A Comparison between CHEK2*1100delC/I157T Mutation Carrier and Noncarrier Breast Cancer Patients: A Clinicopathological Analysis.

OBJECTIVE: The suppressor gene CHEK2 encodes a cell cycle checkpoint kinase, involved in cell cycle regulation, apoptosis and response to DNA damage. The aim of this study was to analyze the differences between CHEK2 mutation carriers (CHEK2*1100delC/I157T) and noncarriers with respect to clinicopathological factors. METHODS: We reviewed the medical records of 100 early breast cancer patients (46 mutation carriers and 54 noncarriers) who were treated with chemotherapy, hormonotherapy or trastuzumab. RESULTS: CHEK2 mutation carriers were older (>65 years) than noncarriers (17 vs. 7%; p = 0.215). Twenty-five (54%) of them had a history of cancer in the family. Gastric cancer in the family history was detected in 11% of mutation carriers and in 2% of noncarriers (p = 0.092). There was a trend for more frequent lymph node metastases in patients without the mutation in comparison to mutation carriers (46 vs. 28%; p = 0.098). Luminal B type breast cancer was detected more often in carriers (39 vs. 20%; p = 0.048). Breast-conserving treatment was also conducted more often in mutation carriers (57 vs. 31%; p = 0.015). Histologic grades G1/G2 were detected more frequently in mutation carriers (82 vs. 70%; p = 0.212). CONCLUSION: Mutation carriers were characterized by older age, a history of gastric cancer in the family, locally advanced disease, lower histologic grade and luminal B type breast cancer.

Treatment related toxicity in BRCA1-associated epithelial ovarian cancer - is DNA repairing impairment associated with more adverse events?

AIM OF THE STUDY: The presence of BRCA germline mutations in patients with ovarian cancer has been shown to have predictive and prognostic significance, including increased platinum-sensitivity. The aim of the study was to evaluate if patients with BRCA1-associated ovarian cancer have more treatment related adverse events and, if so, does it have impact on chemotherapy outcomes. MATERIAL AND METHODS: We conducted a retrospective analysis of medical records of 172 patients with newly diagnosed epithelial ovarian cancer, treated in Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 2007 and 2013. Ninety-six of these patients have known BRCA mutation status - 21 patients were BRCA1(+) and 75 BRCA1(-). Analysed treatment related adverse events (AE's) were: haematological toxicity, nausea/vomiting, neuropathy and mucositis. RESULTS: Grade 3-4 haematological AE's were significantly more common among BRCA1(+) patients (OR = 3.86; 95% CI: 1.14-13.23; p = 0.02). There was no association between BRCA1 mutation status and neuropathy (p = 0.73) or nausea/vomiting (p = 0.91). Occurrence of above mentioned AE's has no significant association with PFS (p = 0.75, 0.64, 0.97 respectively) and OS (p = 0.64, 0.69, 0.73 respectively). CONCLUSIONS: Among patients with BRCA1-associated epithelial ovarian cancer we observed significantly more grade 3-4 haematological complications after chemotherapy. However, occurrence of AE's did not correlate with better outcomes in this subgroup.

The risk factors of toxicity during chemotherapy and radiotherapy in breast cancer patients according to the presence of BRCA gene mutation.

AIM OF THE STUDY: Treatment toxicity may decrease the treatment effectiveness due to the need to reduce the dose or increase the interval between cycles. The aim of this study was to distinguish the risk factors for treatment side effects in breast cancer patients and to assess the impact of BRCA1/2 mutations on the treatment toxicity. MATERIAL AND METHODS: The analysis was conducted on the medical history of 370 patients who were treated with anthracycline-based chemotherapy between 2006 and 2012 in the Clinical Oncology Department, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology in Gliwice in Poland (COI). All patients were tested for the presence of BRCA1 and BRCA2 mutations. RESULTS: In the studied group 13% (48) of the patients were BRCA mutation carriers. Neutropaenia after the first cycle of chemotherapy occurred more commonly in mutation carriers compared to non-carriers (29% vs. 10%), p = 0.0002. Radiotherapy acute skin toxicity was present in 3% of patients with similar rates in both groups, p = 0.950. Toxicity grade 3-4 was present more frequently in patients younger than 70 years (p = 0.02) of age, patients with viral hepatitis (p = 0.045), hypertension (p = 0.039), and cardiovascular disease (p = 0.044). Lower WBC count before treatment was observed more frequently in patients with neutropaenia (p = 0.002), especially in mutation carriers, p = 0.0015. CONCLUSIONS: Risk factors for anthracycline-based chemotherapy side effects were: age below 70 years, lower WBC value at baseline, history of infectious diseases, hypertension, and cardiovascular comorbidity. The presence of BRCA mutations may be a risk factor for neutropaenia, but it did not affect radiotherapy toxicity.

