Hellenic Cooperative Oncology Group HeCOG

Athens, Greece

Hellenic Cooperative Oncology Group HeCOG

Athens, Greece

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Geva R.,Tel Aviv Sourasky Medical Center | Vecchione L.,University Hospital Gasthuisberg | Kalogeras K.T.,Hellenic Cooperative Oncology Group HeCOG | Jensen B.V.,Herlev Hospital | And 25 more authors.
Gut | Year: 2014

Objective We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. Design To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included. Results Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV. Conclusions No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab. © 2014 BMJ Publishing Group Ltd & British Society of Gastroenterology.


Geva R.,Tel Aviv Sourasky Medical Center | Vecchione L.,University Hospital Gasthuisberg | Kalogeras K.T.,Hellenic Cooperative Oncology Group HeCOG | Jensen B.V.,Herlev Hospital | And 25 more authors.
Gut | Year: 2015

Objective We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. Design To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included. Results: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV. Conclusions: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.


PubMed | Shizuoka Cancer Center, National Hospital Organization Shikoku Cancer Center, prus Oncology Center, Norris Comprehensive Cancer Center and Hospital and 19 more.
Type: Journal Article | Journal: Gut | Year: 2015

We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0weeks; 95% CI18.8 to 25.2) versus non-HH (22.0weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4weeks; 95% CI 13.0 to 19.8) versus non-VV (23weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.


Dafni U.,National and Kapodistrian University of Athens | Grimani I.,Hellenic Cooperative Oncology Group HeCOG | Xyrafas A.,National and Kapodistrian University of Athens | Eleftheraki A.G.,Hellenic Cooperative Oncology Group HeCOG | And 2 more authors.
Breast Cancer Research and Treatment | Year: 2010

In the metastatic setting, a detected time trend to improved prognosis could be attributed to the corresponding recent advances in the therapeutic approaches. The aim of the current study was to first assess, in a large cohort of well over a thousand patients, the time trends in survival in MBC for the last 15 years and second to explore its association to prognostic factors affecting outcome including therapeutic regimen. This meta-analysis uses individual patient data collected from all the trials on MBC (6 nonrandomized, 4 randomized) conducted by HeCOG from 1991 through 2006. Four 4-year time periods (1991-1994, 1995-1998, 1999-2002, and 2003-2006) were constructed for exploration of time trends in survival according to the patient's date of metastatic diagnosis. Different first line regimens in the 10 trials include anthracycline monotherapy (epirubicin, in the early 1990s) and taxane-containing regimens either as monotherapy or in different combinations with anthracyclines or other drugs. In two phase II studies and in the last randomized study, trastuzumab was administered in all the patients with HER2 overexpressing tumors. In this study, information is based on a total of 1361 patients with a median follow up of 3.7 years and median survival of 1.9 years (median survival 1.28, 1.68, 2.20, and 2.57 years for 1991-1994, 1995-1998, 1999-2002, and 2003-2006, respectively). Survival improved significantly across diagnosis time periods, by 25, 44, and 51%, respectively, in each time period (1995-1998: HR = 0.75, P = 0.004; 1999-2002: HR = 0.56, P < 0.001; 2003-2006: HR = 0.49, P < 0.001) as compared to the first time period (1991-1994). The effect of metastatic diagnosis time period remains almost unchanged in the presence of the following significant prognostic factors: performance status, hormonal receptor status, previous adjuvant chemotherapy, previous adjuvant hormonal treatment, visceral metastasis at entry, and number of metastatic sites. When exploring the effect of new systemic treatment introduction, taking into account the same significant prognostic factors, the effect of diagnosis time period disappears, and the survival improvement is explained directly by the introduction of new agents (hormonal treatment for metastatic disease: yes vs. no: HR = 0.72, P < 0.001; taxanes at first line: yes vs. no: HR = 0.69, P = 0.002; trastuzumab at first line: yes vs. no: HR = 0.63, P < 0.001). The results of this study provide significant evidence of improvement in prognosis of MBC patients within the last 15 years, taking into account all the important significant prognostic factors, and this improvement can be attributed to the use of new systemic treatment agents in the management of the disease. © 2009 Springer Science+Business Media, LLC.


