Breast Cancer-related Mortality Research Articles

Examining racial disparities in male breast cancer.

6555 Background: Male breast cancer (MBC) accounts for approximately 1% of all breast cancers. Racial disparities have not been examined in MBC. Methods: Within a large, integrated health delivery system, all adult female and male patients who were diagnosed with breast cancer from 01-01-2010 to 12-31-2018 were examined. Bivariate analysis was performed to examine clinical and demographic factors associated with breast cancer-related mortality. We conducted more detailed chart review in the MBC-only group (data period 01-01-2010 to 12-31-2019) to assess the mean time to treatment (from diagnosis to surgery, surgery to chemotherapy, and surgery to radiation) stratified by race using bivariate (t-test, one way ANOVA) analyses. Results: 32,848 female breast cancer and 226 MBC patients were evaluated; MBC patients represented 0.63% of all breast cancer patients. Between males and females, there was no statistically significant difference in race, with an overall distribution of 62% White, 19% Asian, 8% Black, and 11% Hispanic. To our knowledge, this is the largest and most racially diverse sample of MBC patients to date. MBC patients at diagnosis were significantly older (p <.0001), more obese (p < 0.0018), and sicker according to the Charlson Comorbidity Index (CCI) (p < 0.0001) compared to female breast cancer patients. Males were more likely to be diagnosed at an advanced stage (19.2%) compared to females (12.5%) (p = 0.0037). With a mean follow up of 5 years, overall mortality was statistically significantly worse in MBC (23.0%) compared to female breast cancer patients (12.0%) (p < 0.0001). Furthermore, breast cancer-related mortality was significantly higher in males (8.1%) than in females (4.5%) (p = 0.0124). In the MBC-only analysis, stage at diagnosis was not influenced by patient race. Asian and White MBC patients had the shortest mean time from diagnosis to surgery (27 and 29 days, respectively), with Hispanic MBC patients experiencing the longest time to surgery (46 days). Black MBC patients experienced the shortest mean time to chemotherapy after surgery (39 days), whereas Asian MBC patients experienced the longest time to chemotherapy (50 days). In survivorship, Black and Asian patients were least likely to undergo screening mammography (33.3%, and 43.3%, respectively), compared to 52% of White and 50% of Hispanic MBC patients. Ultimately, 13% of Asian and 11% of Hispanic MBC patients died of breast cancer, compared to 6.7% of Black and 6.2% of White MBC patients. Conclusions: While we found no statistically significant differences in mortality by race among MBC patients, our findings indicate that non-white patients had longer time to treatments, less survivorship screening, and worse disease related mortality than their white counterparts. Future study can elucidate these racial inequalities, enabling more equitable breast cancer treatment among patient subgroups.

Hypoxia-inducible factor-dependent ADAM12 expression mediates breast cancer invasion and metastasis

Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.

Abstract PS7-17: Exploring global clinical trial enrollment opportunities in high breast cancer mortality regions

