The breast stromal microenvironment is a pivotal factor in breast cancer development, growth and metastases. Although pathologists often detect morphologic changes in stroma by light microscopy, ...visual classification of such changes is subjective and non-quantitative, limiting its diagnostic utility. To gain insights into stromal changes associated with breast cancer, we applied automated machine learning techniques to digital images of 2387 hematoxylin and eosin stained tissue sections of benign and malignant image-guided breast biopsies performed to investigate mammographic abnormalities among 882 patients, ages 40–65 years, that were enrolled in the Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project. Using deep convolutional neural networks, we trained an algorithm to discriminate between stroma surrounding invasive cancer and stroma from benign biopsies. In test sets (928 whole-slide images from 330 patients), this algorithm could distinguish biopsies diagnosed as invasive cancer from benign biopsies solely based on the stromal characteristics (area under the receiver operator characteristics curve = 0.962). Furthermore, without being trained specifically using ductal carcinoma in situ as an outcome, the algorithm detected tumor-associated stroma in greater amounts and at larger distances from grade 3 versus grade 1 ductal carcinoma in situ. Collectively, these results suggest that algorithms based on deep convolutional neural networks that evaluate only stroma may prove useful to classify breast biopsies and aid in understanding and evaluating the biology of breast lesions.
Aim: To evaluate male breast cancer (MBC) risk among patients with Klinefelter syndrome (KS) and relate this to possible biological explanations.
Methods: A literature review was conducted to ...identify case series and epidemiologic studies that have evaluated MBC risk among patients with KS.
Results: Case reports without expected values have often led to false impressions of risk. Problems include that a diagnosis of cancer can prompt a karyotypic evaluation and that many cases of KS are unrecognized, resulting in incomplete denominators. Few carefully conducted epidemiologic studies have been undertaken given that both KS and MBC are rare events. The largest study found 19.2‐ and 57.8‐fold increases in incidence and mortality, respectively, with particularly high risks among 47,XXY mosaics. These risks were still approximately 70% lower than among females, contradicting case reports that patients with KS have breast cancer rates similar to females. Altered hormone levels (especially the ratio of oestrogens to androgens), administration of exogenous androgens, gynaecomastia and genetic factors have been offered as possible explanations for the high risks.
Conclusions: Additional well‐designed epidemiologic studies are needed to clarify which patients with KS are at a high risk of developing MBC and to distinguish between possible predisposing factors, including altered endogenous hormones.
Menopausal hormone therapy and risk of endometrial cancer Brinton, Louise A.; Felix, Ashley S.
Journal of steroid biochemistry and molecular biology/The Journal of steroid biochemistry and molecular biology,
07/2014, Volume:
142
Journal Article
Peer reviewed
Open access
•Endometrial cancer risk is substantially increased among users of unopposed estrogens, with further enhancements among thin women.•The addition of progestins for >25 days/month reduces risk, to ...levels even somewhat lower than that of non-hormone users.•Users of progestins for <10 days/month remain at an elevated risk.
Endometrial cancer is clearly a hormonally responsive tumor, with a critical role played by estrogens unopposed by progestins. Numerous epidemiologic studies have shown substantial risk increases associated with use of unopposed estrogens, especially among thin women. This risk, however, can be reduced if progestins are added to the therapy. The manner in which progestins are prescribed is a critical determinant of risk. Most studies show that women who have ever used progestins continuously (>25 days/months) are at somewhat reduced risk relative to non-users (meta-analysis relative risk, RR, based on observational studies=0.78, 95 confidence intervals, CI, 0.72–0.86). The reduced risk in greatest among heavy women. In contrast, women who have ever used progestins sequentially for <10 days each month are at increased risk, with meta-analysis results showing on overall RR of 1.76 (1.51–2.05); in contrast, progestins given for 10–24 days/month appear unrelated to risk (RR=1.07, 0.92–1.24). These risks were based on varying patterns of usage, with little information available regarding how endometrial cancer risk is affected by duration of use, type and/or dose of estrogen or progestin, or mode of administration. Effects may also vary by clinical characteristics (e.g., differences for Type I vs. II tumors). Further resolution of many of these relationships may be dependent on pooling data from multiple studies to derive sufficient power for subgroups of users. With changing clinical practices, it will be important for future studies to monitor a wide range of exposures and to account for divergent effects of different usage patterns.
This article is part of a Special Issue entitled ‘Menopause’.
