Use of menopausal hormone therapy and risk of ductal and lobular breast cancer among women 55-74 years of age.

The Women's Health Initiative (WHI) randomized trials found that use of combined estrogen and progestin menopausal hormone therapy (CHT) increases breast cancer risk, but use of unopposed estrogen hormone therapy (EHT) does not. However, several questions regarding the impact of hormone use on risk of different types of breast cancer and what thresholds of use confer elevations in risk remain. We conducted a population-based case-control study among women 55-74 years of age to assess the association between menopausal hormone use and risk of invasive ductal and invasive lobular breast carcinomas. Associations were evaluated using polytomous logistic regression and analyses included 880 ductal cases, 1,027 lobular cases, and 856 controls. Current EHT and CHT use were associated with 1.6-fold [95 % confidence interval (CI): 1.1-2.2] and 2.3-fold (95 % CI: 1.7-3.2) increased risks of lobular breast cancer, respectively, but neither was associated with risk of ductal cancer. Lobular cancer risk was increased after 9 years of EHT use, but after only 3 years of CHT use. Evidence across more than a dozen studies indicates that lobular carcinoma is the type of breast cancer most strongly influenced by menopausal hormones. Here, we characterize what thresholds of duration of use of both EHT and CHT that confer elevations in risk. Despite the rapid decline in hormone therapy use the WHI results were published, study of the hazards associated with these medications remains relevant given the estimated 38 million hormone therapy prescriptions that are still filled in the United States annually.

Nucleotide variation in IL-10 and IL-12 and their receptors and cervical and vulvar cancer risk: a hybrid case-parent triad and case-control study.

Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case-parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3' UTR SNP (OR=1.76, 95% CI=1.15-2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26-0.82; rs2229546, OR=0.43, 95% CI=0.21-0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26-3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12-2.05). Finally, the minor allele of the IL12B rs3181224 3' UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12-0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20-44 years of age.

Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case-control study of women 20-44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers. Detailed reproductive histories were obtained through structured interviewer administered in-person questionnaires. Reproductive histories among control women (n = 941) were compared to those of ER+ cases (n = 781), triple-negative cases (n = 180), and HER2-overexpressing cases (n = 60) using polytomous logistic regression. Age at menarche, parity, and number of full-term pregnancies were similarly associated with risk of all three breast cancer subtypes. In contrast, age at first live birth, the interval between age at menarche and age at first birth, and breastfeeding were inversely associated with risk of triple-negative breast cancer (P values for trend 0.002, 0.006 and 0.018, respectively), but were not associated with risk of ER+ or HER2-overexpressing cancers. A strong inverse association between breastfeeding and risk of triple-negative breast cancer has now been consistently observed across numerous studies, and at present it is the most well-established protective factor for this aggressive and lethal form of breast cancer. Further studies clarifying the biological mechanisms underlying this relationship and confirming our results with respect to age at first birth and the interval between age at menarche and age at first birth are needed.

Use of antihypertensive medications and breast cancer risk.

PURPOSE: Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent. METHODS: We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ≥65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression. RESULTS: Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk. CONCLUSIONS: While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.

Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer.

Breast cancer survivors have a 60 % higher risk of developing a second primary asynchronous contralateral breast cancer (CBC) compared to women's risk of developing a first primary breast cancer (FBC). However, little is known about how expression of tumor markers in first breast cancers influences CBC risk. We conducted a population-based nested case-control study among women 20-74 years of age diagnosed with a first breast cancer between 1996 and 2008 in western Washington State to evaluate the association between their tumor's estrogen receptor (ER), progesterone receptor (PR) and HER2-neu (HER2) expression, and risk of CBC. The study included 482 cases diagnosed with both a FBC and a CBC and 1,506 control women diagnosed only once with breast cancer identified through our local Surveillance, Epidemiology and End Results (SEER) cancer registry. Compared to the women whose FBC was ER+/PR+, those with ER-/PR- first tumors had a 1.6-fold (95 % confidence interval (CI): 1.2-2.3) increased risk of developing a CBC. When evaluated by joint ER/PR/HER2 status, compared to women with ER+/HER2- first cancers, those with HER2-overexpressing (ER-/HER2+) and triple-negative disease (ER-/PR-/HER2-) had 2.0-fold (95 % CI: 1.1-3.8) and 1.4-fold (95 % CI: 0.9-2.3) elevated risks of developing CBC, respectively. Beyond the known higher risks of mortality among patients diagnosed with more aggressive BC subtypes, here, we observe that they may also have increased risks of developing CBC.

