L. A. Brinton

Menopausal oestrogens and breast cancer risk: an expanded case-control study.

A study among 1960 post-menopausal breast cancer cases and 2258 controls identified through a nation-wide screening program enabled evaluation of effects of oestrogen use on breast cancer risk. Ever use was not associated with increased risk (RR = 1.0), but a significant trend was observed with increasing years of use, with users of 20 or more years being at a 50% excess risk. Elevations associated with long-term use were apparent across all menopause subgroups (natural, ovaries retained, ovaries removed). Hormones exerted particularly adverse effects in those initiating use subsequent to a diagnosis of benign breast disease, particularly long-term users (RR = 3.0, 95% CI 1.6-5.5). There was also some indication that effects predominated among the lower stage tumours, an observation similar to that observed for endometrial cancer. These findings support a role for oestrogens in the aetiology of breast cancer, although risk appears to be enhanced only after extended periods of use, and not to the extent observed for other hormonally-sensitive tumours.

Reproductive factors in the aetiology of breast cancer.

An interview study of 1,362 breast cancer cases and 1,250 controls identified through a multi-centre screening project allowed an evaluation of reproductive determinants of breast cancer. Risk increased linearly with age at first livebirth, women with a birth after age 30 showed 4-5-fold excess risks compared to those with a birth prior to 18, while the risk for nulliparous women resembled that for women whose first birth was in their late twenties. The protection conferred by an early first pregnancy prevailed for pregnancies that ended in a livebirth or stillbirth, but not for those that terminated in other outcomes. Among parous women, a first trimester abortion prior to a livebirth was not associated with an elevated risk, except in the event of multiple miscarriages (RR = 2.2, 95% Cl 0.9-5.1). Although numbers were limited, women who reported an induced abortion in the absence of ever having a livebirth showed some elevation in risk. Age at first livebirth explained most associations, but some residual reduction in risk was noted for multiparous women and those with several births at an early age. There was evidence that delays in birth after marriage increased risk, but this did not explain the high risk associated with late age at first birth.

Cancer risk following pernicious anaemia.

A computer-based file of all Veterans Administration (VA) hospitalisation records for the period 1969-1985 was used to identify and follow for cancer development a cohort of 5,161 white males with pernicious anaemia. A total of 34,915 person-years were accrued, with an average length of follow-up of 6.8 years. A total of 481 cancers were diagnosed, slightly higher than the number expected (SIR = 1.2). Significant excesses were observed for cancers of the buccal cavity and pharynx (1.8) and stomach (3.2), and for melanoma (2.1), multiple myeloma (2.1), myeloid leukaemia (3.7) and other and unspecified leukaemia (4.0). Although the excess for stomach cancer was highest in the first year after diagnosis in a VA hospital, risks of 2-fold or greater persisted throughout the study period. The majority of leukaemias occurred in the first year of follow-up, but some excess risk continued beyond this time. The elevated risk of buccal and pharyngeal cancers may relate to heavy alcohol intake among this population, although risks remained high even when the cohort was restricted to patients without an admission for alcoholism. Although an elevated risk of stomach cancer among pernicious anaemia patients is consistent with most previous surveys, the low absolute risk suggests that the cost-effectiveness of intensive screening should be reassessed.

Dietary factors and epithelial ovarian cancer.

Dietary data from a population-based case-control study of 172 epithelial ovarian cancer cases and 172 controls were analysed. A significant (P less than 0.01) dose-response relationship was found between intake of fat from animal sources and risk of ovarian cancer, but plant fat was not associated. Although the effect of animal fat was confounded by education, an adjusted odds ratio of 1.8 persisted for those in the upper quartile compared to the lower quartile of consumption (P for trend = 0.03). After adjustment for animal fat intake, calorific and protein intake had minimal effects on risk. Total vegetables were found to be somewhat protective, but the mechanism of action was unclear. Weight, height and relative weight (weight/height2) were not related to risk of ovarian cancer.

Established breast cancer risk factors by clinically important tumour characteristics.

