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Purpose: Residual risk of relapse remains a substantial concern for patients with hormone receptor–positive breast cancer, with approximately half of all disease recurrences occurring after five years of adjuvant antiestrogen therapy. Experimental Design: The objective of this study was to examine the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression–based signature, for prediction of early (0–5 years) and late (>5 years) risk of distant recurrence in patients with estrogen receptor–positive (ER+), lymph node–negative (LN−) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n = 317) and a multi-institutional cohort (n = 358). Results: Within the Stockholm TAM cohort, BCI risk groups stratified the majority (∼65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. Conclusions: The prognostic sustainability of BCI to assess early- and late-distant recurrence risk at diagnosis has clinical use for decisions of chemotherapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five years. Clin Cancer Res; 19(15); 4196–205. ©2013 AACR.

Purpose: Estrogens have great significance in the development of breast cancer. After menopause, most estrogen biosynthesis is done in peripheral tissue, and the main enzymes involved in balancing the amount of estrone against estradiol are 17β-hydroxysteroid dehydrogenases (17HSD). The aim of this study was to investigate the prognostic and tamoxifen predictive values of 17HSD1 and 17HSD2 expression. Experimental Design: Tumors from low-risk breast cancer patients randomized to adjuvant tamoxifen therapy or no adjuvant treatment were analyzed with immunohistochemistry to investigate protein expression of 17HSD1 and 17HSD2 in 912 cases. All patients had lymph node-negative breast cancer and were postmenopausal at the time of diagnosis. Results: Low 17HSD1 expression was associated with significant benefit from tamoxifen treatment among patients with estrogen receptor (ER)-positive tumors (P < 0.001). For patients with a 17HSD1 score not exceeding that of 17HSD2, tamoxifen increased the rate of distant recurrence-free survival (hazard ratio, 0.37; 95% confidence interval, 0.23-0.60) and breast cancer-specific survival (hazard ratio, 0.30; 95% confidence interval, 0.16-0.54), whereas no apparent effect was observed when the 17HSD1 score was higher than that of 17HSD2. The interaction was significant for both distant recurrence-free survival (P = 0.036) and breast cancer-specific survival (P = 0.014). In the cohort of systemically untreated patients, no prognostic importance was observed. Conclusions: This is the first report that clearly distinguishes between the prognostic and predictive importance of 17HSD1 and 17HSD2 in ER-positive breast cancer treated with or without tamoxifen. Our data suggest that the 17HSD1/17HSD2 ratio might be useful as a predictive factor for tamoxifen treatment in ER-positive breast cancer patients.

mTOR is a central, frequently altered, node for the complex growth signaling in breast cancer. Activation of the PI3K/Akt/mTOR-pathway seems to be one of the mechanisms for patients recurring after adjuvant endocrine treatment. Growth factor signals promote phosphorylation of the estrogen receptor alpha (ER), thereby altering the receptor conformation, stability and its response to tamoxifen treatment. Ongoing studies are investigating the possibility to inhibit the mTOR pathway in addition to endocrine treatment or after endocrine treatment failure. In the present retrospective study, a postmenopausal early breast cancer cohort of 812 patients, randomized to tamoxifen or no endocrine treatment, was analyzed according to the protein expression of mTOR phosphorylated on serine 2448. Downstream targets of mTOR are the S6Kinases, S6K1 and S6K2. S6K1 is thought to directly phosphorylate the ER on serine 167. Here, a positive correlation between p-mTOR and p-ERs167 was shown. However, no correlation was detected between p-mTOR and p-ERs305, indicating that the active mTOR signaling specifically targets the ERs167 residue. Activated 4EBP1, another common mTOR target, did not correlate with the p-mTOR protein expression. No prognostic value, independently of cut-off, was seen for p-mTOR expression in this material. Analyses of p-mTOR as a tool for treatment prediction showed that negative, low and medium expression in the tumor did not affect the patients response to tamoxifen, p=0.0001. High and abundant expression decreased the tamoxifen sensitivity to a non-significant degree, p=0.34. An ER-positive/PgR-positive selection further improved the hypothesis of p-mTOR being an indicator of tamoxifen resistance. Where the p-mTOR negative group responded well to treatment (p In conclusion, the results indicate that risk of recurrence after tamoxifen treatment may increase in patients with high mTOR kinase activity.

The hepatocyte growth factor receptor (HGFR), also known as the Met receptor, promotes cell survival and proliferation by activating signaling pathways such as the PI3K/Akt and RAS/MAPK pathway. HGFR, coded by MET, has been shown to be abundant in several cancers and in some cases it interferes with treatment response. In vitro, HGFR has been shown to be upregulated and activated after radiotherapy, increasing the protection from apoptosis and thus increasing radiation resistance. In this study, it was aimed to determine the number of MET gene copies in breast tumors and correlate these findings with different clinicopathological parameters that were available in this material. Tumors of 172 patients with primary breast cancer were analyzed for MET using qPCR. Increased MET copy number (three or more copies) was found in 34% of the tumors. Five or more gene copies were found in 4.7% of the patients and indicated a significantly higher risk of developing distant metastasis. For the patients that received radiotherapy as the only postoperative treatment, the number of MET copies was associated with increased risk of distant metastasis. In terms of locoregional recurrence, it was found that increased MET copy number was associated with worse response to postoperative radiation therapy compared with chemotherapy. These results suggest that radiotherapy in combination with a Met inhibitor might be an option for patients with increased MET gene copy number to overcome radiation resistance.