The influence of BRCA1/BRCA2 mutations on toxicity related to chemotherapy and radiotherapy in early breast cancer patients.

OBJECTIVE: The presence of BRCA gene mutation and low expressions of BRCA proteins are associated with a greater sensitivity of tumor cells to ionizing radiation and to cytostatics damaging the DNA of the cells. The purpose of this study was to estimate the rate of adverse events in BRCA1/2-associated breast cancer patients receiving anthracycline-based chemotherapy compared to patients without mutation. The authors also compared radiotherapy toxicity in these 2 groups. METHODS: The analysis included 270 early-stage breast cancer patients treated between 2006 and 2012. All patients were examined for the presence of BRCA1/2 mutations. RESULTS: BRCA mutation was detected in 41 (15%) patients. Toxicity grade 3, especially nausea and vomiting, was observed more often in noncarriers (7 vs. 13%, p = 0.0008). Neutropenia was detected more frequently in patients with BRCA1/2 mutation (32 vs. 10%), but only after 1 cycle of chemotherapy (p = 0.0007). There was increased radiation toxicity in BRCA1/2 patients who underwent mastectomy and neoadjuvant chemotherapy (p = 0.016). CONCLUSIONS: BRCA1/2 mutation carriers seemed to be more at risk of neutropenia after the first cycle of the treatment. In terms of other side effects, there was a lack of increased toxicity in this group. Mastectomy and neoadjuvant chemotherapy were risk factors for radiation toxicity in mutation carriers.

[Multiple primary malignancies in BRCA1 mutation carriers--two clinical cases]. / Mnogie nowotwory pierwotne u kobiet nosicielek mutacji genu BRCA1--dwa przypadki kliniczne.

Mutations of BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. So far; risk-reducing salpingo-oophorectomy has been the most effective strategy for gynecological cancer prevention in susceptibility gene mutation carriers. It does not prevent, however from the occurrence of primary peritoneal cancer We present two clinical cases of patients with the BRCA1 gene mutation. Both patients had a family history of cancer and both were presenting with metachronic malignances. The first patient, whose mother suffered from breast and ovarian cancer, was diagnosed with left breast cancer in 2004. The patient was 44 years old at diagnosis. Genetic testing revealed the BRCA1 gene mutation. A breast conserving therapy (BCT) was conducted, followed by chemotherapy, radiotherapy and immunotherapy with trastuzumab due to HER2 overexpression. Due to BRCA1 mutation, in November 2005, prophylactic hysterectomy with appendages was performed. Histological examination revealed bilateral ovarian cancer (adenocarcinoma G3) with metastasis to the paraaortal lymph node. The patient received six cycles of chemotherapy: paclitaxel and carboplatin. Ovarian cancer relapsed 3 years later After that the patient received 5 lines of chemotherapy and finally died due to disease progression in September 2011. The second patient, a 49-year-old woman, was diagnosed with breast cancer in July 2003 and subsequently treated with neoadjuvant chemotherapy breast conserving surgery and radiotherapy Genetic testing was also performed and revealed the BRCA1 gene mutation. A year earlier the patient had undergone hysterectomy with appendages due to uterine myomas. Three of her five sisters suffered from breast and ovarian cancer The patients father died of colorectal cancer The patient remained under surveillance. Because of the increasing level of Ca-125 (since October 2004), PET-CT was performed and revealed a tumor lesion of the peritoneum. Histological examination from the biopsy confirmed primary peritoneal cancer (papillary serous adenocarcinoma--primary peritoneal carcinoma). Reexamination of the tissues from hysterectomy with appendages was also performed and revealed an adenocarcinoma in the right ovary Pathologic examination excluded metastasis of a breast cancer Pathomorphology of the ovarian lesion was also different than in the lesions of the peritoneum. Thus, three different tumor types (breast, ovarian and peritoneal cancer) coexisted independently The patient received chemotherapy: paclitaxel and cisplatin. Later on, due to disease progression she was treated with five consecutive chemotherapy regimens and hormonal therapy The patient died in January 2008. These case illustrate that genetic diagnosis may be critical for the overall treatment plan.

Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy.

PURPOSE: To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen. PATIENTS AND METHODS: From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria. RESULTS: Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin. CONCLUSION: A low rate of pCR was observed in women with breast cancer and a BRCA1 mutation who were treated with AT or CMF. A high rate of pCR was seen after treatment with cisplatin. An intermediate rate of PCR was associated with AC or FAC. The relative benefits of AC and platinum therapy need to be confirmed through follow-up of this and other cohorts.