) chemotherapy was administered as a 75 mg/m2 intravenous (IV) infusion every three weeks, for six cycles. Dexamethasone (8 mg) (PABI-Dexamethason, Polfa, Pabianice, Poland) was administered once daily for three days after chemotherapy. Ondansetron (Zofran™) (Zofran, GlaxoSmithKline, Great Britain was used for anti-nausea prophylaxis.
A total of 18 of the 20 patients received additional lines of chemotherapy subsequent to platinum therapy at the time of progression. These included AT (Doxorubicin, Ebewe, Austria and Docetaxel, Sanofi-Aventis, Poland) (eight patients) ACT (Doxorubicin, Ebewe, Austria and Cyclophosphamide, Baxter, Poland and Docetaxel, Sanofi-Aventis, Poland) (two patients), FAC (5-Fluorouracil, Ebewe, Austria and Doxorubicin, Ebewe, Austria and Cyclophosphamide, Baxter, Poland) (two patients) and AC (Doxorubicin, Ebewe, Austria and Cyclophosphamide, Baxter, Poland) (one patient. Four patients received an aromatase inhibitor after platinum therapy.
Assessments
Baseline assessments included the following: medical history, complete physical examination, assessment of performance status on the ECOG scale, physical and radiological examination of the tumor, and complete blood count (CBC) and complete metabolic profile. Hormone (estrogen receptor (ER)/progesterone receptor (PR)) and Human Epidermal Growth Factor Receptor 2 (HER2) receptor status were performed locally. During treatment, these assessments were performed in the same manner at the start (Day 1) of each cycle, except radiological examination of the tumor which was performed after Cycle 2 and Cycle 6, and every three months thereafter.
Response criteria and toxicity
Objective tumor response rate, defined as the percentage of patients who achieved a complete response or partial response by RECIST criteria [
14], was the primary efficacy end-point. Radiological assessments were carried out via computerized tomography at baseline, after two cycles (6 weeks), after six cycles (18 weeks) and every 3 months thereafter. Secondary end points included one-year survival and toxicity. Safety assessments included adverse events, clinical laboratory tests, ECOG patient safety and physical examinations and vital signs. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTC), version 2.0. After completion of six cycles of cisplatin, the patient was seen in the clinic every two weeks for eight weeks and every four weeks thereafter. A repeat CT scan was done at three-monthly intervals to evaluate progressive disease.
Statistical analysis
The primary objective of this study was to determine the overall response rate of cisplatin in metastatic breast cancer patients with a known BRCA1 mutation (complete or partial response). Secondary objectives for this study included estimating the one-, two- and three-year rates of overall survival and the evaluation of toxicity. The intent-to-treat (ITT) population was defined as all eligible patients enrolled in the study that had no major violations of protocol inclusion and/or exclusion criteria.
The response rate was calculated as the number of responders (best study response recorded as complete response or partial response) divided by the number of patients enrolled. Survival was calculated using the Kaplan-Meier methods. Patients were followed from the date of first receiving cis-platinum until the date of first evidence of progression, or the date of death, depending on the analysis.
Discussion
There has been a recent resurgence in interest in evaluating platinum-based chemotherapies in patients who are known to have an inherited deficiency in DNA repair [
15]. An early study evaluating the role of cisplatin in the first-line therapy of metastatic breast cancer showed an overall response rate of 47% [
16]. In our study, a partial or complete clinical response was achieved in 16 of 20 (80%) patients with a
BRCA1 mutation and metastatic breast cancer who received cis-platinum chemotherapy as a single agent. The median survival time from the start of cisplatinum treatment was 30 months.
There are few studies which report on the survival experiences of cohorts of
BRCA1 patients. In a recent study from the Netherlands, Kriege
et al. reported on 93 women with a
BRCA1 mutation and metastatic breast cancer who were treated with conventional chemotherapy (CMF (Cyclophosphamide, methotrexate, 5-Fluorouracil, or anthracycline-based) [
17]. The objective response rate was 66% and the median progression-free survival was 7.6 months. In our study, the median time to progression was 12 months. The median overall survival in the Kriege study was 15 months, versus 30 months in our study. In an early report of metastatic breast cancer patients treated with the PARP inhibitor olaparib, 33
BRCA1 carriers were included [
18]. The median time to progression was approximately four months for those treated with 100 mg of olaparib twice a day and was seven months for those treated with 400 mg twice a day (specific figures for the
BRCA1-positive subgroup are not given). Thus, the patients in the current study who have been treated with cisplatin appear to have superior outcomes to these historical controls. However, it is difficult to compare the survival experience of different patient cohorts who may have different disease patterns and different baseline characteristics. The numbers of
BRCA1 carriers in these studies are not large and some of the variation may be due to random fluctuation.
