Alteration of the Exhaled Volatile Organic Compound Pattern in Colorectal Cancer Patients after Intentional Curative Surgery-A Prospective Pilot Study.

As current follow-up modalities for colorectal carcinoma (CRC) have restricted sensitivity, novel diagnostic tools are needed. The presence of CRC changes the endogenous metabolism, resulting in the release of a specific volatile organic compounds (VOC) pattern that can be detected with an electronic nose or AeonoseTM. To evaluate the use of an electronic nose in the follow-up of CRC, we studied the effect of curative surgery on the VOC pattern recognition using AeonoseTM. A prospective cohort study was performed, in which 47 patients diagnosed with CRC were included, all of whom underwent curative surgical resection. Breath testing was performed before and after surgery using the AeonoseTM. A machine learning model was developed by discerning between the 94 pre-and postoperative breath samples. The training model differentiated between the pre-and postoperative CRC breath samples with a sensitivity and specificity of 0.78 (95%CI 0.61-0.90) and 0.73 (95%CI 0.56-0.86), respectively, with an accuracy of 0.76 (95%CI 0.66-0.85), and an area under the curve of 0.79 (95%CI 0.68-0.89). The internal validation of the test set resulted in an accuracy of 0.75 (95%CI 0.51-0.91) and AUC of 0.82 (95%CI 0.61-1). In conclusion, our results suggest that the VOC pattern of CRC patients is altered by curative surgery in a short period, indicating that the exhaled VOCs might be closely related to the presence of CRC. However, to use AeonoseTM as a potential diagnostic tool in the clinical follow-up of CRC patients, the performance of the models needs to be improved through further large-scale prospective research.

Diagnostic value of radiological staging and surveillance for T1 colorectal carcinomas: A multicenter cohort study.

BACKGROUND: The role of radiological staging and surveillance imaging is under debate for T1 colorectal cancer (CRC) as the risk of distant metastases is low and imaging may lead to the detection of incidental findings. OBJECTIVE: The aim of this study was to evaluate the yield of radiological staging and surveillance imaging for T1 CRC. METHODS: In this retrospective multicenter cohort study, all patients of 10 Dutch hospitals with histologically proven T1 CRC who underwent radiological staging in the period 2000-2014 were included. Clinical characteristics, pathological, endoscopic, surgical and imaging reports at baseline and during follow-up were recorded and analyzed. Patients were classified as high-risk T1 CRC if at least one of the histological risk factors (lymphovascular invasion, poor tumor differentiation, deep submucosal invasion or positive resection margins) was present and as low-risk when all risk factors were absent. RESULTS: Of the 628 included patients, 3 (0.5%) had synchronous distant metastases, 13 (2.1%) malignant incidental findings and 129 (20.5%) benign incidental findings at baseline staging. Radiological surveillance was performed among 336 (53.5%) patients. The 5-year cumulative incidence of distant recurrence, malignant and benign incidental findings were 2.4% (95% confidence interval (CI): 1.1%-5.4%), 2.5% (95% CI: 0.6%-10.4%) and 18.3% (95% CI: 13.4%-24.7%), respectively. No distant metastatic events occurred among low-risk T1 CRC patients. CONCLUSION: The risk of synchronous distant metastases and distant recurrence in T1 CRC is low, while there is a substantial risk of detecting incidental findings. Radiological staging seems unnecessary prior to local excision of suspected T1 CRC and after local excision of low-risk T1 CRC. Radiological surveillance should not be performed in patients with low-risk T1 CRC.

Possible Value of Faecal Immunochemical Test (FIT) When Added in Symptomatic Patients Referred for Colonoscopy: A Systematic Review.

If Colorectal cancer (CRC) is detected and treated early, the survival rate is high. This is one of the reasons that population-based screening programs for the early detection of CRC using the faecal immunochemical test (FIT) started worldwide. These programs compete with regular colonoscopy programs and increase the waiting time for symptomatic patients. However, the literature has shown that the correlation between intestinal complaints and the gain of colonoscopy is poor. The aim of this study is to assess the diagnostic utility of symptoms for the yield (CRC) of colonoscopy and to compare this with the diagnostic utility of FIT when offered to symptomatic patients. METHODS: We performed a systematic review search for CRC as an outcome of colonoscopy in referred symptomatic patients and separately for CRC as an outcome in symptomatic patients with a positive FIT. We searched systematically for clinical trials or observational studies in databases, followed by hand-searching of reference lists. We used random Meta-Disc to evaluate the diagnostic performance, using the exploration of heterogeneity with a variety of test statistics and by computing the pooled estimates. RESULTS: We included 35 studies, with almost 5 million symptomatic patients. In addition, we included nine prospective studies with a positive FIT in symptomatic patients, with more than 5000 patients. Significant heterogeneity was found for every symptom and the outcome of colonoscopy in the effect size of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. In a random effect model, the pooled sensitivity of colonoscopy in symptomatic patients was very low (25%). However, the pooled sensitivity in symptomatic patients with a positive FIT was 83% and the pooled specificity 77%. A total of 75 symptomatic patients (1.4%) had a false-negative FIT. CONCLUSION: Adding FIT in symptomatic patients seems useful for predicting CRC as an outcome of colonoscopy. FIT seems a potential tool for an improved triage of colonoscopy in symptomatic patients.

Identifying Risk Factors for Recurrence After Cubital Tunnel Release.

PURPOSE: This study investigated specific risk factors for recurrent surgery of ulnar nerve entrapment (ie, ipsilateral clinical symptoms within 5 years after initial cubital tunnel release [CuTR]) in a large cohort. We hypothesized that recurrence is associated with lifestyle variables (eg, smoking, drinking alcohol, a high body mass index [BMI]) or comorbidities). METHODS: A retrospective cohort study was performed using the Current Procedural Terminology codes for all patients who underwent CuTR between January 2012 and November 2018. Demographic data, including sex, age, weight, height, BMI, comorbidities, smoking, and alcohol consumption, were collected. The primary outcome was the need for revision surgery after initial CuTR. Univariate and multivariate analyses were performed to identify potential risk factors for revision surgery. RESULTS: Of the 678 patients who underwent CuTR, 120 patients (18%) needed revision surgery within 5 years. Sixty-six patients required subfascial transposition (55%) and 47 patients (39%) received in situ releases. Also, sex, BMI, smoking, alcohol consumption, and comorbidities (except for spinal disc herniation) were similar between the primary and revision subgroup. Age at first occurrence was significantly lower in the revision group (48 years for revision vs 52 years for primary surgery). Moreover, cervical spinal disc herniation was associated with revision surgery (13% vs 6% in the primary group). CONCLUSIONS: Age and medical history of cervical spinal disc herniation are associated with an increased risk of revision surgery. More importantly, BMI, smoking, alcohol consumption, and other comorbidities are not associated with increased risk of revision surgery within our sample. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

High Yield of Chest X-ray in the Follow-Up of Colorectal Cancer.

PURPOSE: Worldwide, colorectal carcinoma (CRC) has a high incidence and a substantial cancer-related mortality. The recurrence risk is 30-50% and lung metastases are common. Treatment of lung metastases with stereotactic ablative radiotherapy (SABR) or metastasectomy may increase survival. The best modality for thoracic screening in the follow-up, however, remains controversial. In this study, we aimed to unravel the additional value of routine chest X-ray (CXR) for detecting lung metastases during the follow-up of CRC patients treated with curative surgery. METHODS: Between 2013 and 2017, 668 CRC patients were treated with curative intent, of whom 633 patients were included in follow-up, which consisted of CXR, serum Carcino-Embryonic Antigen (CEA) and ultrasound of the liver. Patients who developed lung metastases, diagnosed with CXR and characterised by a normal concomitant serum CEA level, were identified. Number, size and treatment of lung metastases were described. RESULTS: Thirty-four (5.4%) patients developed lung metastases. Seventeen (50%) were detected by CXR without pathological CEA levels. Eleven (65%) of these patients were treated with curative intent, whereas 21% of patients with lung metastases and elevated CEA levels were treated with curative intent (p = 0.049). Higher numbers of lung metastases were associated with a lower chance of curative treatment. CONCLUSIONS: More than 50% of patients with lung metastases on CXR in the follow-up would not have been detected with CEA-triggered imaging only. In addition, patients with colorectal lung metastases without elevated CEA levels were often suitable for curative treatment and, therefore, CXR seems to have additional value within the follow-up of CRC.

