Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland.

Reports on the prognosis of familial breast cancer patients have been contradictory. True differences in survival, if they exist, would have important implications for genetic counselling and in treatment of hereditary breast cancer. We assessed the survival rates of 359 familial breast cancer patients (32 patients from BRCA1-positive families, 43 patients from BRCA2-positive families and 284 patients from BRCA1/2-negative breast cancer families) and compared them with those of all other breast cancer patients diagnosed in Finland from 1953 to 1995 (n = 59,517). Cumulative relative survival rates (RSR) were calculated by dividing the observed survival rates by the expected ones. The expected survival rates were derived from the sex, age and calendar year specific life-tables of the general population in Finland. Regression model was used to calculate relative excess risk of death (RR) and to adjust for confounding factors. The overall 5-year RSR of the patients in the BRCA1 families, BRCA2 families, non-BRCA1/2 families and among sporadic cases was 67%, 77%, 86% and 78%, respectively. However, we found no significant differences in the RR adjusted for age, stage and year of diagnosis between the different familial patient groups or the general breast cancer population. In the BRCA1 families the RR tended to be higher [RR 1.30, 95% confidence interval (CI) 0.63--2.70] and in the BRCA2 families lower (RR 0.78, 95% CI 0.39--1.57) than among the general breast cancer patient population. The RR among patients in the non-BRCA1/2 families did not differ from that of the general patient population.     

miRNA expression patterns in normal breast tissue and invasive breast cancers of BRCA1 and BRCA2 germ-line mutation carriers

miRNA deregulation has been found to promote carcinogenesis. Little is known about miRNA deregulation in hereditary breast tumors as no miRNA expression profiling studies have been performed in normal breast tissue of BRCA1 and BRCA2 mutation carriers. miRNA profiles of 17 BRCA1- and 9 BRCA2-associated breast carcinomas were analyzed using microarrays. Normal breast tissues from BRCA1 and BRCA2 mutation carriers (both n = 5) and non-mutation carriers (n = 10) were also included. Candidate miRNAs were validated by qRT-PCR. Breast carcinomas showed extensive miRNA alteration compared to normal breast tissues in BRCA1 and BRCA2 mutation carriers. Moreover, normal breast tissue from BRCA1 mutation carriers already showed miRNA alterations compared to non-mutation carriers. Chromosomal distribution analysis showed several hotspots containing down- or up-regulated miRNAs. Pathway analysis yielded many similarities between the BRCA1 and BRCA2 axes with miRNAs involved in cell cycle regulation, proliferation and apoptosis. Lesser known pathways were also affected, including cellular movement and protein trafficking. This study provides a comprehensive insight into the potential role of miRNA deregulation in BRCA1/2-associated breast carcinogenesis. The observed extensive miRNA deregulation is likely the result of genome-wide effects of chromosomal instability caused by impaired BRCA1 or BRCA2 function. This study''s results also suggest the existence of common pathways driving breast carcinogenesis in both BRCA1 and BRCA2 germ-line mutation carriers.     

Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose:

The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk.

Patients and methods:

Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.

Results:

Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8% P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36% P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002).

Conclusion:

The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.     

BRCA1 and BRCA2 Common Mutations in Iranian Breast Cancer Patients: a Meta Analysis

Background: To date several common mutations in BRCA1 and BRCA2 associated with breast cancer havebeen reported in different populations. However, the common BRCA1 and BRCA2 mutations among breastcancer patients in Iran have not been described in detail. Materials and Methods: To comprehensively assessthe frequency and distribution of the most common BRCA1 and BRCA2 mutations in Iranian breast cancerpatients, we conducted this meta-analysis on 13 relevant published studies indentified in a literature searchon PubMed and SID. Results: A total of 11 BRCA1 and BRCA2 distinct common mutations were identified,reported twice or more in the articles, of which 10 (c.2311T>C, c.3113A>G, c.4308T>C, c.4837A>G, c.2612C>T,c.3119G>A, c.3548A>G, c.5213G>A c.IVS16-92A/G, and c.IVS16-68A/G) mutations were in BRCA1, and 1(c.4770A>G) was in BRCA2. The mutations were in exon 11, exon 13, intron 16, and exon 20 of BRCA1 andexon 11 of BRCA2. All have been previously reported in different populations. Conclusions: These meta analysisresults should be helpful in understanding the possibility of any first true founder mutation of BRCA1/BRCA2in the Iranian population. In addition, they will be of significance for diagnostic testing, genetic counseling andfor epidemiological studies.     

Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients

Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (< or =30 years) and was 9.0% for single cases of early-onset ovarian cancer (< or =45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan.     

Identification of Germline BRCA1 Mutations among Breast Cancer Families in Northeastern Iran

Background: The purpose of this study was to evaluate the prevalence of BRCA1 (MIM: 113705) foundermutations in familial breast cancer (BC) patients with high risks in Iran. BRCA1 is among the cancer susceptibilitygenes best known for high penetrance mutations. BRCA1 genotyping is now used to determine patient counseling,management decisions, and prognosis of this syndrome. Materials and Method: Thirty nine patients with clinicalBC and 29 high risk healthy women, related to the patients, participated in the study. DNA from blood sampleswas extracted and analyzed by PCR and SSCP methods in order to find 185delAG and 5382insC foundermutations. In addition, a 251bp fragment of BRCA1’s exon 11 was amplified and analyzed for determination ofnew mutations. Results: The data indicated the presence of 185delAG and 5382insC founder mutations in bothgroups studied. Two out of 39 BC patients (5.1%) and one out of 29 relatives (3.4%) were suspected to be carriersof 185delAG mutations. However, we found only one patient (2.6%) to be a carrier of a 5382insC mutation. Also,2 women (5.1%) of the patient group and 3 n (10.3%) of relatives group were identified as carriers of unclarifiedmutations in the 251bp fragment of the BRCA1 gene. The carriers of BRCA1 founder mutations have a highlifetime risk of breast cancer. Conclusions: Therefore, these data are useful in counseling of individuals with asignificant family history of breast cancer.     

BRCA1, BRCA2 and CHEK2 (1100 del C) Germline Mutations in Hereditary Breast and Ovarian Cancer Families in South India

Cancer of the breast is the second most common cancer seen among Indian women. This study describes the use ‍of DHPLC for mutation analysis for BRCA1, BRCA2 and CHEK2 (1100delC) in 22 patients with a family history of ‍breast and/or ovarian cancer and early onset breast cancer (<35 years of age). Three of the 22 patients were found to ‍have a non-sense mutation or a deletion, resulting in a premature stop codon, potentially leading to a truncated ‍protein. Two of these were in BRCA1 (one was a novel 5 base deletion) and one in the BRCA2 gene. No patient was ‍found in our series to have the CHEK2 (1100delC) mutation. DNA from a healthy blood donor and all but one of the ‍22 patients, demonstrated polymorphisms in BRCA1 and/or BRCA2 genes. This is the first study from South India, ‍on BRCA1, BRCA2 & CHEK2 (1100 del C) mutations in patients with a family history of breast and/or ovarian ‍cancer and early onset breast/ovarian cancer, using the sensitive DHPLC approach.     

Clinical significance of large rearrangements in BRCA1 and BRCA2

BACKGROUND:

Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer.

METHODS:

Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as “high‐risk” if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. “Elective” patients did not meet the high‐risk criteria, but underwent LR testing as ordered by the referring health care provider.

RESULTS:

Overall BRCA1/2 mutation prevalence among high‐risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high‐risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high‐risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients.

CONCLUSIONS:

Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. Cancer 2012. © 2012 American Cancer Society.     

