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1. Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis

Author

Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., Cohen S., Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., and Cohen S.

Abstract

Background: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. Methods: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. Results: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05–1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. Conclusions: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.

Published
2024

5. Commissioning experience and beam physics measurements at the SwissFEL Injector Test Facility

Author

Schietinger, T., Pedrozzi, M., Aiba, M., Arsov, V., Bettoni, S., Beutner, B., Calvi, M., Craievich, P., Dehler, M., Frei, F., Ganter, R., Hauri, C. P., Ischebeck, R., Ivanisenko, Y., Janousch, M., Kaiser, M., Keil, B., Löhl, F., Orlandi, G. L., Loch, C. Ozkan, Peier, P., Prat, E., Raguin, J. -Y., Reiche, S., Schilcher, T., Wiegand, P., Zimoch, E., Anicic, D., Armstrong, D., Baldinger, M., Baldinger, R., Bertrand, A., Bitterli, K., Bopp, M., Brands, H., Braun, H. H., Brönnimann, M., Brunnenkant, I., Chevtsov, P., Chrin, J., Citterio, A., Divall, M. Csatari, Dach, M., Dax, A., Ditter, R., Divall, E., Falone, A., Fitze, H., Geiselhart, C., Guetg, M. W., Hämmerli, F., Hauff, A., Heiniger, M., Higgs, C., Hugentobler, W., Hunziker, S., Janser, G., Kalantari, B., Kalt, R., Kim, Y., Koprek, W., Korhonen, T., Krempaska, R., Laznovsky, M., Lehner, S., Pimpec, F. Le, Lippuner, T., Lutz, H., Mair, S., Marcellini, F., Marinkovic, G., Menzel, R., Milas, N., Pal, T., Pollet, P., Portmann, W., Rezaeizadeh, A., Ritt, S., Rohrer, M., Schär, M., Schebacher, L., Scherrer, St., Schmidt, V. Schlott T., Schulz, L., Smit, B., Stadler, M., Steffen, B., Stingelin, L., Sturzenegger, W., Treyer, D. M., Trisorio, A., Tron, W., Vicario, C., Zennaro, R., and Zimoch, D.

Subjects
Physics - Accelerator Physics
Abstract

The SwissFEL Injector Test Facility operated at the Paul Scherrer Institute between 2010 and 2014, serving as a pilot plant and testbed for the development and realization of SwissFEL, the X-ray Free-Electron Laser facility under construction at the same institute. The test facility consisted of a laser-driven rf electron gun followed by an S-band booster linac, a magnetic bunch compression chicane and a diagnostic section including a transverse deflecting rf cavity. It delivered electron bunches of up to 200 pC charge and up to 250 MeV beam energy at a repetition rate of 10 Hz. The measurements performed at the test facility not only demonstrated the beam parameters required to drive the first stage of an FEL facility, but also led to significant advances in instrumentation technologies, beam characterization methods and the generation, transport and compression of ultra-low-emittance beams. We give a comprehensive overview of the commissioning experience of the principal subsystems and the beam physics measurements performed during the operation of the test facility, including the results of the test of an in-vacuum undulator prototype generating radiation in the vacuum ultraviolet and optical range., Comment: 60 pages, 70 figures; final version as published, except with table of contents and Fig. 68 in full resolution

Published
2016
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9. The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations

Author

Narod, S, Metcalfe, K, Finch, A, Chan, A, Armel, S, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Foulkes, W, Neuhausen, S, Eng, C, Olopade, O, Zakalik, D, Couch, F, Cullinane, C, Pal, T, Sun, P, Kotsopoulos, J, Fruscio, R, Narod, Steven A, Metcalfe, Kelly, Finch, Amy, Chan, An-Wen, Armel, Susan Randall, Aeilts, Amber, Eisen, Andrea, Karlan, Beth, Bordeleau, Louise, Tung, Nadine, Foulkes, William D, Neuhausen, Susan L, Eng, Charis, Olopade, Olufunmilayo, Zakalik, Dana, Couch, Fergus, Cullinane, Carey, Pal, Tuya, Sun, Ping, Kotsopoulos, Joanne, Fruscio,Robert, Narod, S, Metcalfe, K, Finch, A, Chan, A, Armel, S, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Foulkes, W, Neuhausen, S, Eng, C, Olopade, O, Zakalik, D, Couch, F, Cullinane, C, Pal, T, Sun, P, Kotsopoulos, J, Fruscio, R, Narod, Steven A, Metcalfe, Kelly, Finch, Amy, Chan, An-Wen, Armel, Susan Randall, Aeilts, Amber, Eisen, Andrea, Karlan, Beth, Bordeleau, Louise, Tung, Nadine, Foulkes, William D, Neuhausen, Susan L, Eng, Charis, Olopade, Olufunmilayo, Zakalik, Dana, Couch, Fergus, Cullinane, Carey, Pal, Tuya, Sun, Ping, Kotsopoulos, Joanne, and Fruscio,Robert

Abstract

Background: It has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations. Methods: We report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up. Results: During the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer. Conclusion: The risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

Published
2024

10. Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author

Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, and Narod, Steven A

Abstract

IMPORTANCE Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. OBJECTIVE To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. DESIGN, SETTING, AND PARTICIPANTS In this international, longitudinal cohort study ofwomen with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. EXPOSURES Self-reported bilateral oophorectomy (with or without salpingectomy). MAIN OUTCOMES AND MEASURES All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. RESULTS There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estima

Published
2024

11. MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author

Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A

Abstract

IMPORTANCE Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. OBJECTIVE To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. DESIGN, SETTING, AND PARTICIPANTS Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. EXPOSURES Entrance into an MRI surveillance program. MAIN OUTCOMES AND MEASURES Cox proportional hazards modelingwas used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. RESULTS A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0

Published
2024

15. Effect of LO Phase Noise on Front-end Receiver Performance

Author

Kumar, Manish, Pal, T. K., Prasad, B. S. V., Arun Kumar, G., Bhanja, Sukhendu, Majumder, Arijit, Angrisani, Leopoldo, Series Editor, Arteaga, Marco, Series Editor, Panigrahi, Bijaya Ketan, Series Editor, Chakraborty, Samarjit, Series Editor, Chen, Jiming, Series Editor, Chen, Shanben, Series Editor, Chen, Tan Kay, Series Editor, Dillmann, Ruediger, Series Editor, Duan, Haibin, Series Editor, Ferrari, Gianluigi, Series Editor, Ferre, Manuel, Series Editor, Hirche, Sandra, Series Editor, Jabbari, Faryar, Series Editor, Jia, Limin, Series Editor, Kacprzyk, Janusz, Series Editor, Khamis, Alaa, Series Editor, Kroeger, Torsten, Series Editor, Liang, Qilian, Series Editor, Ming, Tan Cher, Series Editor, Minker, Wolfgang, Series Editor, Misra, Pradeep, Series Editor, Möller, Sebastian, Series Editor, Mukhopadhyay, Subhas, Series Editor, Ning, Cun-Zheng, Series Editor, Nishida, Toyoaki, Series Editor, Pascucci, Federica, Series Editor, Qin, Yong, Series Editor, Seng, Gan Woon, Series Editor, Veiga, Germano, Series Editor, Wu, Haitao, Series Editor, Zhang, Junjie James, Series Editor, Bera, Rabindranath, editor, Sarkar, Subir Kumar, editor, and Chakraborty, Swastika, editor

Published
2018
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20. The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

Author

Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., Narod S. A., Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., and Narod S. A.

Abstract

Background: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant. Methods: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method. Results: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%. Conclusion: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

Published
2022

21. Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

Author

Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., Cohen S., Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., and Cohen S.

Abstract

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Published
2022

29. Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation

Author

Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A

Abstract

Purpose: Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. Methods: We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. Results: There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40–1.03; P = 0.07). Conclusion: Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

Published
2023

43. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author

Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., and Bordeleau L.

Abstract

Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.

