Dataset Information

The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis.

ABSTRACT:

Background

Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to patients treated with exemestane. Additionally, we assessed the added value of metformin as this drug may lower IGF1R stimulation.

Methods

Of 2,446 Dutch TEAM patients, randomized to either exemestane for 5 years or sequential treatment (tamoxifen for 2-3 years followed by exemestane for another 3-2 years) tumor tissue microarray sections were immunohistochemically stained for IGF1R. Overall Survival (OS), Breast Cancer specific Survival (BCSS) and Relapse-Free Survival (RFS) were assessed in patient subgroups with low and high IGF1R expression, and in patients with or without metformin use.

Results

High IGF1R tumor expression was significantly associated with exemestane therapy for RFS (Hazard Ratio (HR) 0.74, 95% Confidence Interval (CI) 0.58-0.95, p = 0.02). In addition, the combination of metformin with exemestane resulted in improved efficacy, yielding a 5-yrs RFS of 95% (HR 0.32, 95% CI 0.10-1.00, p = 0.02, compared to sequential treatment). No relation was observed in tumors with low IGF-1R expression.

Conclusion

This study suggests IGF1R as a potential biomarker of improved clinical outcome in HR+ve BC patients treated with exemestane. Adding metformin to exemestane treatment may add to this effect.

SUBMITTER: Engels CC

PROVIDER: S-EPMC5423148 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Publications

The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis.

Engels Charla C CC de Glas Nienke A NA Sajet Anita A Bastiaannet Esther E Smit Vincent T H B M VT Kuppen Peter J K PJ Seynaeve Caroline C van de Velde Cornelis J H CJ Liefers Gerrit Jan GJ

Molecular oncology 20151031 4

<h4>Background</h4>Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to pa ...[more]

PMID: 26706833

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Project description:BackgroundResistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.MethodsIn this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.ResultsBaseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).ConclusionsEverolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

Project description:ObjectiveOur objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.EvidenceEach expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.Consensus processA consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.ConclusionsThe major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Dataset Information

The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis.

Background

Methods

Results

Conclusion

Publications

The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis.

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