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Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level. © 2020 UICC

Background This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma. Methods Thirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days). Results Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22). Conclusion Nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation. © 2018 Hellenic Society of Gastroenterology

Metastatic triple-negative breast cancer lacks a standard therapeutic strategy and represents an unmet need for novel therapies. We conducted a phase II study to evaluate the weekly paclitaxel/carboplatin/bevacizumab combination. Forty-six patients were enrolled and 7 (15.2%) complete and 23 (50%) partial responses were observed for an objective response rate of 65.2% with tolerable toxicity. The combination merits further clinical evaluation. Background: Triple-negative breast cancer (TNBC) lacks a standard targeted therapeutic strategy and is treated with conventional cytotoxic agents. Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC. Patients and Methods: This phase II study followed the Simon's 2-stage optimal design. Paclitaxel (90 mg/m 2 ) and carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective response rate (ORR). The null hypothesis that the ORR is ≤ 40% could be rejected if the number of objective responses was ≥ 23 among 46 evaluable patients. Results: A total of 46 patients were enrolled. Seven (15.2%) complete and 23 (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval, 52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2), thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities were observed. Conclusion: The study achieved its primary end point by showing clinical activity for weekly paclitaxel with carboplatin and bevacizumab combination. This regimen merits further evaluation in this setting. © 2017 Elsevier Inc.

Objectives To compare first-line treatment with docetaxel plus gemcitabine (DG) versus gemcitabine (G) in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naïve patients with inoperable stage IIIB/IV NSCLC, ≥ 70 years, with an ECOG performance status (PS) of 0–2 were enrolled. Patients were stratified by PS and disease stage and randomized to either DG (docetaxel 30 mg/m2 plus gemcitabine 900 mg/m2 i.v.) or G (gemcitabine 1200 mg/m2 i.v.) on days 1 and 8, every 3 weeks. The study's primary end-point was overall survival (OS). Results In this prematurely closed study, 106 patients with a median age of 75 years (range, 70–92) were enrolled (DG: n = 54; G: n = 52); 77 (73%) had stage IV disease and 18 (17%) a PS of 2. There was no difference in terms of median OS (14.6 vs 12.2 months; p = 0.121), progression-free survival (PFS) (3.4 vs 2.6 months; p = 0.757) and overall response rate (26.0% vs 15.4%; p = 0.233) between DG and G arm, respectively. Patients with an Instrumental Activities of Daily Living (IADL) score

In the present phase I/II study, the biweekly carboplatin (area under the curve, 2.5) plus gemcitabine (1100 mg/m2) combination in patients aged ≥ 70 years with advanced and metastatic squamous non–small-cell lung cancer achieved an overall response rate of 35.8%, a median progression-free survival of 6.7 months, and a median overall survival of 13.3 months, with favorable toxicity. Background The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non–small-cell lung cancer (NSCLC). Patients and Methods Patients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. Results A total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. Conclusion The biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC. © 2016 Elsevier Inc.

A randomized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer. Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were randomized to receive either 4 cycles of docetaxel (100 mg/m2) followed by 4 cycles of epirubicin (75 mg/m2) plus cyclophosphamide (700 mg/m2) (experimental arm) or 6 cycles of FEC (epirubicin 75 mg/m2, cyclophosphamide 700 mg/m2, and 5-fluorouracil 700 mg/m2; control arm). All regimes were administered every 3 weeks. The primary end point was five-year disease-free survival (DFS). After a median follow-up period of 5 years, 233 (30.8%) relapses had occurred (108 and 125 in the experimental and control arms, respectively; P = 0.181). The five-year DFS was 72.6% (95% CI 63.8-81.3%) and 67.2% (95% CI 58.0-76.4%) for women randomized in the experimental and control arms, respectively (P = 0.041; log rank test). There was no difference in the overall survival between the two arms (83.8 and 81.4% in the experimental and control arms, respectively; P = 0.533). The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5% of the patients as compared with 74.1% in the control arm (P = 0.0001). The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen resulted in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity. © 2009 Springer Science+Business Media, LLC.

