A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Statin use and risks of breast cancer recurrence and mortality.

BACKGROUND: Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. METHODS: In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. RESULTS: Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). CONCLUSIONS: These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.

Agreement of medical record abstraction and self-report of breast cancer treatment with an extended recall window.

BACKGROUND: Medical record abstraction (MRA) and self-report questionnaires are two methods frequently used to ascertain cancer treatment information. Prior studies have shown excellent agreement between MRA and self-report, but it is unknown how a recall window longer than 3 years may affect this agreement. METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based case-control study of controls with unilateral breast cancer individually matched to cases with contralateral breast cancer. Participants who were diagnosed with a first primary breast cancer from 1985 to 2008 before the age of 55 years completed a questionnaire that included questions on treatment. First primary breast cancer treatment information was abstracted from the medical record from radiation oncology clinic notes for radiation treatment and from systemic adjuvant treatment reports for hormone therapy and chemotherapy. Agreement between MRA and self-reported treatment was assessed with the kappa statistic and corresponding 95% confidence intervals (CIs). RESULTS: A total of 2808 participants with MRA and self-reported chemotherapy treatment information, 2733 participants with MRA and self-reported hormone therapy information, and 2905 participants with MRA and self-reported radiation treatment information were identified. The median recall window was 12.5 years (range, 2.8-22.2 years). MRA and self-reported treatment agreement was excellent across treatment modalities (kappachemo, 98.5; 95% CI, 97.9-99.2; kappahorm, 87.7; 95% CI, 85.9-89.5; kapparad, 97.9; 95% CI, 97.0-98.7). There was no heterogeneity across recall windows (pchemo = .46; phorm = .40; prad = .61). CONCLUSIONS: Agreement between self-reported and MRA primary breast cancer treatment modality information was excellent for young women diagnosed with breast cancer and was maintained even among women whose recall window was more than 20 years after diagnosis.

Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds.

Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.

Alcohol consumption, smoking, and invasive breast cancer risk after ductal carcinoma in situ.

PURPOSE: Alcohol is an established risk factor for invasive breast cancer, and women with a prior ductal carcinoma in situ diagnosis are at higher risk of invasive breast cancer than the general population. However, for women with a prior ductal carcinoma in situ diagnosis, few studies have evaluated the association between alcohol and smoking and risk of subsequent invasive breast cancer. METHODS: Utilizing a population-based case-control design nested among women diagnosed with a ductal carcinoma in situ between 1995 and 2013, we compared 243 cases diagnosed with a subsequent invasive breast cancer and 423 individually matched controls never diagnosed with a subsequent breast cancer. RESULTS: Compared with never to occasional drinkers, drinkers consuming at least 7 alcoholic drinks per week on average at ductal carcinoma in situ diagnosis had a higher risk of invasive breast cancer that was borderline significant (OR 1.79, 95% CI 1.01-3.17, P value = 0.04). Smoking was not significantly associated with risk of developing an invasive breast cancer after adjustment for alcohol consumption. CONCLUSIONS: These findings suggest that consuming at least one alcoholic drink per day on average is positively associated with invasive breast cancer for women with a prior ductal carcinoma in situ diagnosis. If confirmed, modulating alcohol consumption could be one strategy for women with a history of ductal carcinoma in situ to impact their risk of invasive breast cancer.

Association between antidepressant use and second breast cancer event after ductal carcinoma in situ diagnosis: a nested case-control study.

PURPOSE: Controversy exists regarding the potential relationship between antidepressant use and risk of breast cancer. No previous studies have evaluated the relationship between antidepressant use after diagnosis of ductal carcinoma in situ (DCIS) and risk of a subsequent breast cancer restricted to women with a history of DCIS. METHODS: We conducted a population-based, nested case-control study in western Washington State. Cases included 337 women diagnosed with DCIS and a subsequent breast cancer and they were compared to 592 individually matched controls (on age, year of DCIS diagnosis, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but not a subsequent breast cancer. Information on antidepressant use after DCIS diagnosis was obtained from comprehensive medical records reviews. Antidepressant use was defined as greater or equal to 3 months of duration. RESULTS: Antidepressant use after initial DCIS was associated with a 1.4-fold increased risk of a subsequent breast cancer event (adjusted OR 1.41, 95% CI 1.02, 1.95). Similar risks were observed when assessing individual antidepressant classes, however, there was no sufficient power across specific classes of antidepressants. CONCLUSIONS: Antidepressant use after DCIS diagnosis was associated with an increased risk of subsequent breast cancer in women. Further studies are needed to confirm the associations observed.

