4121 Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the... more 4121 Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the monoclonal therapeutic antibody cetuximab. Yet, repeated failure of EGFR immunohistochemistry (IHC) in predicting treatment outcome has questioned its value in colorectal cancer (CRC). Therefore search for a valid molecular predictor of cetuximab efficacy is highly justified. Methods: 64 CRC patients were treated with standard chemotherapy plus cetuximab in the metastatic setting. RNA was isolated from fixed tumor tissue samples employing an experimental method based on magnetic beads from Siemens Medical Solutions Diagnostics, followed by kinetic one-step RT-PCR for EGFR, HER-2, HER-3, and HER-4 analysis. EGFR protein levels were also assessed by IHC in 62 of the patients, using the 31G7 clone of the mouse monoclonal antibody (Zymed). Slides scored 1+, 2+ and 3+ were considered EGFR protein positive. Results: After a median follow-up of 17 months, median survival was 15.1 months, while median time to disease progression (TTP) was 6.6 months. For the RT-PCR results an objective cut-off at the 2nd quartile (median) for the HER family was chosen. EGFR RNA levels above the median value, demonstrated predictive value in terms of a prolonged TTP (9.3 vs. 5.5 months, p=0.017). No difference was found in terms of survival (24.6 vs. 12.6 months, p=0.106). EGRF assessed by IHC and the rest of the HER family markers assessed by RT-PCR failed to predict TTP outcome or survival. Finally, no agreement was found between the IHC and RT-PCR methods when assessing EGFR. Conclusions: The results of this retrospective study show a predictive value of EGFR RNA levels assessed by RT-PCR on TTP, as opposed to EGFR protein levels. Prospective validation studies are needed to prove if this biomarker is the missing molecular predictor of response to cetuximab. No significant financial relationships to disclose.
To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line... more To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.
Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved a... more Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS e...
Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the s... more Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m2) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding ev...
Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinan... more Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinant humanized monoclonal antibody, was found to significantly prolongsurvival of patients with metastatic HER2 over-expressing and/or amplified breast cancer. In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), transcriptional profiling and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Results: Central review...
3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework ... more 3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework supports the hypothesis that sequential administration of cytotoxic drugs at adequate doses can maximize the cell kill and overcome drug resistance. The aim of the study was to compare the response rate (RR), the time to tumor progression (TTP), the overall survival (OS) and to assess the toxicity profile of previously untreated patients with advanced CRC randomly assigned between IRI-LV-5FU (arm A) versus IRI-LV-5FU followed by OXA-LV-5FU (arm B). Methods: Intent to treat analysis was performed on 429 patients (219 in arm A and 210 in arm B) who were randomized from 31/10/2001 to 21/10/2004. The treatment schedules consisted of weekly IRI, 80 mg/m2 or OXA, 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5FU, 450 mg/m2 for 6 weeks followed by a 2-week rest period. Treatment was continued for 4 cycles, patients in arm B were treated initially with IRI-LV-5FU for 2 cyc...
e18868Background: Cancer has multiple processes that increase thrombogenicity. Thrombosis is the ... more e18868Background: Cancer has multiple processes that increase thrombogenicity. Thrombosis is the 2nd cause of death in cancer patients. CAT is common, could delay anti-cancer therapy and increase c...
IntroductionWe sought to determine the level of activation of the critical components of the cycl... more IntroductionWe sought to determine the level of activation of the critical components of the cyclin D1-mediated pathway and to evaluate their prognostic significance across the different molecular subtypes of advanced breast cancer.Patients and methodsThe study population comprised 219 female patients with advanced breast cancer who had been found to have human epidermal growth factor receptor 2 (HER2)-positive disease by local testing and were all treated with trastuzumab-based regimens. For all tumours, central testing for HER2 was performed, and cyclin D1 gene (CCND1) amplification, mRNA and protein expression were assessed by FISH, quantitative real-time-PCR and immunohistochemistry, respectively. Prognostic impact on clinical endpoints was evaluated with Cox regression analyses.ResultsAfter central testing, only 134 (61.2%) of 219 patients were confirmed to have HER2 gene amplification by FISH and/or 3+ HER2 protein expression by immunohistochemistry. After a median follow-up t...
