Recent advances in the epidemiology of inflammatory breast cancer.

The survival after the diagnosis of inflammatory breast cancer (IBC) has been steadily improving for the past few decades. This has been due to advances in the knowledge of IBC in a number of fields, including epidemiology, molecular biology, and medical management. In this review we summarize some of the most important recent advances in these fields and suggest possible opportunities for continued improvement.

Circulating and intraprostatic sex steroid hormonal profiles in relation to male pattern baldness and chest hair density among men diagnosed with localized prostate cancers.

BACKGROUND: Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. METHODS: We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (<7 vs ≥7) and race (European American vs. African American). RESULTS: We found strong positive associations of balding status with serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG), and a weak association with elevated intraprostatic testosterone. Conversely, neither circulating nor intraprostatic sex hormones were statistically significantly associated with chest hair density. Age-adjusted correlation between binary balding status and three-level chest hair density was weak (r = 0.05). There was little evidence to suggest that Gleason score or race modified these associations. CONCLUSIONS: This study provides evidence that balding status assessed at a mean age of 60 years may serve as a clinical marker for circulating sex hormone concentrations. The weak-to-null associations between balding status and intraprostatic sex hormones reaffirm differences in organ-specific sex hormone metabolism, implying that other sex steroid hormone-related factors (eg, androgen receptor) play important roles in organ-specific androgenic actions, and that other overlapping pathways may be involved in associations between the two complex conditions.

Relationships between Circulating and Intraprostatic Sex Steroid Hormone Concentrations.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17ß-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. ©2017 AACR.

Importance of hereditary and selected environmental risk factors in the etiology of inflammatory breast cancer: a case-comparison study.

BACKGROUND: To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer. METHODS: IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case-control studies: breast cancer cases (n = 1145) and unaffected controls (n = 1142) from the Cancer Genetic Markers of Susceptibility (CGEMS) study, breast cancer cases (n = 465) and controls (n = 9317) from the Women's Health Initiative (WHI) study, and ovarian cancer cases (n = 260) and controls (n = 331) from a study by University of Toronto (UT). RESULTS: The frequency of first-degree breast cancer family history among IBC cases was 17.0 % compared to 24.4 % for GWU breast cancer cases, 23.9 % and 17.9 % for CGEMS breast cancer cases and controls, respectively, 16.9 % and 12.6 % for WHI breast cancer cases and controls, respectively, and 24.2 % and 11.2 % for UT ovarian cancer cases and controls, respectively. IBC cases had a significantly lower prevalence of parous women than WHI breast cancer cases (OR = 0.46, 95 % CI:0.27-0.81) and controls (OR = 0.31, 95 % CI:0.20-0.49). Oral contraceptive use was significantly higher among IBC cases compared to WHI breast cancer cases (OR = 7.77, 95 % CI:4.82-12.59) and controls (OR = 8.14, 95 % CI:5.28-12.61). IBC cases had a significantly higher frequency of regular alcohol consumption (≥1 drink per day) compared to WHI controls (OR = 1.84, 95 % CI:1.20-2.82) and UT controls (OR = 1.86, 95 % CI:1.07-3.22) and higher (statistically non-significant) prevalence (21.3 %) compared to breast cancer cases from GWU (18.2 %) and WHI (15.2 %). CONCLUSIONS: The prevalence of first-degree breast cancer family history among IBC cases was lower compared to breast and ovarian cancer cases but higher than unaffected individuals. Our multiple-case inflammatory and non-inflammatory breast cancer families may reflect aggregation of common genetic and/or environmental factors predisposing to both types of breast cancer. Our findings that oral contraceptive use and regular alcohol consumption may be associated with IBC warrant further investigations.

Inflammatory breast cancer clusters: A hypothesis.

Cancer clusters have long been a focus of interest because of the possibility of identifying etiologic agents. Only on rare occasions, however, have such cluster investigations been successful. One major difficulty in cluster investigations, particularly in the area of breast cancer, is the long latent period. There have been a number of publications providing a discouraging picture regarding cancer cluster investigations. The possibility of learning from a cluster investigation, however, is greatly increased if the cancer involved is relatively rare and if it has a short latent period. Inflammatory breast cancer (IBC) fits these criteria and is worth pursuing because of the strong evidence that environmental factors play a major role. In this report we describe our experience with several clusters and the lessons learned which are now being utilized to improve investigation of future IBC clusters. The first IBC cluster that we evaluated was in 2000, when we were asked to investigate an apparent cluster of IBC in Castro Valley, California where three women in an office setting of 24 people were diagnosed with IBC in a ten month period from May 1999 to March 2000. Our investigation of this striking cluster did not yield a specific trigger for this cluster but it did indicate that the women involved all had at least two IBC risk factors that may well have made them susceptible to getting IBC. We are now investigating another apparent cluster in Texas and are aware of several others requiring careful consideration. We see a need for a consistent protocol for the evaluation of IBC clusters focusing on the laboratory investigation of environmental triggers, primarily infectious agents and chemical carcinogens.

