There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of ...variable quality, and it remains unclear which of these may be of value in clinical risk assessment.
PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers.
We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only.
Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers
Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.
To estimate risk and mortality reduction stratified by ...mutation and prior cancer status.
Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.
Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.
No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio HR, 0.14; 95% confidence interval CI, 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 95% CI, 0.12-0.69), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 95% CI, 0.41-0.96) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 95% CI, 0.16-0.82). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 95% CI, 0.26-0.61), breast cancer-specific mortality (6% vs 2%; HR, 0.44 95% CI, 0.26-0.76), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 95% CI, 0.06-0.80).
Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.
Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of ...all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model.
During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio HR = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance.
The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.
In Botswana, cervical cancer is the leading cause of cancer death for females. With limited resources, Botswana is challenged to ensure equitable access to advanced cancer care. Botswana's capital ...city, Gaborone, houses the only gynecologic oncology multi-disciplinary team (MDT) and the one chemoradiation facility in the country. We aimed to identify areas where fewer women were presenting to the MDT clinic for care.
This cross-sectional study examined cervical cancer patients presenting to the MDT clinic between January 2015 and March 2020. Patients were geocoded to residential sub-districts to estimate age-standardized presentation rates. Global Moran's I and Anselin Local Moran's I tested the null hypothesis that presentation rates occurred randomly in Botswana. Community- and individual-level factors of patients living in sub-districts identified with higher (HH) and lower (LL) clusters of presentation rates were examined using ordinary least squares with a spatial weights matrix and multivariable logistic regression, respectively, with α level 0.05.
We studied 990 patients aged 22-95 (mean: 50.6). Presentation rates were found to be geographically clustered across the country (p = 0.01). Five sub-districts were identified as clusters, two high (HH) sub-district clusters and three low (LL) sub-district clusters (mean presentation rate: 35.5 and 11.3, respectively). Presentation rates decreased with increased travel distance (p = 0.033). Patients residing in LL sub-districts more often reported abnormal vaginal bleeding (aOR: 5.62, 95% CI: 1.31-24.15) compared to patients not residing in LL sub-districts. Patients in HH sub-districts were less likely to be living with HIV (aOR: 0.59; 95% CI: 0.38-0.90) and more likely to present with late-stage cancer (aOR: 1.78; 95%CI: 1.20-2.63) compared to patients not in HH sub-districts.
This study identified geographic clustering of cervical cancer patients presenting for care in Botswana and highlighted sub-districts with disproportionately lower presentation rates. Identified community- and individual level-factors associated with low presentation rates can inform strategies aimed at improving equitable access to cervical cancer care.
Purpose
Black women are more likely than non-Hispanic White women to be diagnosed with triple negative breast cancer (TNBC), an aggressive subtype with limited treatment options. The study objective ...was to evaluate the associations of known breast cancer risk factors, including breast density, with TNBC among Black women.
Methods
This study included Black women who underwent screening mammography between the ages of 40–84 years at a University of Pennsylvania Health System between 2010 and 2015. Cox proportional hazard models using multiple imputation with chained equations were used to estimate hazard ratios and 95% confidence intervals for risk factors for ER/PR+/HER2− and TNBC.
Results
Among 25,013 Black women, there were 330 incident breast cancers (1.3%) during a mean follow-up of 5.8 years; 218 (66.1%) ER/PR+ HER− and 61 (18.1%) TNBC. Having dense breasts (heterogeneously dense or extremely dense) vs. non-dense breasts (almost entirely fatty or scattered areas of fibroglandular density) increased risk of ER/PR+/HER2− breast cancer almost 80% (HR 1.79, 95% CI 1.32–2.43) and TNBC more than twofold (HR 2.53, 1.45–4.44). Older age was associated with an increased risk for ER/PR+/HER2− (HR 1.04, 1.03–1.06) and TNBC (HR 1.03, 1.00–1.05). Having a BMI of > 30 kg/m
2
was associated with an increased risk (HR 2.77, 1.05–7.30) for TNBC and an increased risk of ERPR+/HER2− breast cancer in postmenopausal but not pre-menopausal women (
p
-interaction = 0.016).
Conclusion
Our results suggest that breast density and obesity are strong risk factors for TNBC among Black women. Understanding breast cancer subtype specific risk factors among Black women can help improve risk assessment.
Bilateral prophylactic salpingo-oophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with
BRCA1 and
BRCA2 mutations. However, the reduction in mortality ...after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in
BRCA1 and
BRCA2 mutation carriers.