Abstract BACKGROUND Globally, breast cancer is the most commonly diagnosed cancer and the most common cause of cancer death for women. Access to high quality treatment and novel therapies vary significantly based on geographic regions and countries. Mortality rate is considerably higher women in developing and low-income regions compared to high income regions. While many factors contribute to disparities in breast cancer specific outcomes, access to clinical trials provide high quality and evidence-based cancer care. Therefore, we evaluated the availability of breast cancer treatment clinical trial among global regions with the highest breast cancer incidence and related mortality. METHODS In this study, we reviewed clinical trials registered with clinicaltrials.gov and published in 3 high impact journals: The New England Journal of Medicine, Lancet Oncology and the Journal of Clinical Oncology between January 2018 and May 2020. For each trial, the countries from which patients enrolled were captured and compared to the countries in the top 5 regions for highest breast cancer incidence and breast cancer related mortality globally per the GLOBOCAN 2018 estimates. RESULTS A total of 77 clinical trials meet this criteria and enrolled patients in 67 different countries. As most trials enrolled in multiple countries, the enrollment countries for every trial was recorded with a total of 697 enrolled countries in these 77 clinical trials. The global regions with the high breast cancer mortality are Melanesia, Micronesia and Polynesia (Hawaii excluded), Northern Africa, Caribbean and Western Africa. These regions together had only 8 clinical trials that accrued patients during this time frame: one trial in Egypt, 4 in New Zealand and 3 in Puerto Rico. This represents about 1% of country accruals in the trials analyzed (8 of 697). The most frequently enrolling countries were the United States, Canada, Belgium, United Kingdom, Italy, France, Germany, and Spain which have high incidence of breast cancer but lower mortality rates compared to other global regions. CONCLUSIONS High impact breast cancer trials currently enroll patients from areas with high incidence of breast cancer but not from areas with high mortality rates. Barriers that lead to these disparities have not been extensively explored and would be of interest in future studies. Exploring creative ways to bridge this gap, such as working with local governments to help develop clinical centers with ability to run clinical trials and train local medical staff, may be part of an effort to decrease global breast cancer mortality. Citation Format: Jean-Pierre A Blaize, Phillip P Acosta, Isiah Gonzalez, Kristen E Ott, Kate Lathrop. Exploring global clinical trial enrollment opportunities in high breast cancer mortality regions [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-17.

Abstract PS17-41: In depth single cell profiling of a case of bone metastases with associated organoid models reveals a precision medicine approach to treatment

Abstract Occurring in 65-80% of metastatic breast cancer (BC), bone metastasis (BoM) is the major cause of BC related mortality. Under current standard of care, 5 year overall survival for patients with BoM is 20-25%, warranting the need of improved treatments. Like other cancers, BC BoM has high inter- and intra-patient heterogeneity. Thus, understanding disease evolution and heterogeneity of BoM at the individual patient level will be key to guide precise application of targeted therapies. In this study, we describe in depth histologic and single cell molecular characterization of a case of invasive lobular breast cancer (ILC) metastasis to bone. We collected fixed primary tumor (ER+/PR-/HER2- ILC) and fresh pelvis and tibia BoMs from a patient. H&E/IHC staining and whole exome sequencing (WES) of DNA and RNA of the samples were performed. Organoids were derived from the two BoMs and single cell RNA sequencing was applied to these cultures and the BoMs. Based on H&E/IHC staining, this case evolved from a ER+ primary ILC to ER- BoM with mixed lobular and ductal carcinoma features. WES revealed 208 missense somatic mutations in the BoMs. 15 were predicted as BC drivers, two of which are druggable including PIK3CA (E545K) and BRCA1 (D1834H, H399P). Notably, BRCA1 (D1834H) was not found in the primary tumor. Based on RNA sequencing, estrogen signaling was downregulated, while TGF-β, Wnt beta catenin and PI3K signaling, epithelial to mesenchymal transition (EMT) and angiogenesis were upregulated, all of which have been reported to be potential targets in BoMs. scRNAseq of BoMs revealed 5 major cell populations and pronounced heterogeneity. The two BoMs showed similar cellular compositions, including epithelial (30-50%), fibroblasts (50%), immune (5-10%), osteoclasts (1-2%) and endothelial cells (1-2%). Within epithelial cells, there were 5 major clusters exhibiting unique transcriptomic features, including a TNF-α signaling high cluster, two clusters showing high partial EMT (pEMT) signatures majorly regulated by PRRX1/2, TWIST1/2, and FOXS1, a cluster in active cell proliferation, and a cluster showing high signatures related to endocrine resistance. In fibroblasts, 3 clusters were identified representing ECM remodeling, angiogenesis (VEGFA high) and myofibroblasts. Immune cells majorly composed of macrophages, CD4+, CD8+ and Treg T cells. 2.2% tumor and 3.2% T cells express PDL1, exceeding the 1% threshold to select patients eligible for anti-PDL1 therapy. Based on CellPhoneDB, epithelial cells with high pEMT signature show the most interactions and uniquely interact with Treg cells through TNFSF4-TNFRSF4 which has been reported to promote Treg cell proliferation, and is investigated in clinic for immune therapy. Organoids were developed to evaluate therapeutic potential of targetable mutations, upregulated genes and susceptible cell populations. WES showed organoids preserved the mutational signatures of the matched tumor. scRNAseq showed all epithelial populations in the tumor were preserved in the matched organoids at comparable abundance. Consistent with the BRCA1 and PIK3CA mutations, organids were responsive to a PARP (Talazoparib: IC50 1.3uM/1.3uM) and PI3K (Alpelisib: IC50 9uM/4uM) inhibitor. We are currently examining the therapeutic potential of inhibiting pEMT, TNF-α, and genes upregulated in BoM. In summary, we have demonstrated a precision medicine approach to understand the evolution and heterogeneity of BC BoM. We have identified potential therapeutic targets and evaluated those in patient-specific organoids, thereby providing insights for the design of a precision medicine based clinical treatment strategy. Citation Format: Kai Ding, Fangyuan Chen, Nolan Priedigkeit, Daniel D. Brown, Tanya Heim, Rebecca Watters, Kurt Weiss, Jennifer Atkinson, Steffi Oesterreich, Adrian Lee. In depth single cell profiling of a case of bone metastases with associated organoid models reveals a precision medicine approach to treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-41.

Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.

Association between Breast Cancer Screening Intention and Behavior in the Context of Screening Cessation in Older Women.

Breast cancer is the most common life-threatening cancer in women and mammography screening is an important intervention that can reduce breast cancer-related mortality and morbidity.1 Not surprisingly, numerous studies have aimed at promoting the adoption of breast cancer screening.2–7 Based on the Theory of Planned Behavior, which posits that intention is the most important and proximal predictor of behavior,8 studies have found moderate association between breast cancer screening intention and receipt of screening,2,3 and a number of interventions have targeted screening intention as the outcome.4–7 All of these studies focused on increasing screening rates. More recently, there is growing recognition that among women aged 75 and older, the harms and burdens of routine mammography screening may outweigh the benefits.9–11 Therefore, the National Cancer Institute and others have called for interventions to reduce overuse and address screening cessation in older women.12 Screening cessation after decades of participation is likely different than the decision to initiate screening and it is not known how older women’s screening intentions relate to screening behavior in the context of de-implementing screening. Given that it can take years and significant resources to learn if an intervention leads to a reduction in overuse of mammography screening in older women, we aimed to examine among women aged 75 and older if lower intentions to be screened predicts lower screening rates in the context of screening cessation.

Does prioritizing patient safety during the COVID-19 pandemic come at the expense of patient satisfaction?

Does prioritizing patient safety during the COVID-19 pandemic come at the expense of patient satisfaction?

Breast Cancer Mortality among Women with a BRCA1 or BRCA2 Mutation in a Magnetic Resonance Imaging Plus Mammography Screening Program.

Simple SummaryWomen with a BRCA1 or BRCA2 gene mutation have up to an 80% lifetime risk of breast cancer unless their breasts are surgically removed, but many decline or defer surgery and choose screening, hoping that if cancer occurs, it will be detected at a curable stage. In this study 489 women with a BRCA1 or BRCA2 mutation aged from 25 to 65 years, who had never had breast or ovarian cancer, were screened annually with breast magnetic resonance imaging (MRI) in addition to mammography and were followed for an average of 13 years (range: 9 to 23 years). Ninety-five of the 489 women enrolled in the study had a bilateral preventive mastectomy in the follow-up period. Of the 91 women diagnosed with breast cancer, four died of breast cancer. The most common cause of death was ovarian cancer. For women with BRCA mutations who choose annual screening with MRI and mammography, the probability of dying of breast cancer within 20 years is 2%.Annual breast magnetic resonance imaging (MRI) plus mammography is the standard of care for screening women with inherited BRCA1/2 mutations. However, long-term breast cancer-related mortality with screening is unknown. Between 1997 and June 2011, 489 previously unaffected BRCA1/2 mutation carriers aged 25 to 65 years were screened with annual MRI plus mammography on our study. Thereafter, participants were eligible to continue MRI screening through the high-risk Ontario Breast Screening Program. In 2019, our data were linked to the Ontario Cancer Registry of Cancer Care Ontario to identify all incident cancers, vital status and causes of death. Observed breast cancer mortality was compared to expected mortality for age-matched women in the general population. There were 91 women diagnosed with breast cancer (72 invasive and 19 ductal carcinoma in situ (DCIS)) with median follow-up 7.4 (range: 0.1 to 19.2) years. Four deaths from breast cancer were observed, compared to 2.0 deaths expected (standardized mortality ratio (SMR) 2.0, p = 0.14). For the 489 women in the study, the probability of not dying of breast cancer at 20 years from the date of the first MRI was 98.2%. Annual screening with MRI plus mammography is a reasonable option for women who decline or defer risk-reducing mastectomy.

