Zacharenia Saridaki

Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer

The CD44(+)/CD24(-/low) and ALDH1(+) cell phenotypes are associated with stemness and enhanced tumorigenic potential in breast cancer. We assessed the expression of CD44, CD24 and ALDH1 on tumor cells circulating in the peripheral blood (CTCs) of patients with metastatic breast cancer using triple-marker immunofluorescence microscopy. Among a total of 1439 CTCs identified in 20 (66.7%) out of 30 patients, 35.2% had the stem-like/tumorigenic phenotype CD44(+)/CD24(-/low), whereas 17.7% of the CTCs analyzed in seven patients, were ALDH1(high)/CD24(-/low). In conclusion, we report the existence of a subpopulation of CTCs with putative stem cell progenitor phenotypes in patients with metastatic breast cancer.

Impact of KRAS, BRAF, PIK3CA Mutations, PTEN, AREG, EREG Expression and Skin Rash in ≥2nd Line Cetuximab-Based Therapy of Colorectal Cancer Patients

Background To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC) patients treated with cetuximab containing salvage chemotherapy. Methods Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded. Results KRAS, BRAF and PIK3CA mutations were present in 37 (33%), 8 (7.2%) and 11 (9.8%) cases, respectively, PTEN was lost in 21 (19.8%) cases, AREG and EREG were overexpressed in 48 (45%) and 51 (49%) cases. In the whole study population, time to tumor progression (TTP) and overall survival (OS) was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively) or BRAF (p = 0.001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively) or EREG (p = 0.002 and p = 0.004, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively) mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively) or EREG (p = 0.0001 and p<0.0001, respectively) and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively). TTP was significantly lower in patients with PIK3CA mutations (p = 0.01) or lost PTEN (p = 0.002). Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001), BRAF mutation (HR: 5.1, p<0.0001), EREG low expression (HR: 1.6, p = 0.021) and absence of severe/moderate skin rash (HR: 4.0, p<0.0001) as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01), BRAF mutation (HR: 3.0, p = 0.001), EREG low expression (HR: 1.7, p = 0.021), absecence of severe/moderate skin rash (HR: 3.7, p<0.0001) and the presence of undifferantited tumours (HR: 2.2, p = 0.001) were revealed as independent prognostic factors for decreased OS. Conclusions These results underscore that KRAS-BRAF mutations and EREG expression can be used as biomarkers to further select patients undergoing anti-EGFR treatment.

Mutational analysis of CDKN2A genes in patients with squamous cell carcinoma of the skin

Summary Background Nonmelanoma skin cancers [squamous cell carcinomas (SCC) and basal cell carcinomas (BCC)] are the most common neoplasias of the Caucasian population.

Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status

IntroductionTo evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse.MethodsThe medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR.ResultsThe incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007–0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51–101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97–12.84; P = 0.001) were independent predictive factors for CNS relapse.ConclusionCNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs.

Prognostic and predictive significance of MSI in stages II/III colon cancer

In colon cancer, classic disease staging remains the key prognosis and treatment determinant. Although adjuvant chemotherapy has an established role in stage III colon cancer patients, in stage II it is still a subject of controversy due to its restriction to a small subgroup of patients with high-risk histopathologic features. Patients with stage II tumors form a highly heterogeneous group, with five-year relative overall survival rates ranging from 87.5% (IIA) to 58.4% (IIC). Identifying those for whom adjuvant chemotherapy would be appropriate and necessary has been challenging, and prognostic markers which could serve in the selection of patients more likely to recur or benefit from adjuvant chemotherapy are eagerly needed. The stronger candidate in this category seems to be microsatellite instability (MSI). The recently reported European Society for Medical Oncology guidelines suggest that MSI should be evaluated in stage II colorectal cancer patients in order to contribute in treatment decision-making regarding chemotherapy administration. The hypothetical predictive role of MSI regarding its response to 5-fluorouracil-based adjuvant chemotherapy has proven a much more difficult issue to address. Almost every possible relation between MSI and chemotherapy outcome has been described in the adjuvant colon cancer setting in the international literature, and the matter is far from being settled. In this current report we critically evaluate the prognostic and predictive impact of MSI status in patients with stage II and stage III colon cancer patients.

BRAFV600E Mutation Analysis in Patients with Metastatic Colorectal Cancer (mCRC) in Daily Clinical Practice: Correlations with Clinical Characteristics, and Its Impact on Patients’ Outcome

Background To prospectively evaluate the usefulness of the BRAFV600E mutation detection in daily clinical practice in patients with metastatic Colorectal Cancer (mCRC). Patients and Methods 504 mCRC patients treated with systemic chemotherapy ± biologics were analyzed. Results A statistically significant higher incidence of the BRAF mutation was observed in patients with ECOG-PS 2 (p=0.001), multiple metastatic sites (p=0.002),> 65 years old (p=0.004), primary tumors located in the colon (p<0.001), high-grade tumors (p=0.001) and in those with mucinous features (p=0.037). Patients with BRAFV600E mutated tumors had a statistically significantly reduced progression-free survival (PFS) compared to wild-type (wt) ones (4.1 and 11.6 months, respectively; p<0.001) and overall survival (OS) (14.0 vs. 34.6 months, respectively; p<0.001). In the multivariate analysis the BRAFV600E mutation emerged as an independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7–6.2; p<0.001) and OS (HR: 5.9, 95% CI 3.7–9.5; p<0.001). Among the 273 patients treated with salvage cetuximab or panitumumab, the BRAFV600E mutation was correlated with reduced PFS (2.2 vs. 6.0 months; p<0.0001) and OS (4.3 vs. 17.4 months; p<0.0001). Conclusions The presence of BRAFV600E-mutation in mCRC characterizes a subgroup of patients with distinct biologic, clinical and pathological features and is associated with very poor patients’ prognosis.

