Age-specific Breast Cancer Risk Research Articles

Breast Cancer Screening Strategies for Women With ATM, CHEK2, and PALB2 Pathogenic Variants

Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women. To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants. This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985. Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years. Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges. The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women. This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

Abstract 4636: Breast cancer age-specific incidence rates among Ghanaian women by breast cancer risk factors: A study using census and population-based case-control study data

Abstract Introduction: Although breast cancer incidence in sub-Saharan African countries, including Ghana, has been historically low, incidence is rising. Evaluating age-specific incidence rates by breast cancer risk factors may provide etiologic insights. Here we present age-specific incidence rates for breast cancer estimated from the Ghana Breast Health Study (GBHS) for key breast cancer risk factors. Methods: GBHS is a population-based case-control study with 1,071 pathologically confirmed incident invasive breast cancer cases (18-74 years old) diagnosed between 2013-2015 in three hospitals in Accra and Kumasi. A total of 2,094 controls were sampled from the population, and frequency matched by site and age to the cases. Sample weights for controls were calculated using data from the 2010 Ghana Census, adjusted for non-response. Data on incident breast cancer cases in Accra (2012-2014) and Kumasi (2013-2015) were obtained from their respective cancer registries and compared to the incidence rates observed in the GBHS. Using data from GBHS adjusted by sampling weights, we estimated 5-year age-specific breast cancer incidence rates and 95% confidence intervals overall and according to breast cancer risk factors. Results: Age-specific breast cancer incidence rates estimated from the GBHS rose quickly until approximately age 50 when the rate plateaued but still rose (Clemmeson's hook), which was consistent with cancer registry data from Kumasi and Accra. The rates from the GBHS are not significantly different from the cancer registry rates under age 50 but are significantly higher after age 50. While the rates from the GBHS and Accra and Kumasi cancer registries were much lower than rates observed in the SEER registries for African American women, the trends were consistent. Analyses of overall rates by breast cancer risk factors showed that age-specific breast cancer risk was elevated among women with a family history of breast cancer across all ages. Data suggested cross-over interactions for other factors, particularly parity, and breastfeeding among parous women. Specifically, incidence rates were higher for parous than nulliparous women aged 20-35 years, while incidence rates were lower for parous and breastfeeding (among parous) women older than 35 years. Conclusions: Age-specific incidence rates of breast cancer that demonstrate cross-over interactions by risk factors may be important in understanding racial disparities in breast cancer incidence, overall as well as for specific breast cancer subtypes. Elevated risk among young parous women may be indicative of the higher risk associated with early-onset (triple-negative) breast cancer. Citation Format: Brittny Davis Lynn, Jonine Figueroa, Richard Biritwum, Beatrice Wiafe Addai, Baffour Awuah, Joe Net Clegg-Lamptey, Robertson Adjei, Lucy Afriyie, Joel Yarney, Naomi Oyoe Ohene Oti, Daniel Ansong, Seth Wiafe, Louise Brinton, Montserrat Garcia-Closas, Barry Graubard. Breast cancer age-specific incidence rates among Ghanaian women by breast cancer risk factors: A study using census and population-based case-control study data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4636.

Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC)

BackgroundThe association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman’s familial risk.MethodsWe conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20 years (mean 10.5 years). There were 896 incident breast cancers (mean age at diagnosis 55.7 years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline.ResultsThe strength and direction of the BMI risk association depended on baseline menopausal status (P < 0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P = 0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk.ConclusionsThe greater a woman’s familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

Adaptive decision-making of breast cancer mammography screening: A heuristic-based regression model

