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Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways., Methods: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers., Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%., Conclusions: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification., (© 2024 American Cancer Society.)

Introduction: Social support, social strain and stressful life events could induce chronic stress, which affects prognosis and survival after breast cancer diagnosis. However, few studies have examined the impact of psychosocial factors on different competing mortality events., Methods: We included 9154 postmenopausal women who were newly diagnosed with invasive breast cancer after enrollment in the Women's Health Initiative, as of March 6th, 2021. Psychosocial factors were collected and stratified into quartiles. Cause of death was verified through adjudicated medical record reviews. Associations between psychosocial factors and all-cause mortality, breast cancer mortality, and cardiovascular disease mortality were examined by competing risk models. Subsequent stratified analyses were performed by race., Results: With a median follow-up time of 8.6 years, 3218 deaths were identified. Compared to participants with less social support, those who had higher social support had significantly lower all-cause mortality (Q4 vs. Q1, HR = 0.89, 95% CI: 0.81, 0.9). The highest quartile of social strain was associated with lower CVD mortality (Q4 vs. Q1: HR = 0.80, 95% CI: 0.65, 0.99). After stratification, a similar relationship was found in White women but not in Black women., Conclusion: Our findings suggest that there was an association between high social support and reduced all-cause mortality regardless of cancer stages at diagnosis. Social support interventions after breast cancer diagnosis could have the potential to reduce overall mortality., (© 2024 The Author(s). Psycho‐Oncology published by John Wiley & Sons Ltd.)

This is the American Cancer Society's biennial update of statistics on breast cancer among women based on high-quality incidence and mortality data from the National Cancer Institute and the Centers for Disease Control and Prevention. Breast cancer incidence continued an upward trend, rising by 1% annually during 2012-2021, largely confined to localized-stage and hormone receptor-positive disease. A steeper increase in women younger than 50 years (1.4% annually) versus 50 years and older (0.7%) overall was only significant among White women. Asian American/Pacific Islander women had the fastest increase in both age groups (2.7% and 2.5% per year, respectively); consequently, young Asian American/Pacific Islander women had the second lowest rate in 2000 (57.4 per 100,000) but the highest rate in 2021 (86.3 per 100,000) alongside White women (86.4 per 100,000), surpassing Black women (81.5 per 100,000). In contrast, the overall breast cancer death rate continuously declined during 1989-2022 by 44% overall, translating to 517,900 fewer breast cancer deaths during this time. However, not all women have experienced this progress; mortality remained unchanged since 1990 in American Indian/Alaska Native women, and Black women have 38% higher mortality than White women despite 5% lower incidence. Although the Black-White disparity partly reflects more triple-negative cancers, Black women have the lowest survival for every breast cancer subtype and stage except localized disease, with which they are 10% less likely to be diagnosed than White women (58% vs. 68%), highlighting disadvantages in social determinants of health. Progress against breast cancer could be accelerated by mitigating racial, ethnic, and social disparities through improved clinical trial representation and access to high-quality screening and treatment., (© 2024 The Author(s). CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: This study aimed to indirectly examine whether the implementation of clinical breast examination-based screening program in Morocco has been successful in downstaging and improving survival rates. Breast cancer patients detected through the screening pathway were compared with those detected through self-referral over the same period in terms of cancer stage at diagnosis, tumor characteristics, care delays, and survival., Methods: A prospective observational study was conducted between April 2019 and August 2020 at two major public oncology centers., Results: A total of 896 women with confirmed breast cancer were recruited (483 were program-referred and 413 were self-referred). The authors did not report any significant difference between the two groups in terms of stage at diagnosis, molecular profile, or histopathological grade. Early-stage cancer (stage I-II) was detected in 55.7% of self-referred participants compared to 55.5% of program-referred participants. Median intervals between symptom recognition, pathological diagnosis, and treatment initiation were not significantly different between the two groups. Similarly, survival after treatment showed no significant difference between patients screened by the program and self-referred patients. The 3-year survival rate after treatment was 94.5% for patients referred through the program and 88.6% for patients not referred through the program (p = .16)., Conclusions: This study highlights the importance of equitable and timely access to high-quality diagnosis and treatment facilities, leading to substantial downstaging and enhanced survival rates. Continued efforts to improve quality and expand coverage to include asymptomatic women will consolidate the health infrastructure gains achieved by the Moroccan breast cancer screening program., (© 2024 World Health Organization; licensed by American Cancer Society. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients., Methods: In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality., Results: Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88)., Conclusions: These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients., (© 2024 American Cancer Society.)

