The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers

Background:

Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation.

Methods:

We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases.

Results:

Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03–5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36–7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family.

Conclusion:

The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies.     

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.     

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

Background:

In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.

Methods:

We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.

Results:

We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93–1.04, P=0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89–1.06, P=0.5) mutation carriers.

Conclusion:

This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.     

Uptake of risk-reducing salpingo-oophorectomy in women carrying a BRCA1 or BRCA2 mutation: evidence for lower uptake in women affected by breast cancer and older women

Background:

Bilateral risk-reducing salpingo-oophorectomy (BRRSO) is the only effective way of reducing mortality from ovarian cancer. This study investigates uptake of BRRSO in 700 BRCA1/2 mutation carriers from Greater Manchester.

Methods:

Dates of last follow-up and BRRSO were obtained, and the following variables were investigated: ovarian cancer risk/gene, age and breast cancer history. The date of the genetic mutation report was the initiation for Kaplan–Meier analysis.

Results:

The uptake of BRRSO in BRCA1 mutation carriers was 54.5% (standard error 3.6%) at 5 years post testing compared with 45.5% (standard error 3.2%) in BRCA2 mutation carriers (P=0.045). The 40–59 years category showed the greatest uptake for BRRSO and uptake was significantly lower in the over 60 s (P<0.0001). Of the unaffected BRCA1 mutation carriers, 65% (standard error 5.1%) opted for surgery at 5 years post-testing compared with 41.1% (standard error 5.1%) in affected BRCA1 mutation carriers (P=0.045).

Conclusion:

The uptake of BRRSO is lower in women previously affected by breast cancer and in older women. As there is no efficient method for early detection of ovarian cancer, uptake should ideally be greater. Counselling should be offered to ensure BRCA1/2 mutation carriers make an informed decision about managing their ovarian cancer risk.     

Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer

Background:

Although BRCA1 has been extensively studied for its role as a tumour-suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer.

Methods:

Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion.

Results:

An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2–14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency.

Conclusions:

Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease.     

Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations

Background:

Little is known regarding cancer risks for relatives of women with very early-onset breast cancer.

Methods:

We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth.

Results:

For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57–26.26) and 12.52 (5.21–30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1–49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64–74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91–5.93), 5.25 (2.50–11.01), 7.73 (4.74–12.62), 5.19 (2.33–11.54) and 4.35 (1.81–10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers.

Conclusion:

First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.     

Contribution of mammography to MRI screening in BRCA mutation carriers by BRCA status and age: individual patient data meta-analysis

Background:

We investigated the additional contribution of mammography to screening accuracy in BRCA1/2 mutation carriers screened with MRI at different ages using individual patient data from six high-risk screening trials.

Methods:

Sensitivity and specificity of MRI, mammography and the combination of these tests were compared stratified for BRCA mutation and age using generalised linear mixed models with random effect for studies. Number of screens needed (NSN) for additional mammography-only detected cancer was estimated.

Results:

In BRCA1/2 mutation carriers of all ages (BRCA1=1219 and BRCA2=732), adding mammography to MRI did not significantly increase screening sensitivity (increased by 3.9% in BRCA1 and 12.6% in BRCA2 mutation carriers, P>0.05). However, in women with BRCA2 mutation younger than 40 years, one-third of breast cancers were detected by mammography only. Number of screens needed for mammography to detect one breast cancer not detected by MRI was much higher for BRCA1 compared with BRCA2 mutation carriers at initial and repeat screening.

Conclusions:

Additional screening sensitivity from mammography above that from MRI is limited in BRCA1 mutation carriers, whereas mammography contributes to screening sensitivity in BRCA2 mutation carriers, especially those ⩽40 years. The evidence from our work highlights that a differential screening schedule by BRCA status is worth considering.     

A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing

Background:

Guidelines for genetic testing for BRCA1 or BRCA2 stipulate that a personal or family history of cancer is necessary to be eligible for testing. Approximately 2% of Ashkenazi Jewish women carry a mutation, but to date population-based testing has not been advocated. Little is known about the relative yield of a conventional genetic testing programme versus a programme of widespread testing in a population with common founder mutations.

Methods:

We provided both referral-based and Jewish population-based testing between 2008 and 2012. We compared the numbers of BRCA mutation carriers identified through the two streams and estimated the number of genetic counselling hours devoted to each programme.

Results:

From 2008 to 2012, 38 female carriers were identified through 487 referrals to our genetics centre (29 unaffected with cancer). During the same time, 6179 Jewish women were tested through our population-based programme and 93 mutation carriers were identified (92 unaffected with cancer). Fewer counsellor hours were devoted to the population-based than to the clinical referral-based testing programme.

Conclusion:

Genetic testing of all Jewish women above the age of 25 years will greatly expand the number of BRCA mutation carriers identified without a commensurate increase in the number of hours required for counselling.     

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

Background:

We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs).

Methods:

Medical records of women enrolled in two carboplatin+olaparib clinical trials ({"type":"clinical-trial","attrs":{"text":"NCT01237067","term_id":"NCT01237067"}}NCT01237067/{"type":"clinical-trial","attrs":{"text":"NCT01445418","term_id":"NCT01445418"}}NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered.

Results:

All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6–65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR.

Conclusion:

Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.     

The prognostic value of CDKN2A hypermethylation in colorectal cancer: a meta-analysis

Background:

The prognostic value of CDKN2A promoter hypermethylation in colorectal cancer remains controversial. We systematically reviewed the evidence for assessment of CDKN2A methylation in colorectal cancer to elucidate this issue.

Methods:

Pubmed, Embase and ISI web of knowledge were searched to identify eligible studies to evaluate the association of CDKN2A hypermethylation and overall survival and clinicopathological features of colorectal cancer patients. Combined hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were pooled using a random-effects model.

Results:

A total of 11 studies encompassing 3440 patients were included in the meta-analysis. CDKN2A hypermethylation had an unfavourable impact on OS of patients with colorectal cancer (HR 1.65, 95% CI 1.29–2.11). Subgroup analysis indicated that CDKN2A hypermethylation was significantly correlated with OS in Europe (HR 1.49; 95% CI 1.28–1.74) and Asia (HR 3.30; 95% CI 1.68–6.46). Furthermore, there was a significant association between CDKN2A hypermethylation and lymphovascular invasion (OR 1.68, 95% CI 1.15–2.47), lymph node metastasis (OR 1.68, 95% CI 1.09–2.59) and proximal tumour location (OR 2.09, 95% CI 1.34–3.26) of colorectal cancer.

Conclusion:

This meta-analysis indicated that CDKN2A hypermethylation might be a predictive factor for unfavourable prognosis of colorectal cancer patients.     

Morphological predictors of BRCA1 germline mutations in young women with breast cancer

Background:

Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.

Methods:

We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.

Results:

The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6–47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7–25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3–5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83–0.90).

Conclusion:

Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.     

The association of diabetes with colorectal cancer risk: the Multiethnic Cohort

Background:

Diabetics have been found to have a greater risk of colorectal cancer than non-diabetics.

Methods:

We examined whether this relationship differed by ethnic group, cancer site or tumour stage in a population-based prospective cohort, including 3549 incident colorectal cancer cases identified over a 13-year period (1993–2006) among 199 143 European American, African American, Native Hawaiian, Japanese American and Latino men and women in the Multiethnic Cohort.

Results:

Diabetics overall had a significantly greater risk of colorectal cancer than did non-diabetics (relative risk (RR)=1.19, 95% confidence interval (CI)=1.09–1.29, P-value (P)<0.001). Positive associations were observed for colon cancer, cancers of both the right and left colon, and cancers diagnosed at a localised and regional/distant stage. The association with colorectal cancer risk was significantly modified by smoking status (P_Interaction=0.0044), with the RR being higher in never smokers (RR=1.32, 95% CI=1.15–1.53, P<0.001) than past (RR=1.19, 95% CI=1.05–1.34, P=0.007) and current smokers (RR=0.90, 95% CI=0.70–1.15, P=0.40).

Conclusion:

These findings provide strong support for the hypothesis that diabetes is a risk factor for colorectal cancer.     

Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers

Background:

BRCAness is defined as shared tumour characteristics between sporadic and BRCA-mutated cancers. However, how to exactly measure BRCAness and its frequency in breast cancer is not known. Assays to establish BRCAness would be extremely valuable for the clinical management of these tumours. We assessed BRCAness characteristics frequencies in a large cohort of triple-negative breast cancers (TNBCs).

Methods:

As a measure of BRCAness, we determined a specific BRCA1-like pattern by array Comparative Genomic Hybridisation (aCGH), and BRCA1 promoter methylation in 377 TNBCs, obtained from 3 different patient cohorts. Clinicopathological data were available for all tumours, BRCA1-germline mutation status and chemotherapy response data were available for a subset.

Results:

Of the tumours, 66–69% had a BRCA1-like aCGH profile and 27–37% showed BRCA1 promoter methylation. BRCA1-germline mutations and BRCA1 promoter methylation were mutually exclusive events (P=1 × 10⁻⁵). BRCAness was associated with younger age and grade 3 tumours. Chemotherapy response was significantly higher in BRCA1-mutated tumours, but not in tumours with BRCAness (63% (12 out of 19) vs 35% (18 out of 52) pathological complete remission rate, respectively).

Conclusion:

The majority of the TNBCs show BRCAness, and those tumours share clinicopathological characteristics with BRCA1-mutated tumours. A better characterisation of TNBC and the presence of BRCAness could have consequences for both hereditary breast cancer screening and the treatment of these tumours.     

Impact of rapid genetic counselling and testing on the decision to undergo immediate or delayed prophylactic mastectomy in newly diagnosed breast cancer patients: findings from a randomised controlled trial

Background:

Female breast cancer patients with a BRCA1/2 mutation have an increased risk of contralateral breast cancer. We investigated the effect of rapid genetic counselling and testing (RGCT) on choice of surgery.

Methods:

Newly diagnosed breast cancer patients with at least a 10% risk of a BRCA1/2 mutation were randomised to an intervention group (offer of RGCT) or a control group (usual care; ratio 2 : 1). Primary study outcomes were uptake of direct bilateral mastectomy (BLM) and delayed contralateral prophylactic mastectomy (CPM).

Results:

Between 2008 and 2010, we recruited 265 women. On the basis of intention-to-treat analyses, no significant group differences were observed in percentage of patients opting for a direct BLM (14.6% for the RGCT group vs 9.2% for the control group; odds ratio (OR) 2.31; confidence interval (CI) 0.92–5.81; P=0.08) or for a delayed CPM (4.5% for the RGCT group vs 5.7% for the control group; OR 0.89; CI 0.27–2.90; P=0.84). Per-protocol analysis indicated that patients who received DNA test results before surgery (59 out of 178 women in the RGCT group) opted for direct BLM significantly more often than patients who received usual care (22% vs 9.2% OR 3.09, CI 1.15–8.31, P=0.03).

Interpretation:

Although the large majority of patients in the intervention group underwent rapid genetic counselling, only a minority received DNA test results before surgery. This may explain why offering RGCT yielded only marginally significant differences in uptake of BLM. As patients who received DNA test results before surgery were more likely to undergo BLM, we hypothesise that when DNA test results are made routinely available pre-surgery, they will have a more significant role in surgical treatment decisions.     

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background:

The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.

Methods:

To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.

Results:

No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, P_trend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, P_trend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, P_trend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, P_trend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.

Conclusion:

There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.     

Germline BRCA1 mutations increase prostate cancer risk

Background:

Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.

Methods:

We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.

Results:

We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45% three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.

Conclusion

This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.     

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study

Background:

Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOC patients treated with intraperitoneal platinum/taxane.

Methods:

The GOG-172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitoneal cisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expression was assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with ⩽10% staining were defined as aberrant and >10% as normal. Correlations between BRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier method and Cox regression analysis.

Results:

Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P=0.014) but not PFS (P=0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P=0.818). In tumours with aberrant BRCA1 expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P=0.0002). Aberrant BRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47–0.97, P=0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IV patients with aberrant vs normal BRCA1 expression had worse survival.

Conclusion:

Decreased BRCA1 expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreased BRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin and paclitaxel.     

BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years

Background:

Triple-negative (TN) tumours are the predominant breast cancer subtype in BRCA1 mutation carriers. Recently, it was proposed that all individuals below 50 years of age with TN breast cancer should be offered BRCA testing. We have evaluated the BRCA1 mutation frequency and the implications for clinical practice of undertaking genetic testing in women with TN breast cancer.

Methods:

We undertook BRCA1 mutation analysis in 308 individuals with TN breast cancer, 159 individuals from unselected series of breast cancer and 149 individuals from series ascertained on the basis of young age and/or family history.

Results:

BRCA1 mutations were present in 45 out of 308 individuals. Individuals with TN cancer <50 years had >10% likelihood of carrying a BRCA1 mutation in both the unselected (11 out of 58, 19%) and selected (26 out of 111, 23%) series. However, over a third would not have been offered testing using existing criteria. We estimate that testing all individuals with TN breast cancer <50 years would generate an extra 1200 tests annually in England.

Conclusion:

Women with TN breast cancer diagnosed below 50 years have >10% likelihood of carrying a BRCA1 mutation and are therefore eligible for testing in most centres. However, implementation may place short-term logistical and financial burdens on genetic services.     

Long-term use of lithium and risk of colorectal adenocarcinoma: a nationwide case–control study

Background:

Lithium accumulates in the colon and inhibits the enzyme GSK-3β that possesses anti-carcinogenic effects. We therefore examined the association between lithium use and colorectal cancer risk in a nationwide study.

Methods:

We used the Danish Cancer Registry to identify all patients diagnosed with incident colorectal adenocarcinoma during 2000–2012 (n=36 248). Using a matched case–control approach, we estimated the association between long-term use (⩾5 years) of lithium and risk of colorectal adenocarcinoma using conditional logistic regression.

Results:

Long-term use of lithium was similar among cases (0.22%) and controls (0.20%), yielding an odds ratio of 1.13 (95% confidence interval (CI), 0.89–1.43) for colorectal adenocarcinoma. Dose–response, subgroup and other subanalyses returned neutral associations. However, ORs differed for colorectal subsites (proximal colon: 1.01 (95% CI, 0.66–1.55; distal colon: 1.52 (95% CI, 1.05–2.20); and rectum: 0.80 (95% CI, 0.50–1.30).

Conclusions:

Lithium use was not associated with an overall increased risk of colorectal adenocarcinoma. The variation by subsite warrants further investigation.     

Tubal ligation in relation to menopausal symptoms and breast cancer risk

Background:

Local inflammation after tubal ligation may affect ovarian function and breast cancer risk.

Methods:

We analysed tubal ligation, menopausal characteristics, and breast cancer risk in the Sister Study cohort (N=50 884 women).

Results:

Tubal ligation was associated with hot flashes (hazard ratio (HR) 1.09; 95% confidence interval (CI): 1.06–1.12) but not menopausal age (HR 0.99; 95% CI: 0.96–1.02). Tubal ligation did not have an impact on breast cancer overall (HR 0.95; 95% CI: 0.85–1.06), but had a suggested inverse relation with oestrogen receptor+/progesterone receptor+ invasive tumours (HR 0.84; 95% CI: 0.70–1.01), possibly because of subsequent hysterectomy/bilateral oophorectomy.

Conclusion:

Tubal ligation does not influence overall breast cancer risk.