Variations in intrinsic breast cancer characteristics in screen-detected breast cancer patients aged between 45 and 69 and above the age of 70.

Increasing age is a well-recognized risk factor for breast cancer. With an increase in life expectancy of women, more older patients are diagnosed with breast cancer. This study aimed to identify the variations in breast cancer attributes and mortality in different age groups in New Zealand. This was a retrospective study of data from the Auckland Breast Cancer Register between 1 June 2000 and 28 February 2017. Patients who were diagnosed through Breast Screen were included. Group A included those aged between 45 and 69 years. Group B included individuals with an age of 70 years or above. From June 2000 to February 2017, a total of 6304 new cases of new breast cancer were diagnosed through Auckland Breast Screen, with 5788 patients in group A and 516 patients in group B. Group B was more likely to have the lower grade invasive cancers, with fewer grade 3 cancers. Oestrogen receptor positivity was more pronounced in group B, along with progesterone receptor positivity. Conversely, HER-2 receptor was less likely to be positive in group B. There was a significantly higher breast cancer-related mortality in group B (6.0% versus 2.7%). Mortality related to other causes was also much higher in group B as compared to that in group A (12.8% versus 2.5%). Women aged 70 years or above generally tend to have a more favourable type of breast cancer, with a lower tumour grade, oestrogen and progesterone receptor positivity, and lower rate of HER-2 overexpression.

Tamoxifen induces hypercoagulation and alterations in ER\u03b1 and ER\u03b2 dependent on breast cancer sub-phenotype ex vivo

Tamoxifen shows efficacy in reducing breast cancer-related mortality but clinically, is associated with increased risk for thromboembolic events. We aimed to determine whether breast tumour sub-phenotype could predict propensity for thrombosis. We present two ex vivo Models of Tamoxifen-therapy, Model 1 in which treatment recapitulates accumulation within breast tissue, by treating MCF7 and T47D cells directly prior to exposure to blood constituents; and Model 2 in which we recreate circulating Tamoxifen by treating blood constituents prior to exposure to cancer cells. Blood constituents included whole blood, platelet-rich plasma and platelet-poor plasma. Hypercoagulation was assessed as a function of thrombin activity, expression of CD62P and CD63 activation markers defined as an index of platelet activation, and platelet morphology; while oestrogen receptor expression was assessed using immunocytochemistry with quantitative analysis. We determined, in concert with clinical studies and contrary to selected laboratory investigations, that Tamoxifen induces hypercoagulation, dependent on sub-phenotypes, with the T47D cell line capacity most enhanced. We determined a weak positive correlation between oestrogen receptor expression, and CD62P and CD63; indicating an association between tumour invasion profiles and hypercoagulation, however, other yet unknown factors may play a predictive role in defining hypercoagulation.

323 Poster - Is socioeconomic status a barrier for individual breast cancer awareness in developing countries?

Introduction: Though the causes Delayed diagnosis of breast cancer remains a major reason for higher breast cancer related mortality in developing countries are multifactorial, low socioeconomic status and illiteracy is often thought of as one of the prime causes in women to pick up a breast lump and report to the health care system.

Novel Approaches to Screening for Breast Cancer.