It is of interest to try to identify predictors of response in these patients to determine which women are more likely to benefit from cisplatin chemotherapy. Our study was too small to be definitive in this regard, but it is of interest that the past use of chemotherapy for metastases was associated with a lower response rate, as was the presence of disease at multiple sites. Also, only 1 of 5 patients with ER-positive breast cancer had a complete response, compared to 8 of 15 ER-negative breast cancers. However, the numbers of patients in these subgroups were small and it is too early to make definite conclusions in this regard.
The results of this study are consistent with our earlier results of the use of cisplatin as a neo-adjuvant treatment of breast cancer. In a study of 102
BRCA1 carriers who received neo-adjuvant chemotherapy, 10 of 12 women with a
BRCA1 mutation who were given cisplatin experienced a complete pathologic response (83%), compared to 14 of 90 patients (16%) treated with other regimens (
P < 0.001; exact test) [
19]. To date, we do not have experience in the use of cisplatin for patients with metastatic breast cancer who had earlier received cisplatin in the adjuvant or neo-adjuvant setting. Studies of ovarian cancer patients might be more informative in this regard. Tan
et al. found that patients with ovarian cancer and a
BRCA1 mutation often responded to cisplatin on multiple occasions during the course of their treatment [
20]. This is in keeping with an earlier study by Cass
et al., who reported that women with ovarian cancer and a
BRCA1 mutation were more likely than non-carriers to respond well to cisplatin [
21]. Swisher
at al. documented revertant mutations in four of the six recurrent platinum-resistant ovarian cancers [
22]. These secondary mutations restored the reading frame of the
BRCA1 protein. We do not have data on the mechanisms of eventual resistance to cis-platinum and it will be of interest to establish whether revertant mutations are also a source of platinum resistance in breast cancer.
In a mouse model which expressed
BRCA1 mutations in mammary tissue, Drost
et al. found that tumors associated with the C61G mutation had, on average, a poorer response to platinum-based drugs than did mice with tumors that were homozygous null for
BRCA1 [
23]. There is no evidence in our clinical study that patients with the C61G mutation were less responsive to platinum than were patients with the more common 5382insC mutation.
There are several limitations to this study. This is a relatively small sample of patients (n = 20) and they originate from three institutions. Nevertheless, this is among the largest series of BRCA1 carriers with metastatic breast cancer to be studied to date, and the underlying Polish population is relatively homogeneous. We conducted computed tomography (CT) scans after two and six cycles due to the constraints of the institutions and, therefore, it is challenging to accurately assess stable disease, duration of response and time to progression. Ideally, we would have had more frequent scans and we would have assessed disease at 16 weeks as well. However, the data regarding overall survival are perhaps the most striking and this endpoint is straightforward to evaluate. A total of 18 of the 20 patients were treated with subsequent lines of chemotherapy after platinum therapy and, therefore, it is not possible to dissociate the effect of the cis-platinum therapy from that of other drugs.
Conclusions
In conclusion, our data suggest that chemotherapy regimens with cisplatin may benefit patients with metastatic breast cancer and a BRCA1 mutation. These early results are encouraging, but they should be confirmed in a larger randomized controlled trial.
Future studies should evaluate the potential of using this therapy for the treatment of hereditary breast cancer due to other genes, including
BRCA2. Given that there do not appear to be founder mutations in
BRCA2 in Poland, it will be necessary that these studies be conducted in other countries (or provinces) where
BRCA2 founder mutations are prevalent (for example, Quebec) [
24]. Other agents that target DNA repair deficiency may also prove to be beneficial in this subgroup of patients.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
TB supervised clinical activities and data collection, and drafted and edited the manuscript. RD helped with study design and edited the manuscript. PB, MF-K and EM recruited patients and helped with clinical monitoring. JG, TH and CC performed genetic testing and recruited patients. RC acted as a clinical advisor on medical imaging, and interpreted and provided images. AE reviewed the manuscript and acted as the clinical advisor for medical oncology. JL was the principal investigator of all activities in Poland. SN was the lead investigator that designed the study, performed the analysis and edited the manuscript. All authors read and approved the final manuscript for publication.