592 Background: High TIL may confer better prognosis to TNBC patients and may interfere with tras... more 592 Background: High TIL may confer better prognosis to TNBC patients and may interfere with trastuzumab (T) benefit in HER2-positive breast cancer (BC) patients. Here, we investigated the effect of TIL on BC patient outcome with respect to immunohistochemical subtypes and treatment. Methods: Intratumoral mononuclear infiltrates were assessed as % of stromal area under low magnification on whole routine sections of 2613 breast carcinomas. Three different cut-offs (c/o) for high/low TIL were used (50%, 35% and 25%). Subtyping revealed 948 Luminal A, 615 Luminal B, 477 Luminal-HER2, 246 HER2-enriched, and 327 TNBC tumors. Patients had been treated in the frame of 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-T era. T was administered sequentially for 1 year. Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively, and were subtype specific. Using the 35% c/o, high TIL were significantly more frequent in TN...
e11577 Background: p85 is an enzyme that belongs to the class 1A phosphatidylinositol 3-kinases (... more e11577 Background: p85 is an enzyme that belongs to the class 1A phosphatidylinositol 3-kinases (PI3Ks). Taking under consideration the activation of p85 by HER2, as well as the role of p85 in the regulation of the PTEN/PI3K/Akt pathway, we sought to investigate the possible relation of the immunohistochemical expression of the p85 protein to the expression of the PTEN and phosphorylated Akt proteins, as well as to PIK3CA mutations in a cohort of metastatic breast cancer patients. The relation of p85 to parameters, such as time to progression and survival was also assessed. Methods: The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients treated with trastuzumab-based regimens in the metastatic setting. All samples were evaluated by immunohistochemistry for p...
4121 Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the... more 4121 Background: The epidermal growth factor receptor (EGFR) protein is the nominal target of the monoclonal therapeutic antibody cetuximab. Yet, repeated failure of EGFR immunohistochemistry (IHC) in predicting treatment outcome has questioned its value in colorectal cancer (CRC). Therefore search for a valid molecular predictor of cetuximab efficacy is highly justified. Methods: 64 CRC patients were treated with standard chemotherapy plus cetuximab in the metastatic setting. RNA was isolated from fixed tumor tissue samples employing an experimental method based on magnetic beads from Siemens Medical Solutions Diagnostics, followed by kinetic one-step RT-PCR for EGFR, HER-2, HER-3, and HER-4 analysis. EGFR protein levels were also assessed by IHC in 62 of the patients, using the 31G7 clone of the mouse monoclonal antibody (Zymed). Slides scored 1+, 2+ and 3+ were considered EGFR protein positive. Results: After a median follow-up of 17 months, median survival was 15.1 months, while median time to disease progression (TTP) was 6.6 months. For the RT-PCR results an objective cut-off at the 2nd quartile (median) for the HER family was chosen. EGFR RNA levels above the median value, demonstrated predictive value in terms of a prolonged TTP (9.3 vs. 5.5 months, p=0.017). No difference was found in terms of survival (24.6 vs. 12.6 months, p=0.106). EGRF assessed by IHC and the rest of the HER family markers assessed by RT-PCR failed to predict TTP outcome or survival. Finally, no agreement was found between the IHC and RT-PCR methods when assessing EGFR. Conclusions: The results of this retrospective study show a predictive value of EGFR RNA levels assessed by RT-PCR on TTP, as opposed to EGFR protein levels. Prospective validation studies are needed to prove if this biomarker is the missing molecular predictor of response to cetuximab. No significant financial relationships to disclose.
To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line... more To evaluate the activity and acute toxicity of the combination of weekly paclitaxel as first-line chemotherapy and trastuzumab, in patients with HER-2/neu overexpressing advanced breast cancer (ABC). Weekly paclitaxel has been shown to be a well tolerated treatment with considerable activity in patients with ABC. Clinical trials with transtuzumab, a humanized anti-p185 HER-2/neu monoclonal antibody have demonstrated that this agent produces objective responses in patients with ABC. From December 1998 to April 2000, 34 patients with HER-2/neu overexpressing ABC were treated with weekly paclitaxel; given by one-hour infusion at a dose of 90 mg/m2 immediately followed by trastuzumab, 4 mg/kg as a loading dose and 2 mg/kg i.v. given over 30 min, thereafter weekly for at least 12 weeks. Expression of HER-2/neu was determined by immunohistochemical analysis on fixed, paraffin-embedded tissues. Eligible patients were required to have > or = 25% stained tumor cells. Thirty-three patients completed at least 12 weeks of combined treatment. After completion of the 12th week of treatment, four patients (12%) achieved complete and 17 (50%) partial response. Median duration of response was 11.6 months. More frequent side effects included anemia (56%). neutropenia (27%), peripheral neuropathy (78%), diarrhea (30%), alopecia (70%), arthralgias/myalgias (62%), fatigue (59%) and hypersensitivity reactions (62%). Median time to progression was nine months while median survival had not been reached The combination of weekly paclitaxel and trastuzumab is a safe and active regimen for patients with HER-2/neu overexpressing ABC. Randomized phase III studies with this combination are warranted.
Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved a... more Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS e...
Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the s... more Background: Cancer patients are at high risk for cancer-associated thrombosis (CAT). CAT is the second leading cause of death in these patients but it can be preventable with thromboprophylaxis. Patients and Methods: An observational, prospective, multicenter study aiming to record CAT management in clinical practice was conducted by the Hellenic Society of Medical Oncology (HeSMO). Results: A total of 426 active cancer patients (mean age 65.3 years, mean BMI: 26.1 kg/m2) who received thromboprophylaxis, were included from 18 oncology units. Tumor types were lung 25.1%, pancreas 13.9%, breast 8.7%, stomach 8.5%, ovarian 7.8%, and others 36%, while 69% had metastases. A total of 71% had a Khorana score ≤2 and 61% received High Thrombotic Risk Chemotherapy Agents (HTRCAs, e.g., platinum). For thromboprophylaxis patients received mainly Low Molecular Weight Heparins (LMWHs), on higher than prophylactic doses in 50% of cases. Overall, 16 (3.8%) thrombotic events and 6 (1.4%) bleeding ev...
Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinan... more Background-aim: Metastatic breast cancer (MBC) is an incurable disease. Trastuzumab, a recombinant humanized monoclonal antibody, was found to significantly prolongsurvival of patients with metastatic HER2 over-expressing and/or amplified breast cancer. In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), transcriptional profiling and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Results: Central review...
3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework ... more 3583 Background: IRI and OXA are both effective in the treatment of CRC. A theoretical framework supports the hypothesis that sequential administration of cytotoxic drugs at adequate doses can maximize the cell kill and overcome drug resistance. The aim of the study was to compare the response rate (RR), the time to tumor progression (TTP), the overall survival (OS) and to assess the toxicity profile of previously untreated patients with advanced CRC randomly assigned between IRI-LV-5FU (arm A) versus IRI-LV-5FU followed by OXA-LV-5FU (arm B). Methods: Intent to treat analysis was performed on 429 patients (219 in arm A and 210 in arm B) who were randomized from 31/10/2001 to 21/10/2004. The treatment schedules consisted of weekly IRI, 80 mg/m2 or OXA, 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5FU, 450 mg/m2 for 6 weeks followed by a 2-week rest period. Treatment was continued for 4 cycles, patients in arm B were treated initially with IRI-LV-5FU for 2 cyc...
e18868Background: Cancer has multiple processes that increase thrombogenicity. Thrombosis is the ... more e18868Background: Cancer has multiple processes that increase thrombogenicity. Thrombosis is the 2nd cause of death in cancer patients. CAT is common, could delay anti-cancer therapy and increase c...
IntroductionWe sought to determine the level of activation of the critical components of the cycl... more IntroductionWe sought to determine the level of activation of the critical components of the cyclin D1-mediated pathway and to evaluate their prognostic significance across the different molecular subtypes of advanced breast cancer.Patients and methodsThe study population comprised 219 female patients with advanced breast cancer who had been found to have human epidermal growth factor receptor 2 (HER2)-positive disease by local testing and were all treated with trastuzumab-based regimens. For all tumours, central testing for HER2 was performed, and cyclin D1 gene (CCND1) amplification, mRNA and protein expression were assessed by FISH, quantitative real-time-PCR and immunohistochemistry, respectively. Prognostic impact on clinical endpoints was evaluated with Cox regression analyses.ResultsAfter central testing, only 134 (61.2%) of 219 patients were confirmed to have HER2 gene amplification by FISH and/or 3+ HER2 protein expression by immunohistochemistry. After a median follow-up t...
592 Background: High TIL may confer better prognosis to TNBC patients and may interfere with tras... more 592 Background: High TIL may confer better prognosis to TNBC patients and may interfere with trastuzumab (T) benefit in HER2-positive breast cancer (BC) patients. Here, we investigated the effect of TIL on BC patient outcome with respect to immunohistochemical subtypes and treatment. Methods: Intratumoral mononuclear infiltrates were assessed as % of stromal area under low magnification on whole routine sections of 2613 breast carcinomas. Three different cut-offs (c/o) for high/low TIL were used (50%, 35% and 25%). Subtyping revealed 948 Luminal A, 615 Luminal B, 477 Luminal-HER2, 246 HER2-enriched, and 327 TNBC tumors. Patients had been treated in the frame of 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-T era. T was administered sequentially for 1 year. Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively, and were subtype specific. Using the 35% c/o, high TIL were significantly more frequent in TN...
e11577 Background: p85 is an enzyme that belongs to the class 1A phosphatidylinositol 3-kinases (... more e11577 Background: p85 is an enzyme that belongs to the class 1A phosphatidylinositol 3-kinases (PI3Ks). Taking under consideration the activation of p85 by HER2, as well as the role of p85 in the regulation of the PTEN/PI3K/Akt pathway, we sought to investigate the possible relation of the immunohistochemical expression of the p85 protein to the expression of the PTEN and phosphorylated Akt proteins, as well as to PIK3CA mutations in a cohort of metastatic breast cancer patients. The relation of p85 to parameters, such as time to progression and survival was also assessed. Methods: The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients treated with trastuzumab-based regimens in the metastatic setting. All samples were evaluated by immunohistochemistry for p...
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