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Background: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy.Methods: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis).Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up.Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome. [ABSTRACT FROM AUTHOR]

Background: The EndoPredict (EP) score is an RNA-based multigene test to predict the likelihood of distant recurrence in ER-positive (ER+), HER2-negative (HER2-) breast cancer (BC) patients treated with adjuvant endocrine therapy. Results from two large randomized phase III trials involving endocrine therapy only (n > 1700) demonstrated a prognostic power of the EP score beyond what can be achieved by combining the commonly used clinicopathological parameters (Filipits M, 2011). The performance of the EP in chemotherapytreated patients has not been evaluated yet. Here, we analyzed the EndoPredict score in node -positive ER+/HER2-BC patients from the GEICAM-9906 trial, treated with adjuvant chemotherapy followed by hormonal therapy. Methods: Patients included in this study participated in the GEICAM/9906 trial and were either treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P) (Martin M, 2008). ESR1 and ERBB2 gene expression were assessed by qRT-PCR in 800 formalin-fixed paraffin embedded (FFPE) tumor samples out of 1246 patients included in the GEICAM/9906 trial. The EndoPredict score (including eight prognostic genes) was successfully determined in 555 out of the 566 ER+/HER2-patients. Patients were assigned into two categories (high/low), according to the predefined EP cut-off value (Filipits M, 2011). The primary endpoint for the analysis was distant metastasis. Metastasis rates were estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox regression. Interaction between treatment effects and EP was tested as well. Results: Twenty-five percent of patients (n = 141) were classified as EP-low-risk. Kaplan Meier analysis demonstrated that the metastasis-free survival (MFS) was 92% in the EP-low risk vs. 69% in the EP-high-risk group (absolute difference of 23%, HR 4.4 (2.3-8.4) p < 0.0001). Multivariate analysis showed that EP is an independent prognostic parameter after adjustment for age, grade, lymph node status and tumor size. EP was found to be prognostic in pre- (p = 0.0002, HR = 5.5 (2.2-13.6)) and postmenopausal (p = 0.0129, HR = 3.3 (1.3-8.2)) BC patients. There were not statistically significant differences in MFS between treatment arms (FEC vs. FEC-P) neither in the high nor in the low-risk groups. Interaction test between chemotherapy arm and EP score was not significant. Conclusions: The results of this study shows that the EndoPredict score is an independent prognostic parameter in node-positive, ER+/HER2- BC patients treated with adjuvant chemotherapy followed by hormonal therapy. EndoPredict was not found to be predictive of weekly paclitaxel efficacy. Novel predictive biomarkers are needed to identify the small subset of patients with ER+/HER2- tumors that actually benefit from weekly paclitaxel-containing regimens. [ABSTRACT FROM AUTHOR]

Background: ER+/HER2-- negative (ER+) breast cancers have a proclivity for late recurrence. A first step to an improved adjuvant treatment of late metastasis is to identify women at risk and understand the underlying biology. Several prognostic multigene tests have been developed for ER+ breast cancer patients. Some of these tests have been validated to predict early recurrence events. However , few gene expression assays have been shown to predict late metastases. Here, we assess whether the prognostic EndoPredict (EP) score, which incorporates both the expression levels of proliferative - and ESR1-related genes, can be used to identify late relapse events in ER+ breast cancer patients. Methods: Patients included in this study participated in the ABCSG-6 (tamoxifen-only arm) or ABCSG-8 phase III adjuvant trial and received either tamoxifen for 5 years or tamoxifen for 2 years followed by anastrozole for 3 years. All 1702 ER+/HER2- breast cancer patients were retrospectively assigned into risk categories based on the EP and on common clinical parameters. The primary endpoint was distant metastasis. Ongoing collection of follow-up events allowed estimation of metastasis rates using the Kaplan-Meier method in an early and late time cohort: 0-5 years/early recurrence and 5-10 years/late recurrence. Results: 49% of all patients were classified as low-risk according to the EP score. Kaplan Meier analysis demonstrated that the EP low-risk group had a significantly improved clinical outcome in the first (0-5 years; p < 0.0001) and second time interval (5-10 years; p = 0.002). Nodal metastasis was also significantly associated with the clinical outcome in both time intervals, with node-positive tumors showing a considerably higher rate of late recurrence events. In contrast, Ki67 levels and grading were not significantly associated with late metastasis. Multivariate analysis showed that EP was an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size and Ki67 in both the first and second time interval. The EPclin -- a combination of the EP and the clinical risk factors nodal status and tumor size -- showed the best performance in predicting late relapse events. Exploratory analyses of proliferative - versus ESR-1 related genes as contributors to early and late distant metastases show differential effects. Conclusions: The EndoPredict test identified a subgroup of patients that have a low likelihood of developing late metastases. The eight genes contained in the test provide complimentary prognostic information to clinico-pathologic parameters. Both the expression of proliferative - and ESR1-related genes contributes to the underlying biology of late distant metastases. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8months in combination arm versus 16.6months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed inmedian overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted. [ABSTRACT FROM AUTHOR]