Elżbieta Marczyk

Breast cancer predisposing alleles in Poland

SummaryMutant alleles of several genes in the DNA repair pathway have been found to predispose women to breast cancer. From a public health perspective, the importance of a given allele in a population is determined by the frequency of the allele and by the relative risk of breast cancer that it confers. In Poland founder alleles of the BRCA1, CHEK2 and NBS1 genes have been associated with an increased risk of breast cancer, but the relative contribution of each of these alleles to the overall breast cancer burden has not yet been determined. We screened 2012 unselected cases of breast cancer and 4000 population controls for 7 different mutations in these genes. Overall, a mutation was found in 12% of the cases and in 6% of the controls. Mutations in BRCA1 and CHEK2 contributed in approximately equal measure to the burden of breast cancer in Poland. A BRCA1 mutation was present in 3% of the cases. The missense BRCA1 mutation C61G was associated with a higher odds ratio for breast cancer (OR=15) than were either of the truncating BRCA1 mutations 4153delA (OR=2.0) and 5382insC (OR=6.2). In contrast, a higher odds ratio was seen for truncating CHEK2 mutations (OR=2.1) than for the missense mutation I157T (OR=1.4). This study suggests that cancer risks may be specific for particular alleles of a susceptibility gene and that these different risks should be taken into account by genetic counselors.

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

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.

Ten-Year Survival in Patients With BRCA1-Negative and BRCA1-Positive Breast Cancer

PURPOSE To estimate 10-year overall survival (OS) rates for patients with early-onset breast cancer, with and without a BRCA1 mutation, and to identify prognostic factors among those with BRCA1-positive breast cancer. PATIENTS AND METHODS A total of 3,345 women with stage I to III breast cancer, age ≤ 50 years, were tested for three founder mutations in BRCA1. Information on tumor characteristics and treatments received was retrieved from medical records. Dates of death were obtained from the vital statistics registry. Survival curves for the mutation-positive and -negative subcohorts were compared. Predictors of OS were determined using the Cox proportional hazards model. RESULTS Of the 3,345 patients enrolled onto the study, 233 (7.0%) carried a BRCA1 mutation. The 10-year survival rate for mutation carriers was 80.9% (95% CI, 75.4% to 86.4%); for noncarriers, it was 82.2% (95% CI, 80.5% to 83.7%). The adjusted hazard ratio (HR) associated with carrying a BRCA1 mutation was 1.81 (95% CI, 1.26 to 2.61). Among BRCA1 carriers with a small (< 2 cm) node-negative tumor, the 10-year survival rate was 89.9%. Among BRCA1 mutation carriers, positive lymph node status was a strong predictor of mortality (adjusted HR, 4.1; 95% CI, 1.8 to 8.9). Oophorectomy was associated with improved survival in BRCA1 carriers (adjusted HR, 0.30; 95% CI, 0.12 to 0.75). CONCLUSION The 10-year survival rate among women with breast cancer and a BRCA1 mutation is similar to that of patients without a BRCA1 mutation. Among women with a BRCA1 mutation, survival was much improved after oophorectomy.

Neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients

502 Background: Neoadjuvant chemotherapy is administered to control disease, make surgical resection possible and increase the possibility of breast tissue conservation. A further advantage of neoadjuvant therapy is that it helps to assess chemo-sensitivity to a particular agent. Induction of a pathological complete response (pCR) is one of the primary goals of neoadjuvant therapy in order to achieve a better disease-free and overall survival. Experimental data suggest that BRCA1 related breast cancer may have increased sensitivity to platinum-based chemotherapy, but clinical data are limited. The aim of this study was to evaluate the frequency of complete pathologic response after neo-adjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. METHODS Twenty five women with breast cancer and a BRCA1 mutation with stage I, II, and III breast cancer between December 2006 and December 2008 were entered into this study. Patients were treated with cisplatin 75 mg/m2 intravenously every three weeks for four cycles. After chemotherapy, patients underwent surgery and were assessed for pathologic response in both the breast and axillary lymph nodes. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla, however ductal carcinoma in situ was allowed. RESULTS Twenty five patients were enrolled in the study. Thirteen patients had tumors of greater than two centimeters (52%) and seven patients had positive lymph nodes at diagnosis (28%). Twenty two patients completed four cycles of cisplatin (88%) and three patients completed two cycles (12%). Clinical complete response was observed in eighteen patients (72%). Pathologic complete response was observed in eighteen patients (72%). CONCLUSIONS Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers. Clinical trials are warranted to determine the optimum treatment for this subgroup of breast cancer patients. No significant financial relationships to disclose.

