Metcalfe, K. A. et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol. Oncol. 96, 222-226

Faculty of Nursing, University of Toronto, 50 St. George Street, Toronto, ON, Canada, M5S 3H4.
Gynecologic Oncology (Impact Factor: 3.77). 02/2005; 96(1):222-6. DOI: 10.1016/j.ygyno.2004.09.039
Source: PubMed


To estimate the risk of ovarian cancer after a primary diagnosis of breast cancer among women with a BRCA1 or BRCA2 mutation and to identify host and treatment-related factors that might modify the risk.
Patients were 491 women with stage I or stage II breast cancer, diagnosed from 1975 to 2000 and for whom a BRCA1 or BRCA2 mutation had been identified. Patients were followed from the initial diagnosis of breast cancer until either ovarian cancer, prophylactic oophorectomy, death, or 2002. The medical treatment records and pathology documents were reviewed. Information that was abstracted from the medical charts included date of breast cancer diagnosis, stage of disease, use of chemotherapy, use of radiation therapy, usage of tamoxifen, oophorectomy, recurrence, second malignancy, and vital status.
The 10-year actuarial risk of ovarian cancer after breast cancer was 12.7% for BRCA1 carriers and 6.8% for BRCA2 carriers (P = 0.03). The use of tamoxifen (OR = 1.79; P = 0.16) and chemotherapy (OR = 0.59; P = 0.15) did not significantly impact on the risk of subsequent ovarian cancer. Twenty-five percent of the deaths in women with stage I breast cancer were due to a subsequent ovarian cancer.
The high incidence of ovarian cancer suggests that oophorectomy should be recommended in female BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer, especially those with stage I disease. Breast cancer systemic therapy did not significantly alter the risk of ovarian cancer.

Download full-text


Available from: Ivo Olivotto, Aug 11, 2014
  • Source
    • "Each person's likelihood contribution P(Hi|γi, xi) will be computed assuming that competing risks are independent given carrier status and auxiliaries [20]. This is plausible for BRCAPRO because time to ovarian cancer and ipsi/contra-lateral breast cancers appear to be mutually independent in BRCA mutation carriers, except for dependence caused by medical interventions like oophorectomy [22,23] and interventions are explicitly handled in this paper. Auxiliaries xi can include all information necessary to make the assumption more plausible [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mendelian models for predicting who may carry an inherited deleterious mutation of known disease genes based on family history are used in a variety of clinical and research activities. People presenting for genetic counseling are increasingly reporting risk-reducing medical interventions in their family histories because, recently, a slew of prophylactic interventions have become available for certain diseases. For example, oophorectomy reduces risk of breast and ovarian cancers, and is now increasingly being offered to women with family histories of breast and ovarian cancer. Mendelian models should account for medical interventions because interventions modify mutation penetrances and thus affect the carrier probability estimate. We extend Mendelian models to account for medical interventions by accounting for post-intervention disease history through an extra factor that can be estimated from published studies of the effects of interventions. We apply our methods to incorporate oophorectomy into the BRCAPRO model, which predicts a woman's risk of carrying mutations in BRCA1 and BRCA2 based on her family history of breast and ovarian cancer. This new BRCAPRO is available for clinical use. We show that accounting for interventions undergone by family members can seriously affect the mutation carrier probability estimate, especially if the family member has lived many years post-intervention. We show that interventions have more impact on the carrier probability as the benefits of intervention differ more between carriers and non-carriers. These findings imply that carrier probability estimates that do not account for medical interventions may be seriously misleading and could affect a clinician's recommendation about offering genetic testing. The BayesMendel software, which allows one to implement any Mendelian carrier probability model, has been extended to allow medical interventions, so future Mendelian models can easily account for interventions.
    BMC Medical Genetics 02/2007; 8(1):13. DOI:10.1186/1471-2350-8-13 · 2.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Women at high risk for breast cancer are often also at high risk for ovarian cancer, reflecting similar risk factors and suggesting intertwined disease pathways and common prevention targets. A novel strategy to overcome obstacles in preventing ovarian neoplasia (low incidence, lack of specific disease markers, and difficulties in tissue sampling), the deadliest gynecologic cancer, may be to develop a prevention strategy that targets breast and ovarian cancer simultaneously. Tamoxifen, a selective estrogen receptor modulator, reduces hormone responsive breast cancer risk by 50% but its effects on risk of ovarian cancer, also hormonal responsive, are unclear. The goals of this work were to 1) develop and characterize a preclinical model of concurrent breast and ovarian cancer and 2) use this dual cancer model to examine the efficacy of tamoxifen to prevent both breast and ovarian cancer. Mammary carcinogens [7,12-dimethylbenz[α]anthracene (DMBA), N-methyl-N-nitrosourea and estradiol (Ey2)] were tested separately in combination with local ovarian DMBA administration to determine the best combined treatment to induce mammary and ovarian cancer concurrently and effectively in the rat. Results showed that systemic Ey2 and ovarian DMBA promoted the highest incidence of dysplasia in the mammary gland and ovary and elevated levels of mammary Ki-67 and cyclooxygenase 2 (COX-2) mimicking the human disease. Next, the ability of tamoxifen to prevent mammary and ovarian cancer simultaneously was evaluated. Tamoxifen which inhibited mammary carcinogenesis and normalized levels of Ki-67 and COX-2, had no effect on (neither accelerated nor inhibited) ovarian cancer progression. In addition, carcinogen treatment increased levels of stem cell markers, Oct-4 and aldehyde dehydrogenase-1, in the mammary gland; interestingly, this expansion was not reversed by tamoxifen. Intriguingly, while examining ovaries from this study, we serendipitously discovered an apparent protective effect of tamoxifen against DMBA-induced follicular destruction and this effect was further investigated. Chemotherapy and environmental toxicants (e.g. DMBA) deplete ovarian follicles and often lead to accelerated ovarian aging and premature ovarian failure; however, there is no established treatment that can protect the ovary from these toxic insults. In vivo, rats were treated with tamoxifen and DMBA or cyclophosphamide (the most ovotoxic chemotherapy) and total numbers of follicles in the ovary were determined. In vitro, ovarian organ culture and oocyte culture were carried out to examine local effects of tamoxifen on DMBA-induced follicle loss and doxorubicin-induced oocyte fragmentation, respectively. We demonstrated for the first time that tamoxifen protects ovarian follicles against not only DMBA- but also chemotherapy (cyclophosphamide and doxorubicin)-induced ovarian damage. Clinically, tamoxifen has already been tested for safe use as an adjuvant therapy for several cancers; therefore, if translated into clinical use, these results may have immediate impact on options for fertility preservation and quality of life in young female cancer patients undergoing chemotherapy. The long term goals of this work are to 1) use the dual cancer model to screen for promising agents that decrease risks for both breast and ovarian cancer and 2) examine the mechanism by which tamoxifen inhibits toxicant-induced ovarian follicle loss.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The extent of the problem The number of cancer survivors has been increasing dramatically and is expected to keep growing in the near future. In the Netherlands, a 38% increase of cancer survivors is estimated from 2005 to 2015, representing an increase from 500,000 to 692,000 (ex-) patients in this period.1 It is well known that individuals who suffered from cancer exhibit a 20% higher risk of subsequent primary malignancies.2 Thus, as the number of cancer survivors increases, the number of patients with multiple primary cancers will increase as well. Because cancer is more frequent among the elderly, the ageing of the Dutch population will cause a further increase in the number of cases with multiple cancers: Only 5%-12% of cancer patients aged 50-64 were previously diagnosed with cancer, versus 12%-26% of those aged over 803. Other forces, including increased awareness of (second) malignancies, the higher use and sensitivity of diagnostic/detection methods, and the recent improvements in cancer treatment and survival will further lead to higher prevalence of multiple cancers. Cancer survivors who develop a second malignancy have a higher risk of dying4 and experience a worsening in their quality of life. Thus, increased interest in second cancer from the epidemiological and clinical perspective is highly relevant.
Show more