Is There a Special Role for Ovarian Hormones in the Pathogenesis of Lobular Carcinoma?

Lobular carcinoma represent the most common special histological subtype of breast cancer, with the majority classed as hormone receptor positive. Rates of invasive lobular carcinoma in postmenopausal women have been seen to increase globally, while other hormone receptor-positive breast cancers proportionally have not followed the same trend. This has been linked to exposure to exogenous ovarian hormones such as hormone replacement therapy. Reproductive factors resulting in increased lifetime exposure to endogenous ovarian hormones have also been linked to an increased risk of lobular breast cancer, and taken together, these data make a case for the role of ovarian hormones in the genesis and progression of the disease. In this review, we summarize current understanding of the epidemiological associations between ovarian hormones and lobular breast cancer and highlight mechanistic links that may underpin the etiology and biology.

Molecularly Confirmed Female Donor-Transmitted Lobular Breast Cancer to Male following Renal Transplantation.

INTRODUCTION: Lobular breast cancer represents 10%-15% of breast cancers in women but is virtually nonexistent in men, related to the typical absence of the anatomic breast lobule structure in male breast tissue. We describe donor-transmitted metastatic lobular carcinoma to a male after kidney transplantation. Determining whether a post-transplant cancer is transplant associated, donor transmitted, or donor derived is significant for treatment, prognosis, and possibly management of other organ recipients. CASE REPORT: A 74-year-old Caucasian male presented to the emergency department with lower abdominal pain and macro-hematuria. Past medical history included two renal transplantations. Computed tomography identified a 4-5-cm space-occupying lesion in the native left kidney. A left native nephrectomy was performed. Histology pathologic examination demonstrated lobular (as opposed to ductal) breast carcinoma. Fluorescent in situ hybridization probes to identify X- and Y-chromosomes showed tumor cells with an XX genotype, whereas the surrounding host cells were of XY genotype. These findings confirmed the female-sex origin (donor) of the tumor within the XY native male (current patient) tissues. DISCUSSION/CONCLUSION: Due to discordance between the donor and recipient sex, fluorescent in situ hybridization as a molecular technique correctly identified the origin of an individual's cancer in the post-transplant setting. The metastatic breast cancer behaved more indolently than usually seen. Expanded criteria donors (ECD) are those who cannot donate under standard criteria for organ transplantation; expanded criteria widen the potential organ donor pool at the expense of increased risk for post-transplant complications (e.g., graft failure, the transmission of malignancy). The case provides a potential area of future research into considering allowing ECDs with a distant history of cancer with very low transmission risk when the biochemical environment of the recipient would, in the unlikely event of transmission, induce the tumor to pursue an indolent clinical course.

Adherence to a western dietary pattern and risk of invasive ductal and lobular breast carcinomas: a case-control study.

Little is known about the role of diet in the risk of invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast, the most common histological subtypes of breast cancer (BC). This is because, the majority of studies on the association of diet and the risk of BC are focused on single food items, and studies considering the overall diet in terms of dietary patterns are limited. Also, the potential heterogeneity in the impact of Western diet (WD) on histological subtypes of BC is not established. This, the age-frequency-matched case-control study included 1009 incident BC cases and 1009 healthy controls. The required data was obtained from the patients' medical files and interviews using a previously validated researcher-designed questionnaire for collecting data on socio-economic and anthropometric statuses and a valid food frequency questionnaire (FFQ) to measure the participants' dietary intake. We used multinomial logistic regression, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. A positive and significant association was observed between higher adherence to a WD and risk of IDC (OR comparing highest with the lowest tertile: 2.45, 95% CI 1.88, 3.17; p-trend < 0.001), whereas no significant association was observed between adherence to the WD and the risk of ILC (OR comparing highest with the lowest tertile: 1.63, 95% CI 0.63, 3.25) (p for heterogeneity = 0.03). The results of an analysis stratified by menopausal status suggested a similar pattern. We provided evidence that adherence to a WD raises the risk of IDC, but not ILC, suggesting different etiological mechanisms for IDC and ILC.

Targetable alterations in invasive pleomorphic lobular carcinoma of the breast.

BACKGROUND: Invasive pleomorphic lobular carcinoma (PLC) of the breast is a subtype of invasive lobular cancer which compromises approximately 1% of all epithelial breast malignancies and is characterized by higher nuclear pleomorphism and poorer prognosis than classic invasive lobular cancer (ILC). Since PLC is more aggressive than classical ILC, we examined the underlying molecular alterations in this subtype of breast cancer to understand the possible benefit from targeted therapies. METHODS: In this study, we investigate the clinical characteristics and molecular alterations in 16 PLC from our institution. Additionally, we examined the clinical and genomic features in 31 PLC from the Cancer Genome Atlas (TCGA). RESULTS: Overall, our analysis of PLC found that 28% had activating ERBB2 mutations, 21% had ERBB2 amplification, and 49% activating PIK3CA mutations. Among cases from our institution, we found 19% with activating ERBB2 mutations, 25% had ERBB2 amplification, and 38% with activating PIK3CA mutations. In data from TCGA, 32% had activating ERBB2 mutations, 19% had ERBB2 amplification, and 55% had activating PIK3CA mutations. While classic ILC in TCGA had similar percentages of PIK3CA alterations compared to PLC, activating ERBB2 alterations were exceedingly rare, with no activating ERBB2 mutations and only one case with ERBB2 amplification. Interestingly, in further examining TCGA data which included FGFR1 and PTEN, 94% of PLC had alterations in ERBB2, FGFR1, or the PI3K pathway. CONCLUSIONS: Our results show a high frequency of ERBB2 and PIK3CA alterations in PLC and suggest all PLC should be tested for potential therapeutic targeting.

Invasive lobular carcinoma of the breast: the increasing importance of this special subtype.

Invasive lobular carcinoma (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast cancer cases. ILCs are noted for their lack of E-cadherin function, which underpins their characteristic discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, tumours are luminal in molecular subtype, being oestrogen and progesterone receptor positive, and HER2 negative. Since last reviewing the lobular literature (McCart Reed et al., Breast Cancer Res 17:12, 2015), there has been a considerable increase in research output focused on this tumour type, including studies into the pathology and management of disease, a high-resolution definition of the genomic landscape of tumours as well as the evolution of several potential therapeutic avenues. There abounds a huge amount of new data, which we will review herein.

Dietary Patterns and Risk of Invasive Ductal and Lobular Breast Carcinomas: A Systematic Review and Meta-analysis.

The histopathologic subtypes of breast cancer, including invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), differ in terms of risk factors, progression, and response to treatment. The PubMed/Medline, Web of Science, and Scopus databases were searched up to February 2020 for published studies on the association between dietary patterns (Western diet [WD] or Mediterranean diet [WD]) and the risk of IDC/ILC of breast. Multivariable adjusted relative risk (RR) and 95% confidence intervals (CIs) comparing the highest and lowest categories of WD and MD patterns were combined by using the random-effects meta-analyses. After searching the databases, 10 eligible studies on the association of diet and IDC (7 articles) and ILC (3 articles) were included in the analysis. A statistically significant adverse association was observed between MD and IDC in case-control studies (RR = 0.47; 95% CI, 0.39-0.55; I2 = 85.1%; P < .001). However, the association was nonsignificant in cohort studies (RR = 0.98; 95% CI, 0.92-1.05; I2 = 88.8%; P = .003). The pooled analysis also suggested a significant and direct association between the WD and the risk of IDC (RR = 1.36; 95% CI, 1.18-1.53; I2 = 63.7%; P = .017). The risk of ILC for the highest compared to the lowest category of MD was highly protective (RR = 0.76; 95% CI, 0.64-0.87; I2 = 89.2%; P < .001), and a marginally significant association was found between the WD and risk of ILC (RR = 1.45; 95% CI, 1.04-1.86), with no heterogeneity (I2 = 0; P = .52). This meta-analysis provides supporting evidence for the association between MD decreased risk of IDC and ILC of the breast and the association between WD and increased risk of IDC and ILC. Further investigations are needed to better understand the reasons behind the etiologic mechanisms of how dietary patterns affect patients differently by common breast cancer subtypes, including IDC and ILC.

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

PURPOSE: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. METHODS: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. RESULTS: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. CONCLUSION: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

Simultaneous Effects of Viral Factors of Human Papilloma Virus and Epstein-Barr Virus on Progression of Breast and Thyroid Cancers: Application of Structural Equation Modeling.

This study aimed to assess effects of the sets of EBV and HPV expressed proteins simultaneously on the sets of cellular/inflammatory factors in breast and thyroid cancers using structural equation modeling. In this multi-center case-control study, according to the inclusion and exclusion criteria, 83 breast and 57 thyroid specimens were collected from the eligible patients. In addition, 31 and 18 histopathological evaluated normal breast and thyroid samples were also examined as age-matched healthy controls. In addition, ELISA and Real-time PCR were used to measure the expression level of viral and cellular/inflammatory genes and proteins. Structural equation modeling was used to test the causal associations between the sets of EBV and HPV expressed proteins with inflammatory factors in breast and thyroid cancers development. Breast cancer patients had a higher incidence of HPV-positively and EBV-positively than healthy controls (OR=1.66, 95%CI=0.79-3.47, P-value=0.177), (OR=3.18, 95%CI=1.52-6.63, P-value=0.002), respectively. In addition, thyroid cancer patients had a significantly higher incidence of EBV-positivity than healthy controls (OR=3.72, 95% CI=1.65-8.36, P-value=0.001). After fitting the SEM model, HPV proteins factor has significant direct and total effects on the cellular/inflammatory factors in breast cancer (direct effect: ß=0.426, P-value=0.01; total effect: ß=0.549, P-value<0.001). However, EBV proteins factor has most significant total effect on the cellular/inflammatory factors in breast cancer (total effect: ß=0.804, P-value<0.001) than the cellular/inflammatory factors in thyroid cancer (total effect: ß=0.789, P-value<0.001). For the first time, a significant association between EBV and HPV -genes, anoikis resistance and the development of breast and thyroid cancers demonstrated by using SEM, Simultaneously.
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Heterogeneity in risk factors for ductal and lobular breast carcinomas: A case-control study.

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast are the most common histological subtypes of breast cancer. However, the associations and heterogeneity between histological subtypes and their risk factors are not well established. This study aimed to investigate risk factors for IDC and ILC. This case-control study included 1,009 incident breast cancer cases and 1,009 hospital controls, frequency-matched by age. Data were obtained from the patients' medical files and an interview administered via a questionnaire. Multinomial logistic regression was used and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The heterogeneity of the associations was assessed using the Wald test. Family history of breast cancer was associated with IDC (OR 2.64, 95% CI: 1.97-3.55) but not ILC (OR 0.81, 95% CI: 0.42-1.57; p for heterogeneity <0.001). Conversely, a history of miscarriage was associated with ILC (OR 1.71, 95% CI: 1.17-2.51) but not IDC (OR 1.18, 95% CI: 0.95-1.46; p for heterogeneity = 0.04). Similarly, type 2 diabetes was associated with ILC but not IDC (p for heterogeneity = 0.02). Age at first delivery and breastfeeding were significantly associated with IDC but not ILC, though p values for heterogeneity did not reach the significance level. Deliberate weight loss and age at menarche were significantly associated with ILC but not IDC (p for heterogeneity ≥0.27). Smoking, history of benign breast disease and BMI were associated with both subtypes. The present study supports the hypothesis that IDC and ILC are etiologically distinct tumours.

Relationships between Reproductive Risk Factors for Breast Cancer and Tumor Molecular Subtypes

Background: Due to wide clinical differences in the various pathological types of breast cancer and also close associations between disease prognosis and molecular subtypes, relationships of the latter with traditional risk factors have been suggested. Hence, the present study aimed to assess any associations. Methods: This bi-center cross-sectional study was performed on 800 consecutive women with known breast cancer referred to two Comprehensive Cancer Centers in Tehran between 2006 and 2016. Baseline information related to reproductive risk profiles as well as pathological tumor diagnosis and molecular subtypes determined using immunohistochemical analysis by immune-staining for ER, PR, and HER2 molecules were collected by reviewing hospital records. Results: Of 800 samples included for immunohistochemical analysis, 314 (39.3%) were diagnosed as of Luminal A subtype, 107 (13.4%) as Luminal B subtype, 153 (19.1%) as HER-2 over-expressing, and 226 (28.3%) as triple negative. Among all reproductive risk factors initially assessed, young age was associated with HER-2 over-expression, greater tumor size and a history of abortion with the luminal B subtype, lower age at pregnancy with the luminal A subtype, and lower gravidity and a shorter duration of breastfeeding with the triple negative subtype. Conclusion: Each molecular subtype of breast cancer in our population may be associated with specific reproductive risk factors.

Breast Cancer following Augmentation Mammaplasty: A Case-Control Study.

BACKGROUND: The purpose of this study was to determine whether augmentation mammaplasty, implant type, and implant location affect breast cancer detection, stage, and treatment. METHODS: An institutional case-control study was performed of patients with prior breast augmentation undergoing breast cancer treatment from 2000 to 2013. Controls were propensity matched and randomized, and data were retrospectively reviewed. RESULTS: Forty-eight cases and 302 controls were analyzed. Palpable lesions were detected at a smaller size in augmentation patients (1.6 cm versus 2.3 cm; p < 0.001). Fewer lesions in augmented patients were detected by screening mammography (77.8 percent of cases versus 90.7 percent of controls; p = 0.010). Patients with implants were more likely to undergo an excisional biopsy for diagnosis (20.5 percent versus 4.4 percent; p < 0.001), rather than image-guided core needle biopsy (77.3 percent versus 95.3 percent; p < 0.001). Earlier staging in augmented patients approached but did not reach statistical significance (p = 0.073). Augmented patients had higher mastectomy rates (74.5 percent versus 57.0 percent) and lower rates of breast-conservation therapy (25.5 percent versus 43 percent; p = 0.023). Neither implant fill type nor anatomic location affected method of diagnosis, stage, or treatment. CONCLUSIONS: Palpable detection of breast cancer is more likely at a smaller size in augmented patients, yet it is less likely on screening mammography than in controls. Augmentation breast cancer patients have a comparable disease stage and are more likely to undergo mastectomy rather than lumpectomy. Both silicone and saline implants, whether placed submuscularly or subglandularly, have comparable effects on breast imaging, biopsy modality, and surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Transmission of Donor-Derived Breast Carcinoma as a Recurrent Mass in a Keratolimbal Allograft.

PURPOSE: To report a case of local transmission of invasive lobular carcinoma from a donor to a recipient in a keratolimbal allograft after cessation of systemic immunosuppressive therapy. METHODS: This is a case report including the clinicopathologic findings. Sections of the donor breast tumor and recipient conjunctival lesions were stained with hematoxylin and eosin. Immunohistochemical studies were performed using pancytokeratin, CK7, CK20, CAM 5.2, CD138, TTF1, estrogen receptor, progesterone receptor, GATA-3, GCDFP-15, and mammaglobin. Polymerase chain reaction-based DNA profiling of tumor cells was performed. RESULTS: Histopathologic examination revealed an infiltrate of atypical cells with large hyperchromatic nuclei consistent with carcinoma. Immunohistochemical analysis showed pancytokeratin, CK7, CAM 5.2, GATA-3, and estrogen receptor positivity and progesterone receptor absence, consistent with the previously determined phenotype of the donor's breast carcinoma. Results of polymerase chain reaction analysis were also consistent with the donor's tumor. After reduced dosing of tacrolimus and mycophenolate mofetil, 2 limbal tumors occurred in the recipient. The immunosuppressive treatment had been stopped completely before the appearance of the third lesion. The recipient had no history of malignancy, and she had routine screenings for breast cancer. CONCLUSIONS: We report a case of donor-derived breast carcinoma in a keratolimbal allograft recipient. The grafted tissue harbored donor-derived tumor cells for more than 4 years after surgery even after systemic immunosuppression was discontinued. Although no similar reports of tumor transfer could be found in the literature, this case suggests the need for increased stringency in donor selection and heightened surveillance for such tumor transmission.

Diagnostic dilemmas and pitfalls in ThinPrep® cytology of breast fine needle aspiration biopsy:: Report of Six Cases with Histological Correlates.

Fine needle aspirations (FNA) of the breast for primary diagnoses have become less popular in the USA and are usually performed for lesions with low or extremely high clinical suspicion. They are also performed for lesions in close proximity to a breast implant. Liquid-based cytological preparations, such as ThinPrep® (TP), provide a practical alternative to clinicians who are performing FNA. Using a selection of cases that represent challenging diagnoses, we describe common diagnostic pitfalls of breast FNA that are specifically associated with this preparation. Well known breast cytology pitfalls, such as fibroadenoma, when solely examined using a TP slide can be even more challenging since the usual stripped bipolar cells seen in the background of smeared slides, can appear singly dispersed with preserved cytoplasm, resembling carcinoma. We describe that large fragments of solid papillary carcinoma are represented by mostly singly dispersed cells with plasmacytoid features that mimic those of a lobular carcinoma. Since nuclear features are more pronounced in TP, prominent nucleoli and cytological atypia can potentially be overcalled. TP processing might also lead to clumping of epithelioid histiocytes that appear atypical, which increases the suspicion of malignancy. The presence of atypical cells in a TP slide of a peri implant seroma should always undergo additional testing, especially in patients with a prior history of breast carcinoma, to determine if it represents recurrent carcinoma or an implant associated anaplastic large cell lymphoma. Familiarity with the aforementioned artifacts associated with TP is essential to avoid diagnostic misinterpretations. Diagn. Cytopathol. 2017;45:655-661. © 2017 Wiley Periodicals, Inc.

Breast cancer and thyroid diseases: analysis of 867 consecutive cases.

INTRODUCTION: The aim of this study was to evaluate the association of breast cancer with thyroid diseases. Many authors have already studied the possible relationship between these two diseases, but the results are nowadays conflicting. MATERIALS AND METHODS: Our study examining 867 patients with breast cancer (862 women and 5 men, average age = 61 years old) of whom 141 also had thyroid disease evaluated the recurrence of thyroid diseases and their association with different types of breast cancer. Statistical analyses were performed using SPSS software for Windows; we used nonparametric tests (Chi-square and Mann-Whitney), and the level of significance was set at p < 0.05. RESULTS: We found a significant association between breast cancer diagnosed after menopause and thyroid disease (p < 0.003). Moreover, we analyzed the role of thyroid autoimmunity identifying an association between chronic autoimmune thyroiditis and breast cancer diagnosed before menopause (p < 0.05). Regarding receptor profile of breast carcinoma, we have found an increased expression of estrogen receptors in patients with autoimmune thyroiditis compared to patients with any other thyroid diseases (p < 0.03). Contrariwise, we do not have found any difference between the group with every thyroid disease and the group without thyroid disease (p < 1.00). We did not find other statistically significant associations with breast cancer's parameters like family history, tumor size, lymph node metastasis, distant metastasis, cancer clinical and pathological stage, differentiation grade and expression of Ki67, p53 and Her2 in the two main groups with or without thyroid disease. Likewise, we did not found other statistically significant association between hypothyroidism or hyperthyroidism and breast cancer.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities.

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend ≤ 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction.

Passive Smoking and Breast Cancer - a Suspicious Link.

BACKGROUND: Breast cancer is the most common malignancy of women in the world. The disease is caused by infectious and non-infectious, environmental and lifestyle factors. Tobacco smoke has been one of the most widely studied environmental factors with possible relevance to breast cancer. The purpose of this study was to assess the impact of tobacco smoking in breast cancer patients in a hospital based cohort and to establish prognostic implications if any. MATERIALS AND METHODS: A retrospective audit of 100 women with pathological diagnosis of invasive breast cancer was included in this study. The verbal questionnaire elicited information on current and previous history of exposure to smoking in addition to active smoking. All analyses were adjusted for potential confounders, including stage at presentation, alcohol intake, hormonal replacement therapy, oral contraceptive intake, obesity and menopausal status. RESULTS: The mean age at presentation of breast cancer was 51.4 ± 10.86 years. Mean age of presentation was 53.1±11.5 and 45.7±11.9 years in never smokers and passive smokers, respectively. Age at presentation varied widely in patients exposed to tobacco smoke for >10 years in childhood from 40.3± 12.0 years to 47.7± 13.9 in patients exposed for > 20 years as adults. Among passive smokers, 60.9% were premenopausal and 39.1% of patients were postmenopausal. In never smokers, 71.4% were post menopausal. Expression of receptors in non-smokers vs passive smokers was comparable with no significant differences. Metastatic potential in lung parenchyma was slightly elevated in passive smokers as compared to never smokers although statistically non-significant. CONCLUSIONS: An inverse relationship exists between the intensity and duration of smoking and the age at presentation and poor prognostic factors. The results strongly suggest efforts should be taken to prevent smoking, encourage quitting and restrict exposure to second hand smoke in India.

Hormone Replacement Therapy, Likely Neither Angel Nor Demon.

PURPOSE: A decline in breast cancer incidence has been attributed to the reduction in hormone replacement therapy (HRT) prescriptions since the publication of the landmark WHIT paper in 2003. Concurrently, a relationship between HRT and cerebrovascular disease incidence has also been suggested. No generalized analysis of HRT prescription rates and breast cancer incidence rates that included more than seven years of data. We hypothesized that detailed analysis of SEER data would clarify the relationship between HRT use and breast cancer incidence. Given the large decline in HRT prescription rates uncovered, analyses of potential complications were also conducted, with the understanding that a small effect or one limited to a subpopulation, such as a single race, might not be detected. METHODS: Incidence rates (per 100,000 women) and standard errors for ductal and lobular breast carcinomas, and endometrioid /endometrial carcinomas in women over 50 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database 1992-2012. From the Medical Expenditure Panel Survey 1996-2012 weighted counts and standard errors of hormone replacement therapy (HRT) prescriptions for women over 50 years were obtained. Using the National Hospital Discharge Survey (NHDS), 1996-2010 weighted counts and standard errors of femoral neck fractures, total hip replacements, acute myocardial infarctions, and cerebral infarctions were obtained for 50+ year men and women. Weighted counts and standard errors were divided by US census figures and multiplied by 100,000. Joinpoint regression was used to analyze rates. MAIN RESULTS: Beginning 2001, HRT prescription rates dropped dramatically, 2001-2012 AAPC -14.9 (95% CI -17.4, -12.4). Breast cancer rates, which began to decline in 1999, increased after 2003; 2012 rates were similar to those seen in 2001 for both ductal, AAPC 0.1 (-0.4, 0.6) and lobular, AAPC 0.5 (-0.4, 1.5), carcinoma. Endometrial carcinoma rates increased, 2001-2012 AAPC 3.5 (3.1, 3.8), arguing against a negative effect of HRT discontinuation of endometrial carcinoma. Tests for parallelism failed to detect APC differences among genders for femoral neck fractures (P = 0.24), for total hip replacements (P = 0.11), for myocardial infarctions (P = 0.10), or for cerebral infarctions (P = 0.19), precluding any assignment of general effect on these disorders by HRT. CONCLUSIONS: Using SEER data, we demonstrated that changes in breast cancer rates cannot be explained by HRT prescription rate changes.

Variation in Breast Cancer-Risk Factor Associations by Method of Detection: Results From a Series of Case-Control Studies.

Concerns about breast cancer overdiagnosis have increased the need to understand how cancers detected through screening mammography differ from those first detected by a woman or her clinician. We investigated risk factor associations for invasive breast cancer by method of detection within a series of case-control studies (1992-2007) carried out in Wisconsin, Massachusetts, and New Hampshire (n=15,648 invasive breast cancer patients and 17,602 controls aged 40-79 years). Approximately half of case women reported that their cancer had been detected by mammographic screening and half that they or their clinician had detected it. In polytomous logistic regression models, parity and age at first birth were more strongly associated with risk of mammography-detected breast cancer than with risk of woman/clinician-detected breast cancer (P≤0.01; adjusted for mammography utilization). Among postmenopausal women, estrogen-progestin hormone use was predominantly associated with risk of woman/clinician-detected breast cancer (odds ratio (OR)=1.49, 95% confidence interval (CI): 1.29, 1.72), whereas obesity was predominantly associated with risk of mammography-detected breast cancer (OR=1.72, 95% CI: 1.54, 1.92). Among regularly screened premenopausal women, obesity was not associated with increased risk of mammography-detected breast cancer (OR=0.99, 95% CI: 0.83, 1.18), but it was associated with reduced risk of woman/clinician-detected breast cancer (OR=0.53, 95% CI: 0.43, 0.64). These findings indicate important differences in breast cancer risk factors according to method of detection.

Lobular breast cancer: incidence and genetic and non-genetic risk factors.

While most invasive breast cancers consist of carcinomas of the ductal type, about 10% are invasive lobular carcinomas. Invasive lobular and ductal carcinomas differ with respect to risk factors. Invasive lobular carcinoma is more strongly associated with exposure to female hormones, and therefore its incidence is more subject to variation. This is illustrated by US figures during the 1987 to 2004 period: after 12 years of increases, breast cancer incidence declined steadily from 1999 to 2004, reflecting among other causes the decreasing use of menopausal hormone therapy, and these variations were stronger for invasive lobular than for invasive ductal carcinoma. Similarly, invasive lobular carcinoma is more strongly associated with early menarche, late menopause and late age at first birth. As for genetic risk factors, four high-penetrance genes are tested in clinical practice when genetic susceptibility to breast cancer is suspected, BRCA1, BRCA2, TP53 and CDH1. Germline mutations in BRCA1 and TP53 are predominantly associated with invasive ductal carcinoma, while BRCA2 mutations are associated with both ductal and lobular cancers. CDH1, the gene coding for the E-cadherin adhesion protein, is of special interest as mutations are associated with invasive lobular carcinoma, but never with ductal carcinoma. It was initially known as the main susceptibility gene for gastric cancer of the diffuse type, but the excess of breast cancers of the lobular type in CDH1 families led researchers to identify it also as a susceptibility gene for invasive lobular carcinoma. The risk of invasive lobular carcinoma is high in female mutation carriers, as about 50% are expected to develop the disease. Carriers must therefore undergo intensive breast cancer screening, with, for example, yearly magnetic resonance imaging and mammogram starting at age 30 years.

Utility of peripheral blood parameters in predicting breast cancer risk.

PURPOSE: We aimed to study the inflammatory parameters of complete blood count in breast cancer cases. MATERIALS AND METHODS: This retrospective study covered 178 breast cancer patients and 107 age and body mass index matched healthy women. Complete blood count parameters, neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR) and MPV/platelet were analyzed. RESULTS: The leukocyte, neutrophil and neutrophil/ lymphocyte ratio were higher in the patient group (p values 0.001, 0.0001 and 0.0001, respectively) while haemoglobin and hematocrit were higher in the control group (p=0.0001 for both). Logistic regression analysis showed that elevated neutrophils and platelet distribution width (PDW) (OR: 0.627, 95%CI: 0.508-0.774, p=0.001 and OR: 1.191 95%CI: 1.057-1.342 p=0.003) were independent variables for predicting breast cancer. The cut- off value for the neutrophil/lymphocyte ratio was 2.56. CONCLUSIONS: According to our study results, neutrophil levels as part of complete blood count may be used as an independent predictor of breast cancer risk.