Estrogen-related genes and their contribution to racial differences in breast cancer risk.

Racial differences in breast cancer risk, including the risks of hormone receptor subtypes of breast cancer, have been previously reported. We evaluated whether variation in genes related to estrogen metabolism (COMT, CYP1A1, CYP1B1, CYP17A1, CYP19A1, ESR1, GSTM1, GSTP1, GSTT1, HSD17B1, SULT1A1, and UGT1A1) contributes to breast cancer risk and/or racial differences in risk within the CARE study, a multi-centered, population-based case-control study of breast cancer. Genetic variation was assessed as single nucleotide polymorphisms (SNPs), haplotypes, and SNP-hormone therapy (HT) interactions within a subset of 1,644 cases and 1,451 controls, including 949 Black women (493 cases and 456 controls), sampled from the CARE study population. No appreciable associations with breast cancer risk were detected for single SNPs or haplotypes in women overall. We detected SNP-HT interactions in women overall within CYP1B1 (rs1800440; p (het) = 0.003) and within CYP17A1 (rs743572; p (het) = 0.009) in which never users of HT were at a decreased risk of breast cancer, while ever users were at a non-significant increased risk. When investigated among racial groups, we detected evidence of an SNP-HT interaction with CYP1B1 in White women (p value = 0.02) and with CYP17A1 in Black women (p value = 0.04). This analysis suggests that HT use may modify the effect of variation in estrogen-related genes on breast cancer risk, which may affect Black and White women to a different extent.

Relationship between diabetes and risk of second primary contralateral breast cancer.

Breast cancer survivors have a substantially higher risk of developing a second primary contralateral breast cancer (CBC) compared to the risk of breast cancer among women in the general population. While data regarding the relationship between diabetes and breast cancer incidence are inconsistent, diabetes is more clearly linked to an elevated risk of all-cause mortality among breast cancer survivors. However, no prior studies have assessed its impact on CBC risk. We assessed the relationship between diabetes, and CBC risk in a population-based nested case-control study consisting of women 40-79 years of age diagnosed with a first primary ER-positive invasive breast cancer. It included 322 women who developed a second primary CBC and 616-matched control women diagnosed only with a first breast cancer. We used conditional logistic regression to quantify associations between diabetes and CBC risk. Compared to women without a history of diabetes, diabetics had a 2.2-fold [95% confidence interval (CI) 1.3-3.6] increased risk of CBC. This risk was more pronounced among women diagnosed with their first breast cancer before age 60 years (odds ratio, OR = 11.5, 95% CI 2.4-54.5), compared to those diagnosed at age 60 years or older (OR = 1.5, 95% CI 0.8-2.7, P for interaction = 0.011). Diabetics diagnosed with breast cancer appear to have an elevated risk of CBC. This is the first study to report this relationship, but if confirmed efforts to insure that diabetic breast cancer survivors are carefully screened for second breast cancers may be warranted.

Age-related variation in the relationship between menopausal hormone therapy and the risk of dying from breast cancer.

Multiple past studies have reported a reduced risk of breast cancer-related mortality (BCM) in relation to pre-diagnostic use of hormone therapy (HT); however, the extent to which this reduction is due to heightened screening or tumor biology is unknown. Using a population-based cohort of 1,911 post-menopausal women diagnosed with invasive breast cancer at ages 45-79 from 1993 to 1999, we investigated the extent to which the reduced risk in BCM observed in relation to HT might be explained by screening patterns or tumor features. Estrogen-progestin therapy (EPT) use was associated with a decreased risk of BCM (after adjustment for age, study, mammography, stage, and treatment), but only among older women (ever use: ≥ 65 years: HR = 0.45 [95% CI 0.26-0.80]; <65 years: HR = 1.03 [95% CI 0.60-1.79]). Estrogen-alone therapy (ET) use was not associated with risk of BCM (ever use: ≥ 65 years: HR = 0.76 [95% CI 0.51-1.12]; <65 years: HR = 1.20 [95% CI 0.71-2.02]). HT users had a much greater frequency of mammography (P value <0.001). EPT use was associated with tumor characteristics related to improved prognosis in older women after adjustment for screening, including an inverse association with poorly differentiated tumors (OR = 0.57 [95% CI 0.38-0.85]) and an association with lobular tumors (OR = 1.68 [95% CI 1.07-2.65]). Beyond the influence of EPT use on screening uptake, these data indicate that the improved survival associated with pre-diagnostic EPT use may be due in part to the development of more favorable tumor characteristics.