Published
2021

44. Antibiotic resistance gene dynamics in the commensal infant gut microbiome over the first year of life

Author

Pål Trosvik, Hanna Theodora Noordzij, and Eric Jacques de Muinck

Subjects
Infant, Gut, Microbiome, Metagenome, Antibiotic resistance genes, Temporal dynamics, Medicine, Science
Abstract

Abstract Colonization of the infant gut is an important developmental process characterized by high carriage of antimicrobial resistance genes (ARGs) and high abundances of pathobionts. The horizontal transfer of ARGs to pathogenic bacteria represents a major public health concern. However, there is still a paucity of longitudinal studies surveilling ARGs in healthy infant guts at high temporal resolution. Furthermore, we do not yet have a clear view of how temporal variation in ARG carriage relates to the dynamics of specific bacterial populations, as well as community virulence potential. Here, we performed deep shotgun metagenomic sequencing of monthly fecal samples from a cohort of 12 infants, covering the first year of life to interrogate the infant gut microbiome for ARG content. We further relate ARG dynamics to the dynamics of taxa, virulence potential, as well as the potential for ARG mobilization. We identify a core resistome dominated by efflux systems typically associated with Enterobacteriaceae. Overall ARG carriage declined over the first year of life and showed strong contemporaneous correlation with the population dynamics of Proteobacteria. Furthermore, the majority of ARGs could be further mapped to metagenome-assembled genomes (MAGs) classified to this phylum. We were able to assign a large number of ARGs to E. coli by correlating the temporal dynamics of individual genes with species dynamics, and we show that the temporal dynamics of ARGs and virulence factors are highly correlated, suggesting close taxonomic associations between these two gene classes. Finally, we identify ARGs linked with various categories of mobile genetic elements, demonstrating preferential linkage among mobility categories and resistance to different drug classes. While individual variation in ARG carriage is substantial during infancy there is a clear reduction over the first year of life. With few exceptions, ARG abundances closely track the dynamics of pathobionts and community virulence potential. These findings emphasize the potential for development of resistant pathogens in the developing infant gut, and the importance of effective surveillance in order to detect such events.

Published
2024
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47. Bilateral Oophorectomy and the Risk of Breast Cancer in BRCA1 Mutation Carriers: a Reappraisal

Author

Kotsopoulos, J, Lubiński, J, Gronwald, J, Menkiszak, J, Mccuaig, J, Metcalfe, K, Foulkes, W, Neuhausen, S, Sun, S, Karlan, B, Eisen, A, Tung, N, Olopade, O, Couch, F, Huzarski, T, Senter, L, Bordeleau, L, Singer, C, Eng, C, Fruscio, R, Pal, T, Sun, P, Narod, S, Kotsopoulos, Joanne, Lubiński, Jan, Gronwald, Jacek, Menkiszak, Janusz, McCuaig, Jeanna, Metcalfe, Kelly, Foulkes, William D, Neuhausen, Susan L, Sun, Sophie, Karlan, Beth Y, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo I, Couch, Fergus J, Huzarski, Tomasz, Senter, Leigha, Bordeleau, Louise, Singer, Christian F, Eng, Charis, Fruscio, Robert, Pal, Tuya, Sun, Ping, Narod, Steven A, Kotsopoulos, J, Lubiński, J, Gronwald, J, Menkiszak, J, Mccuaig, J, Metcalfe, K, Foulkes, W, Neuhausen, S, Sun, S, Karlan, B, Eisen, A, Tung, N, Olopade, O, Couch, F, Huzarski, T, Senter, L, Bordeleau, L, Singer, C, Eng, C, Fruscio, R, Pal, T, Sun, P, Narod, S, Kotsopoulos, Joanne, Lubiński, Jan, Gronwald, Jacek, Menkiszak, Janusz, McCuaig, Jeanna, Metcalfe, Kelly, Foulkes, William D, Neuhausen, Susan L, Sun, Sophie, Karlan, Beth Y, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo I, Couch, Fergus J, Huzarski, Tomasz, Senter, Leigha, Bordeleau, Louise, Singer, Christian F, Eng, Charis, Fruscio, Robert, Pal, Tuya, Sun, Ping, and Narod, Steven A

Abstract

Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case-control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n=4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34- 0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87-1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

Published
2022

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