Margaret McCredie

Cancer in patients on dialysis for end-stage renal disease: an international collaborative study

BACKGROUND Previous studies have suggested that the frequency of cancer is higher in patients with end-stage renal disease (ESRD) than in the general population, but have not established whether this increase is confined to certain cancers or to certain categories of ESRD patients. The aim of this study was to examine the risk of cancer in a large cohort of patients treated by dialysis but not transplantation. METHODS We assembled a cohort of 831,804 patients who received dialysis during the period 1980-94 for ESRD in the USA, Europe, Australia, or New Zealand. We compared the observed frequency of cancer among these patients during 2,045,035 person-years of follow-up with the frequency of cancer in the respective background populations. FINDINGS During average follow-up of 2.5 years, 25,044 (3%) of 831,804 patients developed cancer compared with an expected number of 21,185 (standardised incidence ratio 1.18 [95% CI 1.17-1.20]). We observed a higher risk of cancer in patients younger than 35 years (3.68 [3.39-3.99]), and the risk gradually decreased with increasing age. High risks were observed for cancer of the kidney (3.60 [3.45-3.76]), bladder (1.50 [1.42-1.57]), and thyroid and other endocrine organs (2.28 [2.03-2.54]). Excess cancers appeared in several organs for which viruses have been suspected as causative agents, whereas cancers of the lung, colorectum, prostate, breast, and stomach were not consistently increased. INTERPRETATION The overall risk of cancer is increased in patients with ESRD, and the distribution of tumour types resembles the pattern seen after transplantation (although we have no data to make the comparison with skin cancer). The excess risk can largely be ascribed to effects of underlying renal or urinary-tract disease, or of loss of renal function, on the kidney and bladder, and to increased susceptibility to viral carcinogenesis. The relative risk, which is especially high in younger patients, gradually diminishes with age.

A common coding variant in CASP8 is associated with breast cancer risk

The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 −202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9–15 studies, comprising 11,391–18,290 cases and 14,753–22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85–0.94) and 0.74 (95% c.i.: 0.62–0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; Ptrend = 1.1 × 10−7) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02–1.13) and 1.16 (95% c.i.: 1.08–1.25), respectively; Ptrend = 2.8 × 10−5). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.NOTE: In the version of this article initially published, there was an error that affected the calculations of the odds ratios, confidence intervals, between-study heterogeneity, trend test and test for association for SNP ICAM5 V301I in Table 1 (ICAM5 V301I); genotype counts in Supplementary Table 2 (ICAM5; ICR_FBCS and Kuopio studies) and minor allele frequencies, trend test and odds ratios for heterozygotes and rare homozygotes in Supplementary Table 3 (ICAM5; ICR_FBCS and Kuopio studies). The errors in Table 1 have been corrected in the PDF version of the article. The errors in supplementary information have been corrected online.

Obesity and outcomes in premenopausal and postmenopausal breast cancer.

Purpose: Obesity is associated with adverse outcomes in postmenopausal women with breast cancer. In premenopausal women, the association is less clear. Methods: A population-based sample of 1,360 Australian women with breast cancer before the age of 60 years, 47% diagnosed before age 40, and 74% premenopausal, was studied prospectively for a median of 5 years (range, 0.2-10.8 years). Obesity was defined as a body mass index of ≥30 kg/m2. The hazard ratio (HR) for adverse clinical outcome associated with obesity was estimated using Cox proportional hazard survival models. Results: Obesity increased with age (P < 0.001) and was associated with increased breast cancer recurrence (P = 0.02) and death (P = 0.06), larger tumors (P = 0.002), and more involved axillary nodes (P = 0.003) but not with hormone receptor status (P ≥ 0.6) or with first cycle adjuvant chemotherapy dose reductions (P = 0.1). Adjusting for number of axillary nodes, age at diagnosis, tumor size, grade, and hormone receptor status, obese women of all ages were more likely than nonobese women to have disease recurrence [HR, 1.57; 95% confidence interval (95% CI), 1.11-2.22; P = 0.02] and to die from any cause during follow-up (HR, 1.56; 95% CI, 1.01-2.40; P = 0.05). In premenopausal women, the adjusted HRs were 1.50 (95% CI, 1.00-2.26; P = 0.06) and 1.71 (95% CI, 1.05-2.77; P = 0.04), respectively. Conclusions: Obesity is independently associated with poorer outcomes in premenopausal women, as it is in postmenopausal women, and this is not entirely explained by differences in tumor size or nodal status. Given the high and increasing prevalence of obesity in western countries, more research on improving the treatment of obese breast cancer patients is warranted.

The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study.

Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple‐case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation.

Cancers of the Kidney and Urinary Tract in Patients on Dialysis for End-Stage Renal Disease: Analysis of Data from the United States, Europe, and Australia and New Zealand

Patients on maintenance dialysis have increased risk for cancer, especially in the kidney and urinary tract. In a retrospective cohort of 831,804 patients starting dialysis during 1980 to 1994 in the United States, Europe, or Australia and New Zealand, standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated for kidney and bladder cancers. Risks for cancers of the kidney (SIR 3.6; CI 3.5 to 3.8) and bladder (SIR 1.5; CI 1.4 to 1.6) were increased, relatively more in younger than older patients and more in female patients (kidney: SIR 4.6, CI 4.3 to 4.9; bladder: SIR 2.7, CI 2.4 to 2.9) than male patients (kidney: SIR 3.2, CI 3.0 to 3.4; bladder: SIR 1.3, CI 1.2 to 1.3). SIR for kidney cancer were raised in all categories of primary renal disease, and for bladder cancer in all but diabetes and familial, hereditary diseases. Notably high SIR occurred in toxic nephropathies (chiefly analgesic nephropathy) and miscellaneous conditions (a category that includes Balkan nephropathy), the excess of kidney cancer in these conditions being urothelial in origin. SIR for kidney cancer rose significantly, and those for bladder cancer fell (not reaching significance) with time on dialysis. There was no association with type of dialysis. The pattern of increased risk for renal parenchymal cancer in dialysis patients is consistent with causation through acquired renal cystic disease and of urothelial cancers of the kidney and bladder with the carcinogenic effects of certain primary renal diseases.

Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.

This report notes the differences in the classification of the primary renal disease (PRD) used in different renal dialysis and transplant registries worldwide. The heterogeneity of coding systems complicates the comparative analysis of end-stage renal disease from different regions. Using data collected over two decades in the United States, Europe, and Australia/New Zealand, we present a method for reorganization of the classes of PRD that allows a straightforward comparison of retrospective data from these registries.

International renal cell cancer study. VII. role of diet

We investigated the role of diet in the etiology of renal cell cancer (RCC) in a multi‐center, population‐based case‐control study conducted in Australia, Denmark, Sweden and the United States, using a shared protocol. A total of 1,185 incident histopathologically confirmed cases (698 men, 487 women) and 1,526 controls (915 men, 611 women) frequency‐matched to cases by sex and age were included in the analyses. The association between RCC and diet was estimated by relative risks (RR) and 95% confidence intervals (CI) adjusted for age, sex, study center, body mass index and smoking. A statistically significant positive association was observed for total energy intake (RR = 1.7, 95% CI = 1.4–2.2 for the highest vs. lowest quartile, p value for trend <0.00001), while the hypothesis that protein and fat are risk factors independent of energy was not supported. Fried meats were associated with increased RCC risk, while vegetables and fruits were protective, with the strongest effect observed for the highest quartile of consumption of orange/dark green vegetables but not vitamin C or β carotene. Increased risk was associated with low intake (lowest decile) of vitamin E and magnesium. We observed an apparent protective effect of alcohol confined to women and probably due to chance. Our findings indicate an important role of nutrition in the development of RCC. The apparent positive association of energy intake with risk of RCC needs further investigation in a prospective cohort study to exclude the possible impact of differences in recall between cases and controls.

Fuhrman grading is not appropriate for chromophobe renal cell carcinoma.

This study was undertaken to assess the prognostic effectiveness of Fuhrman nuclear grading and the individual components of this grading system, in a series of chromophobe renal cell carcinomas. Eighty-seven cases of chromophobe renal cell carcinoma were investigated. There were 47 males and 40 females, 28 to 78 years of age. The carcinomas ranged from 25 to 180 mm in size and on TNM staging there were 38 stage I, 25 stage II, 22 stage III, and 2 stage IV tumors. Whole tumor Fuhrman grading was grade 1, 6 cases; grade 2, 72 cases; grade 3, 8 cases; and grade 4, 1 case, whereas focal (single high power field) grading was grade 1, 1 case; grade 2, 62 cases; grade 3, 21 cases; and grade 4, 3 cases. On assignment of nucleolar grading using Fuhrman criteria there were 37 grade 1, 44 grade 2, and 4 grade 3 tumors on whole tumor assessment and 3 grade 1, 63 grade 2, and 21 grade 3 tumors on assessment of the high power field showing the greatest degree of nuclear pleomorphism. Measurements of nuclear size showed nuclear area to range from 26.14 to 100.74 μm2, nuclear perimeter from 19.73 to 39.28 μm, and nuclear major axis from 6.49 to 13.21 μm, whereas the ranges of measures of nuclear shape were; shape factor 0.798 to 0.890, compactness 14.260 to 15.843, and feret diameter 5.694 to 11.242. Follow-up ranged from 1 to 150 months and 8 patients died of tumor-related causes 5 to 53 months from diagnosis. On log rank testing against survival, only patient age (P=0.016) and tumor maximum diameter (P=0.0055) were significant, whereas patient sex and TNM stage were not significant. Whole tumor and focal Fuhrman grading, as well as all measures of nucleolar prominence, nuclear size, and nuclear shape showed no significant association with outcome. It is concluded that neither Fuhrman grading, nor any of the components of the Fuhrman grading system, is useful as prognostic indicators for this tumor type.

Breast cancer in Australian women under the age of 40

Objectives: A case-control-family study of breast cancer in women under the age of 40 was carried out in Melbourne and Sydney, Australia, from 1992 to 1995 to determine the risk factors for these women. Subjects included 467 incident cases identified by state cancer registries and 408 population-based controls. Methods: All participants completed a structured risk-factor questionnaire and family pedigree during an in-person interview. Where possible, cancers in first- and second-degree relatives were verified. Results: Multiple logistic regression analysis showed that the strongest risk factor for breast cancer was a family history of the disease - having at least one affected first-degree relative trebled the risk (relative risk [RR] = 3.3, 95 percent confidence interval [CI] = 1.9-5.8). Risk increased with height by three percent (standard error [SE] of one percent) per cm, and after adjusting for height, there was evidence for a decreased risk in women weighing 73 kg or more. There was an increased risk of breast cancer after the first full-term birth (RR = 1.8, CI = 1.0-3.5) but this risk fell by 30 percent (SE = 11 percent) with each subsequent livebirth. Conclusions: The effects of other reproductive factors and oral contraceptive use, although not nominally significant, were in accord with published findings from similar studies in young women. This study of Australian women has indicated that some risk factors for breast cancer in women under age 40 differ from those reported for older women either in direction (e.g., weight) or relative importance (e.g., family history).

A genome wide linkage search for breast cancer susceptibility genes.

Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome‐wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.