Genetic variation in the progesterone receptor and metabolism pathways and hormone therapy in relation to breast cancer risk.

The relevance of progesterone to breast carcinogenesis is highlighted by evidence indicating that use of combined estrogen-progesterone therapy (EPT) is more strongly related to breast cancer risk than is use of unopposed estrogen therapy. However, few investigators have assessed how genetic variation in progesterone-related genes modifies the effect of EPT on risk. In an analysis combining data from 2 population-based case-control studies of postmenopausal breast cancer (1,296 cases and 1,055 controls) conducted in Washington State in 1997-1999 and 2000-2004, the authors evaluated how 51 single nucleotide polymorphisms in 7 progesterone-related genes (AKR1C1, AKR1C2, AKR1C3, CYP3A4, SRD5A1, SRD5A2, and PGR) influenced breast cancer risk. There was no appreciable association with breast cancer risk overall for any single nucleotide polymorphism. For rs2854482 in AKR1C2, carrying 1 or 2 A alleles was associated with a 2.0-fold increased breast cancer risk in EPT users (95% confidence interval: 1.0, 4.0) but not in never users (P(heterogeneity) = 0.03). For rs12387 in AKR1C3, the presence of 1 or 2 G alleles was associated with a 1.5-fold increased risk among EPT users (95% confidence interval: 1.1, 2.2) but not in never users (P(heterogeneity) = 0.02). Interpretation of these subgroup associations must await the results of similar studies conducted in other populations.

Risk factors for triple-negative breast cancer in women under the age of 45 years.

Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use > or =1 year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (P(heterogeneity) = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (P(heterogeneity) = 0.02 and 0.01, respectively). Among women < or =40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use > or =1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women < or =40 years, nor for triple-negative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology.

Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk.

BACKGROUND: This study investigated whether single nucleotide polymorphisms (SNP) in genes within the catechol estrogen metabolism pathway altered the risk of breast cancer alone or in combination, as well as whether menopausal hormone therapy modified the effect of these SNPs on breast cancer risk. METHODS: In a population-based case-control study of breast cancer, 891 cases and 878 controls were genotyped for six functional SNPs in the COMT, CYP1B1, GSTM1, GSTP1, and GSTT1 genes. RESULTS: Women homozygous with the T allele in CYP1B1*2 (Ser(119); rs1056827) were at 1.69 (95% confidence interval, 1.17-2.46) times the risk of women homozygous with the G allele; women homozygous with the G allele in GSTP1 (Val(105); rs1695) were at 0.73 (95% confidence interval, 0.54-0.99) times the risk of breast cancer compared with women homozygous with the A allele. No other SNPs tested were associated with breast cancer to any appreciable degree. Potential gene-gene and gene-hormone therapy interactions were investigated. CONCLUSION: With the exception of GSTP1 and possibly CYP1B1*2, our findings do not provide support for the role of genetic variation in the catechol estrogen metabolism pathway and breast cancer risk in postmenopausal women.

The association between oral contraceptive use and lobular and ductal breast cancer in young women.

Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers, 1,164 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology.

Timing of menarche and first full-term birth in relation to breast cancer risk.

Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994-1998). For White, parous premenopausal and postmenopausal women, those who had an interval of > or =16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had < or =5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.

Reproductive factors, age at maximum height, and risk of three histologic types of breast cancer.