Purpose: The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer. Patients and methods: Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100 mg/m(2) on days 1-3 and cisplatin 80 mg/m(2) on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20 mg/m(2) on day 1 and etoposide 50 mg/m(2) on day 4 within 5-6 weeks, followed by three courses of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 of a 4-week cycle. Results: There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3-4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6-41.2 months), the median survival time was 19 months (95% CI: 14.5-23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively. Conclusions: Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background: The docetaxel/gemcitabine (DG) combination is an active and well-tolerated regimen against non-small cell lung cancer (NSCLC). A phase II study was conducted in order to evaluate its efficacy in elderly patients with lung adenocarcinomas. Methods: Chemotherapy-naive patients, aged ≥70 years, with locally advanced or metastatic lung adenocarcinomas and performance status (PS) ≤2 (ECOG) received gemcitabine 1100 mg/m2 (days 1 + 8) and docetaxel 100 mg/m2 (day 8) with rhG-CSF support. Results: Seventy-seven patients were enrolled. One (1.3%) complete and 23 (29.9%) partial responses were achieved (intention to treat analysis: ORR 31.2%; 95% CI 20.82-41.51%) whereas tumor growth control was achieved in 53.3% of patients. The median TTP was 4.1 months, the median overall survival 9.4 months and the 1- and 2-year survival rate 37.9% and 10.7%, respectively. Grade 3-4 neutropenia occurred in 18.2% and febrile neutropenia in 3 (3.9%) patients. Non-haematological toxicity was mild with grade 2-3 asthenia occurring in 22.1% patients. Conclusions: The DG regimen is an active and well-tolerated front-line chemotherapy for elderly patients with lung adenocarcinomas and merits further evaluation in prospective randomized trials. © 2008 Elsevier Ireland Ltd. All rights reserved.

Background: To evaluate the efficacy and tolerance of capecitabine (CAP) given every other week and biweekly oxaliplatin (OX; modified CAPOX regimen) in patients with advanced colorectal cancer previously treated with irinote- can-based frontline chemotherapy. Methods: Sixty-seven patients were enrolled; the median age was 62 years and 62 (92.5%) had a performance status (ECOG) of 0-1. OX and CAP were administered at the dose of 100 mg/m2 on day 1 and 2,000 mg/m2 on days 1-7, respectively, every 2 weeks. Results: A total of 429 treatment cycles were administered. Grade 3/4 neutropenia and thrombocytopenia were observed in 4 (6%) and 2 (3%) patients, respectively. Febrile neutropenia complicated 1 treatment cycle. The main nonhematologic toxicities were grade 2/3 peripheral sensory neurotoxicity (10% of patients) and grade 3/4 diarrhea (7%). In an intention-to-treat analysis, 3 (4.5%) complete and 13 (19.4%) partial responses (overall response rate 24%) were observed. Seventeen (24.5%) patients had stable and 27 (40.3%) progressive disease. The median time to tumor progression and overall survival were 5 months and 11.3 months, respectively. Conclusions: The results indicate that the modified CAPOX regimen is safe and effective as salvage treatment in patients with advanced colorectal cancer who were previously treated with irinotecan-based frontline therapy. Copyright © 2008 S. Karger AG.

Purpose: To evaluate the efficacy and tolerance of the docetaxel/gefitinib combination as second-line treatment in patients with advanced pancreatic cancer. Patients and Methods: Twenty-six patients pretreated with gemcitabine-based chemotherapy were enrolled in the study. Docetaxel (75 mg/m2, i.v.) was administered every 3 weeks for a maximum of 6 cycles and gefitinib (250 mg/day, p.o.) was given continuously. Results: Five (19.2%) patients achieved stable disease. The median duration of disease control was 4.8 months (range 1-13.2), the median time to disease progression 2.1 months (range 1-7.3) and the median survival time 2.9 months (range 1-13.9). Grade 3/4 neutropenia was recorded in 9 (34.6%) patients, although only 1 (3.8%) developed grade 2 febrile neutropenia. One (3.8%) patient experienced grade 3 fatigue and 2 (7.7%) grade 3 diarrhea. Grade 1/2 rash was observed in 13 (50%) patients. There were no treatment-related deaths. Conclusion: The docetaxel/gefitinib combination, although safe, has no activity as salvage treatment for advanced pancreatic cancer after failure of gemcitabine-based chemotherapy. Copyright © 2006 S. Karger AG.