Breast cancer is a morphologically and clinically heterogeneous disease; however, it is less clear how risk factors relate to tumour features. We evaluated risk factors by tumour characteristics (histopathologic type, grade, size, and nodal status) in a population-based case–control of 2386 breast cancers and 2502 controls in Poland. Use of a novel extension of the polytomous logistic regression permitted simultaneous modelling of multiple tumour characteristics. Late age at first full-term birth was associated with increased risk of large (>2 cm) tumours (odds ratios (95% confidence intervals) 1.19 (1.07–1.33) for a 5-year increase in age), but not smaller tumours (P for heterogeneity adjusting for other tumour features (Phet)=0.007). On the other hand, multiparity was associated with reduced risk for small tumours (0.76 (0.68–0.86) per additional birth; Phet=0.004). Consideration of all tumour characteristics simultaneously revealed that current or recent use of combined hormone replacement therapy was associated with risk of small (2.29 (1.66–3.15)) and grade 1 (3.36 (2.22–5.08)) tumours (Phet=0.05 for size and 0.0008 for grade 1 vs 3), rather than specific histopathologic types (Phet=0.63 for ductal vs lobular). Finally, elevated body mass index was associated with larger tumour size among both pre- and postmenopausal women (Phet=0.05 and 0.0001, respectively). None of these relationships were explained by hormone receptor status of the tumours. In conclusion, these data support distinctive risk factor relationships by tumour characteristics of prognostic relevance. These findings might be useful in developing targeted prevention efforts.

Genetic variation in five genes important in telomere biology and risk for breast cancer

Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT (−1381C>T, −244C>T, and Ex2-659G>A) may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer (odds ratios 0.73, 0.66, and 0.57, 95% confidence intervals 0.53–1.00, 0.46–0.95 and 0.39–0.84, respectively). In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.

CHLORAMPHENICOL USE AND CHILDHOOD LEUKAEMIA IN SHANGHAI

A population-based case-control interview study of 309 childhood leukaemia cases and 618 age and sex matched controls showed a significant dose-response relation between chloramphenicol and risk of both acute lymphocytic leukaemia (ALL) and acute non-lymphocytic leukaemia (ANLL), treatment for more than 10 days being associated with risks of 11.0 and 12.0, respectively. A significant risk of ANLL was also observed with the use of syntomycin, a drug pharmacologically related to chloramphenicol. The risks remained high when analyses were limited to either first or latest use of these antibiotics more than 2 years before diagnosis. Although the association may have non-causal explanations, the results warrant cautious prescribing patterns and further investigations into the leukaemogenic potential of chloramphenicol.

Reproductive risk factors for endometrial cancer among Polish women

We conducted a population-based case–control study of reproductive factors in Warsaw and Ló∂ź, Poland, in 551 incident endometrial cancer cases and 1925 controls. The reproductive variable most strongly related to risk was multiparity, with subjects with three or more births having a 70% lower risk than the nulliparous women. The reduced risk was particularly strong below 55 years of age. Subjects with older ages at a first birth were also at reduced risk even after adjustment for number of births. Ages at last birth or intervals since last birth were not strongly related to risk. Spontaneous abortions were unrelated to risk, but induced abortions were associated with slight risk increases (odds ratios=1.28, 95% confidence intervals 0.8–2.1 for 3+ vs no abortions). The absence of effects on risk of later ages at, or short intervals since, a last birth fails to support the view that endometrial cancer is influenced by mechanical clearance of initiated cells. Alternative explanations for reproductive effects should be sought, including alterations in endogenous hormones.

Pernicious anaemia and cancer risk in Denmark

A cohort of 5072 patients with pernicious anaemia was identified in the Danish Hospital Discharge Register from 1977 to 1989 and, through linkage to the Danish Cancer Registry, the occurrence of cancer in the cohort was determined up to 1991. Observed numbers of cancer cases during 1-15 years of follow-up were compared with expected numbers based on national incidence rates. Besides the well-established increased risk for stomach cancer, the analysis also revealed a 2-fold increase in the relative risk for cancer of the buccal cavity and pharynx among pernicious anaemia patients in accordance with previous studies; previously reported elevated risks for other digestive tract cancers were not confirmed. There was a non-significantly increased risk for lymphatic and haematological malignancy but the risk tended to disappear after 5 years of follow-up, indicating a possible selection bias. Decreased risks for cervical cancer and non-melanoma skin cancer were also seen.

Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 19(9); 2143–51. ©2010 AACR.