Race, ethnicity and risk of second primary contralateral breast cancer in the United States.

Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in racial/ethnic minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive Stage I-IIB breast cancer diagnosis at ages 20-74 years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause-specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow-up of 5.9 years, 9247 women (2.0%) were diagnosed with CBC. Relative to non-Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio = 1.44, 95% CI 1.35-1.54) and Hispanic women (1.11, 95% CI 1.02-1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status and health insurance did not explain the associations. Therefore, non-Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity.

Racial/ethnic disparities in risk of breast cancer mortality by molecular subtype and stage at diagnosis.

PURPOSE: Previous research has found significant survival disparities between Black and White women among select stages and subtypes of breast cancer, however other racial/ethnic groups have been less well-studied. This study expands on previous research, examining differences in breast cancer-specific mortality across multiple racial and ethnic groups. METHODS: Women diagnosed with a first primary invasive breast cancer between 2010 and 2016 who were 20-85 years of age at diagnosis were identified from 18 Surveillance, Epidemiology, and End Results (SEER) registries. Subtypes were defined by joint hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Cox proportional hazards models for each stage and subtype were fit, with non-Hispanic white women as the reference group. Effect modification by age at diagnosis (< 50, ≥ 50) was found and thus analyses were age-stratified. RESULTS: After multivariable adjustment, younger Black women had greater risks of breast cancer-specific death for all stages of HR+/HER2-, and certain stages of HR+/HER2+ , TN, and HR-/HER2 + breast cancer. Asian/Pacific Islander women generally had a lower hazard of breast cancer-specific death. Older Hispanic White women had a lower hazard of breast cancer-specific death for stages I-III HR + /HER2- and stage II TN breast cancer. CONCLUSIONS: These findings demonstrate that different racial/ethnic groups experience different risks of breast cancer-specific mortality by stage and subtype. Efforts to address survival disparities should place additional focus on young Black women, as they experience meaningful disparities in breast cancer-specific mortality.

Receipt of Screening Mammography by Insured Women Diagnosed With Breast Cancer and Impact on Outcomes.

BACKGROUND: The purpose of this study was to determine factors associated with receipt of screening mammography by insured women before breast cancer diagnosis, and subsequent outcomes. PATIENTS AND METHODS: Using claims data from commercial and federal payers linked to a regional SEER registry, we identified women diagnosed with breast cancer from 2007 to 2017 and determined receipt of screening mammography within 1 year before diagnosis. We obtained patient and tumor characteristics from the SEER registry and assigned each woman a socioeconomic deprivation score based on residential address. Multivariable logistic regression models were used to evaluate associations of patient and tumor characteristics with late-stage disease and nonreceipt of mammography. We used multivariable Cox proportional hazards models to identify predictors of subsequent mortality. RESULTS: Among 7,047 women, 69% (n=4,853) received screening mammography before breast cancer diagnosis. Compared with women who received mammography, those with no mammography had a higher proportion of late-stage disease (34% vs 10%) and higher 5-year mortality (18% vs 6%). In multivariable modeling, late-stage disease was most associated with nonreceipt of mammography (odds ratio [OR], 4.35; 95% CI, 3.80-4.98). The Cox model indicated that nonreceipt of mammography predicted increased risk of mortality (hazard ratio [HR], 2.00; 95% CI, 1.64-2.43), independent of late-stage disease at diagnosis (HR, 5.00; 95% CI, 4.10-6.10), Charlson comorbidity index score ≥1 (HR, 2.75; 95% CI, 2.26-3.34), and negative estrogen receptor/progesterone receptor status (HR, 2.09; 95% CI, 1.67-2.61). Nonreceipt of mammography was associated with younger age (40-49 vs 50-59 years; OR, 1.69; 95% CI, 1.45-1.96) and increased socioeconomic deprivation (OR, 1.05 per decile increase; 95% CI, 1.03-1.07). CONCLUSIONS: In a cohort of insured women diagnosed with breast cancer, nonreceipt of screening mammography was significantly associated with late-stage disease and mortality, suggesting that interventions to further increase uptake of screening mammography may improve breast cancer outcomes.