A phase I-II trial of gefitinib in combination with vinorelbine and oxaliplatin as salvage therapy in women with advanced ovarian cancer (AOC)

5020 Background: To evaluate activity and tolerability of gefitinib (Iressa) in combination with vinorelbine and oxaliplatin as salvage therapy in women with AOC. METHODS Women with AOC recurrent or refractory after ≥ 1 previous line of platinum-containing chemotherapy who had measurable disease by RECIST criteria or assessable by Ca-125 received oral gefitinib 250 mg/day with vinorelbine 25 mg/m2 and oxaliplatin 50 mg/m2 on days 1 and 8 every 3 weeks without prophylactic growth factor support. Gefitinib was continued until disease progression. RESULTS So far 33 patients (pts) have been entered, (10 CDDP-sensitive; 23 CDDP-refractory disease). Among the first 10 pts, 4 DLTs were observed in the first cycle (2 febrile neutropenias, 1 grade 4 neutropenia lasting >5 days, 1 grade 3 diarrhea) resulting in dose reduction for vinorelbine (20 mg/m2) and oxaliplatin (40 mg/m2). In the next 10 pts only 2 DLTs (febrile neutropenia and grade 4 neutropenia lasting >5 days) were observed and the study is ongoing as phase II. All pts were evaluable for toxicity and 29 (19 CDDP-refractory; 10 CDDP-sensitive) for response (2 too early, 1 protocol violation, 1 lost to follow up). Three complete (CR) and 2 partial responses (PR) were seen in the CDDP-refractory group (ORR 23.8%; 95%CI: 5.6-42.0%) and 4 CR with 5 PR in the CDDP-sensitive group (ORR 90%; 95%CI: 71.4-100%). Median duration of response was 5.2 months (range 1-6) for CDDP-refractory and 6.6 (range 1-10) for CDDP-sensitive; median time to progression was 4.1 months (range 1-14) and 8.6 (range 1-12), respectively. So far 8 pts have died (7 disease progression; 1 pulmonary embolism), 14 had disease progression, and 11 continue treatment. 134 cycles have been administered: median 3 (range 1-9) cycles per pt. Τoxicity included grade 3/4 neutropenia each in 8 (24%) pts, febrile neutropenia 4 (12%), grade 3 anemia 1 (3%), grade 3 diarrhea 3 (9%), neurotoxicity 1 (3%), rash 1 (3%) and transaminase elevation 1 (3%). CONCLUSIONS The concurrent administration of gefitinib with vinorelbine and oxaliplatin is feasible and shows promising activity in pretreated pts with AOC. No significant financial relationships to disclose.

A dose escalation study of gemcitabine plus pemetrexed administered biweekly in patients with solid tumors.

Purpose: The study aimed to determine the maximum tolerated doses (MTDs) and identify the dose-limiting toxicities of the biweekly administration of pemetrexed plus gemcitabine in patients with solid tumors. Patients and Methods: Patients with advanced malignancies were treated with escalated doses of gemcitabine and pemetrexed (starting doses 1,250 and 300 mg/m2, respectively) both given on days 1 and 15 in cycles of 4 weeks. Results: Forty-one patients were treated at 7 dose levels. The MTD was reached at the dose of 1,750 mg/m2 for gemcitabine and 450 mg/m2 for pemetrexed. Dose-limiting events were grade IV neutropenia, febrile neutropenia and treatment delay due to grade III hematological toxicities. One partial response in a pretreated patient with ovarian cancer was observed, while 4 other patients experienced stable disease. Conclusions: The biweekly administration of gemcitabine plus pemetrexed at the recommended MTDs is safe, well tolerated and demonstrates antitumor activity which merits further evaluation in phase II studies.

Velour trial biomarkers update: Impact of RAS, BRAF, and sidedness on aflibercept activity.

3538Background: Addition of (ziv)-aflibercept (A) to FOLFIRI in second-line therapy for metastatic colorectal cancer (CRC) has been shown to be beneficial in phase III VELOUR trial (NCT00561470). A...

Second-line Paclitaxel/Carboplatin Versus Vinorelbine/Carboplatin in Patients Who Have Advanced Non-Small-Cell Lung Cancer Pretreated With Non-Platinum-Based Chemotherapy: A Multicenter Randomized Phase II Study

PURPOSE This study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND TREATMENT Patients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m(2) and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m(2) orally and carboplatin AUC3; both drugs were administered on days 1 and 15. RESULTS The overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS Platinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting.