42 results on '"Lubinski J."'
Search Results
2. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers
- Author
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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, and Bordeleau, L
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Heterozygote ,medicine.medical_treatment ,Ovariectomy ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,03 medical and health sciences ,Breast cancer screening ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Genetic Predisposition to Disease ,Prospective Studies ,skin and connective tissue diseases ,Prospective cohort study ,Mastectomy ,Aged ,Aged, 80 and over ,BRCA2 Protein ,medicine.diagnostic_test ,business.industry ,BRCA1 Protein ,Incidence ,Oophorectomy ,Cancer ,Hormone replacement therapy (menopause) ,Middle Aged ,BRCA1 ,medicine.disease ,BRCA2 ,Prophylactic Surgery ,3. Good health ,Prospective ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Female ,business - 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 7.9years, 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
- 2020
3. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients
- Author
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Byrski, T., Huzarski, T., Dent, R., Marczyk, E., Jasiowka, M., Gronwald, J., Jakubowicz, J., Cybulski, C., Wisniowski, R., Godlewski, D., Lubinski, J., and Narod, S. A.
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- 2014
- Full Text
- View/download PDF
4. Vitamin D receptor variants and breast cancer risk in the Polish population
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Gapska, P., Scott, R. J., Serrano-Fernandez, P., Huzarski, T., Byrski, T., Kładny, J., Gronwald, J., Górski, B., Cybulski, C., Lubinski, J., and Dębniak, T.
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- 2009
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5. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients
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Byrski, T., Huzarski, T., Dent, R., Gronwald, J., Zuziak, D., Cybulski, C., Kladny, J., Gorski, B., Lubinski, J., and Narod, S. A.
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- 2009
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6. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers
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Byrski, T., Gronwald, J., Huzarski, T., Grzybowska, E., Budryk, M., Stawicka, M., Mierzwa, T., Szwiec, M., Wiśniowski, R., Siolek, M., Narod, S. A., Lubinski, J., and the Polish Hereditary Breast Cancer Consortium
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- 2008
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7. XPD common variants and their association with melanoma and breast cancer risk
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Dębniak, T., Scott, R. J., Huzarski, T., Byrski, T., Masojć, B., van de Wetering, T., Serrano-Fernandez, P., Górski, B., Cybulski, C., Gronwald, J., Dębniak, B., Maleszka, R., Kładny, J., Bieniek, A., Nagay, L., Haus, O., Grzybowska, E., Wandzel, P., Niepsuj, S., Narod, S. A., and Lubinski, J.
- Published
- 2006
8. The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation
- Author
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Valentini, A, Lubinski, J, Byrski, T, Ghadirian, P, Moller, P, Lynch, Ht, Ainsworth, P, Neuhausen, Sl, Weitzel, J, Singer, Cf, Olopade, Oi, Saal, H, Lyonnet, Ds, Foulkes, Wd, Kim Sing, C, Manoukian, S, Zakalik, D, Armel, S, Senter, L, Eng, C, Grunfeld, E, Chiarelli, Am, Poll, A, Sun, P, Narod, Sa, Hereditary Breast Cancer Clinical Study Group: Gronwald, J, Cybulski, C, Huzarski, T, Robidoux, A, Offit, K, Gershoni Baruch, R, Isaacs, C, Tung, N, Rosen, B, Demsky, R, Mccuaig, J, Eisen, A, Bordeleau, L, Karlan, B, Garber, J, Gilchrist, D, Couch, F, Evans, G, Kwong, A, Maehle, L, Friedman, E, Mckinnon, W, Wood, M, Daly, M, Blum, Jl, Robson, M, Chudley, A, Panchal, S, Mclennan, J, Pasini, Barbara, Rennert, G, Lunn, J, Fallen, T, Rayson, D, Smith, M, Ginsburg, O, Lemire, E, Meschino, W, Vadaparampil, S, Euhus, D, Costalas, Jw, Donenberg, T, Kurz, Rn, Friedman, S, Sweet, K, Cullinane, Ca, Reilly, Re, Kotsopoulos, J, Nanda, S, and Metcalfe, K.
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Heterozygote ,Survival ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,Article ,Cohort Studies ,Breast cancer ,Pregnancy ,Risk Factors ,Internal medicine ,Medicine ,Humans ,skin and connective tissue diseases ,Survival rate ,business.industry ,Proportional hazards model ,Hazard ratio ,BRCA mutation ,BRCA mutations ,Case-control study ,medicine.disease ,Case-Control Studies ,Mutation ,Female ,business ,Cohort study - Abstract
Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan–Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31–1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.
- Published
- 2013
9. Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update
- Author
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Ginsburg, O, Ghadirian, P, Lubinski, J, Cybulski, C, Lynch, H, Neuhausen, S, Kim Sing, C, Robson, M, Domchek, S, Isaacs, C, Klijn, J, Armel, S, Foulkes, Wd, Tung, N, Moller, P, Sun, P, Narod, Sa, Olopade, O, Cummings, S, Couch, F, Rosen, B, Stoppa Lyonnet, D, Gershoni Baruch, R, Horsman, D, Wagner, T, Saal, H, Warner, E, Meschino, W, Offit, K, Trivedi, A, Osborne, M, Gilchrist, D, Eng, C, Weitzel, J, Mckinnon, W, Wood, M, Maugard, C, Pasini, Barbara, Ainsworth, P, Sweet, K, Pasche, B, Karlan, B, Kurz, Rn, Tulman, A, Lemire, E, Mclennan, J, Evans, G, Byrski, T, Huzarski, T, Gronwald, J, Gorski, B, Friedman, E, Eisen, A, Daly, M, Garber, J, and Merajver, S.
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,Heterozygote ,endocrine system diseases ,Adolescent ,Epidemiology ,Genes, BRCA2 ,Genes, BRCA1 ,Breast Neoplasms ,Biochemistry ,Article ,Young Adult ,Breast cancer ,breast cancer ,Mutation Carrier ,Risk Factors ,80 and over ,medicine ,Humans ,Young adult ,skin and connective tissue diseases ,risk ,Aged ,Gynecology ,Aged, 80 and over ,Obstetrics ,business.industry ,BRCA mutation ,Smoking ,Case-control study ,Cancer ,Odds ratio ,Middle Aged ,medicine.disease ,BRCA1 ,BRCA2 ,smoking ,Genes ,Oncology ,Case-Control Studies ,Mutation ,Female ,Breast disease ,business - Abstract
Among women with a mutation in BRCA1 or BRCA2, the risk of breast cancer is high, but it may be modified by exogenous and endogenous factors. There is concern that exposure to carcinogens in cigarette smoke may increase the risk of cancer in mutation carriers. We conducted a matched case-control study of 2,538 cases of breast cancer among women with a BRCA1 (n = 1,920) or a BRCA2 (n = 618) mutation. One non-affected mutation carrier control was selected for each case, matched on mutation, country of birth, and year of birth. Odds ratios were calculated using conditional logistic regression, adjusted for oral contraceptive use and parity. Ever-smoking was not associated with an increased breast cancer risk among BRCA1 carriers (OR = 1.09; 95% CI 0.95-1.24) or among BRCA2 carriers (OR = 0.81; 95% CI 0.63-1.05). The result did not differ when cases were restricted to women who completed the questionnaire within two years of diagnosis. A modest, but significant increase in risk was seen among BRCA1 carriers with a past history of smoking (OR = 1.27; 95% CI 1.06-1.50), but not among current smokers (OR = 0.95; 0.81-1.12). There appears to be no increase in the risk of breast cancer associated with current smoking in BRCA1 or BRCA2 carriers. There is a possibility of an increased risk of breast cancer among BRCA1 carriers associated with past smoking. There may be different effects of carcinogens in BRCA mutation carriers, depending upon the timing of exposure.
