Kidney cancer in the Swedish Family Cancer Database: familial risks and second primary malignancies

BACKGROUND: Familial risks in kidney cancer and association with second primary malignancies were studied using the nationwide Swedish Family Cancer Database. METHODS: Cancer data were retrieved from the Swedish Cancer Registry from years 1961 to 1998 and included 23,137 cases of kidney cancer. Standardized incidence ratios (SIRs) were used to measure the cancer risks. RESULTS: Seventy-one families were identified where both a parent and an offspring had kidney cancer, giving a familial risk for offspring of 1.56 (1.22 to 1.95) and population attributable proportion of 0.78%. A risk for kidney cancer from an affected sibling was considerably higher with a SIR of 4.72 (2.28 to 9.20), giving an attributable proportion of 0.77%. The discordant tumor site that was associated with kidney cancer between two generations was hemangioblastoma of central nervous system. Discordant cancer sites that were associated with kidney cancer in siblings were ovaries, endocrine glands and pancreas. There was an over threefold increase of second primary malignancies of the urinary bladder, nervous system and endocrine gland in kidney cancer patients. The risks for second primary hemangioblastoma following kidney cancer or familial kidney cancer was 21.19 (6.69 to 43.83) and 1206 (114 to 3456), respectively. CONCLUSIONS: The high ratio of sibling risk to offspring risk in kidney cancer may reflect a recessive susceptibility. The high risk for second primary cancers in the patients without family history is consistent with a polygenic model and variable degree of environmental modification.     

Establishing a Family Risk Assessment Clinic for Breast Cancer

Abstract:  Breast cancer is the most common cancer affecting European women and the leading cause of cancer-related death. A total of 15–20% of women who develop breast cancer have a family history and 5–10% a true genetic predisposition. The identification and screening of women at increased risk may allow early detection of breast cancer and improve prognosis. We established a family risk assessment clinic in May 2005 to assess and counsel women with a family history of breast cancer, to initiate surveillance, and to offer risk-reducing strategies for selected high-risk patients. Patients at medium or high risk of developing breast cancer according to NICE guidelines were accepted. Family history was determined by structured questionnaire and interview. Lifetime risk of developing breast cancer was calculated using Claus and Tyrer-Cuzick scoring. Risk of carrying a breast cancer-related gene mutation was calculated using the Manchester system. One thousand two hundred and forty-three patients have been referred. Ninety-two percent were at medium or high risk of developing breast cancer. Formal assessment of risk has been performed in 368 patients, 73% have a high lifetime risk of developing breast cancer, and 72% a Manchester score ≥16. BRCA1/2 mutations have been identified in 14 patients and breast cancer diagnosed in two. Our initial experience of family risk assessment has shown there to be a significant demand for this service. Identification of patients at increased risk of developing breast cancer allows us to provide individuals with accurate risk profiles, and enables patients to make informed choices regarding their follow-up and management.     

The influence of family history on prostate cancer risk: implications for clinical management

? The most recent evidence for the link between a family history of prostate cancer and individual risk for future disease was examined, with the aim of understanding what the existence and nature of a family history of prostate cancer does to a man's risk of developing the disease. ? Our findings highlighted the clear association between a family history of prostate cancer and increased risk of developing the disease; with a greater proximity of relatedness, greater number of family members affected and/or earlier age at diagnosis of the family member elevating risk further. ? These findings have important clinical implications for the identification and subsequent management of men deemed to be at increased risk of developing prostate cancer. The evidence for prostate cancer risk reduction with the mono 5α-reductase inhibitor (5ARI) finasteride in a low-risk population and, more recently, with the dual 5ARI dutasteride in a population at increased risk of developing the disease, has potential to expand management options for men at risk of developing prostate cancer beyond more frequent and/or earlier surveillance. ? Given that family history can be easily assessed in routine clinical practice, it should be regarded as an important parameter to consider alongside PSA level for prostate cancer risk assessment.     