Numerous studies have evaluated the association between factors related to maturation and reproduction and breast cancer risk, but few have assessed how these factors are related to different histologic types of breast cancer among postmenopausal women. We used polytomous logistic regression to assess the effect of age at maximum height and reproductive factors on risk of invasive breast cancer by histologic type in three case groups (524 ductal, 324 lobular, and 196 ductal-lobular) and 469 controls enrolled in a population-based case-control study of women ages 55 to 74 years residing in the Seattle-Puget Sound region of Washington State (2000-2004). Histologic type was determined by a centralized tissue review for 83% of cases. Age at menarche and age at maximum height were inversely associated with risk of ductal-lobular carcinoma (P(trend) = 0.04 for both exposures) but not ductal or lobular carcinoma. Relative to nulliparous women, parous women had a 50% reduced risk of all histologic types of breast cancer. We observed similar increases in risk across histologic types associated with having a first live birth at ages > or = 30 years compared with ages < or = 19 years. Compared with parous women who never breast-fed, those who breast-fed had a reduced risk of ductal carcinoma (odds ratio, 0.7; 95% confidence interval, 0.5-0.9) but not lobular or ductal-lobular carcinoma. Further exploration of breast cancer risk by histology is merited to understand differences in the etiology of ductal, lobular, and ductal-lobular carcinoma.

Body size and risk of luminal, HER2-overexpressing, and triple-negative breast cancer in postmenopausal women.

Although the clinical relevance of molecular subtypes of breast cancer has been documented, little is known about risk factors for different tumor subtypes, especially the HER2-overexpressing and the triple-negative subtypes that have poor prognoses. Obesity may be differentially related to the risk of different subtypes given the various potential mechanisms underlying its association with breast cancer. We pooled two population-based case-control studies of postmenopausal breast cancer for an analysis, including 1,447 controls and 1,008 luminal (hormone receptor positive), 39 HER2-overexpressing (hormone receptor negative, HER2 positive), and 77 triple-negative (hormone receptor and HER2 negative) cases. Associations between anthropometric factors and the risk of different breast cancer subtypes were evaluated using polytomous logistic regression. Among women not currently using menopausal hormone therapy, body mass index (BMI) and weight were associated with the risk of luminal tumors [odds ratio (OR) comparing highest versus lowest quartiles, 1.7; 95% confidence interval (95% CI), 1.2-2.4 and OR, 1.7; 95% CI, 1.2-2.4, respectively] and suggestively associated with risk of triple-negative tumors (OR, 2.7; 95% CI, 1.0-7.5 and OR, 5.1; 95% CI, 1.1-23.0, respectively). Neither BMI nor weight was associated with the risk of any tumor subtype among hormone therapy users. The positive relationship between BMI and luminal tumors among postmenopausal women not using hormone therapy is well characterized in the literature. Although our sample size was limited, body size may also be related to the risk of postmenopausal triple-negative breast cancer among nonusers of hormone therapy. Given the expanding obesity epidemic, the widespread cessation of hormone therapy use, and the poor prognosis of triple-negative tumors, this novel finding merits confirmation.

Effect of prediagnostic alcohol consumption on survival after breast cancer in young women.

BACKGROUND: Alcohol consumption has been comprehensively investigated as an etiologic risk factor for breast cancer but has received little attention in terms of its effect on prognosis after breast cancer, particularly for young women. METHODS: 1,286 women diagnosed with invasive breast cancer at age < or =45 years from two population-based case-control studies in the Seattle-Puget Sound region were followed from their diagnosis of breast cancer (between January 1983 and December 1992) for survival through June 2002, during which time 364 women had died. Cox proportional hazards modeling was used to assess the effect of prediagnostic alcohol consumption on the risk of dying. RESULTS: After adjusting for age and diagnosis year, compared with nondrinkers, women who consumed alcohol in the 5 years before diagnosis had a decreased risk of death [>0 to <3 drinks per week: hazard ratio, 0.7; 95% confidence interval (95% CI), 0.6-0.95; 3 to <7 drinks per week: risk ratio, 0.6; 95% CI, 0.4-0.8;7 drinks per week: risk ratio, 0.7; 95% CI, 0.5-0.9]. This association was unchanged on additional adjustment for potential confounders including most notably treatment, stage at diagnosis, and mammogram history. CONCLUSION: These results suggest that women who consume alcohol before a diagnosis of breast cancer have improved survival, which does not appear to be attributable to differences in stage, screening, or treatment.

Relationship between histamine2-receptor antagonist medications and risk of invasive breast cancer.