The American Cancer Society (ACS) updated their breast cancer screening guidelines in late 2015 and recommends that all women have the choice to start annual mammography screenings beginning at age 40. For women ages 45–54, the ACS explicitly recommends annual mammograms. However, due to the potential harms associated with screening mammography, such as overdiagnosis and unnecessary work-ups, the best strategy to design an appropriate breast cancer mammography screening schedule remains controversial. Instead of recommending a one-size-fits-all screening schedule, this study identifies a personalized mammography screening strategy adaptive to each woman's age-specific breast cancer risk. We present a two-stage decision framework: (1) age-specific breast cancer risk estimation and (2) annual mammography screening decision-making based on estimated risk. The results suggest that the optimal combinations of independent variables used in risk estimation are not the same across age groups. Our optimal decision models outperform the existing mammography screening guidelines in terms of the average loss of life expectancy. While most earlier studies improved the breast cancer screening decisions by offering lifetime screening schedules, our proposed model provides an adaptive screening decision aid by age. Since whether or not a woman should receive a mammogram is determined based on her breast cancer risk at her current age, our “on-line” screening policy adapts to a woman's latest health status, which reflects the current individual risk of each woman more accurately.

Breast-Cancer Risk in Families With Mutations in PALB2

Germline mutations in the BRCA1 and BRCA2 genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2 gene that also increase the risk of breast cancer. PALB2 interacts with BRCA1 and BRCA2 genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2 loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown. The aim of this study was to obtain a robust estimate of the breast cancer risk associated with inherited loss-of-function mutations in PALB2. Data were collected for mutation carriers and their relatives from multiple centers worldwide. The risk of breast cancer was determined for 362 members from 154 families with PALB2 loss-of-function mutations A total of 311 women in these families had PALB2 mutations; 229 of these had breast cancer. The age-specific risk of breast cancer for mutation carriers was estimated using a modified segregation-analysis approach that allowed for the effects of inheritance patterns of disease and PALB2 genotype. Mutation carriers were divided into cohorts of women older than 60 years, between 40 and 60 years of age, and younger than 40 years. Compared with the general population, the risk of breast cancer for women who carried the PALB2 mutation was 8 to 9 times higher among those younger than 40 years, 6 to 8 times higher among those 40 to 60 years of age, and 5 times higher among those older than 60 years. The cumulative risk of breast cancer for female PALB2 mutation carriers was estimated to be 14% (95% confidence interval [CI], 9%–20%) by 50 years of age and 35% (95% CI, 26%–46%) by 70 years of age. Breast cancer risk among mutation carriers increased significantly as the birth cohort became more recent (P < 0.001); risk also was affected by other family factors (P = 0.04). By 70 years of age, the absolute risk of breast cancer for a woman who carried the PALB2 mutation ranged from 33% (95% CI, 25%–44%) if she had no family history of breast cancer to 58% (95% CI, 50%–66%) if she had a strong family history (≥2 first-degree relatives with breast cancer at 50 years of age). These data suggest that the level of breast cancer risk for a PALB2 mutation carrier, with or without a family history of breast cancer, is high. This level of risk may justify adding screening for PALB2 mutations to genetic testing panels used for BRCA1 and BRCA2.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre

Background:Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom.Methods:Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level.Results:The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76–1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66–0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2).Conclusion:BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Assessing risk of breast cancer in an ethnically South-East Asia population (results of a multiple ethnic groups study)