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- 2008
10. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients
- Author
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Byrski, T., primary, Huzarski, T., additional, Dent, R., additional, Gronwald, J., additional, Zuziak, D., additional, Cybulski, C., additional, Kladny, J., additional, Gorski, B., additional, Lubinski, J., additional, and Narod, S. A., additional
- Published
- 2008
- Full Text
- View/download PDF
11. Vitamin D receptor variants and breast cancer risk in the Polish population
- Author
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Gapska, P., primary, Scott, R. J., additional, Serrano-Fernandez, P., additional, Huzarski, T., additional, Byrski, T., additional, Kładny, J., additional, Gronwald, J., additional, Górski, B., additional, Cybulski, C., additional, Lubinski, J., additional, and Dębniak, T., additional
- Published
- 2008
- Full Text
- View/download PDF
12. Oophorectomy and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers
- Author
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Jan Lubinski, Leigha Senter, Steven A. Narod, Susan Armel, Joanne Kotsopoulos, Peter Ainsworth, Fergus J. Couch, Olufunmilayo I. Olopade, Robert Fruscio, Beth Y. Karlan, Ping Sun, Henry T. Lynch, Christian F. Singer, Pål Møller, Susan L. Neuhausen, Jacek Gronwald, Andrea Eisen, Jeffrey N. Weitzel, William D. Foulkes, Nadine Tung, Kotsopoulos, J, Lubinski, J, Lynch, H, Tung, N, Armel, S, Senter, L, Singer, C, Fruscio, R, Couch, F, Weitzel, J, Karlan, B, Foulkes, W, Moller, P, Eisen, A, Ainsworth, P, Neuhausen, S, Olopade, O, Sun, P, Gronwald, J, and Narod, S
- Subjects
Adult ,0301 basic medicine ,Oncology ,Oophorectomy ,Heterozygote ,Cancer Research ,medicine.medical_specialty ,Ovariectomy ,medicine.medical_treatment ,Breast Neoplasms ,Contralateral breast cancer ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,BRCA1/2 ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,Prospective cohort study ,Mastectomy ,Aged ,Proportional Hazards Models ,BRCA2 Protein ,BRCA1 Protein ,business.industry ,Ovary ,BRCA mutation ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Confidence interval ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Female ,business - Abstract
Purpose: Following a diagnosis of breast cancer, BRCA mutation carriers face an increased risk of developing a second (contralateral) cancer in the unaffected breast. It is important to identify predictors of contralateral cancer in order to make informed decisions about bilateral mastectomy. The impact of bilateral salpingo-oophorectomy (i.e., oophorectomy) on the risk of developing contralateral breast cancer is unclear. Thus, we conducted a prospective study of the relationship between oophorectomy and the risk of contralateral breast cancer in 1781 BRCA1 and 503 BRCA2 mutation carriers with breast cancer. Methods: Women were followed from the date of diagnosis of their first breast cancer until the date of diagnosis of a contralateral breast cancer, bilateral mastectomy, date of death, or date of last follow-up. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of contralateral breast cancer associated with oophorectomy. Oophorectomy was included as a time-dependent covariate. We performed a left-censored analysis for those women who reported a primary breast cancer prior to study entry (i.e., from completion of baseline questionnaire). Results: After an average of 9.8years of follow-up, there were 179 (7.8%) contralateral breast cancers diagnosed. Oophorectomy was not associated with the risk of developing a second breast cancer (HR 0.92; 95% CI 0.68–1.25). The relationship did not vary by BRCA mutation type or by age at diagnosis of the first breast cancer. There was some evidence for a decreased risk of contralateral breast cancer among women with an ER-positive primary breast cancer, but this was based on a small number of events (n = 240). Conclusion: Overall, our findings suggest that oophorectomy has little impact on the risk of contralateral breast cancer
- Published
- 2019
13. Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.
- Author
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Kotsopoulos J, Gronwald J, Huzarski T, Aeilts A, Randall Armel S, Karlan B, Singer CF, Eisen A, Tung N, Olopade O, Bordeleau L, Eng C, Foulkes WD, Neuhausen SL, Cullinane CA, Pal T, Fruscio R, Lubinski J, Metcalfe K, Sun P, and Narod SA
- Subjects
- Humans, Female, Raloxifene Hydrochloride adverse effects, Genes, BRCA1, Mutation, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Tamoxifen adverse effects, Breast Neoplasms drug therapy, Breast Neoplasms epidemiology, Breast Neoplasms genetics
- 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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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14. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers.
- Author
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Stjepanovic N, Lubinski J, Moller P, Randall Armel S, Foulkes WD, Tung N, Neuhausen SL, Kotsopoulos J, Sun P, Sun S, Eisen A, and Narod SA
- Subjects
- Aged, Aged, 80 and over, BRCA1 Protein genetics, BRCA2 Protein genetics, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Mastectomy, Middle Aged, Mutation, Ovariectomy, Prospective Studies, Breast Neoplasms epidemiology, Breast Neoplasms genetics
- 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
- Full Text
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15. Oophorectomy and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers.
- Author
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Kotsopoulos J, Lubinski J, Lynch HT, Tung N, Armel S, Senter L, Singer CF, Fruscio R, Couch F, Weitzel JN, Karlan B, Foulkes WD, Moller P, Eisen A, Ainsworth P, Neuhausen SL, Olopade O, Sun P, Gronwald J, and Narod SA
- Subjects
- Adult, Aged, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Mastectomy, Middle Aged, Mutation, Ovariectomy, Ovary pathology, Proportional Hazards Models, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Ovary surgery
- Abstract
Purpose: Following a diagnosis of breast cancer, BRCA mutation carriers face an increased risk of developing a second (contralateral) cancer in the unaffected breast. It is important to identify predictors of contralateral cancer in order to make informed decisions about bilateral mastectomy. The impact of bilateral salpingo-oophorectomy (i.e., oophorectomy) on the risk of developing contralateral breast cancer is unclear. Thus, we conducted a prospective study of the relationship between oophorectomy and the risk of contralateral breast cancer in 1781 BRCA1 and 503 BRCA2 mutation carriers with breast cancer., Methods: Women were followed from the date of diagnosis of their first breast cancer until the date of diagnosis of a contralateral breast cancer, bilateral mastectomy, date of death, or date of last follow-up. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of contralateral breast cancer associated with oophorectomy. Oophorectomy was included as a time-dependent covariate. We performed a left-censored analysis for those women who reported a primary breast cancer prior to study entry (i.e., from completion of baseline questionnaire)., Results: After an average of 9.8 years of follow-up, there were 179 (7.8%) contralateral breast cancers diagnosed. Oophorectomy was not associated with the risk of developing a second breast cancer (HR 0.92; 95% CI 0.68-1.25). The relationship did not vary by BRCA mutation type or by age at diagnosis of the first breast cancer. There was some evidence for a decreased risk of contralateral breast cancer among women with an ER-positive primary breast cancer, but this was based on a small number of events (n = 240)., Conclusion: Overall, our findings suggest that oophorectomy has little impact on the risk of contralateral breast cancer.
- Published
- 2019
- Full Text
- View/download PDF
16. Age-specific risks of incident, contralateral and ipsilateral breast cancer among 1776 Polish BRCA1 mutation carriers.
- Author
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Lubinski J, Huzarski T, Gronwald J, Cybulski C, Debniak T, Sun P, Kim SJ, Kotsopoulos J, and Narod SA
- Subjects
- Adult, Age of Onset, Aged, Breast Neoplasms genetics, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Incidence, Middle Aged, Neoplasm Recurrence, Local genetics, Poland, BRCA1 Protein genetics, Breast Neoplasms epidemiology, Mutation, Neoplasm Recurrence, Local epidemiology, White People genetics
- Abstract
Purpose: Women with an inherited germline BRCA1 mutation have a high lifetime risk of developing breast cancer. We have previously shown that, among BRCA mutation carriers, incidence rates of breast cancer vary by country of residence., Methods: In the current study, we prospectively calculated the cumulative and annual incidence rates of incident breast cancer, contralateral breast cancer and ipsilateral breast cancer recurrence among BRCA1 mutation carriers in Poland. Study subjects comprised a cohort of 1776 Polish women with a BRCA1 mutation who had no prior diagnosis of breast or ovarian cancer at the time of enrollment, the women were followed with a biennial follow-up by questionnaire. Women were followed for an average of 6.1 years (range 0.0-18.2) and 191 new breast cancer cases were diagnosed., Results: The cumulative incidence of breast cancer to age 70 was 52%. The annual risk of breast cancer was estimated at 1.78%; the maximum annual risk was observed between the ages of 30 and 65. Among the 941 women with a prior diagnosis of breast cancer, 106 women developed a contralateral breast cancer. The 20-year cumulative incidence of contralateral breast cancer was 31% and the annual rate of contralateral breast cancer was 1.96%. There were 11 recurrences among the 215 women with breast cancer (ipsilateral breast cancers). The cumulative incidence at 20 years was 17% and the annual rate of an ipsilateral recurrence was 1.03%., Conclusion: Our findings confirm the high annual rates of early-onset incident, contralateral and recurrent breast cancer among Polish BRCA1 mutation carriers. These risk estimates are important in the context of the clinical management of unaffected women as well as in the treatment of newly diagnosed primary breast cancers and can also be used as the basis for the planning of prevention trials.
- Published
- 2019
- Full Text
- View/download PDF
17. The intron 3 16 bp duplication polymorphism of p53 (rs17878362) is not associated with increased risk of developing triple-negative breast cancer.
- Author
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Morten BC, Chiu S, Oldmeadow C, Lubinski J, Scott RJ, and Avery-Kiejda KA
- Subjects
- Aged, Alleles, Female, Genotype, Humans, Middle Aged, Neoplasm Staging, Odds Ratio, Risk Factors, Survival Analysis, Triple Negative Breast Neoplasms mortality, Triple Negative Breast Neoplasms pathology, Gene Duplication, Introns, Polymorphism, Genetic, Repetitive Sequences, Nucleic Acid, Triple Negative Breast Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Purpose: Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of ER, PR and HER2. p53, the tumour suppressor gene, is essential for maintaining genomic stability in response to cellular stress. In breast cancer, the mutation rates of TP53 vary depending on the subtype, such that ER-negative tumours have a high rate, and in ER-positive tumours they are less common. Previous studies have implicated the intronic polymorphism in TP53 (rs17878362; or PIN3) with an increased risk of developing breast cancer, although little has been discerned on its prevalence in different subtypes. In this study, we investigated the prevalence of the PIN3 genotype in the blood of cohorts with ER-positive and the ER-negative subtype TNBC, and assessed its association with outcome., Methods: We genotyped 656 TNBC and 648 ER-positive breast cancer patients, along with 436 controls, and compared the prevalence of polymorphism rs17878362 in these cohorts., Results: We found there to be no differences in the prevalence of the PIN3 genotype between the ER-positive and TNBC cohorts. Furthermore, no statistically significant difference was observed in the outcome of patients in either cohort with respect to their PIN3 genotype., Conclusions: Taken together, our results do not support an association of the PIN3 genotype with increased breast cancer risk, either in ER-positive or ER-negative patients.
- Published
- 2019
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18. Age at first full-term birth and breast cancer risk in BRCA1 and BRCA2 mutation carriers.
- Author
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Kotsopoulos J, Gronwald J, Lynch HT, Eisen A, Neuhausen SL, Tung N, Ainsworth P, Weitzel JN, Pal T, Foulkes WD, Eng C, Singer CF, Senter L, Sun P, Lubinski J, and Narod SA
- Subjects
- Adolescent, Adult, Age Factors, Case-Control Studies, Disease Susceptibility, Female, Humans, Risk Assessment, Risk Factors, Young Adult, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mutation, Reproductive History
- Abstract
Purpose: In the general population, an early age at first full-term birth confers protection against the risk of developing breast cancer. The relationship between age at first birth and breast cancer risk is not clear for women with a mutation in the BRCA1 or BRCA2 gene. Thus, we undertook a case-control study of women with a BRCA1 or BRCA2 mutation to study the effects of age at first full-term birth matched for other reproductive factors., Methods: Information about reproductive factors, including age at first birth as well as medical history, was collected from a routinely administered research questionnaire. There were 2,295 matched pairs of women with a BRCA1 or BRCA2 mutation included in the final analysis., Results: There was no significant difference in the mean age at first full-term birth among the BRCA1 (24.9 vs. 25.2; P = 0.10) or BRCA2 mutation carriers (26.5 vs. 26.6 years; P = 0.80). Findings were similar in the analysis limited to cases who were diagnosed with breast cancer prior to age 45., Conclusion: This matched analysis of a large number of BRCA mutation carriers suggests that age at first birth has little influence on BRCA1 or BRCA2 breast cancer risk.
- Published
- 2018
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19. Physical activity during adolescence and young adulthood and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
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Lammert J, Lubinski J, Gronwald J, Huzarski T, Armel S, Eisen A, Meschino WS, Lynch HT, Snyder C, Eng C, Olopade OI, Ginsburg O, Foulkes WD, Elser C, Cohen SA, Kiechle M, Narod SA, and Kotsopoulos J
- Subjects
- Adolescent, Adult, Age Factors, Breast Neoplasms therapy, Case-Control Studies, Disease Susceptibility, Female, Humans, Odds Ratio, Population Surveillance, Risk Assessment, Risk Factors, Surveys and Questionnaires, Young Adult, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Exercise, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mutation
- Abstract
Background: Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer., Methods: We conducted a case-control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12-13, ages 14-17, ages 18-22, ages 23-29 and ages 30-34 were determined using the Nurses' Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12-34), during adolescence (ages 12-17) and during early adulthood (ages 18-34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status., Results: Overall, there was no significant association between total physical activity and subsequent breast cancer risk (OR
Q4 vs. Q1 = 1.01, 95% CI 0.69-1.47; P-trend = 0.72). Moderate physical activity between ages 12-17 was associated with a 38% decreased risk of premenopausal breast cancer (ORQ4 vs. Q1 = 0.62; 95% CI 0.40-0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause., Conclusions: These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers., Impact: Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.- Published
- 2018
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20. Predictors of survival for breast cancer patients with a BRCA1 mutation.
