Bingshu E. Chen

Breast Cancer Mortality Trends in the United States According to Estrogen Receptor Status and Age at Diagnosis

PURPOSEnSince 1990, overall breast cancer mortality rates in the United States decreased 24%. This decline has been attributed to mammography screening and adjuvant systemic therapy. However, the efficacy of these modalities may depend on estrogen receptor (ER) expression and age. We therefore examined breast cancer mortality trends in the United States according to ER status and age.nnnMETHODSnUsing the Surveillance, Epidemiology, and End Results (SEER) program (1990-2003), we calculated trends in incidence-based mortality (IBM), annual hazard rates for breast cancer deaths after diagnosis, and relative hazard rates for women with ER-positive and ER-negative tumors. Relative hazard rates were assessed with Cox proportional hazards models, adjusted for stage and grade, and stratified by age at diagnosis.nnnRESULTSnDuring the study period, IBM and annual hazard rates for breast cancer deaths decreased among women with ER-positive and ER-negative tumors, although declines were greater for those with ER-positive tumors. Among women younger than 70 years, relative hazard rates declined 38% for those with ER-positive tumors versus 19% for those with ER-negative tumors. Among women 70 years or older, relative hazard rates declined 14% for those with ER-positive tumors versus no significant decline for those with ER-negative tumors.nnnCONCLUSIONnIn the United States, breast cancer mortality rates have declined among women with ER-positive and ER-negative tumors, with greater declines among younger women and those with ER-positive tumors. Although mortality in all groups remains unacceptably high, additional emphasis should be placed on improving outcomes of breast cancer patients older than 70 years and those of all ages with ER-negative tumors.

Epidemiology of inflammatory breast cancer (IBC).

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with unknown etiology and generally poor outcome. It is characterized by diffuse edema (peau dorange) and redness (erythema), although either the disease itself or case definitions have varied over time and place, confounding temporal trends and geographic variations. In this review, we discuss case definitions for IBC and its clinical characteristics; describe its geographic variation, age and racial distribution, incidence and survival patterns, and summarize the very limited information on its epidemiologic risk factors. We also incorporate emerging data from the National Cancer Institutes (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.

Prophylactic Oophorectomy Reduces Breast Cancer Penetrance During Prospective, Long-Term Follow-Up of BRCA1 Mutation Carriers

PURPOSEnBreast cancer penetrance estimates in BRCA1 mutation carriers have varied from 40% to 85%; this heterogeneity has been attributed to variations in risk among different study populations. No study has taken oophorectomy status into account in estimating penetrance. Because prophylactic oophorectomy reduces breast cancer risk by approximately 50%, we hypothesized that population differences in oophorectomy prevalence might significantly influence breast cancer penetrance estimates.nnnMETHODSnFemales from multiple-case breast/ovarian cancer families that segregate deleterious BRCA1 mutations were observed prospectively for breast cancer incidence and oophorectomy.nnnRESULTSnWithin this cohort, 33 cases of breast cancer developed in 98 women with deleterious BRCA1 mutations during follow-up, yielding an estimated cumulative lifetime breast cancer risk of 80%. This estimate increased to 94% when the study participants were censored at the time of oophorectomy. Six of the 33 mutation-positive women who underwent oophorectomy during follow-up developed breast cancer, compared with 27 of 65 mutation carriers with intact ovaries (hazard ratio = 0.38; 95% CI, 0.15 to 0.97). Estimates of absolute breast cancer risk demonstrated that the protective effect of oophorectomy was strongest among women who were premenopausal at the time of surgery. When surgical status was ignored, the strong protective effect of oophorectomy, coupled with the high prevalence of the procedure in these families, led to a significantly lower estimate of the breast cancer penetrance in BRCA1 mutation carriers.nnnCONCLUSIONnDiffering rates of oophorectomy likely represent an underappreciated basis for a portion of the heterogeneity in estimated breast cancer penetrance described in BRCA mutation carriers, particularly mutation carriers from extensively affected, multiple-case families.