BackgroundGail and others developed a model (GAIL) using age-at-menarche, age-at-birth of first live child, number of previous benign breast biopsy examinations, and number of first-degree-relatives with breast cancer as well as baseline age-specific breast cancer risks for predicting the 5-year risk of invasive breast cancer for Caucasian women. However, the validity of the model for projecting risk in South-East Asian women is uncertain. We evaluated GAIL and attempted to improve its performance for Singapore women of Chinese, Malay and Indian origins.MethodsData from the Singapore Breast Screening Programme (SBSP) are used. Motivated by lower breast cancer incidence in many Asian countries, we utilised race-specific invasive breast cancer and other cause mortality rates for Singapore women to produce GAIL-SBSP. By using risk factor information from a nested case-control study within SBSP, alternative models incorporating fewer then additional risk factors were determined. Their accuracy was assessed by comparing the expected cases (E) with the observed (O) by the ratio (E/O) and 95% confidence interval (CI) and the respective concordance statistics estimated.ResultsFrom 28,883 women, GAIL-SBSP predicted 241.83 cases during the 5-year follow-up while 241 were reported (E/O=1.00, CI=0.88 to 1.14). Except for women who had two or more first-degree-relatives with breast cancer, satisfactory prediction was present in almost all risk categories. This agreement was reflected in Chinese and Malay, but not in Indian women. We also found that a simplified model (S-GAIL-SBSP) including only age-at-menarche, age-at-birth of first live child and number of first-degree-relatives performed similarly with associated concordance statistics of 0.5997. Taking account of body mass index and parity did not improve the calibration of S-GAIL-SBSP.ConclusionsGAIL can be refined by using national race-specific invasive breast cancer rates and mortality rates for causes other than breast cancer. A revised model containing only three variables (S-GAIL-SBSP) provides a simpler approach for projecting absolute risk of invasive breast cancer in South-East Asia women. Nevertheless its role in counseling the individual women regarding their risk of breast cancer remains problematical and needs to be validated in independent data.

A PALB2 mutation associated with high risk of breast cancer

IntroductionAs a group, women who carry germline mutations in partner and localizer of breast cancer 2 susceptibility protein (PALB2) are at increased risk of breast cancer. Little is known about by how much or whether risk differs by mutation or family history, owing to the paucity of studies of cases unselected for family history.MethodsWe screened 1,403 case probands for PALB2 mutations in a population-based study of Australian women with invasive breast cancer stratified by age at onset. The age-specific risk of breast cancer was estimated from the cancer histories of first- and second-degree relatives of mutation-carrying probands using a modified segregation analysis that included a polygenic modifier and was conditioned on the carrier case proband. Further screening for PALB2 c.3113G > A (W1038X) was conducted for 779 families with multiple cases of breast cancer ascertained through family cancer clinics in Australia and New Zealand and 764 population-based controls.ResultsWe found five independent case probands in the population-based sample with the protein-truncating mutation PALB2 c.3113G > A (W1038X); 2 of 695 were diagnosed before age 40 years and 3 of 708 were diagnosed when between ages 40 and 59 years. Both of the two early-onset carrier case probands had very strong family histories of breast cancer. Further testing found that the mutation segregated with breast cancer in these families. No c.3113G > A (W1038X) carriers were found in 764 population-based unaffected controls. The hazard ratio was estimated to be 30.1 (95% confidence interval (CI), 7.5 to 120; P < 0.0001), and the corresponding cumulative risk estimates were 49% (95% CI, 15 to 93) to age 50 and 91% (95% CI, 44 to 100) to age 70. We found another eight families carrying this mutation in 779 families with multiple cases of breast cancer ascertained through family cancer clinics.ConclusionsThe PALB2 c.3113G > A mutation appears to be associated with substantial risks of breast cancer that are of clinical relevance.

Estimating age-specific breast cancer risks: a descriptive tool to identify age interactions

Clarifying age-specific female breast cancer risks and interactions may provide important etiologic clues. Using a population-based case-control study in Poland (2000-2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25-74 years, we estimated age-specific breast cancer incidence rates according to risk factors. Breast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA). Notwithstanding overall risks, we observed statistically significant quantitative (non-crossover) and qualitative (crossover) age interactions for all risk factors except for FH and PA. For example, nulliparity compared to parity reduced breast cancer risk among women ages 25-39 years then rates crossed or reversed, after which nulliparity increased relative risks among women ages 40-74 years. Though quantitative age interactions could be expected, qualitative interactions were somewhat counterintuitive. If confirmed in other populations, qualitative interactions for a continuous covariate such as age will be difficult to reconcile in a sequential (multistep or monolithic) 'stochastic' breast cancer model. Alternatively, the reversal of relative risks among younger and older women suggests subgroup heterogeneity with different etiologic mechanisms for early-onset and late-onset breast cancer types.

