RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

RAD50 is a highly conserved DNA double‐strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next‐generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51–2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence‐free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18–5.98; p = 0.018] and disease‐specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58–12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.     

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.     

胚系BRCA基因突变乳腺癌的临床诊治进展

BRCA基因是最常见的乳腺癌易感基因,胚系BRCA突变患者罹患乳腺癌的风险显著增加.随着对BRCA基因的深入研究以及聚ADP-核糖聚合酶(poly ADP-ribose polymerase,PARP)抑制剂的出现,BRCA突变已成为乳腺癌治疗的新靶点.在BRCA突变乳腺癌的治疗中,PARP抑制剂和铂类为两大主要药物选...     

Prevalence of BRCA1 and BRCA2 germline mutations in young breast cancer patients: a population-based study

Our aim was to estimate the prevalence of mutations in the BRCA1 and BRCA2 genes among unselected incident cases of breast cancer in young women. We identified 158 incident breast cancer cases diagnosed before age 46 years in predefined geographic areas in Girona and Tarragona, Spain, during 1995-1997. Of these, 136 (86%) provided information on family history of cancer and were screened for BRCA1 and BRCA2 mutations. Nine of the 136 (6.6%) were found to carry BRCA deleterious mutations (MUT) (1 BRCA1 and 8 BRCA2), and 20 were detected with rare BRCA variants of unknown significance (UV). Both MUT and US BRCA alterations were more frequent in younger patients: 7 (11.6%) MUT and 12 (19.3%) UV carriers were found in the group of 62 patients younger than 40 years, whereas 2 (2.7%) MUT and 9 (12%) US carriers were identified in the group of 74 patients aged 40-45. Family history of breast and ovarian cancers suggestive of hereditary condition (at least 2 first- or second-degree relatives affected with breast cancer or at least 1 relative affected with ovarian cancer or early-onset breast cancer) was absent for 5 of 9 MUT carriers. This suggests that BRCA screening policies based on family history of cancer would miss a considerable proportion of BRCA mutations. Mutations in the BRCA1 and BRCA2 genes explain at least 10% of breast cancer cases diagnosed before age 40 years. The contribution of these genes to early-onset breast cancer is likely to be even higher given that certain UV cases might be disease-associated.     

Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers

Early age at first birth and multiparity have been associated with a decrease in the risk of breast cancer in women in the general population. We examined whether this relationship is also present in women at high risk of breast cancer due to the presence of a mutation in either of the 2 breast cancer susceptibility genes, BRCA1 or BRCA2. We performed a matched case-control study of 1,260 pairs of women with known BRCA1 or BRCA2 mutations, recruited from North America, Europe and Israel. Women who had been diagnosed with breast cancer were matched with unaffected control subjects for year of birth, country of residence, and mutation (BRCA1 or BRCA2). Study subjects completed a questionnaire detailing their reproductive histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. Among BRCA1 carriers, parity per se was not associated with the risk of breast cancer (OR for parous vs. nulliparous = 0.94; 95% CI = 0.75-1.19; p = 0.62). However, women with a BRCA1 mutation and 4 or more children had a 38% decrease in breast cancer risk compared to nulliparous women (OR = 0.62; 95% CI = 0.41-0.94). In contrast, among BRCA2 carriers, increasing parity was associated with an increased risk of breast cancer; women with 2 or more children were at approximately 1.5 times the risk of breast cancer as nulliparous women (OR = 1.53; 95% CI = 1.01-2.32; p = 0.05). Among women with BRCA2 mutations and who were younger than age 50, the (adjusted) risk of breast cancer increased by 17% with each additional birth (OR = 1.17; 95% CI = 1.01-1.36; p = 0.03). There was no significant increase in the risk of breast cancer among BRCA2 carriers older than 50 (OR for each additional birth = 0.97; 95% CI = 0.58-1.53; p = 0.92). In the 2-year period following a birth, the risk of breast cancer in a BRCA2 carrier was increased by 70% compared to nulliparous controls (OR = 1.70; 95% CI = 0.97-3.0). There was a much smaller increase in breast cancer risk among BRCA2 carriers whose last birth was 5 or more years in the past (OR = 1.24; 95% CI = 0.79-1.95). A modest reduction in risk of breast cancer was observed among BRCA1 carriers with 4 or more births. Among BRCA2 carriers, increasing parity was associated with a significant increase in the risk of breast cancer before age 50 and this increase was greatest in the 2-year period following a pregnancy.     