Prevalence of family history of breast and ovarian cancer in a single primary care practice using a self-administered questionnaire

Women at high risk of hereditary breast and/or ovarian cancer require specific management strategies for cancer prevention and early detection. The goal of this study was to determine the prevalence of familial breast and ovarian cancer among patients in a primary care practice. Questionnaires were mailed to the 608 women less than 81 years of age in a single primary care practice. Additional mailings and phone calls were used for nonresponders. Data were analyzed by bloodline, the degree of relative, age of diagnosis and cancer type. Women were grouped into three categories of breast/ovarian family history: "no family history,"insignificant family history," and "significant potentially high-risk family history" (women with two or more relatives in a single bloodline with breast and/or ovarian cancer, a single individual with bilateral breast cancer or breast and ovarian cancer, or breast and/or ovarian cancer at less than 40 years of age). A pedigree analysis of women categorized as "significant potentially high-risk family history" further classified these women as to the likelihood of being at risk for hereditary cancer. Data were obtained from 567 women (93%); 27 patients with a personal diagnosis of breast and/or ovarian cancer were excluded. Of the 540 remaining respondents, 351 (65%) had no family history of cancer, 138 (25.6%) had an insignificant family history, and 51 (9.4%) had a significant family history. Based on pedigree analysis of these 51 patients, 19 were unlikely to be at high risk for hereditary cancer, and 32 (6%) were likely to be at significant risk and warrant intensive evaluation. The large proportion of women identified with a significant family history of breast and/or ovarian cancer has major implications regarding the magnitude of a population-based process to identify and manage high-risk individuals.     

Recruitment strategies and comparison of prostate cancer-specific clinical data on African-American and Caucasian males with and without family history

Prostate cancer is the most common cancer in men in the United States. This is a complex disease with high heterogeneity and the exact causes are unknown in population-specific samples. Family history is a primary risk factor irrespective of race. Identifying prostate cancer families with multiple affected cancer cases is challenging. Herein we document recruitment techniques and present prostate cancer clinical factors described in a cohort of African Americans and Caucasians with or without a strong family history. A total of 521 prostate cancer patients (241 African Americans and 280 Caucasians) were identified using a novel cooperative methodology involving a combination of treating physicians and tumor registries. Higher prostate-specific antigen (PSA, P=0.0269) was found in familial cases as compared to sporadic cases in African-American men. In addition, PSA values for familial cases were higher (P=0.0093) in African-American as compared to Caucasian men. No differences were detected in Gleason score values in either race, regardless of family history. These findings remained the same after adjustment was made for age at diagnosis. In conclusion, methodologies for cohort acquisition, and clinical characteristics, are described for men with and without a family history of prostate cancer using both Caucasian and African-American populations.     

Long-term recurrence and complication rates after incisional hernia repair with the open onlay technique

Background

Family history, male gender and age are significant risk factors for inguinal hernia disease. Family history provides evidence for a genetic trait and could explain early recurrence after inguinal hernia repair despite technical advance at least in a subgroup of patients. This study evaluates if age and family history can be identified as risk factors for early recurrence after primary hernia repair.

Methods

We performed an observational cohort study for 75 patients having at least two recurrent hernias. The impact of age, gender and family history on the onset of primary hernias, age at first recurrence and recurrence rates was investigated.

Results

44% (33/75) of recurrent hernia patients had a family history and primary as well as recurrent hernias occurred significantly earlier in this group (p = 0.04). The older the patients were at onset the earlier they got a recurrent hernia. Smoking could be identified as on additional risk factor for early onset of hernia disease but not for hernia recurrence.

Conclusion

Our data reveal an increased incidence of family history for recurrent hernia patients when compared with primary hernia patients. Patients with a family history have their primary hernias as well as their recurrence at younger age then patients without a family history. Though recurrent hernia has to be regarded as a disease caused by multiple factors, a family history may be considered as a criterion to identify the risk for recurrence before the primary operation.     