BACKGROUND: Histamine(2)-receptor antagonist (H(2) blocker) medications are used to treat heartburn, gastroesophageal reflux disease, and ulcers. Some H(2) blockers, specifically cimetidine and ranitidine, also increase serum prolactin concentrations. Given the positive relationship between prolactin levels and postmenopausal breast cancer risk, use of H(2) blockers is a potential breast cancer risk factor. The few previous studies evaluating this association have been null but have been limited by small sample sizes, and none have evaluated risk by either histologic type or estrogen receptor/progesterone receptor status. METHODS: Combining data from two population-based case-control studies conducted in western Washington, we assessed the relationship between use of H(2) blockers and risk of different types of breast cancer among 1,941 cases and 1,476 controls 55 to 79 years old. Odds ratios and 95% confidence intervals (95% CI) were calculated using polytomous logistic regression. RESULTS: Current use of H(2) blockers overall, cimetidine, and famotidine was not associated with an increased risk of either invasive ductal or invasive lobular breast cancer. Current users of ranitidine had a 2.2-fold (95% CI, 1.1-4.3) increased risk of ductal carcinoma that was confined to a 2.4-fold (95% CI, 1.2-4.9) increased risk of estrogen receptor-positive/progesterone receptor-positive ductal carcinoma. CONCLUSIONS: Use of H(2) blockers in general is not associated with an increased risk of breast cancer, although current use of ranitidine may increase risk of hormone receptor-positive ductal carcinoma. Further studies to confirm this finding are warranted.

Migraine in postmenopausal women and the risk of invasive breast cancer.

BACKGROUND: The frequency of migraine headache changes at various times of a woman's reproductive cycle. Menarche, menses, pregnancy, and perimenopause may carry a different migraine risk conceivably because of fluctuating estrogen levels, and in general, migraine frequency is associated with falling estrogen levels. Given the strong relationship between endogenous estrogen levels and breast cancer risk, migraine sufferers may experience a reduced risk of breast cancer. METHODS: We combined data from two population-based case-control studies to examine the relationship between migraine and risk of postmenopausal invasive breast cancer among 1,199 ductal carcinoma cases, 739 lobular carcinoma cases, and 1,474 controls 55 to 79 years of age. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Women who reported a clinical diagnosis of migraine had reduced risks of ductal carcinoma (OR, 0.67; 95% CI, 0.54-0.82) and lobular carcinoma (OR, 0.68; 95% CI, 0.52-0.90). These associations were primarily limited to hormone receptor-positive tumors as migraine was associated with a 0.65-fold (95% CI, 0.51-0.83) reduced risk of estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) ductal carcinoma. The reductions in risk observed were seen among migraine sufferers who did and did not use prescription medications for their migraines. CONCLUSIONS: These data suggest that a history of migraine is associated with a decreased risk of breast cancer, particularly among ER+/PR+ ductal and lobular carcinomas. Because this is the first study to address an association between migraine history and breast cancer risk, additional studies are needed to confirm this finding.

Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas.

Combined estrogen and progestin hormone therapy (CHT) increases breast cancer risk, but this risk varies by breast cancer type. Several studies indicate that CHT is more strongly related to lobular carcinoma risk than to ductal carcinoma risk, but these studies have been limited in their assessments of recency and duration of use, and none included a centralized pathology review. We conducted a population-based case-control study consisting of 324 lobular, 196 ductal-lobular, and 524 ductal cases diagnosed from 2000 to 2004 and 469 controls ages 55 to 74 years old. Tissue specimens were centrally reviewed for 83% of cases. Associations between hormone use and breast cancer risk were evaluated using polytomous logistic regression. Current CHT users had 2.7-fold [95% confidence interval (95% CI), 1.7-4.2] and 3.3-fold (95% CI, 2.0-5.7) elevated risks of lobular and ductal-lobular carcinomas, respectively, regardless of tumor stage, size, or nodal status. Elevations in risk were observed only among users of CHT for > or =3 years. Among ductal-lobular cases, CHT increased risk of tumors that were > or =50% lobular (odds ratio, 4.8; 95% CI, 2.1-11.1) but not tumors that were <50% lobular (odds ratio, 1.9; 95% CI, 0.9-4.1). Current CHT users for > or =3 years have a substantially increased risk of lobular carcinomas. Although lobular carcinomas are less common than ductal carcinomas ( approximately 16% versus 70% of all invasive breast cancers in the United States), this duration is shorter than the 5 years of use widely cited to be needed to confer an increased risk of breast cancer overall. Further studies focusing on the etiology of lobular carcinomas are needed.

Cervical and vulvar cancer risk in relation to the joint effects of cigarette smoking and genetic variation in interleukin 2.

Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2.