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Narod SA, Huzarski T, Gronwald J, Byrski T, Marczyk E, Cybulski C, Szwiec M, Wisniowski R, Birkenfeld B, Kilar E, Sibilski R, Sun P, and Lubinski J
- Subjects
- Adult, Breast Neoplasms genetics, Breast Neoplasms therapy, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant statistics & numerical data, Female, Follow-Up Studies, Humans, Mastectomy statistics & numerical data, Middle Aged, Mutation, Neoadjuvant Therapy methods, Neoadjuvant Therapy statistics & numerical data, Ovarian Neoplasms genetics, Ovarian Neoplasms therapy, Poland epidemiology, Registries statistics & numerical data, Survival Analysis, Treatment Outcome, Young Adult, Antineoplastic Agents therapeutic use, BRCA1 Protein genetics, Breast Neoplasms mortality, Cisplatin therapeutic use, Ovarian Neoplasms mortality, Ovariectomy
- Abstract
Purpose: To evaluate in a contemporary cohort the impacts of chemotherapy and oophorectomy on survival for breast cancer patients with a BRCA1 mutation., Experimental Design: We reviewed the pathology reports and medical records of 372 women with breast cancer and a BRCA1 mutation, diagnosed from 2005 to 2017, between the ages of 25 and 65 and followed them for death from all causes and death from breast cancer. Death was ascertained through the Poland vital statistics registry. We performed survival analysis to evaluate the impacts of chemotherapy (including neoadjuvant cisplatinum) and of oophorectomy on survival., Results: After a mean follow-up of 5.6 years (median 5.2), 66 of the 372 women died; 56 of the deaths were from breast cancer and 6 were from ovarian cancer. 127 women received neoadjuvant cisplatinum and 245 women received other chemotherapies. Cisplatinum (versus all other therapies) was associated with a hazard ratio of 0.42 (95%CI 0.20-0.87) on breast cancer-specific survival. The 10-year actuarial all-cause survival for women who had both cisplatinum and an oophorectomy was 94.4%. The 10-year all-cause survival for women who had neither cisplatinum nor an oophorectomy was 65.4% (p < 0.01)., Conclusions: Cisplatinum and oophorectomy are effective therapies for women with breast cancer and a BRCA1 mutation.
- Published
- 2018
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21. Serum selenium levels predict survival after breast cancer.
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Lubinski J, Marciniak W, Muszynska M, Huzarski T, Gronwald J, Cybulski C, Jakubowska A, Debniak T, Falco M, Kladny J, Kotsopoulos J, Sun P, and Narod SA
- Subjects
- Adult, Aged, Breast pathology, Breast Neoplasms pathology, Disease-Free Survival, Female, Humans, Middle Aged, Poland epidemiology, Proportional Hazards Models, Risk Factors, Breast Neoplasms blood, Breast Neoplasms epidemiology, Prognosis, Selenium blood
- Abstract
Background: Studies have reported an inverse relationship between serum selenium levels and cancer incidence, but the impact of low serum selenium status on survival after a diagnosis of breast cancer has not been established., Methods: We obtained a blood sample from 546 women diagnosed with a first primary invasive breast cancer between 2008 and 2015 in the region of Szczecin, Poland. Blood was collected after diagnosis, but prior to treatment. Serum selenium was quantified by mass spectroscopy and each patient was assigned to one of four categories (quartiles) based on the distribution in the entire cohort. Patients were followed from diagnosis to death over a mean follow-up of 3.8 years. Vital status was obtained by linkage to the Polish National Death Registry., Results: The 5-year overall actuarial survival was 68.1% for women in the lowest (< 64.4 µg/L) and 82.5% for those in the highest (> 81.0 µg/L) quartile of serum selenium. In an adjusted analysis, the hazard ratio for death was 2.49 (95%CI 1.53-4.04; P = 0.0002) for patients in the lowest quartile of serum selenium, compared to those in all other quartiles. The effect of low selenium on breast cancer-specific mortality was stronger for women who were past smokers (HR 6.03; 95%CI 1.96-18.6; P = 0.0002)., Conclusions: This study suggests that a selenium level in excess of 64.4 µg//L might be beneficial for women undergoing treatment for breast cancer and that selenium supplementation to achieve this level may favorably impact the outcome. Further studies are needed to confirm this association and to evaluate the impact of selenium supplementation on breast cancer survival among women with low post-diagnostic selenium levels.
- Published
- 2018
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22. An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers.
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Madorsky-Feldman D, Sklair-Levy M, Perri T, Laitman Y, Paluch-Shimon S, Schmutzler R, Rhiem K, Lester J, Karlan BY, Singer CF, Van Maerken T, Claes K, Brunet J, Izquierdo A, Teulé A, Lee JW, Kim SW, Arun B, Jakubowska A, Lubinski J, Tucker K, Poplawski NK, Varesco L, Bonelli LA, Buys SS, Mitchell G, Tischkowitz M, Gerdes AM, Seynaeve C, Robson M, Kwong A, Tung N, Tessa N, Domchek SM, Godwin AK, Rantala J, Arver B, and Friedman E
- Subjects
- Adult, Breast Neoplasms genetics, Evidence-Based Medicine, Female, Humans, Magnetic Resonance Imaging, Ovarian Neoplasms genetics, Practice Guidelines as Topic, Prophylactic Mastectomy, Prospective Studies, Surveys and Questionnaires, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms prevention & control, Mutation, Ovarian Neoplasms prevention & control, Prophylactic Surgical Procedures methods
- Abstract
Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed.
- Published
- 2016
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23. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study.
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Kotsopoulos J, Huzarski T, Gronwald J, Moller P, Lynch HT, Neuhausen SL, Senter L, Demsky R, Foulkes WD, Eng C, Karlan B, Tung N, Singer CF, Sun P, Lubinski J, and Narod SA
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Middle Aged, Odds Ratio, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Hormone Replacement Therapy adverse effects, Menopause drug effects, Menopause genetics, Mutation genetics
- Abstract
Many BRCA1 mutation carriers undergo elective surgical oophorectomy (often before menopause) to manage their elevated risk of developing ovarian cancer. It is important to clarify whether or not the use of hormone replacement therapy (HRT) to mitigate the symptoms associated with surgical or natural menopause is safe in women with an inherited BRCA1 mutation and no personal history of breast or ovarian cancer. We conducted a case-control analysis of 432 matched pairs of women with a BRCA1 mutation. Detailed information on HRT use after menopause (duration, type, age at first/last use, formulation) was obtained from a research questionnaire administered at the time of study enrollment. Conditional logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI) associated with HRT use. The mean duration of HRT use after menopause was 4.3 years among the cases and 4.4 years among the controls (P = 0.83). The adjusted OR for breast cancer comparing all women who ever used HRT to those who never used HRT was 0.80 (95 % CI 0.55-1.16; P = 0.24). Findings did not differ by type of menopause (natural vs. surgical), by recency of use, by duration of use, and by formulation type. These findings suggest that a short course of HRT should not be contra-indicated for BRCA1 mutation carriers who have undergone menopause and who have no personal history of cancer.
- Published
- 2016
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24. Does the age of breast cancer diagnosis in first-degree relatives impact on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers?