Screening for breast cancer reduces breast cancer-related mortality and earlier detection facilitates less aggressive treatment. Unfortunately, current screening modalities are imperfect, suffering from limited sensitivity and high false-positive rates. Novel techniques in the field of breast imaging may soon play a role in breast cancer screening: digital breast tomosynthesis, contrast material-enhanced spectral mammography, US (automated three-dimensional breast US, transmission tomography, elastography, optoacoustic imaging), MRI (abbreviated and ultrafast, diffusion-weighted imaging), and molecular breast imaging. Artificial intelligence and radiomics have the potential to further improve screening strategies. Furthermore, nonimaging-based screening tests such as liquid biopsy and breathing tests may transform the screening landscape. © RSNA, 2020 Online supplemental material is available for this article.

Targeting Signaling Pathways in Inflammatory Breast Cancer.

Simple SummaryInflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer; it is highly likely to spread to other sites in the body. There is an urgent need to establish novel treatment strategies to reduce IBC recurrence and metastasis. The aim of this work is to provide a comprehensive overview of signaling pathways in IBC, covering understanding of their function in IBC tumor cells and cells surrounding tumor, and clinical efforts to target these pathways for patients with IBC. The findings described in this work will help guide the development of effective therapies through preclinical and clinical research, eventually improving the treatment of patients with IBC.Inflammatory breast cancer (IBC), although rare, is the most aggressive type of breast cancer. Only 2–4% of breast cancer cases are classified as IBC, but—owing to its high rate of metastasis and poor prognosis—8% to 10% of breast cancer-related mortality occur in patients with IBC. Currently, IBC-specific targeted therapies are not available, and there is a critical need for novel therapies derived via understanding novel targets. In this review, we summarize the biological functions of critical signaling pathways in the progression of IBC and the preclinical and clinical studies of targeting these pathways in IBC. We also discuss studies of crosstalk between several signaling pathways and the IBC tumor microenvironment.

A high neutrophil-lymphocyte ratio and platelet-lymphocyte ratio are associated with a worse outcome in inflammatory breast cancer

IntroductionInflammatory breast cancer (IBC) is an uncommon, but aggressive form of breast cancer that accounts for a disproportionally high fraction of breast cancer related mortality. The aim of this study was to explore the peripheral immune response and the prognostic value of blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), in a large IBC cohort. Patients & methodsWe retrospectively identified 127 IBC patients and collected lab results from in-hospital medical records. The differential count of leukocytes was determined at the moment of diagnosis, before any therapeutic intervention. A cohort of early stage (n = 108), locally advanced (n = 74) and metastatic breast cancer patients (n = 41) served as a control population. ResultsThe NLR was significantly higher in IBC compared to an early stage breast cancer cohort, but no difference between IBC patients and locally advanced breast cancer patients was noted. In the metastatic setting, there was also no significant difference between IBC and nIBC. However, a high NLR (>4.0) remained a significant predictor of worse outcome in IBC patients (HR: 0.49; 95% CI: 0.24–1.00; P = .05) and a lower platelet-lymphocyte ratio (PLR) (≤210) correlated with a better disease-free survival (DFS) (HR: 0.51; 95% CI: 0.28–0.93; P = .03). ConclusionPatients with a high NLR (>4.0) have a worse overall prognosis in IBC, while the PLR correlated with relapse free survival (RFS). Since NLR and PLR were not specifically associated with IBC disease, they can be seen as markers of more extensive disease.

Abstract 2611: Comparison of 3D culture conditions to develop an in vitro model for breast cancer cell emboli formation

