Salma Butt

Active and passive cigarette smoking and breast cancer risk: results from the EPIC cohort.

Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack‐years and a dose‐response relationship with increasing pack‐years of smoking between menarche and first full‐term pregnancy (FFTP). Studies with comprehensive quantitative life‐time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05–1.28], 1.14 [1.04–1.25] and 1.10 [1.01–1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack‐years from menarche to FFTP (1.73 [1.29–2.32] for every increase of 20 pack‐years) while pack‐years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack‐years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.

Parity and age at first childbirth in relation to the risk of different breast cancer subgroups

The aim of the present study was to examine parity and age at first childbirth, in relation to the risk of specific breast cancer subgroups. A prospective cohort, The Malmö Diet and Cancer Study, including 17,035 women were followed with linkage to Swedish Cancer Registry until December 31, 2004. A total of 622 incident breast cancers were diagnosed during follow‐up and were evaluated regarding invasiveness, tumour size, axillary lymph node status, Nottingham grade, tumour proliferation (Ki67), HER2, cyclin D1 and p27. The tumours were also examined for WHO type and hormone receptor status. Nulliparity was associated with an overall increased risk of breast cancer, although not statistically significant (the relative risk was 1.39 with a 95% confidence interval of 0.92–2.08). Nulliparity was also associated with large tumours (>20 mm) (1.89: 0.91–3.91), high Ki67 levels (1.95: 0.93–4.10), high cyclin D1 levels (2.15: 0.88–5.27), grade III (2.93: 1.29–6.64) and HER2 positive tumours (3.24: 1.02–10.25). High parity was not statistically significantly associated with any specific breast cancer subgroup. Older age at first childbirth (>30) was associated with a slightly increased risk of breast cancer (1.39: 0.94–2.07). There was a statistically significant association between late first childbirth and lobular type (2.51: 1.01–6.28), grade III tumours (2.67: 1.19–6.02), high levels of cyclin D1 (2.69: 1.18–6.12) and low levels of p27 (2.23: 1.15–4.35). We conclude that nulliparity and late first childbirth are associated with relatively more aggressive breast cancer subgroups.

Combined effect of low-penetrant SNPs on breast cancer risk

Background:Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.Methods:Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.Results:Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10−20 and 1.5 × 10−25, respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59–2.14; 10 SNPs) and 2.12 (95% CI: 1.80–2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10−4).Conclusion:The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP.

Altered DNA methylation is often seen in malignant cells, potentially contributing to carcinogenesis by suppressing gene expression. We hypothesized that heritable methylation potential might be a risk factor for breast cancer and evaluated possible association with breast cancer for single nucleotide polymorphisms (SNPs) either involving CpG sequences in extended 5′‐regulatory regions of candidate genes (ESR1, ESR2, PGR, and SHBG) or CpG and missense coding SNPs in genes involved in methylation (MBD1, MECP2, DNMT1, MGMT, MTHFR, MTR, MTRR, MTHFD1, MTHFD2, BHMT, DCTD, and SLC19A1). Genome‐wide searches for genetic risk factors for breast cancers have in general not investigated these SNPs, because of low minor allele frequency or weak haplotype associations. Genotyping was performed using Mass spectrometry‐Maldi‐Tof in a screening panel of 538 cases and 1,067 controls. Potential association to breast cancer was identified for 15 SNPs and one of these SNPs (rs7766585 in ESR1) was found to associate strongly with breast cancer, OR 1.30 (95% CI 1.17–1.45; p‐value 2.1 × 10−6), when tested in a verification panel consisting of 3,211 unique breast cancer cases and 4,223 unique controls from five European biobank cohorts. In conclusion, a candidate gene search strategy focusing on methylation‐related SNPs did identify a SNP that associated with breast cancer at high significance.

Endogenous sex steroids and risk of cervical carcinoma : results from the EPIC study

Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC). Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection–related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E2); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone–binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E2 were calculated from absolute concentrations of T, E2, and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression. Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile = 5.16, 95% CI, 1.50–20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E2, fE2, and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR = 3.14; 95% CI, 1.21–9.37), whereas E2 and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women. Conclusions: Our findings suggest for the first time that T and possibly E2 may be involved in the etiology of ICC. Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring. Cancer Epidemiol Biomarkers Prev; 20(12); 2532–40. ©2011 AACR.