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Semple J, Metcalfe KA, Lubinski J, Huzarski T, Gronwald J, Armel S, Lynch HT, Karlan B, Foulkes W, Singer CF, Neuhausen SL, Eng C, Iqbal J, and Narod SA
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms epidemiology, Breast Neoplasms pathology, Family, Female, Germ-Line Mutation genetics, Heterozygote, Humans, Middle Aged, Mutation, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Risk Factors, Age Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics
- Abstract
The purpose of this study is to estimate the age-specific annual risks of breast cancer in a woman with a germline BRCA mutation and an affected first-degree relative according to the age of breast cancer diagnosis in the relative. Women with BRCA mutations with no previous diagnosis of breast cancer and with one first-degree relative with breast cancer were followed for breast cancers for a mean of 5.9 years (minimum 2 years). Age-specific annual breast cancer risks were calculated, according to the age of breast cancer diagnosis in the proband and the first-degree relative. 1114 cancer-free women with a BRCA mutation with a single first-degree relative with breast cancer were eligible for the study. 122 women (11.0 %) were diagnosed with incident breast cancer. The annual risk of breast cancer was 2.0 % for women with BRCA1 mutations and was 1.6 % for women with BRCA2 mutations. The age of breast cancer diagnosis in the first-degree relative did not affect the annual breast cancer risks for BRCA1 mutation carriers. For BRCA2 mutation carriers, the annual breast cancer risk was 4.5 % for women with a first-degree relative diagnosed with breast cancer under the age of 30 years and was 0.7 % for women with a relative diagnosed over the age of 60. Among women with BRCA2 mutations, a family history of early-onset breast cancer is a risk factor for developing breast cancer. Risk assessment for healthy BRCA2 mutation carriers should consider the ages of breast cancers diagnosed in first-degree relatives.
- Published
- 2015
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25. Prospective evaluation of alcohol consumption and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
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Cybulski C, Lubinski J, Huzarski T, Lynch HT, Randall SA, Neuhausen SL, Senter L, Friedman S, Ainsworth P, Singer C, Foulkes WD, Narod SA, Sun P, and Kotsopoulos J
- Subjects
- Adolescent, Adult, Aged, Female, Humans, Middle Aged, Odds Ratio, Population Surveillance, Risk, Risk Factors, Young Adult, Alcohol Drinking adverse effects, Breast Neoplasms epidemiology, Breast Neoplasms etiology, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mutation
- Abstract
Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.
- Published
- 2015
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26. Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.
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Wong-Brown MW, Meldrum CJ, Carpenter JE, Clarke CL, Narod SA, Jakubowska A, Rudnicka H, Lubinski J, and Scott RJ
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- Adult, Aged, Australia epidemiology, Exons, Female, Humans, Middle Aged, Neoplasm Grading, Neoplasm Metastasis, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Prevalence, Risk Factors, Triple Negative Breast Neoplasms epidemiology, Triple Negative Breast Neoplasms pathology, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation, Triple Negative Breast Neoplasms genetics
- Abstract
Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 mutations. Reports to date indicate that up to 20 % of TNBC patients harbour germline BRCA mutations; however, the prevalence of BRCA mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0 years. Samples of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon-intron boundaries of BRCA1 and BRCA2 were amplified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6 %) triple-negative patients. The mutation prevalence was 9.3 % in Australia and was 9.9 % in Poland. In both countries, the mean age of diagnoses of BRCA1 mutation carriers was significantly lower than that of non-carriers, while the age of onset of BRCA2 mutation carriers was similar to that of non-carriers. In the Australian cohort, 59 % of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.
- Published
- 2015
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27. Methylation of the BRCA1 promoter in peripheral blood DNA is associated with triple-negative and medullary breast cancer.
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Gupta S, Jaworska-Bieniek K, Narod SA, Lubinski J, Wojdacz TK, and Jakubowska A
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- Adult, BRCA1 Protein blood, Carcinoma, Medullary blood, Carcinoma, Medullary pathology, Case-Control Studies, DNA-Cytosine Methylases genetics, Female, Germ-Line Mutation, Humans, Promoter Regions, Genetic, Triple Negative Breast Neoplasms blood, Triple Negative Breast Neoplasms pathology, BRCA1 Protein genetics, Carcinoma, Medullary genetics, DNA Methylation genetics, Triple Negative Breast Neoplasms genetics
- Abstract
It has been proposed that methylation signatures in blood-derived DNA may correlate with cancer risk. In this study, we evaluated whether methylation of the promoter region of the BRCA1 gene detectable in DNA from peripheral blood cells is a risk factor for breast cancer, in particular for tumors with pathologic features characteristic for cancers with BRCA1 gene mutations. We conducted a case-control study of 66 breast cancer cases and 36 unaffected controls. Cases were triple-negative or of medullary histology, or both; 30 carried a constitutional BRCA1 mutation and 36 did not carry a mutation. Blood for DNA methylation analysis was taken within three months of diagnosis. Methylation of the promoter of the BRCA1 gene was measured in cases and controls using methylation-sensitive high-resolution melting (MS-HRM). A sample with any detectable level of methylation was considered to be positive. Methylation of the BRCA1 promoter was detected in 15 of 66 cases and in 2 of 36 controls (OR 5.0, p = 0.03). Methylation was present in 15 of 36 women with breast cancer and without germline BRCA1 mutation, but in none of 30 women with breast cancer and a germline mutation (p < 0.01). The association between methylation and breast cancer was restricted to women with no constitutional BRCA1 mutation (OR 12.1, p = 0.0006). Methylation of the promoter of the BRCA1 gene detectable in peripheral blood DNA may be a marker of increased susceptibility to triple-negative or medullary breast cancer.
- Published
- 2014
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28. Mammography screening and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers: a prospective study.
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Giannakeas V, Lubinski J, Gronwald J, Moller P, Armel S, Lynch HT, Foulkes WD, Kim-Sing C, Singer C, Neuhausen SL, Friedman E, Tung N, Senter L, Sun P, and Narod SA
- Subjects
- Adult, Aged, Breast Neoplasms genetics, Canada epidemiology, Female, Follow-Up Studies, Heterozygote, Humans, Incidence, Middle Aged, Neoplasm Staging, Prognosis, Prospective Studies, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Early Detection of Cancer, Genetic Predisposition to Disease, Mammography, Mutation genetics
- Abstract
Women with a genetic predisposition to breast cancer may be at increased risk of cancer after exposure to ionizing radiation. It is unclear whether mammography screening increases the risk of breast cancer among BRCA1 and BRCA2 carriers. We identified 2,346 women with a BRCA1 (n = 1844) or BRCA2 (n = 502) mutation and no breast cancer, and we reviewed their history of mammography exposure. These women were followed for an average of 5.3 years and were observed for new breast cancer diagnoses. At study entry, 1808 women (77.1 %) reported ever having had a mammogram; of these, 204 women (11.2 %) reported having had a mammogram before age 30. We estimated the hazard ratios for the development of invasive breast cancer, conditional on the number of prior mammograms and on the age at first mammogram. Hazard ratios were estimated and stratified by gene (BRCA1 or BRCA2), relative to women with no exposure. We observed no significant association between prior mammography exposure and breast cancer risk for BRCA1 carriers (HR 0.79; 95 % CI 0.53-1.19; P = 0.26) or for BRCA2 carriers (HR 0.90; 95 % CI 0.35-2.34; P = 0.83). An early age at first mammogram (<30 years) did not increase breast cancer risk among BRCA1 carriers (HR 0.75; 95 % CI 0.41-1.37; P = 0.35) or among BRCA2 carriers (HR 0.69; 95 % CI 0.19-2.48; P = 0.57). Exposure to mammography in women with BRCA1 and BRCA2 mutations is not associated with an increased risk of breast cancer.