Background: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials., Methods: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status., Results: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m 2 ; p < .001)., Conclusions: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies., (© 2024 American Cancer Society.)

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset., Methods: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05., Results: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS., Conclusions: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Population-based cancer survival is a key indicator for assessing the effectiveness of cancer control by a health care system in a specific geographic area. Breast cancer is the most common cancer among women in India, accounting for over one quarter of all female cancers. The objective of this study was to estimate the 5-year survival of female patients who were diagnosed with breast cancer between 2012 and 2015 from the existing Population-Based Cancer Registries (PBCRs) in India., Methods: In total, 17,331 patients who had breast cancer diagnosed between 2012 and 2015 from 11 PBCRs were followed until June 30, 2021. Active methods were used to track the vital status of registered breast cancer cases. The study conducted survival analysis by calculating the difference between the date of first diagnosis and the date of death or censoring to estimate observed survival and relative survival using the actuarial survival approach and the Ederer-II approach, respectively., Results: The 5-year age-standardized relative survival (95% confidence interval [CI]) of patients with breast cancer was 66.4% (95% CI, 65.5%-67.3%). Mizoram (74.9%; 95% CI, 68.1%-80.8%), Ahmedabad urban (72.7%; 95% CI, 70.3%-74.9%), Kollam (71.5%; 95% CI, 69.2%-73.6%), and Thiruvananthapuram (69.1%; 95% CI, 67.0%-71.2%) had higher survival rates than the national average. Conversely, Pasighat had the lowest survival rate (41.9%; 95% CI, 14.7%-68.6%). The 5-year observed survival rates for localized, regional, and distant metastasis in the pooled PBCRs were 81.0%, 65.5%, and 18.3%, respectively., Conclusions: The overall disparity in survival rates was observed across 11 PBCRs, with lower survival rates reported in Manipur, Tripura, and Pasighat. Therefore, it is imperative to implement comprehensive cancer control strategies widely throughout the country., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The objective of this study was to evaluate the role of low-carbohydrate diets after breast cancer diagnosis in relation to breast cancer-specific and all-cause mortality., Methods: For 9621 women with stage I-III breast cancer from two ongoing cohort studies, the Nurses' Health Study and Nurses' Health Study II, overall low-carbohydrate, animal-rich low-carbohydrate, and plant-rich low-carbohydrate diet scores were calculated by using food frequency questionnaires collected after breast cancer diagnosis., Results: Participants were followed up for a median 12.4 years after breast cancer diagnosis. We documented 1269 deaths due to breast cancer and 3850 all-cause deaths. With the use of Cox proportional hazards regression and after controlling for potential confounding variables, we observed a significantly lower risk of overall mortality among women with breast cancer who had greater adherence to overall low-carbohydrate diets (hazard ratio for quintile 5 vs. quintile 1 [HR Q5vsQ1 ], 0.82; 95% CI, 0.74-0.91; p trend  = .0001) and plant-rich low-carbohydrate diets (HR Q5vsQ1 , 0.73; 95% CI, 0.66-0.82; p trend < .0001) after breast cancer diagnosis but not animal-rich low-carbohydrate diets (HR Q5vsQ1 , 0.93; 95% CI, 0.84-1.04; p trend  = .23). However, greater adherence to overall, animal-rich, or plant-rich low-carbohydrate diets was not significantly associated with a lower risk of breast cancer-specific mortality., Conclusions: This study showed that greater adherence to low-carbohydrate diets, especially plant-rich low-carbohydrate diets, was associated with better overall survival but not breast cancer-specific survival among women with stage I-III breast cancer., (© 2023 American Cancer Society.)

Background: Turning the Page on Breast Cancer (TPBC) uses a multilevel approach to reduce breast cancer (BC) mortality among Black women. TPBC intervenes by (1) improving health care facilities' ability to conduct effective BC screening, follow-up, and treatment; (2) involving community-based organizations; and (3) providing education and personal risk information through a culturally relevant website. Ohio has among the worst BC mortality rates in the United States for Black women. TPBC is in its third year of providing targeted interventions in 12 Ohio counties with particularly high BC rates among Black women., Methods: TPBC enrolls health care facilities, collects organizational and patient data, and conducts key informant interviews to inform the provision of appropriate evidence-based interventions. TPBC engages Black communities through community-based organizations and social media advertising. The TPBC website offers BC information, connects Black women to community BC resources, and provides access to a risk-assessment tool., Results: TPBC has provided tailored information packets, evidence-based interventions, and systematic support for improving the tracking and follow-up of breast health care among patients in 10 clinical partnerships. The project has provided education at community events monthly since mid-2021. The TPBC website (http://endbreastcancerohio.org) is promoted through social media (primarily Facebook) and community events to reach Black women aged 25-70 years. To date, 4108 unique users have visited the website, of whom 15.9% completed the risk assessment., Conclusions: Novel strategies are needed to address persistent disparities in BC outcomes among Black women. TPBC demonstrates the potential effectiveness of multiple methods of community-based, clinic-based, and web-based engagement., Plain Language Summary: Turning the Page on Breast Cancer (TPBC) aims to reduce breast cancer mortality among Black women in Ohio by conducting multilevel, community-engaged interventions in 12 counties. Women are provided risk information and education at virtual and in-person community events and through a community-friendly website that was launched in November 2020. Almost 4000 women have visited the website, which offers community-targeted information, urges screening for individuals at elevated risk, and offers access to patient navigation services; 655 users have used a breast cancer risk-assessment tool on the site. Community-based organizations conduct educational efforts. TPBC partners with health care facilities, which are taught to improve their ability to conduct effective breast cancer screening, follow-up, and treatment. So far, TPBC has provided educational information, evidence-based intervention lists, tailored information packets, and ongoing quarterly support to partners in 10 counties. Evaluation will focus on aggregated data for screening and genetic testing referral at the clinic level., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Evidence on overall survival (OS) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors is generally limited to data from clinical trials or a few observational studies with limited generalizability to Medicare population. The aim of this study was to determine OS benefits associated with CDK4/6 inhibitors in older Medicare patients with hormone receptor (HR)-positive and human epidermal growth factor receptor-2 overexpressing (HER2-) metastatic breast cancer (MBC)., Methods: In a retrospective cohort design, female patients aged ≥65 years with diagnosis of HR+/HER2- MBC from 2015 to 2017 who initiated first-line systemic therapy within 12 months of MBC diagnosis were selected from the Survey Epidemiology and End Results-Medicare database. The effect of treatment type (endocrine therapy [ET]+CDK4/6 inhibitor vs. ET alone) on OS was analyzed using Kaplan-Meier methods and multivariable Cox regression models. Adjusted hazard ratio (aHR) and 95% CIs were estimated., Results: A total of 630 eligible patients were identified (169 patients treated with ET+CDK4/6 inhibitor and 461 patients treated with ET alone). In the Kaplan-Meier analysis, OS rate at 3 years after first-line treatment initiation was 73.0% for ET+CDK4/6 inhibitor versus 49.1% for ET alone (log-rank p < .0001). In Cox regression analysis, first-line ET+CDK4/6 inhibitor therapy was associated with 41% lower rate of mortality versus ET alone (aHR, 0.590; 95% CI, 0.423-0.823)., Conclusions: The findings of this real-world study demonstrate significant OS benefit associated with ET+CDK4/6 inhibitor therapy over ET alone in an older Medicare population of patients with HR+/HER2- MBC, largely consistent with the evidence from clinical trials., (© 2023 American Cancer Society.)