Parity in relation to survival following breast cancer.

AIM The present study examines the association between parity and survival following breast cancer diagnosis. METHODS Medical records of 4453 women diagnosed with breast cancer in Malmö, Sweden, between 1961 and 1991 were analysed. All women were followed until 31 December 2003, using the Swedish Cause-of-Death Registry. Breast cancer specific mortality rate was calculated in different levels of parity. Corresponding relative risks, with 95% confidence intervals (CI), were obtained using Coxs proportional hazards analysis. All analyses were adjusted for potential prognostic factors and stratified for age, menopausal status and diagnostic period. RESULTS As compared to women with one child, nulliparity (RR 1.27: 95% CI 1.09-1.47), and high parity (four or more children) (1.49: 1.20-1.85) were positively associated with a high mortality from breast cancer. When adjusted for potential confounders, the association was only statistically significant for high parity (1.33: 1.07-1.66). In the analyses stratified on age and menopausal status, there was a similar positive association between high parity and breast cancer death in all strata, although only statistically significant among women older than 45 years of age or postmenopausal. Nulliparity was associated with breast cancer death in women that were younger than 45 years of age (1.28: 0.79-2.09) or premenopausal (1.30: 0.95-1.80), but these associations did not reach statistical significance. There was no association between nulliparity and breast cancer death in women older than 45 years of age or postmenopausal. All associations were similar in analyses stratified for diagnostic period. CONCLUSION Women with four or more children have a poor breast cancer survival as compared to women with one child.

Risk of second primary malignancies in women with breast cancer: Results from the European prospective investigation into cancer and nutrition (EPIC).

Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed‐up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen‐Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval—CI 18–42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43–2.00), lymphoma (SIR 1.80, 95% CI 1.31–2.40), melanoma (2.12; 1.63–2.70), endometrium (2.18; 1.75–2.70) and kidney cancers (2.40; 1.57–3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post‐menopausal status and a history of full‐term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full‐term pregnancy was inversely associated with the risk of second primary cancer.

Tumour-related factors and prognosis in breast cancer detected by screening.

Breast cancer detected by screening has an unexplained prognostic advantage beyond stage shift compared with cancers detected clinically. The aim was to investigate biological factors in invasive breast cancer, with reference to mode of detection and rate of death from breast cancer.

Genetic predisposition, parity, age at first childbirth and risk for breast cancer

BackgroundRecent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk.MethodsThe Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI).ResultsSix of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons.ConclusionsThe results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

Parity, breastfeeding and risk of coronary heart disease: A pan-European case-cohort study

Objective There is uncertainty about the direction and magnitude of the associations between parity, breastfeeding and the risk of coronary heart disease (CHD). We examined the separate and combined associations of parity and breastfeeding practices with the incidence of CHD later in life among women in a large, pan-European cohort study. Methods Data were used from European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD, a case–cohort study nested within the EPIC prospective study of 520,000 participants from 10 countries. Information on reproductive history was available for 14,917 women, including 5138 incident cases of CHD. Using Prentice-weighted Cox regression separately for each country followed by a random-effects meta-analysis, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CHD, after adjustment for age, study centre and several socioeconomic and biological risk factors. Results Compared with nulliparous women, the adjusted HR was 1.19 (95% CI: 1.01–1.41) among parous women; HRs were higher among women with more children (e.g., adjusted HR: 1.95 (95% CI: 1.19–3.20) for women with five or more children). Compared with women who did not breastfeed, the adjusted HR was 0.71 (95% CI: 0.52–0.98) among women who breastfed. For childbearing women who never breastfed, the adjusted HR was 1.58 (95% CI: 1.09–2.30) compared with nulliparous women, whereas for childbearing women who breastfed, the adjusted HR was 1.19 (95% CI: 0.99–1.43). Conclusion Having more children was associated with a higher risk of CHD later in life, whereas breastfeeding was associated with a lower CHD risk. Women who both had children and breastfed did have a non-significantly higher risk of CHD.