Effects of Estrogen Receptor Expression and Histopathology on Annual Hazard Rates of Death from Breast Cancer

BackgroundBreast cancer incidence rates vary according to estrogen receptor expression (ER) and histopathology. We hypothesized that annual mortality rates from breast cancer after initial diagnosis (hazard rates) might also vary by ER and histopathology.MethodsWe accessioned the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER, 1992–2002) program to estimate hazard rates according to ER (positive and negative) and histopathology (duct, tubular, lobular, medullary, inflammatory, papillary, and mucinous types). We used spline functions to model hazard rates free of strongly parametric assumptions for ER negative and positive cases overall and by histopathology.ResultsHazard rates for ER negative and ER positive cases were distinct and non-proportional. At 17xa0months, ER negative hazard rates peaked at 7.5% per year (95% CI, 7.3–7.8% per year) then declined, whereas ER positive hazard rates lacked a sharp early peak and were comparatively constant at 1.5–2% per year. Falling ER negative and constant ER positive hazard rates crossed at 7xa0years; after which, prognosis was better for ER negative cases. Among ER positive and negative cases, there were proportional and non-proportional hazards according to histopathologic type, but the two basic ER-associated patterns were maintained.ConclusionsHazard rates differed quantitatively and qualitatively according to ER and histopathology. These large-scale population-based results seem consistent with genomic studies, demonstrating two main classes of breast cancers with distinct prognoses according to ER expression.

Variants in Inflammation Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China

To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.

Estimating age-specific breast cancer risks: A descriptive tool to identify age interactions

ObjectiveClarifying age-specific female breast cancer risks and interactions may provide important etiologic clues.MethodUsing a population-based case–control study in Poland (2000–2003) of 2,386 incident breast cancer cases and 2,502 control subjects aged 25–74 years, we estimated age-specific breast cancer incidence rates according to risk factors.ResultsBreast cancer risks were elevated among women with positive family history (FH), younger age at menarche, older age at first full-term birth, nulliparity, exogenous hormonal usage, and reduced physical activity (PA). Notwithstanding overall risks, we observed statistically significant quantitative (non-crossover) and qualitative (crossover) age interactions for all risk factors except for FH and PA. For example, nulliparity compared to parity reduced breast cancer risk among women ages 25–39 years then rates crossed or reversed, after which nulliparity increased relative risks among women ages 40–74 years.ConclusionThough quantitative age interactions could be expected, qualitative interactions were somewhat counterintuitive. If confirmed in other populations, qualitative interactions for a continuous covariate such as age will be difficult to reconcile in a sequential (multistep or monolithic) ‘stochastic’ breast cancer model. Alternatively, the reversal of relative risks among younger and older women suggests subgroup heterogeneity with different etiologic mechanisms for early-onset and late-onset breast cancer types.

Polymorphisms of Genes in the Lipid Metabolism Pathway and Risk of Biliary Tract Cancers and Stones: A Population-Based Case-Control Study in Shanghai, China

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by TaqMan assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones [95% confidence interval (95% CI), 1.2-2.4], a 1.8-fold risk of gallbladder cancer (95% CI, 1.0-3.3), a 3.7-fold risk of bile duct cancer (95% CI, 2.0-7.0), and a 4-fold risk of ampullary cancer (95% CI, 1.4-12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI, 1.2-3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI, 1.1-2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had a 1.5-fold risk of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct. (Cancer Epidemiol Biomarkers Prev 2008;17(3):525–34)

Polymorphism of genes related to insulin sensitivity and the risk of biliary tract cancer and biliary stone: a population-based case-control study in Shanghai, China

Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-γ, PPAR-δ, RXR-α, RXR-β and INS genes with biliary cancer and stones in a population-based case–control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-β C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR)u2009=u20091.67; 95% confidence interval (CI)u2009=u20090.99–2.84], with a more pronounced association among men (ORu2009=u20092.30; 95% CIu2009=u20091.14–4.65; P interactionu2009=u20090.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (≥23 kg/m2) (ORu2009=u20091.80; 95% CIu2009=u20091.09–2.94), although the interaction with BMI was not statistically significant (P interactionu2009=u20090.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones.

Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China

Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3-3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8-6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism.