Spectrum of BRCA1/2 Mutations in Romanian Breast and Ovarian Cancer Patients.

Background: About 10,000 women are diagnosed with breast cancer and about 2000 women are diagnosed with ovarian cancer each year in Romania. There is an insufficient number of genetic studies in the Romanian population to identify patients at high risk of inherited breast and ovarian cancer. Methods: We evaluated 250 women of Romanian ethnicity with BC and 240 women of Romanian ethnicity with ovarian cancer for the presence of damaging germline mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively) using Next-Generation Sequencing (NGS) technology. Results: Of the 250 breast cancer patients, 47 carried a disease-predisposing BRCA mutation (30 patients (63.83%) with a BRCA1 mutation and 17 patients (36.17%) with a BRCA2 mutation). Of the 240 ovarian cancer patients, 60 carried a BRCA mutation (43 patients (72%) with a BRCA1 mutation and 17 patients (28%) with a BRCA2 mutation). In the BRCA1 gene, we identified 18 variants (4 in both patient groups (ovarian and breast cancer patients), 1 mutation variant in the BC patient group, and 13 mutation variants in the ovarian cancer patient group). In the BRCA2 gene, we identified 17 variants (1 variant in both ovarian and breast cancer patients, 6 distinct variants in BC patients, and 10 distinct variants in ovarian cancer patients). The prevailing mutation variants identified were c.3607C>T (BRCA1) (18 cases) followed by c.5266dupC (BRCA1) (17 cases) and c.9371A>T (BRCA2) (12 cases). The most prevalent mutation, BRCA1 c.3607C>T, which is less common in the Romanian population, was mainly associated with triple-negative BC and ovarian serous adenocarcinoma. Conclusion: The results of our analysis may help to establish specific variants of BRCA mutations in the Romanian population and identify individuals at high risk of hereditary breast and ovarian cancer syndrome by genetic testing.

Pathological complete response following cisplatin or carboplatin-based neoadjuvant chemotherapy for triple-negative breast cancer: A systematic review and meta-analysis.

The addition of platinum compounds to standard neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) is highly controversial. Platinum agents, such as cisplatin and carboplatin, are DNA-damaging agents which exhibit activity in breast cancer, particularly in the TNBC subgroup. In order to assess the efficacy of each most representative platinum agent (cisplatin and carboplatin) in patients with TNBC treated with NACT, the present study performed a systematic review and meta-analysis of all available published studies on TNBC. A search of PubMed was performed to identify studies that investigated platinum-based NACT in patients with TNBC. The primary endpoints were the pooled rate of the pathological complete response (pCR) between cisplatin vs. carboplatin-based NACT. A total of 24 studies were selected (17 studies for carboplatin and 6 studies for cisplatin and 1 study with both carboplatin and cisplatin, with 20 prospective studies) for the analysis of 1,711 patients with TNBC. Overall, the pooled rate of pCR in patients treated with platinum-based NACT was 48%. No significant differences were observed between the rates of pCR obtained under carboplatin vs cisplatin treatment. The carboplatin pCR rate was 0.470 [95% confidence interval (CI), 0.401-0.539], while the cisplatin pCR rate was 0.473 (95% CI, 0.379-0.568). The comparison between these two categories revealed no significant differences (P=0.959). In the whole, the present study demonstrates that neoadjuvant platinum-based chemotherapy improves the pCR rate in patients with TNBC, regardless of the platinum agent used. Carboplatin may thus represent a viable option due to its more favorable toxicity profile.

Partnering bevacizumab with irinotecan as first line-therapy of metastatic colorectal cancer improves progression free survival-A retrospective analysis.

Colorectal cancer remains one of the most frequent malignancies (third place at both genders) worldwide in the last decade, owing to significant changes in modern dietary habits. Approximately half of the patients develop metastases during the course of their disease. The available therapeutic armamentarium is constantly evolving, raising questions regarding the best approach for improving survival. Bevacizumab remains one of the most widely used therapies for treating metastatic colorectal cancer and can be used after progression. This study aimed to identify the best chemotherapy partner for bevacizumab after progression. We performed a retrospective analysis of patients with metastatic colorectal cancer who were treated with bevacizumab as first- and second-line chemotherapy. Data were collected for 151 patients, 40 of whom were treated with double-dose bevacizumab after the first progression. The two standard chemotherapy regimens combined with bevacizumab were FOLFIRI/CAPIRI and FOLFOX4/CAPEOX. The initiation of first-line treatment with irinotecan-based chemotherapy improved progression-free survival and time to treatment failure but not overall survival. After the first progression, retreatment with the same regimen as that used in the induction phase was the best approach for improving overall survival (median overall survival: 46.5 vs. 27.0 months for the same vs. switched strategy, respectively). No correlations were observed between the dose intensity of irinotecan, oxaliplatin, 5-fluorouracil, or bevacizumab and the overall survival, progression-free survival in the first-/second-line treatment, and time to treatment failure. Interaction between an irinotecan-based regimen as a second-line treatment and double-dose bevacizumab after progression was associated with an improved overall survival (p = 0.06). Initiating systemic treatment with an irinotecan-based regimen in combination with bevacizumab improved the progression-free survival in the first-line treatment and time to treatment failure. In terms of overall survival, bevacizumab treatment after the first progression is better partnered with the same regimen as that used in the induction phase.

Doubling the Dose of Bevacizumab Beyond Progression in Metastatic Colorectal Cancer-the Experience of a Tertiary Cancer Center.

Background: Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities. Methods: We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at "Prof Dr. Ion Chiricuta" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks-depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome. Results: One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41-71) and 57 years (range 19-75), respectively. The median overall survival in the DDB group was 41 months (range 27-49) compared to 25 months (range 23-29) in the SDB group (p = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (p = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival. Conclusion: Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.

Treatment beyond progression in metastatic colorectal cancer: to double or not to double the dose of bevacizumab?

PURPOSE: Bevacizumab or cetuximab represent the standard treatment in association with classical chemotherapy in confirmed metastatic colorectal cancer (mCRC). Bevacizumab could be continued after the first disease progression with an overall survival (OS) advantage, compared to chemotherapy alone, but the optimal dose remains a debatable issue. METHODS: In a retrospective analysis of mCRC patients treated with bevacizumab, we selected patients with administration beyond progression, and stratified them according to the dose received- same dose bevacizumab (SDB) as first-line chemotherapy or double dose bevacizumab (DDB). For each group we evaluated OS, time to treatment failure (TTF) and progression-free survival in the first-line (PFS1) and in the second-line (PFS2). RESULTS: In the first-line therapy, oxaliplatin backbone regimen was used in 73% SDB, compared with 22.5% DDB patients, while irinotecan was used in 75% DDB and 27% SDB patients. Second-line oxaliplatin was given to 50% DDB and 29.7% SDB patients, while irinotecan was administered to 47.5% DDB and 70.3% SDB patients. The median values were: OS - 41 months in the DDB group and 25 months in the SDB group (p = 0.01); TTF - 24 months in the DDB group and 19 months in the SDB group (p=0.009); PFS1 - 17 months in the DDB group and 12 months in the SDB group (p=0.008); PFS2 - 9 months in the DDB group and 5 months in the SDB group (p = 0.03). CONCLUSIONS: Doubling the dose of bevacizumab at progression seems to provide OS and PFS advantage for mCRC patients.