Clinical outcome of decompressing colostomy for acute left-sided colorectal obstruction: a consecutive series of 100 patients.

PURPOSE: Aim of our study was to evaluate the outcomes of a consecutive series of patients who were treated with a decompressing colostomy (DC) for acute left-sided colorectal obstruction. METHOD: A consecutive series of 100 patients with acute left-sided colorectal obstruction who underwent DC from January 2015 to August 2020 was retrospectively analyzed. Demographic characteristics, etiology of the obstruction, postoperative morbidity- and mortality rates, DC-related complication and stoma reversal rates were evaluated. RESULTS: Of the 100 included patients, 64 had malignant- and 36 had benign obstruction. The mean age was 69 years, 42% was male, and the ASA score was 2. Morbidity and mortality rates after DC construction were 20 and 2%, respectively. In 39% of the patients, DC ended up as a permanent stoma and in 61% as bridge to surgery (BtS). DC related complication rate was 32%, with a re-intervention rate of 9%. Elective colorectal resection was performed in 59 cases (59%) with subsequent postoperative morbidity rate of 20%. Stoma reversal rate was 77% for the patients who underwent DC as BtS. Stoma reversal was performed in 66% of the patients with benign obstruction and in 36% for oncological obstruction. CONCLUSION: DC as bridge to possible elective resection for acute left-sided colorectal obstruction is an effective strategy with low morbidity and mortality rates and a high stoma reversal rate, especially for benign obstruction. However, DC is less appropriate for patients in whom DC turns out to be a permanent stoma due to a relatively high stoma related complications.

High correlation of the Oxford Knee Score with postoperative pain, but not with performance-based functioning.

PURPOSE: The Oxford Knee Score (OKS) is a widely known patient-related outcome measure (PROM) to determine pain and knee functioning before and after total knee arthroplasty (TKA). Self-reported function is mainly influenced by change in pain; therefore, it was hypothesized that the OKS correlates more with pain than with performance-based functioning. METHODS: In a prospective cohort of 88 patients, who had a cementless mobile-bearing TKA, included in a randomized clinical trial, the correlation between the overall OKS, and its subscales for pain (PCS) and function (FCS), with performance-based functioning using the DynaPort® Knee Score (DKS), visual analogue scale score for pain (VAS) and the Knee Society Score (KSS) was evaluated. All scores were measured preoperatively, 6 months and 1 year after surgery. Overall change in outcome over time was analysed until 5 years after surgery. RESULTS: All scores improved over time. The DKS was influenced by sex, preoperative BMI and age. The internal consistency of the OKS PCS increased over time, whereas the OKS FCS remained the same. The mean postoperative OKS FCS showed moderate correlation with the DKS (r = 0.65, p < 0.001), and the mean postoperative OKS and OKS PCS showed high correlation with the VAS (r = -0.79 and r = -0.82, respectively, p < 0.001). The mean postoperative KSS showed high correlations with the OKS (r = 0.80, p < 0.001), the OKS PCS (r = 0.72 p < 0.001) and OKS FCS (r = 0.74, p < 0.001). CONCLUSION: The postoperative OKS and the OKS PCS showed high correlation with pain, but only the postoperative OKS FCS was well correlated with performance-based functioning. This suggests that the OKS is more related to pain and tells us less on postoperative functioning. This is important when the OKS as PROM is used to evaluate the quality of orthopaedic care of patients with TKA. LEVEL OF EVIDENCE: III.

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers.

PURPOSE: Recommendations for treating patients who carry a BRCA1/2 gene are mainly based on cumulative lifetime risks (CLTRs) of breast cancer determined from retrospective cohorts. These risks vary widely (27% to 88%), and it is important to understand why. We analyzed the effects of methods of risk estimation and bias correction and of population factors on CLTRs in this retrospective clinical cohort of BRCA1/2 carriers. PATIENTS AND METHODS: The following methods to estimate the breast cancer risk of BRCA1/2 carriers were identified from the literature: Kaplan-Meier, frailty, and modified segregation analyses with bias correction consisting of including or excluding index patients combined with including or excluding first-degree relatives (FDRs) or different conditional likelihoods. These were applied to clinical data of BRCA1/2 families derived from our family cancer clinic for whom a simulation was also performed to evaluate the methods. CLTRs and 95% CIs were estimated and compared with the reference CLTRs. RESULTS: CLTRs ranged from 35% to 83% for BRCA1 and 41% to 86% for BRCA2 carriers at age 70 years width of 95% CIs: 10% to 35% and 13% to 46%, respectively). Relative bias varied from -38% to +16%. Bias correction with inclusion of index patients and untested FDRs gave the smallest bias: +2% (SD, 2%) in BRCA1 and +0.9% (SD, 3.6%) in BRCA2. CONCLUSION: Much of the variation in breast cancer CLTRs in retrospective clinical BRCA1/2 cohorts is due to the bias-correction method, whereas a smaller part is due to population differences. Kaplan-Meier analyses with bias correction that includes index patients and a proportion of untested FDRs provide suitable CLTRs for carriers counseled in the clinic.

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. CONCLUSION: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

Local infiltration analgesia following total knee arthroplasty: effect on post-operative pain and opioid consumption--a meta-analysis.

INTRODUCTION: Local infiltration analgesia (LIA) is a popular method for decreasing post-operative pain after total knee arthroplasty (TKA). The goal of this meta-analysis is to compare the effect of LIA with placebo on the intensity of post-operative pain and the consumption of opioids. METHODS: A search was performed in the PubMed/MEDLINE, Cochrane, EMBASE and TRIP databases. All (quasi)-randomized controlled trials (RCTs) were included. LIA consists of intra-operative infiltration with at least one analgesic component. Data were pooled using Cochrane software. RESULTS: Seven placebo-controlled RCTs were included, involving 405 TKAs. On the first post-operative day, LIA provides an average decrease in VAS scores at rest of 12.3 % compared to placebo. Six RCTs studied opioid consumption in patients following TKA. There was a decrease in opioid consumption of 14.8 % compared to placebo 24 h after surgery. This suggests a reduced pain perception due to LIA. On the second post-operative day, the effect on both outcome measures was diminished and no longer significant. Heterogeneity between the studies was 71 % for pain and 39 % for opioid consumption (p = 0.002 and p = 0.0005). No major complications were reported with the use of LIA. CONCLUSION: LIA might be able to decrease pain and the use of opioids on the first post-operative day following TKA. However, due to the high level of heterogeneity between the studies, no firm conclusions can be drawn. LEVEL OF EVIDENCE: Meta-analysis, Level II.

No clinical benefit of titanium nitride coating in cementless mobile-bearing total knee arthroplasty.

PURPOSE: Titanium nitride (TiN) coating of cobalt-chromium-molybdenum (CoCrMo) implants has shown to improve the biomechanical properties of the implant surface and to reduce adhesive wear in vitro. It is yet unknown whether TiN coating of total knee prosthesis (TKP) affects the postoperative clinical outcome of total knee arthroplasty (TKA). METHODS: In a double-blind randomized controlled clinical trial, 101 patients received an uncemented mobile-bearing CoCrMo TKP, either TiN coated or uncoated. Primary outcome measure visual analogue scale (VAS) score for pain, and secondary outcome measures Knee Society Score (KSS), revision rate and adverse events, range of motion of the knee as well as knee circumference and knee skin temperature were assessed 6 weeks, 6 months, 1 year and 5 years postoperative. Repeated measures analysis was used to evaluate the postoperative outcome measures over time. RESULTS: There was no difference between the two groups in VAS score, KSS, revision rate, range of motion of the knee, knee circumference and knee skin temperature. There were no adverse events that could be related to the TiN coating. CONCLUSIONS: TiN-coated TKP does not influence the postoperative outcome of uncemented mobile-bearing TKA regarding postoperative pain, revision rate, range of motion, swelling and temperature of the knee. Therefore, TiN coating of CoCrMo TKP has no clinical benefit on the outcome of cementless mobile-bearing TKA. LEVEL OF EVIDENCE: Therapeutic study, Level I.

Variation in mutation spectrum partly explains regional differences in the breast cancer risk of female BRCA mutation carriers in the Netherlands.

BACKGROUND: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. METHODS: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum. RESULTS: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09). CONCLUSIONS: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. IMPACT: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.

Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations.

BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. RESULTS: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. CONCLUSIONS: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.

Body weight and risk of breast cancer in BRCA1/2 mutation carriers.

Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a nationwide retrospective cohort study, including 719 BRCA1/2 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. All time-varying Cox proportional hazards analyses were stratified by menopausal status. For premenopausal breast cancer, no statistically significant associations were observed for any of the anthropometric measures. The association between body mass index (BMI) at age 18 and premenopausal breast cancer risk suggested a trend of decreasing risk with increasing BMI (HR(22.50-24.99 vs. 18.50-22.49) = 0.83, 95% CI = 0.47-1.44 and HR(≥ 25.00 vs. 18.50-22.49) = 0.41, 95% CI = 0.13-1.27). For postmenopausal breast cancer, being 1.67 m and taller increased the risk 1.7-fold (HR = 1.67, 95% CI = 1.01-2.74) when compared to a height <1.67 m. Compared with a current body weight < 72 kg, a current body weight of ≥ 72 kg increased the risk of postmenopausal breast cancer 2.1-fold (95% CI = 1.23-3.59). A current BMI of ≥ 25.0 kg/m², an adult weight gain of 5 kg or more, and a relative adult weight gain of 20% or more were all non-significantly associated with a 50-60% increased risk of postmenopausal breast cancer [HR = 1.46 (0.86-2.51), HR = 1.56 (95% CI = 0.85-2.87), and HR = 1.60 (95% CI = 0.97-2.63), respectively], when compared with having a healthy or stable weight. No associations for body weight or BMI at age 18 were observed. In conclusion, menopausal status seemed to modify the association between body weight and breast cancer risk among BRCA1/2 carriers. We observed no clear association between body weight and premenopausal breast cancer, while overweight and weight gain increased postmenopausal breast cancer risk. Carriers may reduce their risk of postmenopausal breast cancer by maintaining a healthy body weight throughout life.

Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers.

BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR(low versus never) = 0.93, 95%CI = 0.60-1.43; HR(medium versus never) = 0.81, 95%CI = 0.51-1.29; HR(high versus never) = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR(medium versus low) = 0.60, 95%CI = 0.38-0.96; HR(high versus low) = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.

Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.

BACKGROUND & AIMS: Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers. METHODS: We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk. RESULTS: A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers. CONCLUSION: We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.

Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group.

PURPOSE Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full-term pregnancy, was associated with an increased risk of breast cancer for both BRCA1 and BRCA2 mutation carriers (4 or more years of use before first full-term pregnancy: HR = 1.49 [95% CI, 1.05 to 2.11] for BRCA1 carriers and HR = 2.58 [95% CI, 1.21 to 5.49] for BRCA2 carriers). CONCLUSION No evidence was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk of breast cancer among both BRCA1 and BRCA2 mutation carriers.