A simple tool for identifying unaffected women at a moderately increased or potentially high risk of breast cancer based on their family history

Family history of breast cancer is a more important aspect of clinical management following the discovery of the genes BRCA1 and BRCA2. The authors developed a short questionnaire to categorize risk according to breast cancer history in close relatives. It was completed by 559 women attending for screening mammograms in Sydney, Australia. Twenty-three per cent reported a family history sufficient to be classified at a moderately increased or potentially high risk according to national guidelines (category II or III). Only 29 women (5%) made errors such that their risk category could not be determined. Validation of responses from 89 women, 44 from category II or III, found 100% agreement with classification after interview by a genetic counsellor. This questionnaire has the potential to accurately triage risk based on a woman's knowledge of her family history, and could be used in a variety of settings to identify women who may require further assessment, management and referral advice.     

Limitations of the Gail model in the specialized breast cancer risk assessment clinic

The Gail model is a risk assessment tool that is accurate for general breast cancer risk screening. Because of the limited way that this model incorporates family history information, however, there are concerns that it may underestimate risk for many women attending specialized breast cancer risk assessment clinics. We collected comprehensive breast cancer risk factor information for 213 women attending a specialized breast cancer risk assessment clinic using a modified version of the CancerGene software. Breast cancer risk was calculated using the models of Gail and Claus as well as BRCAPRO and the tables of Bodian (for women with lobular neoplasia). Eighty-six percent of the women had a family history of breast cancer. Although 74% of women had risk factor histories that are thought to confound the Gail model (family history of breast cancer in second-degree relatives, family history of breast cancer before the age of 50, family history of bilateral breast cancer, family history of ovarian cancer, or personal history of lobular neoplasia), the inclusion of other models increased the risk level assignment in only 13% of the cases. We conclude that the Gail model is an appropriate risk assessment tool for most women attending specialized clinics, although the inclusion of models better able to account for family history information and personal history of lobular neoplasia is required to accommodate all women.     

Practice of breast self-examination and the treatment of primary breast cancer

Past experience of breast self-examination (BSE), family history of breast cancer, method of detection of the tumour, tumour size, node status, tumour attachment and type of treatment used for primary breast cancer, were surveyed on a sample of 117 female breast cancer patients diagnosed in Tasmania during May 1986-June 1987. Family history of breast cancer was associated with higher levels of BSE practice. Three-monthly or more frequent BSE in the year prior to diagnosis was associated with smaller tumours at presentation and less axillary node involvement. Breast-conserving surgery was utilized in 38% of all cases treated, and 84% of these patients received radiotherapy as part of primary treatment.     

Family history of breast cancer,mammographic breast density and breast cancer risk: Findings from a cohort study of Korean women

BackgroundThis study investigated whether the association between family history of breast cancer in first-degree relatives and breast cancer risk varies by breast density.MethodsWomen aged 40 years and older who underwent screening between 2009 and 2010 were followed up until 2020. Family history was assessed using a self-reported questionnaire. Using Breast Imaging Reporting and Data System (BI-RADS), breast density was categorized into dense breast (heterogeneously or extremely dense) and non-dense breast (almost entirely fatty or scattered areas of fibro-glandular). Cox regression model was used to assess the association between family history and breast cancer risk.ResultsOf the 4,835,507 women, 79,153 (1.6%) reported having a family history of breast cancer and 77,238 women developed breast cancer. Family history led to an increase in the 5-year cumulative incidence in women with dense- and non-dense breasts. Results from the regression model with and without adjustment for breast density yielded similar HRs in all age groups, suggesting that breast density did not modify the association between family history and breast cancer. After adjusting for breast density and other factors, family history of breast cancer was associated with an increased risk of breast cancer in all three age groups (age 40–49 years: aHR 1.96, 95% confidence interval [CI] 1.85–2.08; age 50–64 years: aHR 1.70, 95% CI 1.58–1.82, and age ≥65 years: aHR 1.95, 95% CI 1.78–2.14).ConclusionFamily history of breast cancer and breast density are independently associated with breast cancer. Both factors should be carefully considered in future risk prediction models of breast cancer.     