Reproductive and menopausal factors and risk of second primary breast cancer after in situ breast carcinoma.

PURPOSE: In situ breast cancer patients have a higher risk of developing a second primary breast cancer than women in the general population have of developing breast cancer. We have limited understanding of why some women with a previous in situ breast cancer develop second primary breast cancers while others do not. METHODS: In this population-based nested case-control study, we evaluated the association between reproductive and menopausal factors and risk of developing a second primary breast cancer among women with a previous in situ breast cancer. Using conditional logistic regression, these associations were evaluated in 552 cases and 1032 individually matched controls. RESULTS: Older age at menarche was associated with risk of second primary breast cancer among women with a previous in situ breast cancer (compared to age < 12, age 13: OR 0.60 (0.42, 0.85); age ≥ 14: OR 0.69 (0.47, 1.00); Ptrend = 0.07). Breastfeeding for > 12 months was associated with a decreased risk of developing a second primary breast cancer (OR 0.62 (0.39, 0.98)). No associations were observed for other reproductive or menopausal factors evaluated. CONCLUSIONS: Results from this study suggest that reproductive factors may play a role in development of a second primary breast cancer after diagnosis of in situ breast carcinoma.

CYP2D6-inhibiting medication use and inherited CYP2D6 variation in relation to adverse breast cancer outcomes after tamoxifen therapy.

PURPOSE: Tamoxifen is widely used to reduce the risk of breast cancer (BC) recurrence and extend disease-free survival among women with estrogen-sensitive breast cancers. Tamoxifen efficacy is thought to be attributable to its active metabolite, which is formed through a reaction catalyzed by the P450 enzyme, CYP2D6. Inhibition of tamoxifen metabolism as a result of germline genetic variation and/or use of CYP2D6-inhibiting medications ("inhibitors") is hypothesized to increase the risk of adverse BC outcomes among women taking tamoxifen. METHODS: The present cohort study of 960 women diagnosed with early-stage BC between 1993 and 1999 examined the association between concomitant use of CYP2D6 inhibitors and adjuvant tamoxifen and the risk of adverse BC outcomes (recurrence, second primary BC, BC mortality), both overall and according to CYP2D6 metabolic phenotype. RESULTS: Six or more months of CYP2D6 inhibitor use concomitant with tamoxifen was not associated with any appreciable increase in risk of recurrence or second primary BC or BC mortality, and there was no clear evidence of variation by CYP2D6 metabolic phenotype. CONCLUSIONS: These results are consistent with the relatively few other large, population-based studies conducted to date that have not observed an increased risk of adverse BC outcomes associated with CYP2D6 inhibition.

Pre-diagnosis alcohol consumption and mortality risk among black women and white women with invasive breast cancer.