Selenium and the risk of cancer in BRCA1 carriers

It has not been established if dietary factors or nutritional supplements impact on the incidence of cancer in high-risk women. We randomised 1135 women with a BRCA1 mutation to 250 micrograms daily of elemental selenium as sodium selenite, or to placebo, in a double-blind trial. After a median follow-up period of 35 months (range 6 to 62 months), there were 60 incident cases of cancer diagnosed in the selenium-supplemented group, versus 45 cases in the placebo group (hazard ratio 1.4; 95% CI: 0.9 to 2.0). Selenium supplementation was not associated with a reduction in the risk of primary breast cancer (hazard ratio 1.3; 95% CI: 0.7 to 2.5), of contralateral breast cancer (hazard ratio 1.5; 95% CI: 0.7 to 3.2), or of ovarian cancer (hazard ratio 1.3; 95% CI: 0.6 to 2.7). The results of this study do not support the recommendation that selenium supplementation should be offered to BRCA1 carriers for chemoprevention. Part II Adnexectomy, genotypes and selenium level as markers of the risk of cancer In these part we conducted a nested case-control study of 68 women with breast cancer and 17 women with ovarian cancer and 170 controls matched 1 to 2. Cases and controls were matched for age at enrolment, past history of breast cancer, oophorectomy and whether they received selenium supplement or placebo during cancer chemoprevention trial. Combinations of clinical status, genotypes and selenium levels strongly associated with extremely low risk of cancer have been identified. The strongest associations have been found for GPX4 variants: a. all nTT and Se level 60-80µg/l – OR 0.32, p: 0.0009 b. all TT and Se level >80µg/l – OR 0.10, p: 0.047 c. for carriers without adnexectomy and with TT variant, Se level >80µg/l – OR 0.038, p: 0.014.

Neoadjuvant chemotherapy with Cisplatin in BRCA1 mutation carriers – results of treatment

Material and methods Between December 2006 and August 2011 seventy five women with BRCA1 mutation and diagnosed with breast cancer stage I to III were enrolled. Patients were treated with Cisplatin at dose 75 mg/m2 every three weeks for four cycles. After chemotherapy mastectomy was performed and followed with conventional chemotherapy. Seven patients had prior chemotherapy for a previous cancer diagnosis. Four patients received prior chemotherapy for their current cancer diagnosis and then received therapy according to our protocol. In the group of 67 patients treated with Cisplatin in first line of treatment 32 met the standard criteria for neoadjuvant chemotherapy, and in 35 cases the criteria were not met. Pathologic complete response was determined by review of surgical specimens. Complete pathologic response was defined as no residual invasive disease in both the breast and axilla. Information was collected on clinical stage, grade, hormone receptor status and HER2 status prior to treatment.

Metachronic cancers among women with brest cancer and BRCA1 mutation

Background: Breast cancer is the most common malignancy among women worldwide and in Poland. Mutation in BRCA1 gene is responsible for approximately 6% breast cancers in Poland diagnosed before the age of 50. BRCA1 dependent cancers occur early and frequently are bilateral. The purpose of this work was to evaluate the frequency of metachronic cancers in the population of 42 patients with breast cancer and BRCA1 mutation. Material and methods: Medical histories of 196 patients with confirmed mutation in BRCA1 gene consulted in the Krakow Branch of the Maria Sklodowska Curie Memorial Cancer Centre and Institute of Oncology between 2005 and 2016 were analyzed. Medical histories of 42 patients with breast cancer were chosen for further analysis in the aspect of metachronic cancers. Results: During the observation period (mean of 10 years) 21 (50%) metachronic cancers were diagnosed, breast cancer was the most common one occurring in 16 (38%) cases. Additionally, 2 synchronic breast cancers occurred, and in 3 other cases breast cancer was the metachronic one. Conclusions: In light of the obtained results, the medical community should be aware of the scale of the problem of metachronic cancers among the patients with diagnosed BRCA1 mutation. Intensified surveillance for early detection of metachronic cancer and perspective of prophylactic mastectomy and adnexectomy for women treated from BRCA1 positive breast cancer should be considered.

Pathological complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients

Purpose: To estimate the frequency of complete pathologic response (pCR) after neoadjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. Patients and Methods: 107 women with breast cancer and a BRCA1 mutation, who presented with stage I to III breast cancer between December 2006 and June 2014 were treated with cisplatin 75 mg/m 2 every three weeks for four cycles, followed by mastectomy and conventional chemotherapy (AC). Information was collected on clinical stage, grade, hormone receptor status and Her2neu (HER2) status prior to treatment. Pathologic complete response was determined by review of surgical specimens.

Why choose the treatment with cisplatin for BRCA1 breast cancers patients

ted with cisplatin 75 mg/m 2 every three weeks for four cycles, followed by mastectomy and conventional chemotherapy. Eight patients had prior chemotherapy for a previous cancer diagnosis. Three patients received prior chemotherapy for their current cancer diagnosis but received protocol therapy and thus were followed for toxicity and evaluated for response. Information was collected on clinical stage, grade, hormone receptor status and Her2neu (HER2) status prior to treatment. Pathologic complete response was determined by review of surgical specimens. Results 47 patients were enrolled in the study, including 39 patients for whom this was the first primary breast cancer and who had no previous chemotherapy and 8 patients who had previously received chemotherapy. A pathologic complete response (pCR) was observed in 34 patients (68%) including 82% of women who had no previous chemotherapy and 18% of women who had previously received chemotherapy. Conclusions Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancer, but may be less effective in women who have been previously been treated with another form of chemotherapy.

Impact of BRCA1 mutation on survival after early onset breast cancer

Patients and methods 3354 women who were diagnosed with stage I to stage IV breast cancer, at or below 50 years of age, between January 1996 and December 2006 were contributed from 17 clinical centers in Poland. All patients were offered genetic testing for three founder mutations in BRCA1 (5382insC, C61G, 4184delA). Information on tumour characteristics at presentation and on treatments received was retrieved by reviewing the medical records. Mortality and dates of death were obtained by linkage to the vital statistics database of the Polish Ministry of Administration and Internal Affairs. Survival curves for the mutation-positive and mutation-negative sub-cohorts were constructed using Kaplan–Meier statistics and compared. Predictors of survival were determined using the Cox proportional hazards method.