Bilateral malignant testicular germ cell cancer

Twenty-six of approximately 1300 patients (1.9%) with unilateral testicular cancer developed a second primary germ cell cancer (seminoma 18; non-seminoma 8). Patients with previous seminoma had a significantly higher risk of developing a new seminoma than those with a previous non-seminoma. The diagnosis of second primary was made within 3 years of the first diagnosis in only 50% of the patients. In patients with a history of undescended and/or atrophic testes the interval significantly decreased between the diagnosis of the two testicular cancers. The prognosis of bilateral testicular cancer is generally good. Patients in whom the second testicular cancer is at clinical stage I (no metastases) at diagnosis can safely be observed without further treatment after orchiectomy. A patient with unilateral testicular cancer should be informed of the increased risk of developing a second primary germ cell tumour and should be encouraged to perform regular examination of the remaining testis. The need for life-long follow-up visits for patients with testicular cancer is questionable.     

Colonoscopy for screening and follow up of patients with a family history of colorectal cancer

Objective To determine the minimum family history of colorectal cancer (CRC), which justifies colonoscopy and to establish whether further colonic assessment is necessary after a negative screening colonoscopy. Method A retrospective review of every colonoscopy undertaken for family screening at the Royal Berkshire and Battle Hospitals, Reading between October 1996 and July 2004. Results Four hundred and thirty‐two patients (261 women) with an average age of 48 years (range 14–84) were screened. Three cancers in patients over the age of 60 years and 49 adenomas were found in 37 patients. Twenty three of 281 (8%) patients with a ‘low‐risk’ family history (one in 12 or less lifetime risk of developing CRC) had either a cancer or an adenoma. Eighteen of 151 (12%) patients with a ‘high‐risk’ family history (one in 10 or greater) had a similar positive colonoscopy. Thirteen of 15 patients who had an adenoma aged under 45 years had a high‐risk family history. Seventy‐three patients subsequently underwent two or more follow‐up colonoscopies. There were 22 adenomatous polyps found in 12 patients (16%) at the first screening, nine adenomas in seven patients in the second colonoscopy and four adenomas found in four patients in all subsequent colonoscopies. Conclusion Patients with a low‐risk family history have a similar adenoma pick‐up to that of the general population. These patients need not be screened below the age of 50 unless symptomatic. Follow up of low‐risk family history (FH) patients with a negative screening colonoscopy is unlikely to be beneficial.     

Bilateral testicular cancer: a preventable problem? Experience from a large cancer centre

OBJECTIVE: To report a retrospective review of patients with a testicular germ cell tumour treated in a large cancer centre who developed a second tumour, as 1.8-5% of such patients will subsequently develop a new primary tumour in the contralateral testis. PATIENTS AND METHODS: From a database of 570 men treated for testicular cancer in the West of Scotland between 1989 and 1998, all those who developed bilateral testicular tumours were identified. RESULTS: Nineteen men (3.3%) developed a second primary testicular malignancy; the mean age at diagnosis of the first tumour was 29.5 years, with the mean (range) interval to diagnosis of the second tumour of 76 (11-181) months (except for one man with synchronous tumours). The first tumour was teratoma in 11 and seminoma in seven; one patient had synchronous bilateral teratoma. The second primary was teratoma in 10 and seminoma in eight. Known risk factors for carcinoma in situ were present in nine patients, i.e. a small atrophic contralateral testis in five, a family history of testicular cancer in two, a history of infertility in two and unilateral undescended testis in one. Two patients had had contralateral testicular biopsies at the first diagnosis; both were negative for intratubular germ cell neoplasia (IGCN). Eight patients had chemotherapy to treat the first tumour and 14 for the second. All underwent bilateral orchidectomy. Overall, 18 of 19 men are alive and disease-free, with a median follow-up of 51 months. Pathology for 12 of the second testicular tumours was available for review; there was no IGCN in any of the slides from three patients, it was only present focally around the tumour in seven, and was diffuse in two patients. CONCLUSIONS: Chemotherapy for the first testicular tumour does not eliminate the risk of developing a contralateral tumour. Despite careful follow-up, in most patients the second primary tumour was not diagnosed early enough to avoid chemotherapy. The focal nature of IGCN in the second testis in most patients questions the value of biopsy of the contralateral testis. Improved methods of detecting patients at risk of second testicular tumours are needed.     

Carcinomas associated with Lynch syndrome: a family history

Lynch syndrome is a rare and inherited defect disorder. People who have Lynch syndrome are strongly predisposed to develop colorectal cancer as well as several other types of cancer. The aim of this study was to explore features of ovarian cancers arising in families with Lynch syndrome. This study was a case report based on family history examining three patients with a new diagnosis of colorectal adenocarcinoma with ovarian cancer. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing. The clinical criteria of the Amsterdam II guidelines for Lynch syndrome were used in this study. This is a maternal history of a 27-year-old woman sharing the destiny of her 48-year-old mother and 45-year-old aunt, both of which were suffering from Lynch syndrome associated with ovarian cancer. The maternal grandmother and maternal uncle of this young woman also suffered from colon cancer in their forties. The medical implications for the carrier relatives were considered as the maternal branch of the family.     

Family history? The forgotten question in high‐risk colorectal cancer patients

Aim  The aim of the study was to investigate the frequency and detail of family history recorded for patients diagnosed with potentially high-risk colorectal cancer, and to determine the proportion of these patients referred to a high-risk assessment clinic.
Method  Medical records of patients diagnosed with colorectal cancer under the age of 50 admitted to a major Sydney teaching hospital were reviewed. The proportion of records containing information about family history was calculated. Associations between recording of family history and demographic and clinical characteristics of patients were investigated. Logistic regression modelling was performed to identify significant, independent predictors of study outcomes.
Results  Of 113 patients with colorectal cancer diagnosed under the age of 50 years, 61 (54%, 95% CI: 44–63%) had an entry in their hospital medical record about family history. Family history was significantly less likely to be recorded for females, for those admitted via the Emergency Department, and for those with shorter lengths of stay. A significant family history was found in 51% of the 61 patients who had a family history recorded. Records of patients attending specialist colorectal surgeons were significantly more likely to contain information about family history than those who attended other specialists ( P  = 0.04). Only 14 patients (12%, 95% CI: 7–20%) were formally referred for further genetic assessment.
Conclusion  These results suggest that family history is still being neglected in routine clinical practice, and high-risk assessment services are underutilized, implying the need for further dissemination of guidelines with regard to the recognition and management of hereditary colorectal cancer.     

Mammographic screening of the high-risk woman

Annual screening mammography beginning at age 40 is recommended for the general population. For some women at high risk for developing breast cancer at a younger age, annual screening may be appropriate starting at an earlier age. These women include those with a personal history of breast cancer, nontherapeutic radiation to the breasts especially for Hodgkin's disease, BRCA positive women, women with a family history of a first-degree relative with breast cancer at a young age, and women with a biopsy diagnosis of lobular carcinoma in situ or atypical ductal hyperplasia. Women with a biopsy diagnosis of atypical lobular hyperplasia develop breast cancer after age 40 and do not need earlier screening, unless they have a family history of breast cancer. Although increasing a woman's risk for breast cancer, radial scar does not increase risk for women younger than 40 years old and therefore does not require screening at a young age.     