Breast Cancer Risk Estimates for Relatives of White and African American Women With Breast Cancer in the Women's Contraceptive and Reproductive Experiences Study

Family history is a well-recognized risk factor for breast cancer. Familial aggregation and segregation analyses have estimated breast cancer risk based on family history primarily for white women; such information is limited for African American (AA) women. The purpose of this report is to update breast cancer risk estimates associated with a family history of breast cancer for white and AA women. We used family cancer history from 2,676 white and 1,525 AA women with breast cancer (probands) in the population-based National Institute of Child Health and Human Development's Women's Contraceptive and Reproductive Experiences (CARE) Study to estimate age-specific breast cancer risks in their first degree adult female relatives. Cumulative hazard curves were calculated for relatives of all probands using Cox proportional hazards models, and were stratified by the proband's race and age at diagnosis and number of relatives affected. Breast cancer risks for white and AA women with a family history of the disease are similar through age 49 years, but diverge afterwards, with higher risks by age 79 in white women than in AA women (17.5% [SE, 0.9%] v 12.2% [SE, 1.1%]; P < .001). These risks increase as the number of affected first degree relatives increases, reaching 25.2% (SE, 3.4%) and 16.9% (SE, 4.0%) in white and AA women with more than one affected relative, respectively (P = .3). We found age-related racial differences in breast cancer risk in women with a family history of breast cancer and have updated risk estimates for white and AA women for clinical use.

Racial differences in breast cancer risk to relatives of cases in the women's contraceptive and reproductive experiences (CARE) study

9514 Background: Family history of breast cancer (BRCA) is a well-recognized risk factor for the disease, suggesting a role for genes, shared environment and/or cultural factors. Familial aggregation studies based primarily on Caucasian (CAU) women have given rise to age-specific and lifetime BRCA risk estimates, but less information is available on comparable risks for African American (AA) women. Methods: We used the family cancer history collected from CAU and AA participants with BRCA (cases) in the National Institute of Child Health and Human Development Women's CARE Study to compare the age-specific BRCA rates in their first-degree relatives (FDR). Kaplan-Meier cumulative hazard curves were obtained for FDR of CARE cases using PROC LIFETEST (SAS version 8.2). Analyses were pooled over all ages at diagnosis and stratified by age at diagnosis (< 45 vs. = 45) and race. Results: Age-specific risks (and standard errors) of BRCA to FDR of CARE cases, by race and age at BRCA diagnosis in the case, are presented in the table. By 40 years of age, BRCA risk to FDR is greater in AA than CAU, with the greatest risk, .023, in FDR of AA cases diagnosed by 45 years of age. By 70 years of age, BRCA risk to FDR is greater in CAU than AA, with the greatest risk, 0.16, in FDR of CAU cases diagnosed by 45 years of age. Conclusions: These results illustrate racial differences in age-specific BRCA risk and provide a recent update of these risks for both CAU and AA women that can be utilized in the clinical setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration National Institute of Child Health and Human Development; National Cancer Institute; Emory University; Fred Hutchinson Cancer Research Center; Karmanos Cancer Institute at Wayne State University; University of Pennsylvania; University of Southern California; Centers for Disease Control and Prevention; The Barbara Ann Karmanos Cancer Institute; United Foundation of Detroit; Michigan Health Care Education and Research Foundation

Racial differences in breast cancer risk to relatives of cases in the women's contraceptive and reproductive experiences (CARE) study