A cluster of inflammatory breast cancer (IBC) in an office setting: additional evidence of the importance of environmental factors in IBC etiology.

We investigated a cluster of three cases of inflammatory breast cancer (IBC) diagnosed within 10 months in an office setting of 24 people. Information about medical history, pregnancy history, family history of breast cancer, oral contraceptive use/hormone replacement therapy, exposure to possible oncogenic agents and tumor promoters were obtained to determine whether there were differences in risk factors for IBC between cases and controls. The physical environment and location of the cases' office raised concern about air and water quality as well as radiation as being contributory risk factors for developing IBC. Of the three women with IBC, two had high exposures to pesticides/herbicides, all three used oral contraceptives and two used hormone replacement therapy at the time of diagnosis, two had a family history of breast cancer, and two were obese. Among fifteen controls four had pesticide/herbicide exposure, one had a family history of breast cancer, nine used oral contraceptives, seven used hormone replacement therapy, and five were obese. No specific environmental causes were established for this cluster. Several promoting factors have been suggested that could result in subclinical breast cancer emerging as IBC. Among them are exogenous hormones and exposure to herbicides/pesticides.

What is inflammatory breast cancer? Revisiting the case definition.

The case definition for inflammatory breast cancer (IBC) is controversial. The American Joint Committee on Cancer defines IBC as redness, warmth and edema involving at least half the breast. The SEER program relies on a pathologic finding of dermal lymphatic invasion and recently added those with clinical involvement of more than 3/4 of the breast. We established a registry to collect information and specimens from IBC patients to clarify the epidemiology and biology of these tumors. The goals of this report are to suggest improvements regarding case definitions and provide data on the variety of presentations relevant to early diagnosis.

Early age at first childbirth associated with advanced tumor grade in breast cancer.

BACKGROUND: Many studies have investigated risk factors for developing breast cancer, but few have explored whether these risk factors are associated with the aggressiveness of the tumor. This case-case study examined the relationship between risk factors for breast cancer and the histological grade of the tumor at diagnosis, an important indicator of breast cancer aggressiveness. METHODS: We interviewed 215 breast cancer patients and obtained information on their demographics, reproductive history and hormone use. Grade of tumor was obtained from a review of the patients' pathological reports. The relationships between tumor aggressiveness (classified by tumor grade) and risk factors of interest were analyzed using multi-variable logistic regression. Maximum likelihood estimates of the odds ratio were obtained and 95% confidence intervals (CI) were calculated. RESULTS: In multivariable analyses we found that when comparing women who had their first child before age 20 with those who had their first child age 20 and older, women who had their first child before age 20 had approximately a 3.2 increased odds of having a higher-grade tumor (OR=3.20; 95% CI=1.20, 8.49). Long-term use of oral contraceptives, measured in years of oral contraceptive use, was also positively associated with a higher-grade tumor (OR=1.12; 95% CI=1.03-1.23). In addition we found that younger age at diagnosis was a strong predictor of a higher-grade tumor, with a 4% increased odds of having a higher-grade tumor for each year younger (OR=0.96; 95% CI=0.93-0.995). CONCLUSIONS: Early age at first birth, long-term use of oral contraceptives, and younger age at diagnosis were associated with advanced tumor grade.

The epidemiology of inflammatory breast cancer.

The epidemiology of inflammatory breast cancer (IBC) has been of great interest to a number of investigators, but epidemiological research has been hampered by the lack of an agreed upon case definition and the relatively small number of patients available to any single investigator or institution. Several features of IBC have become apparent through population-based studies, which, although varying somewhat in case definition, generally agree on some key features of the disease. These include the incidence of the disease, apparently less than 3% of breast cancer cases in the United States, the younger age of onset compared to non-inflammatory breast cancer, the much higher incidence in Black women compared to White, the generally poor outcome of this disease compared to non-inflammatory breast cancer, and the continued increase in reported incidence, particularly as compared with non-inflammatory breast cancer in general and locally advanced breast cancer (LABC) in particular. There is an apparent striking geographic pattern, with a higher percentage of cases reported from North Africa, best documented in Tunisia. The risk factors for developing IBC are suggested by smaller studies with concordant conclusions, and some appear to be different than the risk factors for developing breast cancer in general. For example, obesity appears to be a risk factor for premenopausal IBC but is not for premenopausal non-inflammatory breast cancer. In addition, there is evidence that a young age at first birth predisposes to IBC but is protective against developing non-inflammatory breast cancer. In some malignancies, the use of molecular markers is helpful in defining subgroups that could assist in improving case definition as well as predicting prognosis. The increasing combination of improved epidemiologic and laboratory methods will hopefully accelerate our understanding of this challenging disease.