Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers

Background:

The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes.

Methods:

Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.

Results:

Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039).

Conclusion:

Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.     

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.     

Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study

Background:

The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes.

Methods:

We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person–years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries.

Results:

Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54–1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30–1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77–7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33–1.00) for women aged 50 years and above.

Conclusion:

The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.     

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.     

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.     

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.     

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.     

Short-term psychological impact of the BRCA1/2 test result in women with breast cancer according to their perceived probability of genetic predisposition to cancer

Background:

The effect of BRCA1/2 gene test result on anxiety, depression, cancer-related thought intrusion or avoidance and perceived control over cancer risk was assessed in breast cancer (BC) patients, according to their perceived probability of genetic predisposition to cancer.

Methods:

Two hundred and forty-three (89% response rate) women with BC completed questionnaires after an initial genetic counselling visit (T1), of which 180 (66%) completed questionnaires again after receiving the BRCA1/2 results (T2). The discrepancy between women''s perceived probability of cancer genetic predisposition at T1 and the geneticist''s computed estimates was assessed.

Results:

In all, 74% of women received a negative uninformative (NU), 11% a positive BRCA1/2 and 15% an unclassified variant (UV) result. On hierarchical regression analysis, in women with a positive BRCA1/2 result (vs NU or UV), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted lower levels of anxiety at T2 (β=−0.28; P<0.01), whereas in women receiving a UV result (vs NU or positive BRCA1/2), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted higher levels of anxiety (β=0.20; P<0.01), depression (β=0.19; P<0.05) and intrusion (β=0.18; P<0.05) at T2.

Conclusion:

The type of BRCA1/2 test result differently affects distress according to women''s perceived probability of genetic predisposition before testing.     

Employment and social benefits up to 10 years after breast cancer diagnosis: a population-based study

Background:

Little is known about employment outcomes after breast cancer (BC) beyond the first years after treatment.

Methods:

Employment outcomes were compared with a general population comparison group (N=91 593) up to 10 years after BC for 26 120 patients, diagnosed before age 55 between 2000–2005, with income and social benefits data from Statistics Netherlands. Treatment effects were studied in 14 916 patients, with information on BC recurrences and new cancer events.

Results:

BC survivors experienced higher risk of losing paid employment (Hazard Ratio (HR): 1.6, 95% Confidence Interval (95% CI) 1.4–1.8) or any work-related event up to 5–7 years (HR 1.5, 95% CI 1.3–1.6) and of receiving disability benefits up to 10 years after diagnosis (HR 2.0, 95% CI 1.6–2.5), with higher risks for younger patients. Axillary lymph node dissection increased risk of disability benefits (HR 1.5, 95% CI 1.4–1.7) or losing paid employment (HR 1.3, 95% CI 1.2–1.5) during the first 5 years of follow-up. Risk of disability benefits was increased among patients receiving mastectomy and radiotherapy (HR 1.2; 95% CI 1.1–1.3) and after chemotherapy (HR 1.7; 95% CI 1.5–1.9) during the first 5 years after diagnosis.

Conclusions:

BC treatment at least partly explains the increased risk of adverse employment outcomes up to 10 years after BC.     

Dietary fat intake and risk of epithelial ovarian cancer by tumour histology

Background:

Studies of fat intake and epithelial ovarian cancer (EOC) risk have reported inconsistent findings, hence we hypothesised that associations may vary by histologic subtype.

Methods:

We evaluated fat intake in a New England case–control study including 1872 cases and 1978 population-based controls (1992–2008). Epithelial ovarian cancer risk factors and diet were assessed using a food frequency questionnaire at enrolment. Logistic regression was used to estimate associations between fat intake and EOC risk and polytomous logistic regression was used to test whether associations varied by histologic subtype.

Results:

We observed a decreased risk of EOC when comparing the highest vs lowest quartiles of intake of omega-3 (odds ratio (OR)=0.79, 95% confidence interval (CI) 0.66–0.96, P-trend=0.01) and omega-6 (OR=0.77, 95% CI 0.64–0.94, P-trend=0.02) and an increased risk with high consumption of trans fat (OR=1.30, 95% CI 1.08–1.57, P-trend=0.002). There was no significant heterogeneity by tumour histologic subtype; however, we observed a strong decreased risk for endometrioid invasive tumours with high intake of omega-3 (quartile (Q) 4 vs Q1, OR=0.58, 95% CI 0.41–0.82, P-trend=0.003).

Conclusions:

These findings suggest that higher intake of omega-3 may be protective for EOC overall and endometrioid tumours in particular, whereas greater consumption of trans fat may increase risk of EOC overall.     

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.     

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.     

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study

Background:

Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25–70 years at recruitment from 1992 to 2000.

Methods:

Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre.

Results:

After a mean follow-up of 3.6 years (±3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR=0.80, 95% CI=0.62–1.03) and a significant survival benefit in long-term MHT users (⩾5 years use vs never use, HR=0.70, 95% CI=0.50–0.99, P_trend=0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk.

Conclusions:

Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.     

Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy

Background:

We assessed the sensitivity to adjuvant chemotherapy in cell cycle checkpoint kinase 2 (CHEK2) vs non-CHEK2 breast cancer patients by comparing the contralateral breast cancer incidence and distant disease-free and breast cancer-specific survival between both groups, stratified for adjuvant chemotherapy.

Methods:

One Dutch hereditary non-BRCA1/2 breast cancer patient cohort (n=1220) and two Dutch cohorts unselected for family history (n=1014 and n=2488, respectively) were genotyped for CHEK2 1100delC. Hazard ratios for contralateral breast cancer, distant disease-free and breast cancer-specific death for mutation carriers vs noncarriers were calculated using the Cox proportional hazard method, stratified for adjuvant chemotherapy.

Results:

The CHEK2 mutation carriers (n=193) had an increased incidence of contralateral breast cancer (multivariate hazard ratio 3.97, 95% confidence interval 2.59–6.07). Distant disease-free and breast cancer-specific survival were similar in the first 6 years in mutation carriers compared with noncarriers, but diverted as of 6 years after breast cancer diagnosis (multivariate hazard ratios and 95% confidence intervals 2.65 (1.79–3.93) and 2.05 (1.41–2.99), respectively). No significant interaction between CHEK2 and adjuvant chemotherapy was observed.

Conclusions:

The CHEK2 1100delC-associated breast cancer is associated with a higher contralateral breast cancer rate as well as worse survival measures beyond 6 years after diagnosis. No differential sensitivity to adjuvant chemotherapy was observed in CHEK2 patients.     

Quantifying the natural history of breast cancer

Background:

Natural history models of breast cancer progression provide an opportunity to evaluate and identify optimal screening scenarios. This paper describes a detailed Markov model characterising breast cancer tumour progression.

Methods:

Breast cancer is modelled by a 13-state continuous-time Markov model. The model differentiates between indolent and aggressive ductal carcinomas in situ tumours, and aggressive tumours of different sizes. We compared such aggressive cancers, that is, which are non-indolent, to those which are non-growing and regressing. Model input parameters and structure were informed by the 1978–1984 Ostergotland county breast screening randomised controlled trial. Overlaid on the natural history model is the effect of screening on diagnosis. Parameters were estimated using Bayesian methods. Markov chain Monte Carlo integration was used to sample the resulting posterior distribution.

Results:

The breast cancer incidence rate in the Ostergotland population was 21 (95% CI: 17–25) per 10 000 woman-years. Accounting for length-biased sampling, an estimated 91% (95% CI: 85–97%) of breast cancers were aggressive. Larger tumours, 21–50 mm, had an average sojourn of 6 years (95% CI: 3–16 years), whereas aggressive ductal carcinomas in situ took around half a month (95% CI: 0–1 month) to progress to the invasive ⩽10 mm state.

Conclusion:

These tumour progression rate estimates may facilitate future work analysing cost-effectiveness and quality-adjusted life years for various screening strategies.     

Relationship between aspirin use after diagnosis of colorectal cancer and patient survival: a meta-analysis of observational studies

Background:

Epidemiological evidence suggests that use of aspirin after the diagnosis of colorectal cancer can lengthen survival. However, the supporting data vary between studies, and this hypothesis remains controversial. We conducted a meta-analysis to provide a quantitative assessment of the association between use of aspirin after diagnosis of colorectal cancer and patient survival.

Methods:

We searched the Medline and Embase databases up to April 2014 to identify studies related to aspirin use after diagnosis and all-cause mortality or colorectal cancer-specific mortality. Summary effect estimates with 95% confidence intervals (CIs) were derived using a fixed or random effects model, depending on the heterogeneity between the included studies.

Results:

Seven epidemiologic studies that consisted of six cohort studies and one nested case–control study were included in this meta-analysis. The hazard ratio (HR) of the association between aspirin use after colorectal cancer diagnosis and overall mortality, which was reported in five studies, was 0.74 (95% CI, 0.62–0.89) using a random model (heterogeneity test P=0.003, I²=75.3%), and for colorectal cancer-specific mortality (four studies), it was 0.75 (95% CI, 0.51–1.10) using a random model (heterogeneity test P=0.001, I²=84.1%). In addition, we analysed postdiagnosis aspirin use according to whether aspirin was also used before diagnosis. The HR for the overall mortality of patients who did not use aspirin before diagnosis, which was reported in four studies, was 0.84 (95% CI, 0.70–1.00), and for colorectal cancer-specific mortality (three studies), it was 0.79 (95% CI, 0.61–1.02). For those who did use aspirin before diagnosis, the HR for overall mortality (four studies) was 0.88 (95% CI, 0.83–0.93), and for colorectal cancer-specific mortality (three studies), it was 0.80 (95% CI, 0.59–1.09). Subgroup analysis showed that use of aspirin after diagnosis was associated with longer overall survival among patients with the variant PIK3CA gene but not for those with wild-type PIK3CA.

Conclusions:

Based on current evidence, the use of aspirin after diagnosis does not reduce colorectal cancer-specific mortality, but it does reduce all-cause mortality for colorectal cancer patients.     

Supplemental folic acid in pregnancy and childhood cancer risk

Background:

We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999–2010, and 799 children diagnosed later with cancer.

Methods:

Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed.

Results:

Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89–1.76, P_Trend 0.20), lymphoma (HR 0.96; 95% CI 0.42–2.21, P_Trend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42–1.10, P_Trend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53–2.06, P_Trend 0.85), Wilms'' tumour (HR 1.16; 95% CI 0.52–2.58, P_Trend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34–1.75, P_Trend 0.90).

Conclusions:

Folic acid supplementation was not associated with risk of major childhood cancers.     

Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia

Background:

It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status.

Methods:

Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF^c.1799T>A mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC.

Results:

Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15–2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27–2.58; P=0.001), and BRAF^c.1799T>A mutation (HR 2.16; 95% CI 1.25–3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09–5.75; P=0.77).

Conclusion:

Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.     

Quaternary cytoreductive surgery in ovarian cancer: does surgical effort still matter?

Background:

To evaluate surgical outcome and survival benefit after quaternary cytoreduction (QC) in epithelial ovarian cancer (EOC) relapse.

Methods:

We systematically evaluated all consecutive patients undergoing QC in our institution over a 12-year period (October 2000–January 2012). All relevant surgical and clinical outcome parameters were systematically assessed.

Results:

Forty-nine EOC patients (median age: 57; range: 28–76) underwent QC; in a median of 16 months (range:2–142) after previous chemotherapy. The majority of the patients had an initial FIGO stage III (67.3%), peritoneal carcinomatosis (77.6%) and no ascites (67.3%). At QC, patients presented following tumour pattern: lower abdomen 85.7% middle abdomen 79.6% and upper abdomen 42.9%. Median duration of surgery was 292 min (range: a total macroscopic tumour clearance could be achieved. Rates of major operative morbidity and 30-day mortality were 28.6% and 2%, respectively.Mean follow-up from QC was 18.41 months (95% confidence interval (CI):12.64–24.18) and mean overall survival (OS) 23.05 months (95% CI: 15.5–30.6). Mean OS for patients without vs any tumour residuals was 43 months (95% CI: 26.4–59.5) vs 13.4 months (95% CI: 7.42–19.4); P=0.001. Mean OS for patients who received postoperative chemotherapy (n=18; 36.7%) vs those who did not was 40.5 months (95% CI: 27.4–53.6) vs 12.03 months (95% CI: 5.9–18.18); P<0.001.Multivariate analysis indentified multifocal tumour dissemination to be of predictive significance for incomplete tumour resection, higher operative morbidity and lower survival, while systemic chemotherapy subsequent to QC had a protective significant impact on OS. No prognostic impact had ascites, platinum resistance, high grading and advanced age.

Conclusion:

Even in this highly advanced setting of the third EOC relapse, maximal therapeutic effort combining optimal surgery and chemotherapy appear to significantly prolong survival in a selected patients ‘group''.