9514 Background: Family history of breast cancer (BRCA) is a well-recognized risk factor for the disease, suggesting a role for genes, shared environment and/or cultural factors. Familial aggregation studies based primarily on Caucasian (CAU) women have given rise to age-specific and lifetime BRCA risk estimates, but less information is available on comparable risks for African American (AA) women. Methods: We used the family cancer history collected from CAU and AA participants with BRCA (cases) in the National Institute of Child Health and Human Development Women's CARE Study to compare the age-specific BRCA rates in their first-degree relatives (FDR). Kaplan-Meier cumulative hazard curves were obtained for FDR of CARE cases using PROC LIFETEST (SAS version 8.2). Analyses were pooled over all ages at diagnosis and stratified by age at diagnosis (< 45 vs. = 45) and race. Results: Age-specific risks (and standard errors) of BRCA to FDR of CARE cases, by race and age at BRCA diagnosis in the case, are presented in the table. By 40 years of age, BRCA risk to FDR is greater in AA than CAU, with the greatest risk, .023, in FDR of AA cases diagnosed by 45 years of age. By 70 years of age, BRCA risk to FDR is greater in CAU than AA, with the greatest risk, 0.16, in FDR of CAU cases diagnosed by 45 years of age. Conclusions: These results illustrate racial differences in age-specific BRCA risk and provide a recent update of these risks for both CAU and AA women that can be utilized in the clinical setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration National Institute of Child Health and Human Development; National Cancer Institute; Emory University; Fred Hutchinson Cancer Research Center; Karmanos Cancer Institute at Wayne State University; University of Pennsylvania; University of Southern California; Centers for Disease Control and Prevention; The Barbara Ann Karmanos Cancer Institute; United Foundation of Detroit; Michigan Health Care Education and Research Foundation

The HER2 I655V polymorphism and breast cancer risk in Ashkenazim.

BACKGROUND Over-expression of the human epidermal growth factor receptor 2 (Her2) protooncogene is associated with poor prognosis among female patients with breast cancer. A polymorphism in the HER2 gene (I655V) has been associated with an elevated risk of breast cancer in some ethnic groups. METHODS Subjects from a community-based study of 5318 Ashkenazim from the Washington, DC area were selected for analysis of the I655V HER2 germline polymorphism. We estimated age-specific breast cancer risk from HER2 I655V based on the family history data, using the female first-degree relatives of the study participants and a novel extension of the kin cohort method. RESULTS The estimated cumulative risk of breast cancer to age 70 was approximately 30% higher among HER2 I655V carriers than noncarriers (RR = 1.33; 95% confidence interval [CI] = 1.03-1.83). The effect of the allele seems stronger at younger ages (among women younger than 50 years, RR = 2.11; CI = 1.39-3.28) and especially among younger women with a family history of breast cancer (RR = 8.9; CI = 1.9-19.7). Increased risk of breast cancer associated with the I655V allele was also observed among BRCA1/2 mutation carriers, although these results are based on small numbers. CONCLUSION These analyses suggest that the HER2 valine allele might be associated with increased risk of breast cancer, especially in young women and in women with a family history of the disease.

Breast cancer and the pill

In the UK 11% of women will develop breast cancer by age 85. Breast cancer is the most frequently diagnosed cancer in women.1 However, compared with lifetime risk, the age-specific risk of breast cancer is low. At age 50 the risk is 2% and at 25 it is 0.05% (1 in 2000). Whatever the actual risk, the notion of getting breast cancer is terrifying, and women overestimate the likelihood of acquiring and dying from this disease by a factor of 25.2 Less than 5% of deaths in women are attributed to breast cancer; more than half of all women die of cardiovascular disease. Public anxiety about breast cancer tends to be fuelled by the media. Qualitative research suggests that cancer stories are overreported in the popular press, and both broadsheets and tabloid newspapers are 70% more likely to publish bad news than good news. They are also more inclined to report observational studies than randomized trials.3 In American magazines throughout the 1990s there was disproportionate reporting of breast cancer in a 2:1 ratio to cardiovascular disease.4

Modification of BRCA1-Associated Breast Cancer Risk by the Polymorphic Androgen-Receptor CAG Repeat

Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.