Abstract Inflammatory breast cancer (IBC) is a rare type of breast cancer accounting for 2-4% of all breast cancer patients, but accounts for 7-10% of breast cancer related mortality. IBC is characterized by extensive skin invasion and the formation of tumor cell emboli within the breast and dermal lymphatic system. Characteristics of emboli include cell to cell adhesions mediated by E-cadherin, encoded by the gene CDH1. Studies from our laboratory show that CEBPD is expressed in IBC patient emboli and promotes emboli formation in vitro. Mechanistically we found that CEBPD promotes cell-cell adhesion within emboli at least in part by supporting the expression of E-cadherin adhesion complex proteins. In this study, we compared an in vitro model for intra-lymphatic emboli formation with conditions of tumor sphere formation to begin to address the role of fluid shear in emboli formation and emboli-specific molecular events, if any. We conducted experiments under slow rocking and non-rocking culture conditions with 4 different culture media. We found that the mechanical shear forces (achieved by low speed rocking) generated large, well-compacted emboli-like structures within 24 hours of suspension culture. In the absence of fluid shear, the cells assembled into smaller and more irregular aggregates. In agreement with this, our preliminary data suggest that E-cadherin expression is modestly higher under fluid shear conditions in addition to overall increase under 3D conditions. We are now validating the mechanisms for higher expression of emboli in 3D culture conditions and are designing experiments to address the functional relevance of the pathways for IBC emboli biology. Understanding the molecular mechanisms of emboli formation may provide valuable insights into the uniquely aggressive nature of IBC. Citation Format: Ariana Vitale, Esta Sterneck, Balamurugan Kuppusamy. Comparison of 3D culture conditions to develop an in vitro model for breast cancer cell emboli formation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2611.

Long-term Incidence and Mortality Trends for Breast Cancer in Germany.

Introduction Changes in risk factors and the introduction of mammography screening in 2005 have led to dramatic changes in the breast cancer-associated burden of disease in Germany. This study aimed to investigate long-term disease-related incidence and mortality trends in women from East and West Germany since the reunification of Germany. Methods Total and stage-specific incidence rates were evaluated based on data obtained from selected cancer registries. Sufficiently complete data going back to 1995 were available for 4 East German and 3 West German regions. The figures were weighted for population size, and rates were calculated for the whole of Germany based on the rates for East and West Germany. The study particularly focused on 3 different age groups: women eligible for mammography screening (50 – 69 years), younger women (30 – 49 years) and older women (70+ years). All rates were standardised for age. The mortality rates obtained from the official statistics on cause of death since 1990 were processed accordingly. Results Incidence rates in the observation period increased, as they were affected by the increasing number of cases with early-stage cancers being diagnosed in the screening age group. The total incidence for this group, which included the incidence of non-invasive breast cancers, increased by 14.5% between 2005 and 2016. Early-stage cancers (UICC stages 0 and I) increased by 48.1% while late-stage diagnoses (UICC stages III and IV) decreased by 31.6%. Qualitatively similar changes were noted for the other age groups, although they were less pronounced. The decrease in breast cancer mortality observed since the mid-1990s ended around 2008 for the group of younger women but continued in the screening age group. After 2008, an increase in mortality was observed in the group of older women. The differences in disease burden between East and West Germany (in favour of East Germany) decreased in younger women during the observation period but tended to increase in the group of older women. Conclusion The analysis suggests that the introduction of mammography screening contributed to a decrease in the incidence of advanced-stage breast cancers and in breast cancer-related mortality rates but also resulted in a substantial number of overdiagnoses. The relatively unfavourable incidence trend in the group of younger women, particularly in East Germany, should be interpreted in the context of lifestyle changes. The slight increase in mortality observed in the group of older women after 2008 requires further analysis.

Microbial Alterations and Risk Factors of Breast Cancer: Connections and Mechanistic Insights.

Breast cancer-related mortality remains high worldwide, despite tremendous advances in diagnostics and therapeutics; hence, the quest for better strategies for disease management, as well as the identification of modifiable risk factors, continues. With recent leaps in genomic technologies, microbiota have emerged as major players in most cancers, including breast cancer. Interestingly, microbial alterations have been observed with some of the established risk factors of breast cancer, such as obesity, aging and periodontal disease. Higher levels of estrogen, a risk factor for breast cancer that cross-talks with other risk factors such as alcohol intake, obesity, parity, breastfeeding, early menarche and late menopause, are also modulated by microbial dysbiosis. In this review, we discuss the association between known breast cancer risk factors and altered microbiota. An important question related to microbial dysbiosis and cancer is the underlying mechanisms by which alterations in microbiota can support cancer progression. To this end, we review the involvement of microbial metabolites as effector molecules, the modulation of the metabolism of xenobiotics, the induction of systemic immune modulation, and altered responses to therapy owing to microbial dysbiosis. Given the association of breast cancer risk factors with microbial dysbiosis and the multitude of mechanisms altered by dysbiotic microbiota, an impaired microbiome is, in itself, an important risk factor.

