Changes in 4 Proteins Could Guide New Approaches to Breast Cancer
Abnormal activation or production of four proteins involved in translation, the final step of creating other proteins, are associated with reduced survival among patients with hormone receptor-positive breast cancer.
Findings presented at the AACR Annual Meeting 2012 in Chicago, if validated in additional research, could lead to new prognostic indicators, new targets for drugs, and better selection of patients for existing therapies.
All of the aberrantly activated translational proteins are regulated by the PI3K/mTOR molecular signaling pathway, which has been implicated in development and progression of various cancers and in resistance to standard endocrine therapy in estrogen-receptor positive breast cancer.
"These data underline the importance of the PI3K/mTOR pathway in hormone receptor-positive breast cancer," says Funda Meric-Bernstam, M.D., professor in MD Anderson's Department of Surgical Oncology and medical director of the Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy.
Meric-Bernstam and colleagues systematically analyzed major translation-regulating proteins in tumors from 190 patients with stage 1 to stage 3 hormone receptor-positive breast cancer. Median follow-up was 96 months. They found four aberrations that are independent predictors of reduced overall survival or recurrence-free survival.
Increased phosphorylation of ribosomal protein S6 (pS6) and of translation initiation factor 4E-binding protein 1 (p4E-BP1).
Increased expression of eukaryotic elongation factor 2 kinase (eEF2K).
Decreased expression of programmed cell death protein 4 (pdcd4).
Greater understanding of the role of these proteins could lead to markers that help select patients with a high risk of relapse if treated with traditional endocrine therapy alone and identify those who might benefit from an additional targeted therapy.
Results from a major phase III clinical trial presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium showed that the mTOR inhibitor everolimus increased progression-free survival when combined with the hormonal therapy exemestane to treat resistant hormone receptor-positive breast cancer.
Temsirolimus and everolimus are approved for treatment of other cancers and dozens of other mTOR inhibitors are in clinical trials.
"As we understand how to select patients better we'll be able to more efficiently use these targeted therapies to improve outcomes for breast cancer patients," Meric-Bernstam says.