The shape of age-incidence curves of female breast cancer by hormone-receptor status.

Substantial decline of ovarian hormones at menopause plays an important role in breast cancer etiology. Hormones must bind to specific receptors to elicit biological responses, however. We therefore hypothesized and examined whether the age-specific risk of breast cancer, especially its change at menopause, differs by estrogen and progesterone receptor (ER/PR) status. Age-specific incidence rates, stratified by ER/PR status, were estimated by multiplying the age-specific ER/PR distribution among 3359 cases in the Danish Breast Cancer Cooperative Group by Danish national age-specific incidence rates. International variations in the age-incidence curve were also reviewed in relation to the hypothesis. The incidence of ER +/PR + subtype (62.9% of all cases) increased with age continually, with a sudden decrease in the rate of increase around age 44. The incidence of ER-/PR- subtype (17.6%) increased with age prior to about age 50 but remained unchanged subsequently. The incidence of ER+ /PR- subtype (13.9%) increased rapidly during the menopausal period but only slightly afterwards. The incidence of ER-/PR+ subtype (5.6%) increased until about age 43 and decreased subsequently. The international comparison revealed Western women, particularly the elderly, might be at substantially higher risk for ER+ /PR+ subtype compared to Japanese women. Age-specific risk of breast cancer differs by ER/PR status. The large international variation of breast cancer incidence rates may be explained largely by the risk difference for ER+ /PR+ subtype.

Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history.

The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a first-degree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.

Likelihood Ratios for Modern Screening Mammography

<h3>Objective.</h3> —To determine the sensitivity, specificity, and likelihood ratios (LRs) for modern screening mammography by decade of age and mammographic interpretation. <h3>Design.</h3> —Cross-sectional. <h3>Setting.</h3> —Nine counties in northern California. <h3>Participants.</h3> —A total of 26 057 women aged 30 years and older who underwent a total of 41 747 first and subsequent screening mammographic examinations at the Mobile Mammography Screening Program of the University of California, San Francisco, from April 1985 to September 1991. <h3>Measurements.</h3> —Breast cancer risk profile, 2 standard mammographic views per breast, and follow-up of abnormal and normal mammograms by contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results tumor registry. False-negative examinations were normal examinations that occurred within 13 months of a diagnosis of invasive breast cancer or ductal carcinoma in situ. <h3>Results.</h3> —The sensitivity of first screening mammography increased with age: 77.3% for ages 30 to 39 years, 86.7% for ages 40 to 49 years, 93.6% for ages 50 to 59 years, 94.1% for ages 60 to 69 years, and 91.2% for ages 70 years and older (<i>P</i>=.04). Specificity was similar for all ages, ranging from 92.6% to 95.2%. Of all abnormal first screening examinations, 92.9% were reported as "additional evaluation needed." The LRs for that category ranged from 5.2 to 8.8 and did not vary with age. Based on the risk of breast cancer before mammography, which increases with age, the risk of breast cancer after mammography associated with these LRs were 0.01 for ages 30 to 39 years, 0.02 for ages 40 to 49 years, 0.05 for ages 50 to 59 years, 0.07 for ages 60 to 69 years, and 0.07 for ages 70 years and older. The LRs for mammography reported as "suspicious for malignancy" ranged from 88 to 144 and did not vary across age groups. These LRs were associated with a risk of breast cancer about 10 times greater than when mammography was reported as "additional evaluation needed." <h3>Conclusions.</h3> —Most abnormal first screening mammography are interpreted as "additional evaluation needed" and are associated with LRs of about 7. Given this low LR, the risk of breast cancer after mammography is primarily influenced by a woman's age-specific risk of breast cancer before mammography. The LRs for screening mammography interpreted as "suspicious for malignancy" are high (about 124) and are associated with a substantial increase in the risk of breast cancer irrespective of age, but these interpretations comprise only a small proportion of abnormal mammography.