Background: Although racial disparities in breast cancer (BC) mortality have been well documented in the United States, little is known about the impact of coexisting cardiovascular disease (CVD) and other clinical factors on Black-White survival disparities after the diagnosis of BC. This study examined the associations of race, CVD, and clinical factors at diagnosis with the hazard of BC and CVD-related mortality among patients with BC identified from the Maryland Cancer Registry., Methods: A total of 36,088 women (25,181 Whites and 10,907 Blacks) diagnosed with incident invasive BC between 2007 and 2017 were included. Subdistribution hazard ratios (sdHRs) for CVD-related and BC mortality were estimated with Fine and Gray regression models, which accounted for the influence of competing events., Results: After a median follow-up of 5.8 years, 8019 deaths occurred; 3896 were BC deaths, and 1167 deaths were CVD-related. Black women had a higher hazard of BC mortality (sdHR, 1.66; 95% confidence interval [CI], 1.55-1.77) and CVD mortality (sdHR, 1.33; 95% CI, 1.17-1.51) in comparison with White women. Associations with CVD mortality were significantly stronger among Black women aged 50 to 59 years (sdHR, 2.86; 95% CI, 1.84-4.44; P for interaction < .001). Among Black women with CVD, the hazard of BC death was 41% higher in comparison with White women. By treatment, a significant association with CVD mortality was observed only among Black women undergoing surgery and radiation (sdHR, 1.61; 95% CI, 1.22-2.13)., Conclusions: Clinicians should consider the impact of younger age, preexisting CVD, and BC treatments among Black patients. Early identification of those at risk for worse survival may improve surveillance and outcomes., (© 2021 American Cancer Society.)

Background: Breast cancer (BC) is an age-related disease. Long noncoding RNAs (lncRNAs) have been proven to be crucial contributors in tumorigenesis. This study aims to develop a novel lncRNA-based signature to predict elderly BC patients' prognosis., Methods: The RNA expression profiles and corresponding clinical information of 182 elderly BC patients were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) between BC and adjacent normal samples were used to construct the signature in the training set through univariate Cox regression analysis, LASSO regression analysis, and multivariate Cox regression analysis. Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the predictive performance. Besides, we developed the nomogram. Gene set enrichment analysis (GSEA) was performed to reveal the underlying molecular mechanisms., Results: We constructed the five-lncRNA signature (including LEF1-AS1, MEF2C-AS1, ST8SIA6-AS1, LINC01224, and LINC02408) in the training set, which successfully divided the patients into low- and high-risk groups with significantly different prognosis (p = 0.000049), and the AUC at 3 and 5 years of the signature was 0.779 and 0.788, respectively. The predictive performance of this signature was validated in the test and entire set. The 5-lncRNA signature was an independent prognostic factor of OS (p = 0.007) and the nomogram constructed by independent prognostic factors was an accurate predictor of predicting overall survival probability. Besides, several pathways associated with tumorigenesis have been identified by GSEA., Conclusions: The 5-lncRNA signature and nomogram are reliable in predicting elderly BC patients' prognosis and provide clues for clinical decision-making., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Ferroptosis is a novel iron-dependent form of cell death, which is implicated in various diseases including cancers. However, the influence of ferroptosis-related genes on the prognosis of breast cancer remains unclear., Methods: RNA sequencing data of 1053 breast cancer tissue samples and 111 normal tissue samples from The Cancer Genome Atlas (TCGA) were analyzed. Expression levels of 259 ferroptosis-related genes were compared. Gene Ontology (GO) and the Kyoto Gene and Genomic Encyclopedia (KEGG) analyses were conducted on differentially expressed genes. Cox univariate analysis was conducted to explore the potential prognostic biomarkers of breast cancer. Infiltrating immune cell status was assessed., Results: A total of 66 ferroptosis-related genes were differentially expressed in breast cancer tissues. The enriched GO terms included Biological Process (mainly included response to oxidative stress, cellular response to chemical stress, multicellular organismal homeostasis, cofactor metabolic process, response to metal ion, response to steroid hormone, cellular response to oxidative stress, transition metal ion homeostasis, iron ion homeostasis, and cellular iron ion homeostasis), Cellular Component (mainly included apical plasma membrane, early endosome, apical part of cell, lipid droplet, basolateral plasma membrane, blood microparticle, clathrin-coated pit, caveola, astrocyte projection, and pronucleus) and Molecular Function (mainly included iron ion binding, ubiquitin protein