Purpose: A phase I study was conducted to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the pegylated liposomal doxorubicin (PLD) and oxaliplatin combination in patients with advanced solid tumors. Patients and Methods: Forty-five patients with advanced-stage solid tumors received escalating doses of PLD 25-50 mg/m2 as 60-min intravenous (i.v.) infusion and oxaliplatin 80-130 mg/m2 as 2- to 4-hour i.v. infusion on day 1 every 3 weeks without growth factors. Results: MTD was defined at PLD 45 mg/m2 and oxaliplatin 130 mg/m2. Eleven dose levels were evaluated and DLTs were grade 2-3 neutropenia resulting in treatment delays, grade 3 neurotoxicity and nausea/vomiting. A total of 187 cycles were administered with two episodes of febrile neutropenia and one toxic death due to sepsis. Two (4%) and 6 (13%) patients developed grade 4 and 3 neutropenia, respectively, 2 (4%) and 1 (2%) grade 4 and 3 thrombocytopenia, and 1 (2%) grade 4 anemia. The most common nonhematological toxicities were grade 2-3 nausea/vomiting and asthenia observed in 27 (60%) and 16 (36%) of patients, respectively. One complete and eight partial responses were observed. Conclusion: The combination of PLD and oxaliplatin has an acceptable toxicity profile with promising activity and merits further evaluation in phase II studies. Copyright © 2006 S. Karger AG.

Background: A multicenter phase II study was conducted in order to evaluate the efficacy and safety of oxaliplatin as first-line treatment of patients with locally advanced or metastatic carcinoma of the biliary tract. Patients and Methods: Twenty-nine chemo-naïve patients with locally advanced or metastatic biliary tract carcinoma received oxaliplatin 130 mg/m2 i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. Results: An objective response (3 complete responses, 3 partial responses) was achieved in 6 patients (20.6%, 95% CI 5.95-35.4). Disease control (complete response, partial response and stable disease) was observed in 14 patients (48.2%). The median time to tumor progression was 3 months (range 0.7-39) and the median overall survival was 7 months (range 1-39). The 1-year survival rate was 32%. Toxicity was mild. Conclusion: Oxaliplatin is an active agent against biliary tract carcinoma and therefore should be further investigated in combination with other cytotoxic drugs. Copyright © 2006 S. Karger AG.

Purpose: To evaluate the activity and tolerance of gemcitabine in combination with oxaliplatin (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Thirty-two patients with advanced NSCLC who had disease progression after a cisplatin- and taxane-based front-line regimen were treated with gemcitabine (1500 mg/m2 on days 1 and 8) and oxaliplatin (130 mg/m2 on day 8) every 3 weeks. The patients' median age was 62 years and the performance status (WHO) was 0 for 11, 1 for 17 and 2 for 4 patients. The treatment was second line for 22 (69%) and ≥third line for 10 (31%) patients. Results: Partial response was achieved in 5 (16%) patients, stable disease in 8 (25%) and progressive disease in 19 (59%). Two patients with stable disease and one patient with progressive disease while on previous chemotherapy experienced a partial response with GEMOX regimen. The median duration of response was 2.5 months (range, 1-11.5), the median time to tumor progression 3 months (range, 1-18) and the median survival 5.6 months (range, 1-31). Grade III neutropenia occurred in five (16%) patients, grade III thrombocytopenia in two (6%) and grade III anemia in three (9%); moreover, grades II-III asthenia was reported in eight (25%) patients and grades II-III neurotoxicity in three (9%). Conclusion: The GEMOX combination is a relatively active and well tolerated second-line regimen in NSCLC patients pretreated with a taxane- and/or platinum-based chemotherapy. © 2006 Elsevier Ireland Ltd. All rights reserved.

