No abstract

Breast cancer is the most common cancer among women. Up to 75% of breast cancers express the estrogen receptor (ER)α and/or the progesterone receptor (PR). Patients with hormone receptor-positive metastatic breast cancer are typically treated with endocrine therapy. Yet, not all patients with metastatic breast cancer respond to endocrine treatments and are considered to have primary (de novo) resistance. Furthermore, all patients who initially respond to endocrine treatment will eventually develop acquired resistance. Several mechanisms have been linked to the development of endocrine resistance, including reduced expression of ERα, altered regulation of the ER pathway, and activation of various growth factor signaling pathways, among them the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is involved in critical processes including cell survival, proliferation, and angiogenesis, and plays a central role in breast cancer development. Recent laboratory and clinical data implicate this pathway as mediating endocrine resistance, and agents directed against critical components of this pathway are either already approved for clinical use in breast cancer patients or are currently being tested in clinical trials. In this review, we describe the interaction between the PI3K/Akt/mTOR pathway and the ER cascade, its role in mediating endocrine resistance, and the clinical implications of this interaction.

Background: The 21-Gene Recurrence Score® Assay (Oncotype DX®) has been validated as a prognostic and predictive tool in estrogen receptor (ER)+ breast cancer in multiple studies using archival specimens of clinical trials with long term follow up. Prospective outcome data from patients where treatment decisions incorporated the Recurrence Score results have not been reported. We evaluated treatments and clinical outcomes in patients undergoing Recurrence Score testing in 9 medical centers within Clalit Health Services (CHS), the largest HMO in Israel. Methods: Medical records of patients with N0/Nmic ER+ HER2-negative disease undergoing testing from 12/2004 to 12/2010 in 9 medical centers (Rabin, Lin, Soroka, Meir, Kaplan, Hadassah, Ha'emek, Rambam, and Shaare Zedek) within CHS were individually reviewed to verify treatments given, recurrence, and survival status. 5-year Kaplan-Meier (KM) and standard error estimates for distant recurrence and breast cancer specific survival were determined. Results: 1594 patients were evaluated with 5.9 years median follow-up. Median age, 61 (25-85) years; N0/Nmic (90%/10%); Grade I (16%), II (48%), III (16%), N/A (19%); histology, IDC (80%), lobular (13%), other (7%). Distribution of Recurrence Score risk groups (Recurrence Score results of <18, 18-30, ≥31): low (51%), intermediate (38%), and high (11%), with chemotherapy (CT) use of 1%, 26%, and 89%, respectively. Distant recurrence was reported in 17/813, 33/612, and 24/169 patients in the low, intermediate, and high Recurrence Score groups, respectively. In the high Recurrence Score group, distant recurrence was reported in 20/150 (13.3%) of CT-treated patients and in 4/19 (21.1%) of untreated patients. In the intermediate Recurrence Score group, the respective values were 9/162 (5.6%) and 24/450 (5.3%). The 5-year KM estimate for distant recurrence rate was 1.4% (95% CI: 0.9-2.3%) for the entire cohort, and 0.5% (95% CI: 0.2-1.6%), 1.2% (95% CI: 0.6-2.8%), and 6.9% (95% CI: 3.7-12.9), for the low, intermediate, and high Recurrence Score groups, respectively. The 5-year KM estimate for breast cancer specific survival was 98.4% (95% CI: 97.6-98.9%) for the entire cohort, and 99.9% (95% CI: 99.0-99.98%), 98.5% (95% CI: 97.1-99.2%) and 90.6% (95% CI: 84.5-94.4%), for the low, intermediate, and high Recurrence Score groups, respectively. Conclusions: These are the first prospective long term clinical outcome data from approximately 1600 patients for whom the 21-gene Recurrence Score assay has been incorporated in real-life clinical decision making. The documented use of CT was appropriately based on the Recurrence Score result, and the outcomes for recurrence and survival are consistent with previously reported prospective-retrospective studies of the 21-gene assay. The 5 year KM estimates for distant recurrence rate in patients with low and intermediate Recurrence Score results who were treated based upon their Recurrence Score results were very low (0.5% and 1.2%, respectively). Citation Format: Stemmer SM, Steiner M, Rizel S, Soussan-Gutman L, Geffen DB, Nisenbaum B, Ben-Baruch N, Isaacs K, Fried G, Rosengarten O, Uziely B, Svedman C, Rothney M, Klang SH, Ryvo L, Kaufman B, Evron E, Zidan J, Shak S, Liebermann N. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score result: 5-year KM estimate for breast cancer specific survival with recurrence score results ≤30 is >98%. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-02.