The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers

BACKGROUND:

We assessed the efficacy of taxane chemotherapy in BRCA1‐ and BRCA2‐associated patients compared with sporadic metastatic breast cancer patients.

METHODS:

Response rates (RRs) to and progression‐free survival (PFS) after taxane chemotherapy of 35 BRCA1‐associated and 13 BRCA2‐associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third).

RESULTS:

Among BRCA1‐associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)‐negative patients, BRCA1‐associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec‐positive patients were similar in BRCA1‐associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2‐associated patients, who were mainly HRec‐positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively).

CONCLUSIONS:

BRCA1‐associated, HRec‐negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec‐negative patients. HRec‐positive BRCA1‐ and BRCA2‐associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients. Cancer 2012;. © 2011 American Cancer Society.     

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers in a large cohort of unselected Chinese breast cancer patients

To estimate the cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers in a large cohort of unselected Chinese breast cancer patients. Our study comprised 9,401 unselected Chinese breast cancer patients and BRCA1/2 germline mutations were determined in all patients. After a median follow-up of 5.7 years, 181 patients developed CBC in this cohort. Compared to noncarriers, BRCA1 and BRCA2 carriers had a 4.52-fold (95% CI, 2.63–7.76) and 5.54-fold (95% CI, 3.51–8.74) increased risk of CBC, respectively. The 10-year cumulative risk of CBC was 15.5% (95% CI, 9.9–24.2) for BRCA1 carriers, 17.5% (95% CI, 10.9–28.0) for BRCA2 carriers and 3.2% (95% CI, 2.5–4.1) for noncarriers. Younger age at first breast cancer diagnosis was significantly associated with an increased 10-year risk of CBC for BRCA1 carriers (≤40 years vs. >40 years: 21.5% vs. 11.9%, unadjusted hazard ratio [HR] = 2.51, 95% CI, 1.03–6.15, p = 0.044), but not for BRCA2 carriers and noncarriers. The 10-year cumulative CBC risk was significantly higher in both BRCA1 and BRCA2 carriers who had a family history of breast cancer than in those who did not (BRCA1: 27.5% vs. 9.4%, adjusted HR = 2.64, 95% CI, 1.01–6.97, p = 0.049; BRCA2: 27.1% vs. 12.8%, adjusted HR = 2.29, 95% CI, 1.04–5.06, p = 0.040). In conclusion, the risk of CBC was a substantial high in BRCA1/2 carriers in unselected Chinese breast cancer patients, and CBC risk is much more remarkable in both BRCA1 and BRCA2 carriers who had a family history of breast cancer. Younger age at first breast cancer diagnosis also enhanced CBC risk in BRCA1 carriers.     

Olaparib efficacy in patients with germline BRCA-mutated,HER2-negative metastatic breast cancer: Subgroup analyses from the phase III OlympiAD trial

In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.     

BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families and their implications for genetic counseling.

BACKGROUND: The Sardinian population is genetically homogeneous and could be useful in understanding better the genetics of a complex disease like breast cancer (BC). PATIENTS AND METHODS: Using a screening assay based on a combination of single-strand conformation polymorphism, denaturing high-performance liquid chromatography and sequence analysis, 47 Sardinian families with three or more BC cases were screened for germline mutations in BRCA1 and BRCA2 genes. RESULTS: Three BRCA1/2 germline sequence variants were identified. While BRCA2-Ile3412Val is a missense variant with unknown functional significance, BRCA2-8765delAG and BRCA1-Lys505ter are two deleterious mutations (due to their predicted effects on protein truncation), which were found in seven families (15%). BRCA2-8765delAG was found in six of eight (75%) BRCA1/2-positive families and seven of 501 (1.4%) unselected and consecutively collected BC patients. Prevalence of BRCA1/2 mutations in BC families was significantly correlated with the total number of female BCs (P <0.01) and increased by the presence of (i) at least one case of ovarian or male BC, or (ii) three generations affected, or (iii) bilateral BC. CONCLUSIONS: Identification of such features should address BC patients and their families to genetic counseling and BRCA1/2 mutational analysis. In addition, this is the first report of a detailed BRCA1/2 mutation screening in Sardinia, having immediate implications for the clinical management of BC families.     