BACKGROUND: Alcohol consumption is associated with increased risk of breast cancer; however, its association with subsequent risk of breast cancer death is unclear. METHODS: We followed 4523 women with complete information on relevant risk factors for mortality; these women were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. During follow up (median, 8.6 years), 1055 women died; 824 died from breast cancer. The information on alcohol consumption before diagnosis was collected shortly after breast cancer diagnosis (average: 5.1 months) during an in-person interview which used a structured questionnaire. Multivariable Cox proportional hazards regression models provided hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific mortality, mortality due to causes other than breast cancer, and all-cause mortality associated with alcohol consumption from age 15 years until breast cancer diagnosis and during recent periods of time prior to breast cancer diagnosis. RESULTS: Average weekly alcohol consumption from age 15 years until breast cancer diagnosis was inversely associated with breast cancer-specific mortality (Ptrend = 0.01). Compared to non-drinkers, women in the highest average weekly alcohol consumption category (≥7 drinks/week) had 25% lower risk of breast cancer-specific mortality (HR = 0.75, 95% CI = 0.56-1.00). Breast cancer mortality risk was also reduced among women in the highest average weekly alcohol consumption category in two recent time periods (5-year period ending 2-years prior to breast cancer diagnosis, HR = 0.74, 95% CI = 0.57-0.95; 2-year period immediately prior to breast cancer diagnosis: HR = 0.73, 95% CI = 0.56-0.95). Furthermore, analyses of average weekly alcohol consumption by beverage type from age 15 years until breast cancer diagnosis suggested that wine consumption was inversely associated with breast cancer-specific mortality risk (wine Ptrend = 0.06, beer Ptrend = 0.24, liquor Ptrend = 0.74). No association with any of these alcohol consumption variables was observed for mortality risk due to causes other than breast cancer. CONCLUSIONS: Overall, we found no evidence that alcohol consumption before breast cancer diagnosis increases subsequent risk of death from breast cancer.

CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study.

BACKGROUND: Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these. METHODS: We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ≥ 6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points. RESULTS: For %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to < 50% density (OR 0.69, 95% CI 0.49, 0.98). Similar, but weaker, associations were noted for %MD measurements prior to/at diagnosis. The relationship appeared strongest in women aged < 45 years and non-existent in women aged 50 to 54 years. A decrease of ≥ 10% in %MD between first and second mammogram was associated marginally with reduced risk of CBC (OR 0.63, 95% CI 0.40, 1.01) compared to change of <10%. Both tamoxifen and chemotherapy were associated with statistically significant 3% decreases in %MD (p < 0.01). CONCLUSIONS: Post-diagnosis measures of %MD may be useful to include in CBC risk prediction models with consideration of age at diagnosis. Chemotherapy is associated with reductions in %MD, similar to tamoxifen.

Body mass index at age 18 years and recent body mass index in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes in white women and African-American women: a pooled analysis.

BACKGROUND: Although it has been well-documented that obesity is associated with decreased risk of premenopausal breast cancer and increased risk of postmenopausal breast cancer, it is unclear whether these associations differ among breast cancer subtypes defined by the tumor protein expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). METHODS: We evaluated the associations of body mass index (BMI) at age 18 years and recent BMI in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes, in 6320 women (3934 case-patient participants, 2386 control participants) aged 35-64 years, who participated in one of three population-based case-control studies. We estimated multivariable-adjusted odd ratios (ORs) and corresponding 95% confidence intervals (CIs) using polychotomous unconditional logistic regression methods for case-control comparisons in premenopausal women and postmenopausal women. RESULTS: BMI at age 18 years was inversely associated with risk of breast cancer, particularly among premenopausal women (≥ 25 vs. < 20 kg/m2, OR = 0.72, 95% CI = 0.53-0.96; per 5 kg/m2 increase, OR = 0.83, 95% CI = 0.73-0.95). This inverse association did not differ across ER/PR/HER2-defined subtypes or by race (white women, African-American women). Recent BMI was not associated with risk of premenopausal breast cancer after adjustment for BMI at age 18 years; nevertheless, the analysis for the joint effects of BMI at age 18 years and recent BMI showed that premenopausal women in the highest categories of the two BMI measures (≥ 25 kg/m2 at age 18 years and ≥ 30 kg/m2 for recent BMI) had 46% lower risk of breast cancer than premenopausal women in the lowest categories of the two BMI measures (< 20 kg/m2 at age 18 years and < 25 kg/m2 for recent BMI; OR = 0.54, 95% CI = 0.38-0.78). Neither measure of BMI was statistically significantly associated with risk of postmenopausal breast cancer. CONCLUSION: Our findings indicate that high BMI near the end of adolescence decreases risk of all ER/PR/HER2-defined subtypes of premenopausal breast cancer and also suggest that this benefit could be maximized among premenopausal women who consistently have high BMI during their premenopausal years.

Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population.

BACKGROUND: Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. METHODS: The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. RESULTS: Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. CONCLUSIONS: Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.

Reproductive factors and the risk of triple-negative breast cancer in white women and African-American women: a pooled analysis.

BACKGROUND: Early age at menarche, nulliparity, late age at first completed pregnancy, and never having breastfed, are established breast cancer risk factors. However, among breast cancer subtypes, it remains unclear whether all of these are risk factors for triple-negative breast cancer (TNBC). METHODS: We evaluated the associations of these reproductive factors with TNBC, in 2658 patients with breast cancer (including 554 with TNBC) and 2448 controls aged 20-64 years, who participated in one of the three population-based case-control studies: the Women's Contraceptive and Reproductive Experiences Study, the Women's Breast Carcinoma in situ Study, or the Women's Learning the Influence of Family and Environment Study. We used multivariable polychotomous unconditional logistic regression methods to conduct case-control comparisons among breast cancer subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression status. RESULTS: TNBC risk decreased with increasing duration of breastfeeding (P trend = 0.006), but age at menarche, age at first completed pregnancy, and nulliparity were not associated with risk of TNBC. Parous women who breastfed for at least one year had a 31% lower risk of TNBC than parous women who had never breastfed (odds ratio, OR = 0.69; 95% confidence interval, CI = 0.50-0.96). The association between breastfeeding and risk of TNBC was modified by age and race. Parous African-American women aged 20-44 years who breastfed for 6 months or longer had an 82% lower risk of TNBC than their counterparts who had never breastfed (OR = 0.18, 95% CI = 0.07-0.46). CONCLUSIONS: Our data indicate that breastfeeding decreases the risk of TNBC, especially for younger African-American women.

Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study.

Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases (N = 1,521) had asynchronous CBC and controls (N = 2,212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR = 1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR = 1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ≥10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR = 1.50, 95% CI 1.08-2.08; p-trend = 0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC.

Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.

Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study.

BACKGROUND: Treatment with tamoxifen or chemotherapy reduces the risk of contralateral breast cancer (CBC). However, it is uncertain how long the protection lasts and whether the protective effect is modified by patient, tumor, or treatment characteristics. METHODS: The population-based WECARE Study included 1521 cases with CBC and 2212 age- and year of first diagnosis-matched controls with unilateral breast cancer recruited during two phases in the USA, Canada, and Denmark. Women were diagnosed with a first breast cancer before age 55 years during 1985-2008. Abstraction of medical records provided detailed treatment information, while information on risk factors was obtained during telephone interviews. Risk ratios (RRs) and 95 % confidence intervals (CIs) for CBC were obtained from multivariable conditional logistic regression models. RESULTS: Compared with never users of tamoxifen, the RR of CBC was lower for current users of tamoxifen (RR = 0.73; 95 % CI = 0.55-0.97) and for past users within 3 years of last use (RR = 0.73; 95 % CI = 0.53-1.00). There was no evidence of an increased risk of estrogen receptor-negative CBC associated with ever use of tamoxifen or use for 4.5 or more years. Use of chemotherapy (ever versus never use) was associated with a significantly reduced RR of developing CBC 1-4 years (RR = 0.59; 95 % CI = 0.45-0.77) and 5-9 years (RR = 0.73; 95 % CI = 0.56-0.95) after first breast cancer diagnosis. RRs of CBC associated with tamoxifen or with chemotherapy use were independent of age, family history of breast cancer, body mass index and tumor characteristics of the first breast cancer with the exception that the RR of CBC was lower for lobular histology compared with other histologies. CONCLUSION: Our findings are consistent with previous studies showing that treatment with tamoxifen or chemotherapy is associated with a lower risk of CBC although the risk reduction appears to last for a limited time period after treatment is completed.