Global international trends in female breast cancer incidence have been described previously but no comparable analysis of male breast cancer incidence rates has been conducted. We obtained male and ...female case and population data using Cancer Incidence in Five Continents (CI5). We calculated age‐adjusted, sex‐specific incidence rates and female‐to‐male incidence rate ratios (FMIRRs) and compared trends of such for the period 1988–2002. This analysis included 8,681 male breast cancer cases and 1.14 million female breast cancer cases. The highest male incidence rate was observed in Israel at 1.24 per 100,000 man‐years, and the highest female incidence rate was observed in the United States at 90.7 per 100,000 woman‐years. The lowest incidence rates for males (0.16) and females (18.0) were observed in Thailand. In general, male breast cancer incidence trends were variable; a minority of countries displayed evidence for an increase. In contrast, female incidence rates have been increasing in a majority of countries. The Pearson correlation coefficient (r) for male and female breast cancer incidence rates by country during 1988–2002 was 0.69. Male breast cancer rates were generally less than 1 per 100,000 man‐years, in contrast to the much higher rates of female breast cancer, providing for an overall FMIRR of 122. The differences in both incidence rates and time trends between males and females may reflect sex differences in underlying risk factors, pathogenesis, and/or overdiagnosis. Conversely, the high correlation between male and female breast cancer incidences may indicate that both sexes share some common risk factors for breast cancer.
What's new?
Are the causes of breast cancer in men similar to those in women? Is male breast cancer a different disease entity, or is it the same in men and women? In this study, the authors have compiled the first epidemiologic analysis comparing international trends for male and female breast‐cancer incidence. They conclude that, while incidence patterns are similar, there may also be sex‐specific processes that play a role in the pathogenesis of this disease.
Summary Background Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological ...subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. Methods 12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. Findings 2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21–0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55–0·91; p=0·0080), but weak PR expression was not (1·02, 0·89–1·18; p=0·74). Interpretation PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. Funding Carraresi Foundation and others.
Increases in the incidence of postmenopausal breast cancers have been linked to screening and menopausal hormone use, but younger women have received less attention. Thus, we analyzed trends in ...breast cancer incidence (N = 387 231) using the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program 13-Registry database (1992–2004). Whites had higher incidence rates than blacks after age 40 years, but the reverse was true among younger women (black–white crossover). Among younger women, the rate per 100 000 woman-years was 16.8 for black vs 15.1 for white women; the highest black–white incidence rate ratio (IRR) was seen among women younger than 30 years (IRR = 1.52, 95% confidence interval = 1.34 to 1.73). This risk pattern was not observed in other ethnic groups. The black–white crossover among younger women was largely restricted to breast cancers with favorable tumor characteristics. The annual percentage change in the incidence of invasive breast cancers decreased modestly among older women but increased among younger (<40 years) white women. Continued surveillance of trends is needed, particularly for molecular subtypes that preferentially occur among young women.
The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with ...immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS.
ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women.
Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years.
Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.
Metabolic syndrome and its component feature, central obesity, are associated with endometrial cancer risk. It remains unclear whether associations with the other metabolic factors that comprise ...metabolic syndrome are independent of the obesity-endometrial cancer association. Furthermore, the link with specific endometrial cancer subtypes remains ill-defined, despite evidence of etiologic heterogeneity among these tumors.
In a case-control study within the SEER-Medicare linked database, we examined whether metabolic factors, individually or combined, were associated with endometrial cancer. Cases (n = 16,323) were women diagnosed with endometrial cancer from 1993 through 2007. Controls (n = 100,751) were a 5% sample of female Medicare enrollees residing in the same SEER registry area as cases. Metabolic syndrome was defined using ICD-9-CM codes from inpatient/outpatient diagnoses 1 to 3 years before case diagnosis and a comparable time period in controls. ORs and 95% confidence intervals (CI) were estimated using logistic regression.
Endometrial cancer risk was associated with metabolic syndrome OR (95% CI): 1.39 (1.32-1.47) and its component factors: overweight/obesity 1.95 (1.80-2.11), impaired fasting glucose 1.36 (1.30-1.43), high blood pressure 1.31 (1.25-1.36), and high triglycerides 1.13 (1.08-1.18). After adjusting for overweight/obesity, the increased risks associated with the metabolic syndrome factors remained. Heterogeneity of associations by subtype were not identified (Pheterogeneity = 0.82).
Among women age 65 and older in the United States, metabolic syndrome, and its component factors, increased endometrial cancer risk similarly across endometrial cancer subtypes.
Strategies to reduce the prevalence of metabolic syndrome factors might have a favorable effect on endometrial cancer incidence.
Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown.
We used ...information on traditional risk factors and 10 common genetic variants associated with breast cancer in 5590 case subjects and 5998 control subjects, 50 to 79 years of age, from four U.S. cohort studies and one case-control study from Poland to fit models of the absolute risk of breast cancer. With the use of receiver-operating-characteristic curve analysis, we calculated the area under the curve (AUC) as a measure of discrimination. By definition, random classification of case and control subjects provides an AUC of 50%; perfect classification provides an AUC of 100%. We calculated the fraction of case subjects in quintiles of estimated absolute risk after the addition of genetic variants to the traditional risk model.
The AUC for a risk model with age, study and entry year, and four traditional risk factors was 58.0%; with the addition of 10 genetic variants, the AUC was 61.8%. About half the case subjects (47.2%) were in the same quintile of risk as in a model without genetic variants; 32.5% were in a higher quintile, and 20.4% were in a lower quintile.
The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information.
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