MRI Screening in a Clinic Population with a Family History of Breast Cancer

Background Breast MRI is increasingly being used in patients at increased risk for breast cancer; however, guidelines for MRI screening are inadequately defined. We describe our experience with MRI screening in a large population of women with a family history of breast cancer. Methods We retrospectively reviewed the Memorial Sloan–Kettering breast cancer surveillance program prospective database from April 1999 to July 2006. Patients with a family history of breast cancer and at least 1 year follow-up were identified. All patients were offered biannual clinical breast examination (CBE) and annual mammography (MMG). MRI screening was performed at the discretion of the physician and patient. Results Family history profiles revealed 1,019 eligible patients; median follow-up was 5.0 years. MRI screening was performed in 374 (37%) patients resulting in a total of 976 MRIs during the study period. Cancer was detected in 9/374 patients (2%) undergoing MRI screening. Seven cancers were detected by MRI only, for a cancer detection rate of 0.7% (7/976) for screening MRI. When stratified by family risk profile, the positive predictive value (PPV) of MRI was higher (13%) in those patients with the strongest family histories and lower (6%) in patients with less significant family histories. Conclusions MRI screening can be a useful adjunct to CBE and MMG in patients with high-risk family histories of breast cancer, yet it has low yield in patients with lower-risk family histories. These data suggest that MRI screening should be reserved for those at highest risk. Patrick I. Borgen is currently affiliated with Maimonides Cancer Center, Brooklyn, NY, USA.     

Family History and Risk of Osteoporotic Fracture

The importance of family history of fractures as a risk factor for fractures is unclear. The aim of this study was to test the hypothesis that family history of fracture increased a woman's risk of hip, wrist and other osteoporotic fracture and determine whether the influence of family history is independent of low bone density. We tested this hypothesis in a prospective study of 9704 Caucasian women, age 65 years or older, by assessing family history and bone density of the radius and calcaneus at baseline; 7963 women had femoral bone density measurements two years later. Fractures occurring during an average of 7.1 years of follow-up since baseline and 5.2 years since the second examination were confirmed by radiographic report. After adjusting for age, risk of hip fracture was increased in those with a maternal (1.48; 95% CI = 1.03–2.11); sister's (1.83; 1.20–2.80) or brother's history of hip fracture (2.26; 1.16–4.42). Risk of wrist fracture was increased by maternal (1.52; 1.10–2.11) and paternal (2.41; 1.14–5.07) history of wrist fracture. Adjustment for bone density did not consistently and substantially affect the strength of the associations. Family history of hip fracture was not associated with an increased risk of wrist fracture and family history of wrist fracture did not increase the risk of hip fracture. We conclude that family history is an important risk factor for fracture that may act, at least in part, through means besides bone density. Furthermore, the effect of family history is not a general but site-specific predisposition to fracture. Received: 12 September 1997 / Revised: 6 February 1998     

Understanding Mathematical Models for Breast Cancer Risk Assessment and Counseling

Abstract: Chemoprevention and prophylactic surgery are effective interventions for lowering breast cancer incidence. However, these approaches are associated with risks of their own. Accurate individualized breast cancer risk assessment is an essential component of the risk/benefit analysis that must take place prior to implementing either of these strategies. Several mathematical models for estimating individual breast cancer risk have been proposed over the last decade. The Gail model is the most generally applicable model; however, it neglects family history information in second-degree relatives, treats pre- and postmenopausal breast cancer the same, and ignores personal histories of lobular neoplasia. The Claus model is a better family history model, but it does not assign any special relevance to histories of bilateral breast cancer or ovarian cancer, and neglects all of the nonfamily history information accounted for by the Gail model. BRCAPRO is a Bayesian family history model that calculates individual breast cancer probabilities based on the probability that a family carries a mutation in one of the BRCA genes. Though its treatment of family history information is more thorough than the other models, it neglects the nonfamily history risk factors accounted for by the Gail model and may not appreciate familial clustering unrelated to BRCA gene mutation. A thorough understanding of the principles of risk analysis and the available mathematical models is essential for anyone wishing to perform intervention counseling. This review describes the basic components of risk analysis, explains how the mathematical models work and compares the strengths and weaknesses of the various models. CancerGene is a software tool for running all of these models. It may be obtained without charge at http://www.swmed.edu/home_pages/cancergene .