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Background: With the introduction of investigational human epidermal growth factor receptor 2 (HER2) targeting treatments, thorough understanding of breast cancer with different HER2 expression levels is critical. The aim of this study was to compare clinicopathologic characteristics and survival of patients with metastatic breast cancer according to the level of HER2 expression. Methods: Women with distant metastatic breast cancer during 2008–2016 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO Database Network. Breast cancer samples were categorised as HER2 immunohistochemistry score 0 (IHC0), HER2-low or HER2+. Results: Among women with hormone receptor (HR) positive metastatic breast cancer (n = 989), 373 (38%) cancers were HER2 IHC0, 472 (48%) were HER2-low and 144 (15%) were HER2+. Among HR negative patients (n = 272), the proportion of HER2 IHC0, HER2-low and HER2+ was 110 (40%), 104 (38%) and 58 (21%) respectively.Within the HR + cohort, patients with HER2 IHC0 or HER2-low cancer were significantly older compared to HER2+ patients. This age difference was not seen in the HR-cohort. The localisation of distant metastases differed significantly between HER2 IHC0 or HER2-low versus HER2+ cases. Survival rates did not differ markedly by subtypes. Conclusion: Substantial proportion of patients had a HER2-low breast cancer. No clear differences in survival were found when comparing HER2 and HR status. Getting more granular insights in the level of HER2 expression and addressing HER2-low as a separate category could help to assess the impact of emerging treatment strategies. Therefore, more detailed information on HER2 expression should be routinely reported.

Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes., Patients and Methods: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]., Results: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype)., Conclusions: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Benzo[a]pyrene (BaP) is an endocrine-disrupting pollutant formed during incomplete combustion of organic materials. It has been recognized as a reproductive and developmental toxicant, however epidemiological evidence of the long-term effect of ambient air BaP on breast cancer (BC) is limited. Thus we evaluated associations between ambient air BaP exposure and risk of BC, overall and according to menopausal status and molecular subtypes (estrogen receptor negative/positive (ER−/ER+) and progesterone receptor negative/positive (PR−/PR+)), stage and grade of differentiation of BC in the French E3N cohort study. Methods: Within a nested case-control study of 5222 incident BC cases and 5222 matched controls, annual BaP exposure was estimated using a chemistry-transport model (CHIMERE) and was assigned to the geocoded residential addresses of participants for each year during the 1990–2011 follow-up period. Multivariable conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Overall, cumulative airborne BaP exposure was significantly associated with the overall risk of BC, for each 1 interquartile range (IQR) increase in the concentration levels of BaP (1.42 ng/m3), the OR = 1.15 (95% CI: 1.04–1.27). However, by menopausal status, the significant positive association remained only in women who underwent menopausal transition (i.e. premenopausal women at inclusion who became postmenopausal at diagnosis), OR per 1 IQR = 1.20 (95% CI: 1.03–1.40). By hormone receptor status, positive associations were observed for ER+, PR + and ER + PR + BC, with ORs = 1.17 (95% CI: 1.04–1.32), 1.16 (95% CI: 1.01–1.33), and 1.17 (95% CI: 1.01–1.36) per 1 IQR, respectively. There was also a borderline positive association between BaP and grade 3 BC (OR per 1 IQR = 1.15 (95% CI: 0.99–1.34). Conclusions: We provide evidence of increased risk of BC associated with cumulative BaP exposure, which varied according to menopausal status, hormone receptor status, and grade of differentiation of BC. Our results add further epidemiological evidence to the previous experimental studies suggesting the adverse effects of BaP.

Background: With the introduction of investigational human epidermal growth factor receptor 2 (HER2) targeting treatments, thorough understanding of breast cancer with different HER2 expression levels is critical. The aim of this study was to compare clinicopathologic characteristics and survival of patients with metastatic breast cancer according to the level of HER2 expression., Methods: Women with distant metastatic breast cancer during 2008-2016 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO Database Network. Breast cancer samples were categorised as HER2 immunohistochemistry score 0 (IHC0), HER2-low or HER2+., Results: Among women with hormone receptor (HR) positive metastatic breast cancer (n = 989), 373 (38%) cancers were HER2 IHC0, 472 (48%) were HER2-low and 144 (15%) were HER2+. Among HR negative patients (n = 272), the proportion of HER2 IHC0, HER2-low and HER2+ was 110 (40%), 104 (38%) and 58 (21%) respectively. Within the HR + cohort, patients with HER2 IHC0 or HER2-low cancer were significantly older compared to HER2+ patients. This age difference was not seen in the HR-cohort. The localisation of distant metastases differed significantly between HER2 IHC0 or HER2-low versus HER2+ cases. Survival rates did not differ markedly by subtypes., Conclusion: Substantial proportion of patients had a HER2-low breast cancer. No clear differences in survival were found when comparing HER2 and HR status. Getting more granular insights in the level of HER2 expression and addressing HER2-low as a separate category could help to assess the impact of emerging treatment strategies. Therefore, more detailed information on HER2 expression should be routinely reported., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of this study was to evaluate the association between metabolic syndrome (MetS) and the immunohistochemical profile of breast cancer (BC) in postmenopausal women., Methods: This cross-sectional cohort study included 189 women, aged 45 to 75years and amenorrhea >12 months, with newly diagnosed BC and no previous cancer treatment. Clinical, anthropometric and biochemical data were collected, as well as data on BC hormone status (estrogen receptor, ER; progesterone receptor, PR; human epidermal growth factor receptor-2, HER-2), and epithelial proliferative activity (Ki-67). Tumors were divided into 5 subtypes:luminal A, luminal B HER-2 negative, luminal B HER-2 positive, non-luminal HER-2, and triple negative. Women with three or more of the following criteria were diagnosed with MetS: waist circumference ≥88cm; triglycerides ≥150mg/dL; HDL-cholesterol <50mg/dL; blood pressure ≥130/85mmHg; glucose ≥100mg/dL., Results: Sixty-three (33.3%) of the 189 patients had MetS at the time of diagnosis. Women with MetS had a higher frequency of tumors ≤ 2cm than women without MetS (49.2% vs. 31.8%) (P = .038). There were no differences in histological grade, staging, or axillary lymph node metastasis (P > .05). The proportion of PR-positive (P = .006), HER-2-negative (P = .034), and luminal B HER-2-negative (P = .038) tumors was higher among patients with MetS compared to women without MetS (79.4% vs. 61.8%, 89.9% vs. 78.6% and 44.5% vs. 27.8%, respectively). Multivariate analysis adjusted for age, time since menopause and BMI showed a higher risk for luminal B HER-2-negative tumors among women with MetS (OR 2.00, 95% CI 1.03-3.89), obese patients (OR 2.03, 95% CI 1.06-3.90), and women with abdominal obesity (OR 1.96, 95% CI 1.01-4.03)., Conclusion: In postmenopausal women with newly diagnosed BC, the presence of MetS was associated with smaller tumor size, PR-positive and HER-2-negative status, and the luminal B tumor subtype., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This viewpoint is a personal reflection on the values and merits of immunohistochemistry in current breast cancer diagnosis. Immunohistochemistry is a validated mainstay in molecular subtyping of invasive breast cancer. Immunohistochemical assessment of hormone receptor status and HER2 expression is used to determine the clinico-pathological surrogate of breast cancer intrinsic subtypes, which guide neoadjuvant and adjuvant therapy. The advent of genomic prognostic signatures and qualitative mRNA-based assays makes some clinicians and researchers wonder whether immunohistochemistry should be abandoned. However, the perils and pitfalls of these mRNA-based tests cannot be neglected. This viewpoint offers a brief overview of quality issues in immunohistochemistry and qPCR, as well as a concise summary of currently available evidence on the correlation of immunohistochemistry and mRNA-based testing for prognostic and predictive markers in invasive breast cancer. We strongly advocate the use of immunohistochemistry as it integrates valuable spatial information with quantification of protein expression., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Bony metastasis predominantly affects the spinal column and has been commonly associated in patients with breast cancer. There are two types of lesions that can occur with spine cancer-osteolytic or osteoblastic. Some patients may have mixed lesions, which include lytic and blastic in one vertebra or lytic and blastic in different vertebrae. Previous studies have shown that patients with breast cancer have an increased likelihood for development of lytic spinal metastases., Methods: A retrospective chart review was conducted to more closely examine the association between hormone receptor status and spinal lesion type. A total of 195 patients were initially identified through the City of Hope Cancer Registry. Of the 195, only 153 patients had hormone receptor marker status available. Associations between spinal lesion and hormone receptor status were evaluated using χ(2) tests with alpha = 0.05 significance level. In a secondary analysis, the Oncomine Platform was used, which integrated The Cancer Genome Atlas (TCGA) datasets, to identify osteogenic genes that may be relevant to invasive breast cancers., Results: Contrary to previous studies, our findings revealed progesterone receptor positive (PR+) patients were significantly more likely to present with blastic than lytic or mixed lesions. Furthermore, using TCGA analysis, COL1A1 and COL1A2 were found to be up-regulated, which could provide a molecular explanation for the development of blastic metastases., Conclusions: By integrating clinical and bioinformatic techniques, this study provides a novel discovery of the relationship between blastic and PR + breast cancers, which may have important implications for diagnostic strategies concerning vertebral metastases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Causes of racial disparities in breast cancer incidence and mortality between white and African American women remain unclear. This study evaluated associations of menstrual and reproductive factors with breast cancer risk by race and cancer subtypes., Patients and Methods: Included in the study were 1866 breast cancer cases and 2306 controls recruited in the Nashville Breast Health Study, a population-based case-control study. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: African American women were more likely to have estrogen receptor-negative (ER(-)), progesterone receptor-negative (PR(-)), and triple-negative (ER(-)PR(-)HER2(-)) breast cancer than white women. Age at menarche (≥ 14 years) and multiparity (≥ 3 live births) were inversely associated with ER(+) tumors only, whereas late age at first live birth (> 30 years) and nulliparity were associated with elevated risk; such associations were predominantly seen in white women (OR = 0.70, 95% CI = 0.55-0.88; OR = 0.72, 95% CI = 0.56-0.92; OR = 1.42, 95% CI = 1.13-1.79; OR = 1.32, 95% CI = 1.06-1.63, respectively). Age at menopause between 47 and 51 years was associated with elevated risk of ER(-) tumors in both white and African American women. Among women who had natural menopause, positive association between ever-use of hormone replacement therapy and breast cancer risk was seen in white women only (OR = 1.39, 95% CI = 1.03-1.87)., Conclusion: This study suggests that certain hormone-related factors are differentially associated with risk of breast cancer subtypes, and these associations also differ by race., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER-) breast cancer tissues were investigated using GC-TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER- subtype. Beta-alanine demonstrated the strongest change between ER- and ER+ breast cancer (fold change=2.4, p=1.5E-20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R=-0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER- breast cancer. In a Kaplan-Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR=0.6, p=3.2E-15)., Biological Significance: It is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER- breast as different diseases requiring different treatment strategies. Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER- breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER- subtype as a preferential target for glutaminase inhibitors. For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER- breast cancer., (© 2013.)

We investigated treatment effects by oestrogen receptor (ER) status among women with metastatic breast cancer (MBC) receiving capecitabine (C) plus docetaxel (D) or D alone in a randomised phase III trial. Data were retrospectively analysed from patients whose disease had recurred following (neo)adjuvant anthracyclines. ER status was identified in 356/506 patients. In patients with ER-positive tumours, median overall survival from enrolment was 17.7 months with CD versus 12.5 months with D (hazard ratio [HR] 0.65, 95% confidence interval [CI]: 0.47-0.89; P = 0.007) and median time to progression (TTP) was 6.8 and 5.4 months, respectively (HR 0.62, 95% CI: 0.46-0.84; P = 0.002). For patients with ER-negative tumours, significantly longer TTP was seen with CD (5.2 versus 3.5 months; HR 0.73, 95% CI: 0.53-0.98; P = 0.038). Whether there is an additional C to D treatment benefit in ER-positive versus ER-negative MBC requires further evaluation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)