ligase binding, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor, ferric iron binding, aldo-keto reductase (NADP) activity, oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, steroid dehydrogenase activity, alditol:NADP+1-oxidoreductase activity, and alcohol dehydrogenase (NADP+) activity). The enriched KEGG pathway mainly included the HIF-1 signaling pathway, NOD-like receptor signaling pathway, ferroptosis, IL-17 signaling pathway, central carbon metabolism in cancer, PPAR signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. Among them, 38 ferroptosis-related genes were significantly associated with the prognosis of breast cancer. The prognostic model was constructed, and breast cancer patients in low-risk group had a better prognosis. In addition, risk score of ferroptosis prognostic model was negatively correlated with B cells (r = -0.063, p = 0.049), CD8+ T cells (r = -0.083, p = 0.010), CD4+ T cells (r = -0.097, p = 0.002), neutrophils (r = -0.068, p = 0.033), and dendritic cells (r = 0.088, p = 0.006)., Conclusions: The ferroptosis pathway plays a key role in breast cancer. Some differentially expressed ferroptosis-related genes can be used as prognostic biomarkers for breast cancer., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Retrospective analyses suggest that capecitabine may carry superior activity in hormone receptor-positive relative to hormone receptor-negative metastatic breast cancer. This review examined the veracity of that finding and explored whether this differential activity extends to early breast cancer., Objectives: To assess effects of chemotherapy regimens containing capecitabine compared with regimens not containing capecitabine for women with hormone receptor-positive versus hormone receptor-negative breast cancer across the three major treatment scenarios: neoadjuvant, adjuvant, metastatic., Search Methods: On 4 June 2019, we searched the Cochrane Breast Cancer Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5) in the Cochrane Library; MEDLINE; Embase; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov., Selection Criteria: Randomised controlled trials looking at chemotherapy regimens containing capecitabine alone or in combination with other agents versus a control or similar regimen without capecitabine for treatment of breast cancer at any stage. The primary outcome measure for metastatic and adjuvant trials was overall survival (OS), and for neoadjuvant studies pathological complete response (pCR)., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and odds ratios (ORs) for dichotomous outcomes, and meta-analysis was performed using a fixed-effect model., Main Results: We included 26 studies with outcome data by hormone receptor: 12 metastatic studies (n = 4325), 6 neoadjuvant trials (n = 3152), and 8 adjuvant studies (n = 13,457). Capecitabine treatment was added in several different ways across studies. These could be classified as capecitabine alone compared to another treatment, capecitabine substituted for part of the control chemotherapy, and capecitabine added to control chemotherapy. In the metastatic setting, the effect of capecitabine was heterogenous between hormone receptor-positive and -negative tumours. For OS, no difference between capecitabine-containing and non-capecitabine-containing regimens was observed for all participants taken together (HR 1.01, 95% confidence interval (CI) 0.98 to 1.05; 12 studies, 4325 participants; high-certainty evidence), for those with hormone receptor-positive disease (HR 0.93, 95% CI 0.84 to 1.04; 7 studies, 1834 participants; high-certainty evidence), and for those with hormone receptor-negative disease (HR 1.00, 95% CI 0.88 to 1.13; 8 studies, 1577 participants; high-certainty evidence). For progression-free survival (PFS), a small improvement was seen for all people (HR 0.89, 95% CI 0.82 to 0.96; 12 studies, 4325 participants; moderate-certainty evidence). This was largely accounted for by a moderate improvement in PFS for inclusion of capecitabine in hormone receptor-positive cancers (HR 0.82, 95% CI 0.73 to 0.91; 7 studies, 1594 participants; moderate-certainty evidence) compared to no difference in PFS for hormone receptor-negative cancers (HR 0.96, 95% CI 0.83 to 1.10; 7 studies, 1122 participants; moderate-certainty evidence). Quality of life was assessed in five studies; in general there did not seem to be differences in global health scores between the two treatment groups at around two years' follow-up. Neoadjuvant studies were highly variable in design, having been undertaken to test various experimental regimens using pathological complete response (pCR) as a surrogate for disease-free survival (DFS) and OS. Across all patients, capecitabine-containing regimens resulted in little difference in pCR in comparison to non-capecitabine-containing regimens (odds ratio (OR) 1.12, 95% CI 0.94 to 1.33; 6 studies, 3152 participants; high-certainty evidence). By subtype, no difference in pCR was observed for either hormone receptor-positive (OR 1.22, 95% CI 0.76 to 