We identified a prospective cohort of 666 women with disease-associated germline mutations in
BRCA1 or
BRCA2 and no previous cancer diagnosis. In our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for centre, mutation (
BRCA1 vs BRCA2), and birth year.
In the primary analysis, mean follow-up from BPSO to censoring was 3·1 years SD 2·4 in the BPSO group and 2·1 years 2·0 in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0·24 (95% CI 0·08–0·71), for breast-cancer-specific mortality was 0·10 (0·02–0·71), and for ovarian-cancer-specific mortality was 0·05 (0·01–0·46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0·28 95% CI 0·10–0·74), but not with breast-cancer-specific mortality (0·15 0·02–1·18 or ovarian-cancer-specific mortality (0·23 0·02–1·87. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality.
If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing.
Cervical cancer is the leading cause of female cancer mortality in Botswana with the majority of cervical cancer patients presenting with late-stage disease. The identification of factors associated ...with late-stage disease could reduce the cervical cancer burden. This study aims to identify potential patient level clinical and sociodemographic factors associated with a late-stage diagnosis of cervical cancer in Botswana in order to help inform future interventions at the community and individual levels to decrease cervical cancer morbidity and mortality.
There were 984 women diagnosed with cervical cancer from January 2015 to March 2020 at two tertiary hospitals in Gaborone, Botswana. Four hundred forty women (44.7%) presented with late-stage cervical cancer, and 674 women (69.7%) were living with HIV. The mean age at diagnosis was 50.5 years. The association between late-stage (III/IV) cervical cancer at diagnosis and patient clinical and sociodemographic factors was evaluated using multivariable logistic regression with multiple imputation. Women who reported undergoing cervical cancer screening had lower odds of late-stage disease at diagnosis (OR: 0.63, 95% CI 0.47-0.84) compared to those who did not report screening. Women who had never been married had increased odds of late-stage disease at diagnosis (OR: 1.35, 95% CI 1.02-1.86) compared to women who had been married. Women with abnormal vaginal bleeding had higher odds of late-stage disease at diagnosis (OR: 2.32, 95% CI 1.70-3.16) compared to those without abnormal vaginal bleeding. HIV was not associated with a diagnosis of late-stage cervical cancer. Rural women who consulted a traditional healer had increased odds of late-stage disease at diagnosis compared to rural women who had never consulted a traditional healer (OR: 1.61, 95% CI 1.02-2.55).
Increasing education and awareness among women, regardless of their HIV status, and among providers, including traditional healers, about the benefits of cervical cancer screening and about the importance of seeking prompt medical care for abnormal vaginal bleeding, while also developing support systems for unmarried women, may help reduce cervical cancer morbidity and mortality in Botswana.
Inherited mutations in
BRCA1
or
BRCA2
(
BRCA1/2
) confer very high risk of breast and ovarian cancers. Genetic testing and counseling can reduce risk and death from these cancers if appropriate ...preventive strategies are applied, including risk-reducing salpingo-oophorectomy (RRSO) or risk-reducing mastectomy (RRM). However, some women who might benefit from these interventions do not take full advantage of them. We evaluated RRSO and RRM use in a prospective cohort of 1,499 women with inherited
BRCA1/2
mutations from 20 centers who enrolled in the study without prior cancer or RRSO or RRM and were followed forward for the occurrence of these events. We estimated the age-specific usage of RRSO/RRM in this cohort using Kaplan–Meier analyses. Use of RRSO was 45 % for
BRCA1
and 34 % for
BRCA2
by age 40, and 86 % for
BRCA1
and 71 % for
BRCA2
by age 50. RRM usage was estimated to be 46 % by age 70 in both
BRCA1
and
BRCA2
carriers.
BRCA1
mutation carriers underwent RRSO more frequently than
BRCA2
mutation carriers overall, but the uptake of RRSO in
BRCA2
was similar after mutation testing and in women born since 1960. RRM uptake was similar for both
BRCA1
and
BRCA2
. Childbearing influenced the use of RRSO and RRM in both
BRCA1
and
BRCA2
. Uptake of RRSO is high, but some women are still diagnosed with ovarian cancer before undergoing RRSO. This suggests that research is needed to understand the optimal timing of RRSO to maximize risk reduction and limit potential adverse consequences of RRSO.
The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the ...role of concomitant hysterectomy is controversial.
To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy.
This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range IQR, 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression.
Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database.
Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected O:E ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001; BRCA2: 0.16 expected O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors.
Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.
BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the ...PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non‐African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision‐making in African descent individuals worldwide.
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