Female breast cancer mortality in relation to puberty on Staten Island, New York.

Pursuant to a Congressional act in 2008, the Department of Health and Human Services established the Interagency Breast Cancer and Environmental Research Coordinating Committee to address the burden of breast cancer in the United States. Subsequently, the Committee recommended researchers study the timing of exposure to breast cancer risk factors. Given the high breast cancer mortality rate on Staten Island, this paper presents a case-control study investigating breast cancer risk associated with puberty while living on Staten Island. The dataset combined New York City Department of Health and Mental Hygiene female death certificate information between 1985 and 2006, with life history information from newspaper obituaries. Data analyzed included: age, length of residence on Staten Island, birth on Staten Island, and residence on Staten Island during puberty. Cases were individuals who died of breast cancer and controls were individuals who died of non-malignant causes. Analysis included multivariate logistic regression on the full dataset and multiple replicates of randomized one case to two controls simulations. Results indicated that living on Staten Island during puberty (ages 9–19) was associated with an elevated risk of dying from breast cancer (odds ratio 1.35, p < 0.001, 95% CI = 1.18, 1.55). This paper suggests the importance of studying puberty as a window of susceptibility for breast cancer risk.

Lymph node ratio as an independent prognostic factor for breast cancer-related mortality in patients with node-positive breast cancer.

This study assessed whether prognostic information could be obtained in patients with lymph node (LN)-positive breast cancer based on their LN ratios (LNRs) and explored the relationships between other potential prognostic factors and survival. This was a retrospective clinical study. This study included 608 women with node-positive nonmetastatic breast cancer. Clinical and pathologic data were retrospectively evaluated. The median age was 51 years (range: 23-84 years). All patients received adjuvant radiotherapy after radical surgery. A total dose of 50 Gy was administered to the chest wall or breast and LN regions with 2 Gy daily fractions. A 10-Gy boost was administered to the breast tumor bed. The cutoff value of LNR was defined as low risk (<0.21) in 278 patients, intermediate risk (0.21-0.65) in 217 patients, and high risk (>0.65) in 113 patients. Prognostic variables included patient characteristics, disease characteristics, and interventional factors. The primary endpoint was overall survival and the secondary endpoint was breast cancer-related mortality. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. P value was required to be <0.05. Within a median follow-up period of 95.4 months (range: 5-232.4 months), overall survival rates for 10 and 15 years were 66% and 53%, respectively. Multivariate analysis revealed that LNR (P = 0.026), estrogen receptor status (ERS) (P = 0.021), age (P = 0.04), and smoking (P = 0.024) were independent significant prognostic factors for overall survival. Breast cancer-related mortality rates at 10 and 15 years were 70.7% and 60%, respectively. LNR (P = 0.03) and ERS (P = 0.002) were independent significant prognostic factors for breast cancer-related mortality. LNR and ERS were significant prognostic factors for survival at all endpoints.

Adjuvant bisphosphonate therapy in early-stage breast cancer-Treating the soil to kill the seed.

Bisphosphonates alter the tumor microenvironment, possibly preventing cancer cell growth in the bone. Analyses of data from numerous clinical trials and a large individual patient-level data meta-analysis have suggested an anti-tumor effect for bisphosphonates in patients with early-stage breast cancer who are postmenopausal. The absolute benefit from the use of bisphosphonates on breast cancer-related mortality reduction mirrors that seen with the use of anthracycline-based chemotherapy versus a first-generation chemotherapy regimen (CMF). In this review, we discuss the evidence base for the use of adjuvant bisphosphonates in early-stage breast cancer and provide recommendations for clinical use.