Lack of Germ-line Mutations at the Specific BRCA1-IRIS Coding Sequence in 114 Spanish High-risk Breast/ovarian Families

A new BRCA1 locus product called BRCA1-IRIS has been identified recently. High-risk breast/ovarian families have not been screened for germ-line mutations at the specific BRCA1-IRIS coding sequence, as it was considered merely as part of BRCA1 intron 11. Here we report the first comprehensive screening of germ-line mutations in a cohort of 116 index cases from high-risk breast/ovarian families in which no germ-line mutation was identified in BRCA1 or BRCA2. We did not find germ-line mutations at the specific BRCA1-IRIS coding sequence in any sample. The only heterozygous patter identified by DGGE was caused by a C to A substitution in the non-coding 3′ sequence, 123 bases downstream of the BRCA1-IRIS stop codon (IVS11+268C/A). The data indicates that it is probably a neutral change not associated with cancer risk. Our analysis suggests that the role of germ-line mutations at the specific BRCA1-IRIS sequence in breast cancer susceptibility, if any, is marginal and do not explain a significant fraction of high-risk breast/ovarian families, at least in the population analyzed.     

Cancer risks among BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction.     

家族性乳腺癌患者及家系成员乳腺癌易感基因携带情况调查

目的 乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)和BRCA2基因已经证实与家族性乳腺癌密切相关.本研究旨在分析中国汉族家族性乳腺癌患者及家系成员BRCA1和BRCA2突变特征及携带情况.方法 收集2013 12-02-2015-06-08军事医学科学院附属医院确诊的中国汉族家族性乳腺癌患者55例及家系成员48名,共计103例样本.柚取外周静脉血提取DNA,应用聚合酶链反应(polymerase chain reaction,PCR) DNA直接测序方法检测BRCA1和BRCA2基因全编码外显子序列.结果 55例家族性乳腺癌患者中发现5个BRCA基因致病性突变位点,1个突变位点乳腺癌信息库中见报道(BRCA1:4730insG),4个为新发现突变位点(BRCA1:1937insC,4538insAG;BRCA2:1382delA,2820delA).家族性乳腺癌患者BRCA1/2突变率为9.09％(BRCA1,5.45％;BRCA2,3.64％),其中三阴性乳腺癌患者突变率为22.22％(x2 =1.99,P=0.20),早发性乳腺癌患者(≤35岁)突变率为20.00％,x2=0.79,P=0.39.48例家系成员检测到3个新发现突变位点(BRCA1:1370insA,3459insA;BRCA2:6502insT),总突变率为6.25％.结论 中国汉族家族性乳腺癌患者BRCA基因突变率显著低于国外,应重点关注有家族史的三阴性乳腺癌患者和早发性乳腺癌患者;家系成员中发现BRCA基因致病性突变,家系成员突变率和发病风险有待进一步研究,应引起重视.     

Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations

BACKGROUND:

Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

METHODS:

The authors reviewed the medical histories of 6052 women with a BRCA1 or BRCA2 mutation, half of whom had been diagnosed with breast cancer. They estimated the odds ratio for breast cancer, given a self‐report of diabetes. They then estimated the hazard ratio for a new diagnosis of diabetes associated with a history of breast cancer.

RESULTS:

There was no excess of diabetes in the period before the diagnosis of breast cancer, compared with controls with no diagnosis of breast cancer. The risk of diabetes was doubled among BRCA carriers in the 15‐year period after the diagnosis of breast cancer (relative risk, 2.0; 95% confidence interval [CI], 1.4‐2.8; P = .0001), compared with carriers without cancer. The risk was particularly high for women with a body mass index (BMI) >25.0 kg/m² (odds ratio, 5.8; 95% CI, 4.0‐8.6; P = .0001).

CONCLUSIONS:

After a diagnosis of breast cancer, women with a BRCA1 or BRCA2 mutation face a 2‐fold increase in the risk of diabetes, which is exacerbated by a high BMI. Cancer 2011. © 2010 American Cancer Society.     

Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is approximately 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30-0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24-2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65).     

Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Purpose

To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy.

Patients and methods

Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups.

Results

Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01). Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10) and to have positive lymph nodes (34% vs. 18%; p = 0.11) compared to women with prior bilateral oophorectomy.

Conclusions

Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.

     

Collaboration of breast cancer clinic and genetic counseling division for BRCA1 and BRCA2 mutation family in Japan

BACKGROUND: BRCA1 and BRCA2 mutations cause high breast cancer incidence rates as high as 80% Although prophylactic therapy is still controversial, several prophylactic therapies have been proposed and tried for BRCA1 and BRCA2 mutation carriers. Prophylactic surgery, chemo-prevention and precise screening have been proposed as prophylactic therapy. All BRCA1 and BRCA2 mutation carriers need knowledge about their disease and the countermeasures that are used to protect against onset of disease. Counseling plays an important role in this regard for people with genetic diseases. Therefore, collaboration between breast cancer clinics and genetic counseling services is the most important issue in clinical practice. Our group consists of three national universities and a general hospital. In this article we describe our trial to construct a clinical system against hereditary breast cancer as an interim report for the Japanese Ministry of Health, Labour and Welfare. PATIENTS AND METHODS: Twenty familial breast cancer patients were registered in this study. The whole sequence of BRCA1 and BRCA2 were analyzed. If pathological mutations were detected, their first degree families were introduced to the counseling division at each institute when candidates visited counseling divisions. RESULTS AND DISCUSSION: Four cases of a deleterious mutation in BRCA1 or BRCA2 were detected among 20 cases. Their first degree relatives are now under consideration for visiting counseling divisions. The clinical system described in this study should play a role to protect BRCA1 or BRCA2 mutation carriers in Japan.     

International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers

Several options for cancer prevention are available for women with a BRCA1 or BRCA2 mutation, including prophylactic surgery, chemoprevention and screening. The authors report on preventive practices in women with mutations from 9 countries and examine differences in uptake according to country. Women with a BRCA1 or BRCA2 mutation were contacted after receiving their genetic test result and were questioned regarding their preventive practices. Information was recorded on prophylactic mastectomy, prophylactic oophorectomy, use of tamoxifen and screening (MRI and mammography). Two thousand six hundred seventy-seven women with a BRCA1 or BRCA2 mutation from 9 countries were included. The follow-up questionnaire was completed a mean of 3.9 years (range 1.5-10.3 years) after genetic testing. One thousand five hundred thirty-one women (57.2%) had a bilateral prophylactic oophorectomy. Of the 1,383 women without breast cancer, 248 (18.0%) had had a prophylactic bilateral mastectomy. Among those who did not have a prophylactic mastectomy, only 76 women (5.5%) took tamoxifen and 40 women (2.9%) took raloxifene for breast cancer prevention. Approximately one-half of the women at risk for breast cancer had taken no preventive option, relying solely on screening. There were large differences in the uptake of the different preventive options by country of residence. Prophylactic oophorectomy is now generally accepted by women and their physicians as a cancer preventive measure. However, only the minority of women with a BRCA1 or BRCA2 mutation opt for prophylactic mastectomy or take tamoxifen for the prevention of hereditary breast cancer. Approximately one-half of women at risk for breast cancer rely on screening alone.     

The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers

Tobacco smoke is an established carcinogen, but the association between tobacco smoking and cancer risk in BRCA mutation carriers is not clear. The aim of this study was to evaluate prospectively the association between tobacco smoking and cancer incidence in a cohort of BRCA1 and BRCA2 mutation carriers. The study population consisted of unaffected BRCA mutation carriers. Information on lifestyle including smoking histories, reproductive factors, and past medical histories was obtained through questionnaires. Incident cancers were updated biennially via follow‐up questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using time‐dependent Cox regression models. There were 700 incident cancers diagnosed over 26,711 person‐years of follow‐up. The most frequent cancers seen in BRCA mutation carriers were breast (n = 428; 61%) and ovarian (n = 109; 15%) cancer. Compared to nonsmokers, (ever) smoking was associated with a modest increased risk of all cancers combined (HR = 1.17; 95%CI 1.01–1.37). Women in the highest group of total pack‐years (4.3–9.8) had an increased risk of developing any cancer (HR = 1.27; 95%CI 1.04–1.56), breast cancer (HR = 1.33, 95%CI 1.02–1.75), and ovarian cancer (HR = 1.68; 95%CI 1.06–2.67) compared to never smokers. The associations between tobacco smoking and cancer did not differ by BRCA mutation type or by age at diagnosis. This prospective study suggests that tobacco smoking is associated with a modest increase in the risks of breast and ovarian cancer among women with BRCA1 or BRCA2 mutation.     

Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: A national cohort study

Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as “unfavourable.” Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79‐9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60‐year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile.