Bisphosphonates are traditionally used for treatment of osteoporosis and more recently for treatment and prevention of bone metastases in various malignancies. The use of 2nd-generation oral bisphosphonates has been reported to reduce the risk of developing breast and colon cancer but their influence on cancer survival has not been studied. Methods Two large cohorts of consecutively diagnosed cases with breast or colorectal cancer were studied for the association between use of 2nd-generation oral bisphosphonates and cancer survival. Using computerized prescription records, sustained use of alendronate/risedronate was assessed in postmenopausal women with newly diagnosed breast (n = 2,843) or colorectal cancer (n = 1,706). Overall survival and cancer-specific survival were evaluated using time dependent analysis. Results Postmenopausal women with breast cancer previously unexposed to bisphosphonates who used 2nd-generation bisphosphonates after diagnosis for at least one year had a significantly better survival than non-users, adjusted for age, tumor stage and grade (Overall survival: HR = 0.53, 0.33-0.86, breast cancer-specific survival: HR = 0.26, 0.10-0.71, p = 0.009). A similar advantageous hazard ratio was found in users with ER positive, ER negative and HER2neu positive tumors. A similar significantly better survival was noted for colorectal cancer after adjustment for age, tumor stage and grade (Overall survival: HR = 0.53, 0.33-0.85, colorectal cancer-specific survival: HR = 0.44, 0.21-0.88, p = 0.02). Women who used bisphosphonates before diagnosis did not exhibit a significant survival benefit. Pharmacogenetic studies of F(D)PPS (Farnesyl Pyrophosphate Synthase), a gene coding a key step in the mevalonate pathway revealed direct correlation between a minor homozygous status and survival in bisphosphonate users. Conclusions The use of 2nd-generation bisphosphonates initiated after diagnosis was associated with a significant improvement in overall and in cancer-specific survival of postmenopausal women with breast or colon cancers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-03.

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Background: Emerging evidence demonstrates the effectiveness of targeted gene sequencing panels as a practical method for the diagnosis of inherited susceptibility to breast cancer. Sequencing of multiple high and moderate risk genes simultaneously accelerates the discovery of deleterious mutations (DM) or variants of unknown significance (VUS). However, a consequence of Multiplex Gene Panel (MGP) testing is the discovery of unexpected DMs in high or moderate risk genes other than BRCA1 or BRCA2 (BRCA1/2). The overall clinical utility and incremental gain of information conferred by MGP testing in hereditary cancer risk assessment is still unknown. Methods: We are conducting a multicenter prospective cohort study of patients undergoing cancer-risk assessment using a 25 gene sequencing panel, which includes APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Patients were recruited from August 2014 to June 2015 at three medical centers. Patients are enrolled if they meet standard criteria for genetic testing or are predicted to have a ≥ 2.5% probability of inherited susceptibility to cancer calculated by validated risk prediction models. We present a planned interim analysis after enrolling 500 of 2000 total participants. Results: HCP testing was performed for 332 patients referred for clinical suspicion of hereditary breast and ovarian cancer (HBOC). In this cohort, 96.7% were female (n=321) and the mean age was 50 years (standard deviation, SD=12.2); race/ethnicity was 43.1% Hispanic (n=143), 37% Non-Hispanic White (n=123), 4.2% Black (n=14), 10.5% Asian (n=35), and 1.8% other (n=6). Among this cohort, 37 tested positive for one deleterious mutation (DM) (11.1%: 95% confidence interval (CI), 8.2% to 15%) and 118 patients carried at least one variant of uncertain significance (VUS) (35.5%: 95% CI, 30.6% to 69%). Excluding BRCA1 or BRCA2, 14 patients (4.3%: 95% CI, 2.6% to 7.2%) have a DM in ATM (n=3), CHEK2 (n=2), MSH6 (n=1), MUTYH (n=3), PALB2 (n=1), PMS2 (n=1), RAD51C (n=2), and TP53 (n=2). In a patient with an unexpected PMS2 mutation, enhanced cancer surveillance based on Lynch Syndrome guidelines was recommended. Among 160 patients with a history of invasive breast cancer or breast DCIS, 19 patients carried a DM (11.8 %: 95 CI, 7.7% to 17.8%). Conclusion: In this multicenter prospective cohort study among a diverse group of participants undergoing 25-gene MGP testing, 11.1% of participants tested positive for a DM. Among participants testing negative for BRCA1 and BRCA2, MGP testing identified DMs in 4.3% of participants prompting clinically appropriate risk reduction recommendations and enhanced cancer surveillance. Ongoing recruitment and long-term follow-up are in progress. Citation Format: Idos GE, Kurian AW, Mcdonnell KJ, Ricker CN, Sturgeon DY, Culver JO, Lowstuter K, Hartman A-R, Allen B, Teeter C-R, Kingham KE, Koff R, Lebensohn A, Chun NM, Mills MA, Petrovchich I, Hong C, Ladabaum U, Ford JM, Gruber SB. Interim analysis of multiplex gene panel testing for inherited susceptibility to breast cancer. [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 PD7-01.

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