Elham Kharazmi

Background: Gallstones affect women more frequently than men, and symptomatic gallstones are increasingly treated with surgical removal of the gallbladder (cholecystectomy). Breast, endometrial, and ovarian cancer share several risk factors with gallstones, including overweight, obesity, and exposure to female sex hormones. We intended to assess the association between cholecystectomy and female cancer risk, which has not been comprehensively investigated. Methods: We investigated the risk of female cancers after cholecystectomy leveraging the Swedish Cancer, Population, Patient, and Death registries. Standardized incidence ratios (SIRs) adjusted for age, calendar period, socioeconomic status, and residential area were used to compare cancer risk in cholecystectomized and non-cholecystectomized women. Results: During a median follow-up of 11 years, 325,106 cholecystectomized women developed 10,431 primary breast, 2888 endometrial, 1577 ovarian, and 705 cervical cancers. The risk of ovarian cancer was increased by 35% (95% confidence interval (CI) 2% to 77%) in the first 6 months after cholecystectomy. The exclusion of cancers diagnosed in the first 6 months still resulted in an increased risk of endometrial (19%, 95%CI 14% to 23%) and breast (5%, 95%CI 3% to 7%) cancer, especially in women cholecystectomized after age 50 years. By contrast, cholecystectomized women showed decreased risks of cervical (−13%, 95%CI −20% to −7%) and ovarian (−6%, 95%CI −10% to −1%) cancer. Conclusions: The risk of ovarian cancer increased by 35% in a just short period of time (6 months) following the surgery. Therefore, it is worth ruling out ovarian cancer before cholecystectomy. Women undergoing cholecystectomy showed an increased risk of breast and endometrial cancer up to 30 years after surgery. Further evaluation of the association between gallstones or gallbladder removal on female cancer risk would allow for the assessment of the need to intensify cancer screening in cholecystectomized women.

Background: Colorectal cancer (CRC) incidence is increasing among young adults below screening age, despite the effectiveness of screening in older populations. Individuals with diabetes mellitus are at increased risk of early-onset CRC. We aimed to determine how many years earlier than the general population patients with diabetes with/without family history of CRC reach the threshold risk at which CRC screening is recommended to the general population.Methods and findings: A nationwide cohort study (follow-up:1964–2015) involving all Swedish residents born after 1931 and their parents was carried out using record linkage of Swedish Population Register, Cancer Registry, National Patient Register, and Multi-Generation Register. Of 12,614,256 individuals who were followed between 1964 and 2015 (51% men; age range at baseline 0–107 years), 162,226 developed CRC, and 559,375 developed diabetes. Age-specific 10-year cumulative risk curves were used to draw conclusions about how many years earlier patients with diabetes reach the 10-year cumulative risks of CRC in 50-year-old men and women (most common age of first screening), which were 0.44% and 0.41%, respectively. Diabetic patients attained the screening level of CRC risk earlier than the general Swedish population. Men with diabetes reached 0.44% risk at age 45 (5 years earlier than the recommended age of screening). In women with diabetes, the risk advancement was 4 years. Risk was more pronounced for those with additional family history of CRC (12–21 years earlier depending on sex and benchmark starting age of screening). The study limitations include lack of detailed information on diabetes type, lifestyle factors, and colonoscopy data.Conclusions: Using high-quality registers, this study is, to our knowledge, the first one that provides novel evidence-based information for risk-adapted starting ages of CRC screening for patients with diabetes, who are at higher risk of early-onset CRC than the general population.

Background: The question of whether having a family history of prostatic borderline or in situ neoplasia (PBISN) is associated with an increased risk of invasive prostate cancer (PCa) or death from PCa remains unanswered. The objective of the current study was to provide an evidence‐based risk estimation for the relatives of patients with PBISN.Methods: Nationwide Swedish family cancer data sets were used for the current study, including data regarding all residents of Sweden who were born after 1931 and their parents. Standardized incidence ratios (SIRs), standardized mortality ratios (SMRs), and lifetime cumulative risks of PCa were calculated for men with different constellations of family history. Family history was defined as a dynamic (time‐dependent) variable considering changes during follow‐up (1958‐2015).Results: Of the 6,343,727 men in the current study, a total of 238,961 developed invasive PCa and 5756 were diagnosed with PBISN during the follow‐up. Men with 1 first‐degree relative who was diagnosed with PBISN had a 70% increased risk of invasive PCa (SIR, 1.7; 95% confidence interval, 1.5‐1.9) and PCa death (SMR, 1.7; 95% confidence interval, 1.3‐2.2) compared with men with no family history of PBISN or invasive PCa. These were rather close to estimates in men with 1 first‐degree relative diagnosed with invasive PCa (SIR, 2.1 and SMR, 1.8). A higher risk of PCa in family members was found among patients with a family history of PBISN and/or PCa diagnosed before age 60 years. The results in terms of cumulative risk resembled this trend.Conclusions: A family history of PBISN appears to be as important as a family history of invasive PCa with regard to an increased risk of invasive PCa or PCa mortality. Such a history should not be overlooked in PCa screening recommendations or in future research regarding familial PCa.

In Reply We thank Hemminki for his comments on our proposed risk-adapted starting age of screening in women (not patients, as written in the first sentence of the comments) with a family history of breast cancer.¹ Hemminki compared our results with those in an article written in 2010 by Brandt and colleagues,² including Hemminki and a coauthor of our article, although results of these studies with different risk measures should not be compared in the first place. Prediction of age-specific 10-year cumulative risk (ie, risk of developing breast cancer in the next 10 years at each age) presented in our study¹ and comparison with a threshold risk in women at the age of initial screening in the general population has clinical relevance and application, whereas it is hard to find a clear application for comparing cumulative risk (ie, risk from birth to a certain age) between those with a family history and those without a family history, which was presented in their study.² Identify all potential conflicts of interest that might be relevant to your comment. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. Err on the side of full disclosure. If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response. Not all submitted comments are published. Please see our commenting policy for details.

Background: Familial breast cancer risk studies usually overlook the dynamic nature of family history. Methods: The authors assessed the effect of incorporating the timing of cancer diagnosis events into the assessment of familial risks of breast cancer in first‐degree and second‐degree relatives in a nationwide cohort study of 5,099,172 women (follow‐up was between 1958‐2015). Family history was assessed using 3 approaches: 1) as a static variable (ever having a relative with breast cancer); 2) as accumulative history; and 3) as a dynamic variable (time‐dependent variable). Results: For women aged <50 years, familial risk was mostly higher when family history was assessed as a dynamic variable compared with using a static or accumulative family history. For example, the cumulative risk of receiving a breast cancer diagnosis until age 50 years for women with a history of breast cancer in 1 first‐degree relative was 2.6% (95% CI, 2.5%‐2.7%) using the static method, 2.4% (95% CI, 2.3%‐2.4%) using the accumulative method, and 3.1% (95% CI, 3.0%‐3.2%) using the dynamic method. Relative risk in women aged <50 years with a breast cancer diagnosis in a sister was 1.40‐fold (95% CI, 1.31‐fold to 1.48‐fold) using the static method, 1.66‐fold (95% CI, 1.57‐fold to 1.76‐fold) using the accumulative method, and 2.28‐fold (95% CI, 2.07‐fold to 2.51‐fold) using the dynamic method. Conclusions: The results of the current study demonstrated that assessing family history as static, accumulative, or dynamic results in different familial risk estimates. The answer as to which method to use for family history assessment depends on the implications of the study, with the dynamic method appearing to be better suited for risk stratification studies, the accumulative method being the most convenient in practice and the least favored for risk prediction, and the static method being suitable for etiological impact and risk attribution studies.

Breast cancer is a major cause of morbidity and mortality in women worldwide,^1,2 accounting for one-quarter of all new cancer cases and 15% of all cancer deaths in women.³ Family history is a nonmodifiable risk factor for the disease.⁴ Breast cancer risk associated with family history varies with age of the individual, nature and number of affected relatives, and age at which the relative received a diagnosis.^5-7 Family history of breast cancer among the extended family, such as second-degree relatives (SDRs), has also been reported as a major factor in breast cancer risk and should be considered in risk assessment.⁸

Objective To explore the risk of colorectal cancer in family members of patients with colorectal cancer, with an emphasis on subtypes of second degree relatives, especially half siblings, which were lacking in the literature. Design Ambidirectional cohort study. Setting Nationwide Swedish Family Cancer Data (record linkage). Participants All people residing in Sweden and born after 1931, with their biological parents, totalling >16 million individuals (follow-up: 1958-2015); of those with clear genealogy, 173 796 developed colorectal cancer. Main outcome measures Lifetime (0-79 years) cumulative risk and standardised incidence ratio of colorectal cancer among first degree relatives and second degree relatives. Results The overall lifetime cumulative risk of colorectal cancer in siblings of patients was 7%, which represents a 1.7-fold (95% confidence interval 1.6 to 1.7; n=2089) increase over the risk in those without any family history of colorectal cancer. A similarly increased lifetime cumulative risk (6%) was found among half siblings (standardised incidence ratio 1.5, 95% confidence interval 1.3 to 1.8; n=140). The risk in people with colorectal cancer in both a parent and a half sibling (standardised incidence ratio 3.6, 2.4 to 5.0; n=32) was close to the risk in those with both an affected parent and an affected sibling (2.7, 2.4 to 3.0; n=396). Family history of colorectal cancer in only one second degree relative other than a half sibling (without any affected first degree relatives), such as a grandparent, uncle, or aunt, showed minor association with the risk of colorectal cancer. Conclusion Family history of colorectal cancer in half siblings is similarly associated with colorectal cancer risk to that in siblings. The increase in risk of colorectal cancer among people with one affected second degree relative was negligible, except for half siblings, but the risk was substantially increased for a combination of family history in one affected second degree relative and an affected first degree relative (or even another second degree relative). These evidence based findings provide novel information to help to identify people at high risk with a family history of colorectal cancer that can potentially be used for risk adapted screening.