Oncogene-mediated metabolic gene signature predicts breast cancer outcome

Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

IMPACT OF DIABETES MELLITUS ON BREAST CANCER OUTCOME

Diabetes mellitus is a comorbid condition that is commonly seen in Indian population. Breast cancer is the second most common cancer among women. This can occur due to modifiable and non-modifiable risk factors. This study aims to analyses about the impact of diabetes mellitus on breast cancer outcomes. This study is a hospital record based descriptive cross – sectional study. Ethical clearance for the study was obtained from the institutional review board. All the patients diagnosed and on treatment for carcinoma breast in the year 2020 in the hospital was taken into consideration. Details about their age, stage at the time of diagnosis, presence of diabetes, their outcome at the end of study period was collected. The data were analysed with the help of a statistician. Diabetic patients had a slight chance of later stage of presentation as well as outcome in comparison with the non-diabetic counterparts. So, Care should be taken in diagnosing by screening and treating the diabetic patients with breast cancer.

Spatial distribution of B cells and lymphocyte clusters as a predictor of triple-negative breast cancer outcome

While tumor infiltration by CD8+ T cells is now widely accepted to predict outcomes, the clinical significance of intratumoral B cells is less clear. We hypothesized that spatial distribution rather than density of B cells within tumors may provide prognostic significance. We developed statistical techniques (fractal dimension differences and a box-counting method ‘occupancy’) to analyze the spatial distribution of tumor-infiltrating lymphocytes (TILs) in human triple-negative breast cancer (TNBC). Our results indicate that B cells in good outcome tumors (no recurrence within 5 years) are spatially dispersed, while B cells in poor outcome tumors (recurrence within 3 years) are more confined. While most TILs are located within the stroma, increased numbers of spatially dispersed lymphocytes within cancer cell islands are associated with a good prognosis. B cells and T cells often form lymphocyte clusters (LCs) identified via density-based clustering. LCs consist either of T cells only or heterotypic mixtures of B and T cells. Pure B cell LCs were negligible in number. Compared to tertiary lymphoid structures (TLS), LCs have fewer lymphocytes at lower densities. Both types of LCs are more abundant and more spatially dispersed in good outcomes compared to poor outcome tumors. Heterotypic LCs in good outcome tumors are smaller and more numerous compared to poor outcome. Heterotypic LCs are also closer to cancer islands in a good outcome, with LC size decreasing as they get closer to cancer cell islands. These results illuminate the significance of the spatial distribution of B cells and LCs within tumors.

Differential Genomic Interactions Drive Progesterone Receptor Isoform Specific Functions in Breast Cancer

Progesterone is critical for normal breast development and function, and has been shown to stimulate proliferation of normal breast epithelial cells by increasing stem and progenitor cell numbers. Breast cancer incidence is increased in women exposed to progesterone analogues in combined estrogen plus progestin hormone replacement therapy, but not in women taking estrogen alone. Classical progesterone signaling is mediated through the nuclear progesterone receptor (PR), which occurs as two related but functionally different isoforms, PRA and PRB. PRA and PRB are co-expressed equally in normal breast tissue but become dysregulated in breast cancer where PRA often becomes predominant. PRA predominance in breast cancer is associated with poorer outcome and higher risk of distant metastasis in tamoxifen treated patients. We show using integrated analysis of ChIP-seq, ATAC-seq and transcriptomic profiling in a breast cancer cell line model of acquired PRA predominance that: 1) PRA and PRB have different requirements with regard to chromatin accessibility; 2) PRA predominance reshapes the PR cistrome and the associated transcriptome to affect genes not normally regulated by PR when PRA and PRB are equivalently expressed, possibly through assisted loading with multiple other transcription factors; 3) Genes regulated by PR only when PRA is predominant are associated with poorer breast cancer outcome and involved in multiple cancer-associated pathways including those that regulate cell proliferation and adhesion. Our data suggest a mechanism for the poorer disease outcome seen in breast cancers with a predominance of PRA.

Metabolic Syndrome and Breast Cancer: Prevalence, Treatment Response, and Prognosis

Metabolic syndrome is a type of multifactorial metabolic disease with the presence of at least three factors: obesity, diabetes mellitus, low high-density lipoprotein, hypertriglyceridemia, and hypertension. Recent studies have shown that metabolic syndrome and its related components exert a significant impact on the initiation, progression, treatment response, and prognosis of breast cancer. Metabolic abnormalities not only increase the disease risk and aggravate tumor progression but also lead to unfavorable treatment responses and more treatment side effects. Moreover, biochemical reactions caused by the imbalance of these metabolic components affect both the host general state and organ-specific tumor microenvironment, resulting in increased rates of recurrence and mortality. Therefore, this review discusses the recent advances in the association of metabolic syndrome and breast cancer, providing potential novel therapeutic targets and intervention strategies to improve breast cancer outcome.

Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation

Breast cancers that occur in young women up to 5 to 10 years' postpartum are associated with an increased risk for metastasis and death compared with breast cancers diagnosed in young, premenopausal women during or outside pregnancy. Given the trend to delay childbearing, this frequency is expected to increase. The (immuno)biology of postpartum breast cancer is poorly understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. The poorer prognosis of women diagnosed within 10 years of a completed pregnancy is most often contributed to the effects of mammary gland involution. We will discuss the most recent data and mechanistic insights of the most important processes associated with involution and their role in the adverse effects of a postpartum diagnosis. We will also look into the effect of lactation on breast cancer outcome after diagnosis. In addition, we will discuss the available treatment strategies that are currently being used to treat postpartum breast cancer, keeping in mind the importance of fertility preservation in this group of young women. These additional insights might offer potential therapeutic options for the improved treatment of women with this specific condition.

Association of Obesity with Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis

Background Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity/overweight at diagnosis of non-metastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2-), HER2 positive (HER2+), and triple negative (TNBC). Methods We searched MEDLINE, EMBASE and COCHRANE databases until January 1, 2019. Study eligibility were performed independently by two authors. Studies reporting hazard ratios (HR) of OS and/or DFS for obesity/overweight in BC subtypes were included. Pooled HR were computed and weighted using generic inverse variance and random effects models. Results 27 studies were included. Obese, compared to non-obese, women, had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P < .001) for HR+HER2-BC, 1.16 (95%CI = 1.06 to 1.26, P < .001) for HER2+ BC, and 1.17 (95%CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs non-obese women (HR+HER2-BC HR = 1.39, 95%CI = 1.20 to 1.62, P < .001; HER2+BC HR = 1.18, 95%CI = 1.05 to 1.33, P = .006 and TNBC HR = 1.32, 95%CI = 1.13 to 1.53, P < .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+BC (HR = 1.02, 95%CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95%CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95%CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95%CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2-BC, being overweight was associated with worse OS (HR = 1.14, 95%CI = 1.07 to 1.22, P < .001). Conclusions Obesity was associated with modestly worse DFS and OS in all BC subtypes.

The variant T allele of PvuII in ESR1 gene is a prognostic marker in early breast cancer survival

The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480–0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411–0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380–0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.

Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: an innovative patient-centred treatment

SummaryIn the randomised TARGIT-A trial, risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy was non-inferior to whole-breast external beam radiotherapy, for local recurrence. In the long-term, no difference was found in any breast cancer outcome, whereas there were fewer deaths from non-breast-cancer causes. TARGIT-IORT should be included in pre-operative consultations with eligible patients.