BRCA1 andBRCA2 germline mutations in Japanese with hereditary breast cancer families

We examined germline mutations inBRCA1 andBRCA2 in 23 Japanese breast cancer families, using PCR-SSCP analysis. The same nonsense mutation (exon 5, Leu63ter) ofBRCA1 was detected in two different families. Three different mutations resulting in a truncatedBRCA2 protein (exon 9, 20, 24) were detected in three different families, including one male case of breast cancer. One base substitution mutation inBRCA2, A10462G, was detected in the other two families. Although the mean age of onset for breast cancer in families with theBRCA1- mutation was 50 years, the age of onset in families with theBRCA2-mutation was from 28 to 43 years. Among the 23 families examined, two families had members with ovarian cancers, three had members with prostate cancers, and one had a pancreatic cancer. However, none of these families was positive for theBRCA1 orBRCA2 mutation. Histopathologically, we observed a prevalence of histological grade 3 inBRCA2-associated familial breast cancers, because of nuclear atypia, structural atypia and mitotic activity. It is suggested thatBRCA2 may play a more important role thanBRCA1 in Japanese familial breast cancers, and these mutations are related to the aggressive nature and highly proliferative activity of the tumors.     

A new germline mutation in BRCA1 gene in a sicilian family with ovarian cancer

Summary A group of 103 sicilian patients with hereditary and familiar breast and/or ovarian cancer were screened for Breast Cancer 1 gene (BRCA1) mutations by direct sequencing PCR products spanning the coding region and partial intronic regions of the BRCA1 gene. In this study, we report a new germline mutation in BRCA1 gene, not previously reported in the BIC database, in a woman with ovarian cancer at 46 years old. Mother’s proband has been diagnosed the same histotype of ovarian cancer at 42 age. The mutational analyses that shown a 4843delC frameshift mutation in exon 16 of BRCA1 gene was extended to other family members including the proband’s brother and her two sons. Direct automatic sequencing of DNA extracted from the lymphocytes showed exactly the same 4843delC frameshift mutation only in the brother. In conclusion, the characterization of this mutation could help in the identification of a founder mutation of sicilian area and this may provide significant advantages for genetic counselling.  *Both authors have contributed equally to this work     

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5+3A>G, 2478-2479insG, E1221X and BRCA2 IVS6+1G>A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (P<0.001), and the presence of a relative with ovarian cancer (P<0.0001) or multiple primary breast cancers (P=0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P=0.002). Mutations in the 5'-end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast-ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families.     

Molecular analysis of the BRCA1 and BRCA2 genes in 32 breast and/or ovarian cancer Spanish families

It is estimated that about 5-10% of breast cancer cases may be due to inherited predisposition. Until now, two main susceptibility genes have been identified: BRCA1 and BRCA2. The first linkage and mutational studies suggested that mutations in these two genes would account for the majority of high-risk breast cancer families, but recent studies show how the proportion of families due to BRCA1 or BRCA2 mutations strongly depends on the population and the types of family analyzed. It is now clear that, in the context of families with a modest cancer profile, which are the most commonly found in the clinical practice, the percentage of mutations found is much lower than that suggested by the first studies. In the present study, we analyze a group of 32 Spanish families, which contained at least three cases of female breast cancer (at least one of them diagnosed before the age of 50 years), for the presence of mutations in the BRCA genes. The total proportion of mutations was low (25%), although the percentage of mutations in the BRCA1 and BRCA2 genes was higher, considering the breast and ovarian cancer families and the male breast cancer families respectively. Our results are in agreement with the idea that a great proportion of moderate-risk cancer families could be due to low penetrance susceptibility genes distinct from BRCA1 or BRCA2.     

Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer

This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two-hundred and ninety-eight Korean women diagnosed with high-grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first-line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.     

Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation

Background:

The BRCA2 gene is responsible for a high number of hereditary breast and ovarian cancers, and studies of the BRCA2 biological functions are limited by the lack of models that resemble the patient''s tumour features. The aim of this study was to establish and characterise a new human breast carcinoma xenograft obtained from a woman carrying a germline BRCA2 mutation.

Methods:

A transplantable xenograft was obtained by grafting a breast cancer sample into nude mice. The biological and genetic profiles of the xenograft were compared with that of the patient''s tumour using histology, immunohistochemistry (IHC), BRCA2 sequencing, comparative genomic hybridisation (CGH), and qRT–PCR. Tumour response to standard chemotherapies was evaluated.

Results:

Histological profile identified the tumour as a basal-like triple-negative breast cancer. Targeted BRCA2 DNA sequencing of the xenograft showed the presence of the mutation previously identified in the carrier. Comparative genomic hybridisation array profiles of the primary tumour and the xenograft revealed a high number of similar genetic alterations. The therapeutic assessment of the xenograft showed sensitivity to anthracyclin-based chemotherapy and resistance to docetaxel. The xenograft was also highly sensitive to radiotherapy and cisplatin-based treatments.

Conclusions:

This study describes a new human breast cancer xenograft obtained from a BRCA2-mutated patient. This xenograft provides a new model for the pre-clinical drug development and for the exploration of the drug response biological basis.     

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.     

Prognostic value of BRCA1 mutations in familial breast cancer patients affected by a second primary cancer

The aim of this prospective study is to assess the prognostic value of BRCA1 mutations in familial breast cancer patients affected by a second primary cancer. The study group comprised 19 women having multiple primary breast cancers (breast-breast, breast-other primary) who were either BRCA1 mutation carriers, or not. Appearance of a second primary cancer was recognised as the event and survival and second primary free cancer survival was calculated from the date of diagnosis to the secondary primary cancer. The results of this study show that the event free survival of women with familial breast cancer affected by a second primary cancer, who are BRCA1 mutation carriers is better, compared with women from the general population with breast cancer selected for second primary cancer sites and all second primary sites—P = 0.009 and P = 0.0078 respectively. In contrast, the event free survival of women with breast cancer affected by a second primary cancer, without a breast cancer family history, who are not BRCA1 mutation carriers is the same, as for women from the general population with breast cancer selected for second primary cancer sites and all second primary sites—P = 0.6417 and P = 0.4859 respectively. The median time from diagnosis of the first to second primary cancer in the mutation carrying, and non-carrying, groups was 8,7 and 1,9 years respectively. In the study group, the highest event free survival rates had been observed among those carrying the said mutations—66.7% at 5 years, and 33.3% at 10 years—in contrast with those not carrying the mutations, with rates of 30.8% and 15.4% respectively.     

Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer

BACKGROUND:

Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast‐pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.

METHODS:

A clinical database review (2000‐2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first‐, second‐, or third‐degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed‐to‐expected (O:E) mutation prevalence was calculated for the entire group.

RESULTS:

Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first‐, second‐, or third‐degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15).

CONCLUSIONS:

BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast‐pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence. Cancer 2011;. © 2011 American Cancer Society.     

Breast conservation in BRCA1 or BRCA2 mutation carriers with early stage breast cancer

The role of breast conservation therapy (limited surgery and irradiation of the breast with/without axilla) in the approximately 5% of breast cancer patients who harbour a germline mutation in BRCA1 or BRCA2, is a largely unexplored area and is seen by some as controversial. The relatively high cumulative risk of second primary cancers in such patients and concern about a possible decreased ability of mutation carriers to repair DNA damage caused by radiation has fuelled this controversy. Published studies of breast conservation therapy in carriers of a mutation in BRCA1 or BRCA2 are reviewed, with particular attention to their methodology. These studies have not demonstrated any increase in radiation sensitivity of normal tissues in mutation carriers, either in terms of increased early or late toxicity or tumourigenesis. Likewise, tumour sensitivity to radiotherapy, which might be expected based on the known functions of the BRCA1 and BRCA2 genes, has not been documented to date in mutation carriers. Further, methodologically rigorous studies of large numbers of breast cancer patients who carry a mutation in BRCA1 or BRCA2 are required to fully elucidate these issues.     

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.