Likelihood ratios for modern screening mammography. Risk of breast cancer based on age and mammographic interpretation

To determine the sensitivity, specificity, and likelihood ratios (LRs) for modern screening mammography by decade of age and mammographic interpretation. Cross-sectional. Nine counties in northern California. A total of 26,057 women aged 30 years and older who underwent a total of 41,747 first and subsequent screening mammographic examinations at the Mobile Mammography Screening Program of the University of California, San Francisco, from April 1985 to September 1991. Breast cancer risk profile, 2 standard mammographic views per breast, and follow-up of abnormal and normal mammograms of contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results tumor registry. False-negative examinations were normal examinations that occurred within 13 months of a diagnosis of invasive breast cancer or ductal carcinoma in situ. The sensitivity of first screening mammography increased with age: 77.3% for ages 30 to 39 years, 86.7% for ages 40 to 49 years, 93.6% for ages 50 to 59 years, 94.1% for ages 60 to 69 years, and 91.2% for ages 70 years and older (P = .04). Specificity was similar for all ages, ranging from 92.6% to 95.2%. Of all abnormal first screening examinations, 92.9% were reported as "additional evaluation needed." The LRs for that category ranged from 5.2 to 8.8 and did not vary with age. Based on the risk of breast cancer before mammography, which increases with age, the risk of breast cancer after mammography associated with these LRs were 0.01 for ages 30 to 39 years, 0.02 for ages 40 to 49 years, 0.05 for ages 50 to 59 years, 0.07 for ages 60 to 69 years, and 0.07 for ages 70 years and older. The LRs for mammography reported as "suspicious for malignancy" ranged from 88 to 144 and did not vary across age groups. These LRs were associated with a risk of breast cancer about 10 times greater than when mammography was reported as "additional evaluation needed." Most abnormal first screening mammography are interpreted as "additional evaluation needed" and are associated with LRs of about 7. Given this low LR, the risk of breast cancer after mammography is primarily influenced by a woman's age-specific risk of breast cancer before mammography. The LRs for screening mammography interpreted as "suspicious for malignancy" are high (about 124) and are associated with a substantial increase in the risk of breast cancer irrespective of age, but these interpretations comprise only a small proportion of abnormal mammography.

Combined effect of childbearing, menstrual events, and body size on age-specific breast cancer risk.

Pike et al. (Nature 1983;303:767-70) and Moolgavkar et al. (JNCI 1980;65:59-69) proposed quantitative theories for the effect on age-specific breast cancer risk of ages at menarche, first childbirth, and menopause. Here the incidence rate functions predicted by these theories are fit to data for 1,884 women of all ages with breast cancer and 3,432 matched controls admitted to San Francisco Bay area hospitals in 1970-1977. A third function describing age-specific breast cancer risk based on the timing of childbearing and menstrual events is presented, and its fit to the data is compared with that of the functions of Pike et al. and Moolgavkar et al. None of the three fully accounted for the protective effects of early age at first childbirth in premenopausal women or of early age at menopause in parous postmenopausal women. To account for the effects of total parity and body mass (Quetelet) index on risk of breast cancer occurrence, the authors developed a fourth incidence rate function by extending the third. Goodness of fit to the data of the fourth function is demonstrated. Age-specific relative risks of breast cancer according to childbearing, menstrual events, and body size are estimated from the fourth function. The main qualitative findings are that 1) the protective effects of late menarche and of early first full-term pregnancy are greater in premenopausal than in postmenopausal women; 2) first full-term pregnancy initially boosts the level of risk, but incidence rates increase with age more slowly thereafter; 3) among the parous, multiparity is protective both in premenopausal and postmenopausal women, regardless of age at first full-term pregnancy; 4) both nulliparous and lean women are more protected by early menopause than are parous and overweight women; 5) increased body mass index is protective before, but detrimental after, menopause; and 6) postmenopausal incidence rates increase with age more rapidly among overweight than among lean women.