Golfinopoulos V.,University of Ioannina | Golfinopoulos V.,Hellenic Cooperative Oncology Group HeCOG | Pentheroudakis G.,University of Ioannina | Pentheroudakis G.,Hellenic Cooperative Oncology Group HeCOG | And 14 more authors.
Annals of Oncology | Year: 2012

Background: Hypothesising that cancer of unknown primary (CUP) may harbour unique characteristics, we present a translational study of the immunohistochemical expression and clinical correlation of key PTEN/AKT pathway molecules. Patients and methods: We collected 100 paraffin-embedded CUP tissue blocks. We studied using tissue microarrays the expression of PTEN, phospho-AKT, Cyclin D1, p21, phospho-RPS6. From the percentage of staining tumour cells and the literature, we selected cut-offs to classify the expression of each biomolecule. We correlated IHC expression with clinical data. Results: PTEN, pAKT, and pRPS6 showed frequent expression. At univariate analysis, high IHC expression of pAKT and pRPS6 displayed statistically significant association with worse survival. Prognosis was worse upon concurrent high IHC expression of pMAPK and pAKT {median overall survival = 8 months [95% confidence interval (CI) 5.3-10.7] versus 17 months [95% CI 13.1-20.9]}. In multivariate analysis, high p21 was associated with better survival (risk ratio [RR] = 0.34 [95% CI 0.16-0.73], P = 0.005). High expression of pAKT (RR = 2.39 [95% CI 1.23-4.66], P = 0.01) or pRPS6 (RR = 2.76 [95% CI 1.31-5.84], P = 0.008) was associated with worse survival. Conclusions: p21 expression conferred favourable prognosis, while high pAKT or pRPS6 expression predicted worse prognosis. Concurrent MAPK and pAKT expression had a marked adverse impact on survival. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Sakellari I.,George Papanicolaou Hospital | Mallouri D.,George Papanicolaou Hospital | Batsis I.,George Papanicolaou Hospital | Apostolou C.,George Papanicolaou Hospital | And 13 more authors.
Leukemia and Lymphoma | Year: 2015

Optimal conditioning remains a challenge in lymphomas. We designed a regimen consisting of Busulfex, etoposide and melphalan (BuEM). We retrospectively analyzed the outcome of patients conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM) or BuEM in matched-pair analysis on a planned 2:1 ratio. Eighty-seven patients treated with BEAM who fulfilled the matching criteria were randomly selected. Two-year progression-free survival/overall survival (PFS/OS) were 63.2%/76.7% for BEAM vs. 65.6%/79.8% for BuEM after 64.7 and 42.7 months, respectively. Furthermore, marginally better PFS and OS were noted in Hodgkin lymphoma (HL) after BuEM. In multivariate analysis, PFS was superior in HL, chemosensitive disease and complete remission post-transplant. BEAM correlated with faster engraftment, reduced infections, less mucositis and liver toxicity, and BuEM with less need for blood cell and platelet transfusions and granulocyte colony-stimulating factor administration. In conclusion, BuEM was well tolerated and equally highly efficacious as BEAM for non-Hodgkin lymphoma and offered marginally significantly improved PFS and OS in HL with acceptable toxicity and zero mortality. © 2015 Informa UK, Ltd.


PubMed | Hellenic Cooperative Oncology Group HeCOG
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

e21110 Background: It is well recognized that breast cancer is a heterogeneous disease that is composed of several molecular subtypes with substantial differences in growth rate, invasiveness and treatment response. Estrogen receptors (ER), progesterone receptors (PgR) and HER2 are important determinants of these molecular subtypes, since they drive specific targeted treatments, such as antiestrogens, aromatase inhibitors and trastuzumab.595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel (E-T-CMF vs. E-CMF) in the context of a randomized Phase III study. ER, PgR, HER2, Ki67, EGFR, and CK5 were evaluated in 298 formalin-fixed tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH) using ZYMED (InVitrogen) technology and was used to determine HER2 status for patients that had a score different than +3 by IHC. Identification of the immunophenotypic subtypes was based initially on ER and PgR protein expression. HER2 status and Ki67 protein expression differentiated luminal subtypes (luminal A tumors being HER2- and Ki67-negative), while EGFR and CK5 protein overexpression identified basal-like tumors.Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2-enriched, and 36 (12%) as triple-negative breast cancer. In the latter group there were 25 tumors (69%) that expressed EGFR and/or CK5 (basal-like tumors). Patients with luminal A tumors had the best prognosis, with improved DFS (log-rank, p=0.033) and OS (p=0.006) compared to the other three tumor subtypes. No benefit from paclitaxel treatment was detected in any of the four subtypes. Evaluation of ER, PgR and HER2 mRNA expression using RT-PCR will also be used for identification of triple-negative disease in the same cohort.The results of this study confirm that immunophenotypic classification of breast cancer is of prognostic value, without benefit however being detected in our cohort from paclitaxel treatment in any of the four tumor subtypes.