- Published
- 2014
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29. Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.
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Gronwald J, Robidoux A, Kim-Sing C, Tung N, Lynch HT, Foulkes WD, Manoukian S, Ainsworth P, Neuhausen SL, Demsky R, Eisen A, Singer CF, Saal H, Senter L, Eng C, Weitzel J, Moller P, Gilchrist DM, Olopade O, Ginsburg O, Sun P, Huzarski T, Lubinski J, and Narod SA
- Subjects
- Adult, Aged, Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms epidemiology, Case-Control Studies, Female, Humans, Middle Aged, Neoplasms, Second Primary epidemiology, Odds Ratio, Risk Factors, Tamoxifen therapeutic use, Time Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Heterozygote, Mutation, Neoplasms, Second Primary etiology, Neoplasms, Second Primary pathology, Tamoxifen adverse effects
- Abstract
Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.
- Published
- 2014
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30. Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers.
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Kotsopoulos J, Lubinski J, Moller P, Lynch HT, Singer CF, Eng C, Neuhausen SL, Karlan B, Kim-Sing C, Huzarski T, Gronwald J, McCuaig J, Senter L, Tung N, Ghadirian P, Eisen A, Gilchrist D, Blum JL, Zakalik D, Pal T, Sun P, and Narod SA
- Subjects
- Adult, Age Factors, Breast Neoplasms pathology, Case-Control Studies, Contraceptives, Oral administration & dosage, Female, Genetic Association Studies, Heterozygote, Humans, Middle Aged, Mutation, Risk Factors, BRCA1 Protein genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Contraceptives, Oral adverse effects
- Abstract
It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.
- Published
- 2014
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31. Should all BRCA1 mutation carriers with stage I breast cancer receive chemotherapy?
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Narod SA, Metcalfe K, Lynch HT, Ghadirian P, Robidoux A, Tung N, Gaughan E, Kim-Sing C, Olopade OI, Foulkes WD, Robson M, Offit K, Jakubowska A, Byrski T, Huzarski T, Sun P, and Lubinski J
- Subjects
- Adult, Breast Neoplasms mortality, Breast Neoplasms pathology, Female, Humans, Middle Aged, Neoplasm Staging, Proportional Hazards Models, Young Adult, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Genes, BRCA1, Heterozygote, Mutation
- Abstract
To estimate the 15-year survival following a diagnosis of stage I breast cancer among women who carry a BRCA1 mutation and to determine predictors of mortality, including the use of chemotherapy. Patients were 379 women with stage I breast cancer for whom a BRCA1 mutation had been identified, in herself or in a close family member. Patients were followed for up to 15 years from the initial diagnosis of breast cancer. Survival rates were estimated for women by age, tumor size (≤ 1 cm; > 1 cm), ER status (±), and by chemotherapy (yes/no). 42 women died of breast cancer in the follow-up period (11.2 %). Survival rates were similar for women with cancers of size 0-1.0 cm and size 1.1-2.0 cm. Of the 267 women in the study who used chemotherapy, 21 had died (7.9 %) compared to 21 deaths among 112 women who did not receive chemotherapy (18.8 %; p = 0.002). The 15-year survival was 89.4 % for women who received chemotherapy and was 73.1 % for women who did not receive chemotherapy (p = 0.08; log rank). The adjusted hazard ratio for death following a diagnosis of stage I breast cancer associated with chemotherapy was 0.53 (95 % CI 0.28-1.07; p value 0.06) after adjusting for age of diagnosis, tumor size, and estrogen receptor status. This was statistically significant only among women with ER-negative breast cancers (HR = 0.28; 95 % CI 0.10-0.79; p = 0.02). BRCA1 positive women who are treated for stage I breast cancer with chemotherapy have better survival than those who do not receive chemotherapy. The difference cannot be explained by other prognostic factors. All women with invasive breast cancer and a BRCA1 mutation should be considered to be candidates for chemotherapy.
- Published
- 2013
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32. The HOXB13 p.Gly84Glu mutation is not associated with the risk of breast cancer.
- Author
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Akbari MR, Kluźniak W, Rodin R, Li S, Wokołorczyk D, Royer R, Kashyap A, Menkiszak J, Lubinski J, Narod SA, and Cybulski C
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Canada, Case-Control Studies, Female, Heterozygote, Humans, Middle Aged, Poland, Young Adult, Breast Neoplasms genetics, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Mutation
- Abstract
Recently, the HOXB13 gene has been shown to be a susceptibility gene for prostate cancer. HOXB13 is overexpressed in breast cancer tissues and HOXB13 expression in combination with low expression of IL17BR is predictive for a tamoxifen response in ER-positive breast cancers. Based on observations, we hypothesized that the HOXB13 p.Gly84Glu mutation might be associated with breast cancer risk. We genotyped this mutation in the germline DNA of 4,037 women with breast cancer (including 1,082 familial cases) and in 2,762 controls from Canada and Poland. Seven heterozygous carriers of the HOXB13 p.Gly84Glu mutation were found in the cases (0.17 %) compared to four carriers among the controls (0.14 %; OR = 1.2, 95 % CI = 0.34-4.1, p = 1.0). Only one of the seven carriers had a family history of breast cancer. This study does not support the hypothesis that women who carry the HOXB13 Gly84Glu mutation are at increased risk of breast cancer.
- Published
- 2012
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33. Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer.
- Author
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Domagala P, Wokolorczyk D, Cybulski C, Huzarski T, Lubinski J, and Domagala W
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast metabolism, Carcinoma, Lobular metabolism, Case-Control Studies, Checkpoint Kinase 2, Codon, Nonsense, Dyspnea, Female, Genetic Association Studies, Genotype, Humans, Infant, Newborn, Middle Aged, Mutation, Missense, Phenotype, Young Adult, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Lobular genetics, Germ-Line Mutation, Protein Serine-Threonine Kinases genetics
- Abstract
Germline mutations in BRCA1 were already linked to basal-like subtype of immunophenotypic molecular classification of breast cancer (BC). However, it is not known whether mutations in other BC susceptibility genes are associated with molecular subtypes of this cancer. We tested the hypothesis that distinct mutations in another BC susceptibility gene involved in DNA repair, i.e., CHEK2 may be associated with particular immunophenotypic molecular subtypes of this cancer. Two groups of patients: 1255 with BCs and 5496 healthy controls were genotyped for four CHEK2 mutations (I157T and three truncating mutations: 1100delC, IVS2 + 1G > A, del5395). BCs were tested by immunohistochemistry on tissue microarrays for ER, PR, HER-2, EGFR, and CK5/6 and were assigned to appropriate subtypes of immunophenotypic molecular classification. There was a significant association between CHEK2 mutations and the immunophenotypic molecular classification (P = 0.004). CHEK2-associated cancers were predominantly luminal (108/117 = 92.3%). CHEK2-I157T variant was associated with the luminal A subtype (P = 0.01), whereas CHEK2-truncating mutations were associated with the luminal B subtype (P = 0.005). Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC. To our knowledge, this is the first study showing that specific mutations in the same susceptibility gene are associated with different immunophenotypic molecular subtypes of BC. This association represents independent evidence supporting the biological significance of immunophenotypic molecular classification of BC.
- Published
- 2012
- Full Text
- View/download PDF
34. PARP-1 expression in breast cancer including BRCA1-associated, triple negative and basal-like tumors: possible implications for PARP-1 inhibitor therapy.
- Author
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Domagala P, Huzarski T, Lubinski J, Gugala K, and Domagala W
- Subjects
- BRCA1 Protein genetics, Biomarkers, Tumor genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cell Line, Tumor, ErbB Receptors biosynthesis, ErbB Receptors genetics, Female, Genotype, Humans, In Situ Hybridization, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases genetics, Polymerase Chain Reaction, Receptors, Estrogen biosynthesis, Receptors, Estrogen genetics, Receptors, Progesterone biosynthesis, Receptors, Progesterone genetics, Tissue Array Analysis, BRCA1 Protein biosynthesis, Breast Neoplasms genetics, Poly(ADP-ribose) Polymerases biosynthesis
- Abstract
Despite ongoing trials of PARP inhibitors in the treatment of breast cancer (BC), the extent of poly(ADP-ribose)polymerase-1 (PARP-1) protein expression in BCs, which may influence treatment results, is not known. The purpose of this report is to assess expression of PARP-1 in BC including BRCA1-associated, triple negative (TN), and basal-like tumors. Immunohistochemistry with a PARP-1 antibody on tissue microarrays from 130 BRCA1-associated and 594 BRCA1-non-related BCs was used. The vast majority of breast carcinomas expressed high level of nuclear PARP-1 protein and a small percentage of tumors exhibited both nuclear and cytoplasmic PARP-1 expression. There was a significant difference between the mean nuclear PARP-1 quickscore in BRCA1-associated versus BRCA1-non-associated carcinomas in all tumors (P < 0.0001), in the basal-like group (P = 0.0086), TN (P = 0.0015), and non-basal-like groups (P = 0.016) but not in the non-TN group. Among BRCA1-associated BCs, low PARP-1 expression was found in 18.5% of all cases, 18.9% of basal-like and 21% of TN cancers. Among BRCA1-non-related tumors, low PARP-1 expression was found in 8.8% of all cases, 3.1% of basal-like, and 2.7% of TN cancers. PARP-1 expression is significantly associated with BRCA1 status in basal-like and TN BCs. The assessment of PARP-1 expression in tumor samples may improve the selection of BC patients for PARP inhibitor therapy.
- Published
- 2011
- Full Text
- View/download PDF
35. The CYP17A1 -34T > C polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers.
- Author
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Kaufman B, Laitman Y, Ziv E, Hamann U, Torres D, Lahad EL, Beeri R, Renbaum P, Jakubowska A, Lubinski J, Huzarski T, Tołoczko-Grabarek A, Jaworska K, Durda K, Sprudle AB, Chenevix-Trench G, Simard J, Easton DF, Antonis A, Szabo C, and Friedman E
- Subjects
- Adult, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Neoplasms, Multiple Primary diagnosis, Neoplasms, Multiple Primary epidemiology, Odds Ratio, Ovarian Neoplasms diagnosis, Ovarian Neoplasms epidemiology, Proportional Hazards Models, Young Adult, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Neoplasms, Multiple Primary genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide, Steroid 17-alpha-Hydroxylase genetics
- Abstract
Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (-34 T > C; rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n = 1693) or BRCA2 (n = 528) germline mutations from seven centers were genotyped for the -34 T > C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89-1.17, p = 0.74) and 1.10 (95% CI 0.72-1.67, p = 0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94-1.46, p = 0.17) and 0.91 (0.31-2.67, p = 0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the -34 T > C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
- Published
- 2011
- Full Text
- View/download PDF
36. The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers.
- Author
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Jakubowska A, Rozkrut D, Antoniou A, Hamann U, and Lubinski J
- Subjects
- Adult, Breast Neoplasms pathology, Female, Genetic Predisposition to Disease genetics, Heterozygote, Humans, Ovarian Neoplasms pathology, Proportional Hazards Models, White People genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Integrin beta3 genetics, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
Integrins containing the beta(3) subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the beta(3) subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00-1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96-1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89-1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
- Published
- 2010
- Full Text
- View/download PDF
37. A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer.
- Author
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Bogdanova N, Cybulski C, Bermisheva M, Datsyuk I, Yamini P, Hillemanns P, Antonenkova NN, Khusnutdinova E, Lubinski J, and Dörk T
- Subjects
- Adult, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms epidemiology, Breast Neoplasms ethnology, Carcinoma, Ductal, Breast epidemiology, Carcinoma, Ductal, Breast ethnology, Carcinoma, Lobular epidemiology, Carcinoma, Lobular ethnology, Case-Control Studies, Cell Cycle Proteins physiology, DNA-Binding Proteins physiology, Family Health, Female, Founder Effect, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Odds Ratio, Poland epidemiology, Protein Serine-Threonine Kinases physiology, Republic of Belarus epidemiology, Russia epidemiology, Sequence Analysis, DNA, Tumor Suppressor Proteins physiology, Ukraine epidemiology, Ukraine ethnology, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, Carcinoma, Lobular genetics, Cell Cycle Proteins genetics, Codon, Nonsense, DNA-Binding Proteins genetics, Point Mutation, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics
- Abstract
Blood relatives of patients with ataxia-telangiectasia (A-T) have an increased risk to develop breast cancer. Allelic heterogeneity has made it difficult to confirm the role of ATM, the gene mutated in A-T, for breast cancer susceptibility in the general population. We now report that a nonsense mutation, p.E1978X (c.5932G>T), is both a classical A-T mutation and a breast cancer susceptibility allele in Eastern European populations. In a case-control study from Belarus, the E1978X mutation was identified in 10/1,891 Byelorussian breast cancer cases (0.5%) compared with 1/1,019 population controls [odds ratio (OR): 5.4; 95% confidence interval (95% CI), 0.7-42.4, P = 0.1]. A second case-control study from Russia identified the E1978X mutation in two Russian and one Ukrainian cases out of 611 breast cancer patients but not in any Russian or Ukrainian controls (P = 0.1). In a third case-control study from Poland, E1978X was observed in 7/3,910 Polish breast cancer cases (0.2%) compared with 1/2,010 cancer-free population controls (OR: 3.6; 95% CI: 0.4-29.3, P = 0.4). In the combined analysis, E1978X was significantly associated with breast cancer (Mantel-Haenszel OR: 5.6, 95% CI: 1.3-21.4, P = 0.01). Taken together, this study provides first evidence for the association of a common A-T causing mutation with breast cancer in Eastern European founder populations.
- Published
- 2009
- Full Text
- View/download PDF
38. Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update.