Background: The purpose of this study was to investigate the toxicity and efficacy of the sequential administration of gemcitabine (GMB) in combination with cisplatin (CDDP) followed by docetaxel (Taxotere) as first-line treatment of advanced urothelial carcinoma. Patients and methods: Patients [aged ≤70 years and performance status (PS) (Eastern Cooperative Oncology Group) 0-2] with previously untreated locally advanced/recurrent or metastatic urothelial carcinoma were eligible. Study treatment consisted of GMB (1000 mg/m2, days 1 and 8) and CDDP (70 mg/m2, day 1) (GP regimen), every 21 days for a total of four cycles followed by docetaxel (D; 100 mg/m2, day 1) every 21 days for four cycles. Results: Thirty-eight patients with a median age of 67 years were enrolled; 67% of them had PS 0 and 87% stage IV disease. Patients received a median of four GP and four D cycles per patient. Grade 3-4 neutropenia occurred in 27% and 63% patients with GP and D, respectively. Grade 3-4 thrombocytopenia occurred in 11% of patients, only with the GP regimen. Other toxic effects were mild. There was no toxic death. The objective response rate was 55.2% [95% CI: 39.45%-71.07%]. Five patients had complete response (13.15%) and 16 patients had partial response (42.1%), while nine patients had disease stabilization (23.7%) (intention-to-treat analysis). After a median follow-up period of 13 months (range 1.5-40.5 months), the median time to progression was 6.8 months (range 1-40.5 months), the median overall survival 13 months (range 1.5-40.5 months), and the 1-year survival rate 55.3%. Conclusion: The sequential administration of GP followed by D is active and well tolerated as first-line treatment of advanced urothelial carcinoma and merits to be further evaluated. © 2006 Oxford University Press.

To compare the efficacy and toxicity of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOXIRI) vs irinotecan and 5-FU/LV (FOLFIRI) as first-line treatment of patients with metastatic colorectal cancer (MCC). A total of 283 chemotherapy-naïve patients with MCC were enrolled (FOLFIRI arm: n = 146; FOLFOXIRI arm: n = 137). In the FOLFOXIRI arm, CPT-11 (150 mg m-2) was given on d1, L-OHP (65 mg m-2) on d2, LV (200 mg m-2) on days 2 and 3 and 5-FU (400 mg m-2 as i.v. bolus and 600 mg m -2 as 22 h i.v. continuous infusion) on days 2 and 3. In the FOLFIRI arm, CPT-11 (180 mg m-2) was given on d1 whereas LV and 5-FU were administered in the same way as in the FOLFOXIRI regimen. Both regimens were administered every 2 weeks. There was no difference in terms of overall survival (median OS: 19.5 and 21.5 months, for FOLFIRI and FOLFOXIRI, respectively; P = 0.337), median time to disease progression (FOLFIRI: 6.9 and FOLFOXIRI: 8.4 months; P = 0.17), response rates (33.6 and 43% for FOLFIRI and FOLFOXIRI, respectively; P = 0.168). Patients treated with FOLFOXIRI had a significantly higher incidence of alopecia (P = 0.0001), diarrhoea (P = 0.0001) and neurosensory toxicity (P = 0.001) compared with patients treated with FOLFIRI. The present study failed to demonstrate any superiority of the FOLFOXIRI combination compared with the FOLFIRI regimen, although the observed median OS is one of the best ever reported in the literature. © 2006 Cancer Research UK.

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m(2) per week and increments of 10 mg/m(2) per week) and cisplatin (starting dose 70 mg/m(2) and increments of 5 mg/m(2)). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m(2) per week and cisplatin 75 mg/m(2)). The maximum-tolerated dose was 40 mg/m(2) per week for docetaxel and 70 mg/m(2) every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3-39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.