PubMed | Hellenic Cooperative Oncology Group HeCOG
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

e21059 Background: The prognostic/predictive value of HER2 and topoisomerase II alpha (TOP2A) gene status in patients with breast cancer treated with adjuvant dose-dense sequential chemotherapy is not well defined. Anthracyclines and taxanes are considered to be important drugs in this setting.Formalin-fixed tumor tissue samples were obtained from 354 patients participating in a phase III trial, in which 595 high-risk breast cancer patients were randomized to receive postoperative dose-dense sequential chemotherapy with epirubicin and CMF, with or without paclitaxel. HER2 and TOP2A gene amplification was evaluated by chromogen in situ hybridization (CISH) using ZYMED (InVitrogen) technology in 285 and 266 patients, respectively and protein expression was assessed by immunohistochemistry (IHC) in 297 and 248 patients, respectively.Among the 52 tumors classified HER2-positive by IHC (3+, strong membranous staining in 30% of the tumor cells), 50 tumors (96%) were amplified by CISH. As for TOP2A, among the 153 tumors classified positive by IHC (2+ and 3+, moderate and strong nuclear staining in 5% of the tumor cells), only 13 (9%) of the tumors were amplified by CISH. 64% of the HER2-positive tumors were also TOP2A-positive when assessed by IHC, while only 21% of the HER2-amplified tumors were also TOP2A-amplified by CISH. Univariate Cox regression analysis did not show any association of HER2 and TOP2A gene amplification or IHC-positivity with OS or DFS, except for an increased risk for progression (HR=1.71, 95% CI: 1.07-2.73, Wald p=0.024) in HER2-positive patients by IHC. No benefit from paclitaxel treatment was detected for HER2 or TOP2A gene amplified or protein overexpressing tumors.HER2 and TOP2A gene amplification or protein overexpression do not appear to be predictive for response to paclitaxel in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy. Evaluation of mRNA expression and gene amplification of HER2 and TOP2A by RT-PCR and FISH is in progress and the data will be presented at the meeting.


PubMed | Hellenic Cooperative Oncology Group HeCOG
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

4212 Background: In an attempt to improve response rates and mainly survival in patients with advanced gastric cancer, new chemotherapy regiment need to be tested. Based on impressive results of an Italian intensive weekly chemotherapy regimens (PELF) and the effectiveness of Docetaxel, Epirubicin and Carboplatin in gastric cancer, we decided to conduct a phase II trial of intensive weekly chemotherapy with these three drugs (docetaxel, Epirubicin, Carboplatin - DEC) in patients with advanced gastric cancer.patients with advanced gastric cancer, and no previous chemotherapy for metastatic disease, were treated with: docetaxel 30mg/mA total of 74 patients (55 males and 19 females) with median age of 65 years and median PS=1 were entered in this trial. The sites of disease were: locoregional 36%, liver 51%, lymphnodes 36%, lung 16%, bones 7% and others 34%. The number of metastatic sites was: 1 (41%), 2 (32%) and 3 (27%). A total of 179 cycles (each cycle represents 6 weeks) were delivered (median 2 cycles per patient). Among 74 patients, 61 are evaluable for response: Overall response 15/61 (24.5%) (CR=11.5%, PR=13%), stable disease 16/61 (26.3%), progressive disease 30/61 (49.2%). With a median follow - up of 22.4 months the median time to progression was 5.2 months (range 0.5 - 35.37) and the median overall survival was 7.3 months (range 0.5 - 35.37). The main grade III - IV toxicities of patients were: neutropenia 36% (febrile 5.5%), thrombocytopenia 13.5%, anemia 7% and alopecia 20%.These results showed that the above intensive weekly regiment was tolerable but with moderate activity in advanced gastric cancer. No significant financial relationships to disclose.

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