- Author
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Ginsburg O, Ghadirian P, Lubinski J, Cybulski C, Lynch H, Neuhausen S, Kim-Sing C, Robson M, Domchek S, Isaacs C, Klijn J, Armel S, Foulkes WD, Tung N, Moller P, Sun P, and Narod SA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Heterozygote, Humans, Middle Aged, Mutation, Risk Factors, Young Adult, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Smoking adverse effects
- Abstract
Among women with a mutation in BRCA1 or BRCA2, the risk of breast cancer is high, but it may be modified by exogenous and endogenous factors. There is concern that exposure to carcinogens in cigarette smoke may increase the risk of cancer in mutation carriers. We conducted a matched case-control study of 2,538 cases of breast cancer among women with a BRCA1 (n = 1,920) or a BRCA2 (n = 618) mutation. One non-affected mutation carrier control was selected for each case, matched on mutation, country of birth, and year of birth. Odds ratios were calculated using conditional logistic regression, adjusted for oral contraceptive use and parity. Ever-smoking was not associated with an increased breast cancer risk among BRCA1 carriers (OR = 1.09; 95% CI 0.95-1.24) or among BRCA2 carriers (OR = 0.81; 95% CI 0.63-1.05). The result did not differ when cases were restricted to women who completed the questionnaire within two years of diagnosis. A modest, but significant increase in risk was seen among BRCA1 carriers with a past history of smoking (OR = 1.27; 95% CI 1.06-1.50), but not among current smokers (OR = 0.95; 0.81-1.12). There appears to be no increase in the risk of breast cancer associated with current smoking in BRCA1 or BRCA2 carriers. There is a possibility of an increased risk of breast cancer among BRCA1 carriers associated with past smoking. There may be different effects of carcinogens in BRCA mutation carriers, depending upon the timing of exposure.
- Published
- 2009
- Full Text
- View/download PDF
39. CYP1B1 and predisposition to breast cancer in Poland.
- Author
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Matyjasik J, Cybulski C, Masojć B, Jakubowska A, Serrano-Fernandez P, Górski B, Debniak T, Huzarski T, Byrski T, Gronwald J, Złowocka E, Narod SA, Scott R, and Lubinski J
- Subjects
- Aryl Hydrocarbon Hydroxylases, Breast Neoplasms enzymology, Cytochrome P-450 CYP1B1, Female, Haplotypes, Humans, Poland, Breast Neoplasms genetics, Cytochrome P-450 Enzyme System genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
- Abstract
Background: The CYP1B1 gene is a polymorphic member of the P450 gene family and is considered to be a candidate gene for cancers of various types., Objective: We inquired whether four SNPs in the CYP1B1 gene, alone or in combination, might be associated with breast cancer risk in Poland., Methods: We genotyped 2017 cases of breast cancer and 876 controls, for four SNPs in the CYP1B1 gene. Genotype and haplotype frequencies were compared in cases and controls., Results: In combinations of the R48G, A119S and L432V SNPs, four of the eight CYP1B1 haplotypes were more common in controls than in cases and each of these appeared to have a significant protective effect. A large reduction in risk was observed for women who were homozygous for one of these four haplotypes (OR = 0.2; 95%; CI = 0.05-0.5; P = 0.001) compared to women who were homozygous for the most common haplotype. In contrast, women who were homozygous for the GTC haplotype were at increased risk (OR = 1.5; 95%; CI = 1.0-2.1; P = 0.03) compared to women with the most common haplotype., Conclusions: The CYP1B1 gene appears to influence breast cancer susceptibility in Poland.
- Published
- 2007
- Full Text
- View/download PDF
40. Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
- Author
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Kotsopoulos J, Lubinski J, Lynch HT, Klijn J, Ghadirian P, Neuhausen SL, Kim-Sing C, Foulkes WD, Moller P, Isaacs C, Domchek S, Randall S, Offit K, Tung N, Ainsworth P, Gershoni-Baruch R, Eisen A, Daly M, Karlan B, Saal HM, Couch F, Pasini B, Wagner T, Friedman E, Rennert G, Eng C, Weitzel J, Sun P, Narod SA, Garber J, Osborne M, Fishman D, McLennan J, McKinnon W, Merajver S, Olsson H, Provencher D, Pasche B, Evans G, Meschino WS, Lemire E, Chudley A, Rayson D, and Bellati C
- Subjects
- Adolescent, Adult, Age Distribution, Breast Neoplasms epidemiology, Case-Control Studies, Female, Heterozygote, Humans, Middle Aged, Odds Ratio, Parity, Pregnancy, Registries, Risk Factors, Time Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Mutation, Pregnancy Complications, Neoplastic
- Abstract
An early age at first full-term birth is associated with a reduction in the subsequent development of breast cancer among women in the general population. A similar effect has not yet been reported among women who carry an inherited BRCA1 or BRCA2 mutation. We conducted a matched case-control study on 1816 pairs of women with a BRCA1 (n = 1405) or BRCA2 (n = 411) mutation in an attempt to elucidate the relationship between age at first full-term pregnancy and the risk of developing breast cancer. Information about the age at first childbirth and other pregnancy-related variables was derived from a questionnaire administered to women during the course of genetic counselling. There was no difference in the mean age at first full-term birth in the cases and controls (24.9 years vs. 24.8 years; P = 0.81, respectively). Compared to women whose first child was born at or before 18 years of age, a later age at first full-term birth did not influence the risk of developing breast cancer (OR = 1.00 per year; 95% CI 0.98-1.03; P-trend = 0.67). Stratification by mutation status did not affect the results. These findings suggest that an early first full-term birth does not confer protection against breast cancer in BRCA mutation carriers. Nonetheless, BRCA mutation carriers opting for a prophylactic oophorectomy as a breast and/or ovarian cancer risk-reducing strategy should complete childbearing prior to age 40 when this prevention modality is most effective.
- Published
- 2007
- Full Text
- View/download PDF
41. Male to female ratio among offspring of BRCA1 mutation carriers.
- Author
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Gronwald J, Byrski T, Huzarski T, Narod SA, and Lubinski J
- Subjects
- Breast Neoplasms epidemiology, Breast Neoplasms genetics, Female, Genetic Testing, Humans, Male, Middle Aged, Genes, BRCA1, Germ-Line Mutation, Heterozygote, Sex Ratio
- Published
- 2006
- Full Text
- View/download PDF
42. Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland.
- Author
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Gronwald J, Byrski T, Huzarski T, Cybulski C, Sun P, Tulman A, Narod SA, and Lubinski J
- Subjects
- Adolescent, Adult, Aged, Breast Neoplasms prevention & control, Case-Control Studies, Child, Contraceptives, Oral therapeutic use, Female, Germ-Line Mutation, Heterozygote, Humans, Middle Aged, Ovarian Neoplasms prevention & control, Parity, Pregnancy, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Life Style, Mutation, Ovarian Neoplasms genetics
- Abstract
It has been estimated that the lifetime risk of breast cancer among women who inherit a BRCA1 or BRCA2 mutation is as high as 80%, and the risk estimates for ovarian cancer range from 15 to 40%. Several environmental and lifestyle factors are believed to contribute to the development of breast cancer in the general population and it is of interest to establish if these factors operate among mutation carriers as well. To evaluate the effects of age of menarche, parity, breast-feeding, oophorectomy and oral contraceptive use, as well as smoking and coffee consumption, on the risks of breast and ovarian cancer, we conducted a matched case-control study of Polish women with BRCA1 mutations. There were 348 breast cancer patients, 150 ovarian cancer patients and similar numbers of age-matched controls. BRCA1 carriers with late age of menarche, lower parity and long-term breast-feeding were less likely to develop breast cancer. Oral contraceptives protected against ovarian cancer.
- Published
- 2006
- Full Text
- View/download PDF
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