1.95; 4 studies, 964 participants; moderate-certainty evidence) or hormone receptor-negative tumours (OR 1.28, 95% CI 0.61 to 2.66; 4 studies, 646 participants; moderate-certainty evidence). Four studies with 2460 people reported longer-term outcomes: these investigators detected no difference in either DFS (HR 1.02, 95% CI 0.86 to 1.21; high-certainty evidence) or OS (HR 0.97, 95% CI 0.77 to 1.23; high-certainty evidence). In the adjuvant setting, a modest improvement in OS was observed across all participants (HR 0.89, 95% CI 0.81 to 0.98; 8 studies, 13,547 participants; moderate-certainty evidence), and no difference in OS was seen in hormone receptor-positive cancers (HR 0.86, 95% CI 0.68 to 1.09; 3 studies, 3683 participants), whereas OS improved in hormone receptor-negative cancers (HR 0.72, 95% CI 0.59 to 0.89; 5 studies, 3432 participants). No difference in DFS or relapse-free survival (RFS) was observed across all participants (HR 0.93, 95% CI 0.86 to 1.01; 8 studies, 13,457 participants; moderate-certainty evidence). As was observed for OS, no difference in DFS/RFS was seen in hormone receptor-positive cancers (HR 1.03, 95% CI 0.91 to 1.17; 5 studies, 5604 participants; moderate-certainty evidence), and improvements in DFS/RFS with inclusion of capecitabine were observed for hormone receptor-negative cancers (HR 0.74, 95% CI 0.64 to 0.86; 7 studies, 3307 participants; moderate-certainty evidence). Adverse effects were reported across all three scenarios. When grade 3 or 4 febrile neutropenia was considered, no difference was seen for capecitabine compared to non-capecitabine regimens in neoadjuvant studies (OR 1.31, 95% CI 0.97 to 1.77; 4 studies, 2890 participants; moderate-certainty evidence), and a marked reduction was seen for capecitabine in adjuvant studies (OR 0.55, 95% CI 0.47 to 0.64; 5 studies, 8086 participants; moderate-certainty evidence). There was an increase in diarrhoea and hand-foot syndrome in neoadjuvant (diarrhoea: OR 1.95, 95% CI 1.32 to 2.89; 3 studies, 2686 participants; hand-foot syndrome: OR 6.77, 95% CI 4.89 to 9.38; 5 studies, 3021 participants; both moderate-certainty evidence) and adjuvant trials (diarrhoea: OR 2.46, 95% CI 2.01 to 3.01; hand-foot syndrome: OR 13.60, 95% CI 10.65 to 17.37; 8 studies, 11,207 participants; moderate-certainty evidence for both outcomes)., Authors' Conclusions: In summary, a moderate PFS benefit by including capecitabine was seen only in hormone receptor-positive cancers in metastatic studies. No benefit of capecitabine for pCR was noted overall or in hormone receptor subgroups when included in neoadjuvant therapy. In contrast, the addition of capecitabine in the adjuvant setting led to improved outcomes for OS and DFS in hormone receptor-negative cancer. Future studies should stratify by hormone receptor and triple-negative breast cancer (TNBC) status to clarify the differential effects of capecitabine in these subgroups across all treatment scenarios, to optimally guide capecitabine inclusion., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The majority of women in Nigeria present with advanced-stage breast cancer. To address the role of geospatial access, we constructed a geographic information-system-based model to evaluate the relationship between modeled travel time, stage at presentation, and overall survival among patients with breast cancer in Nigeria., Methods: Consecutive patients were identified from a single-institution, prospective breast cancer database (May 2009-January 2019). Patients were geographically located, and travel time to the hospital was generated using a cost-distance model that utilized open-source data. The relationships between travel time, stage at presentation, and overall survival were evaluated with logistic regression and survival analyses. Models were adjusted for age, level of education, and socioeconomic status., Results: From 635 patients, 609 were successfully geographically located. The median age of the cohort was 49 years (interquartile range [IQR], 40-58 years); 84% presented with ≥stage III disease. Overall, 46.5% underwent surgery; 70.8% received systemic chemotherapy. The median estimated travel time for the cohort was 45 minutes (IQR, 7.9-79.3 minutes). Patients in the highest travel-time quintile had a 2.8-fold increase in the odds of presenting with stage III or IV disease relative to patients in the lowest travel-time quintile (P = .006). Travel time ≥30 minutes was associated with an increased risk of death (HR, 1.65; P = .004)., Conclusions: Geospatial access to a tertiary care facility is independently associated with stage at presentation and overall survival among patients with breast cancer in Nigeria. Addressing disparities in access will be essential to ensure the development of an equitable health policy., (© 2020 American Cancer Society.)

Background: Data from a nationwide sample of US breast cancer survivors were used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health-related quality of life (HRQOL). Associations between postdiagnosis HRQOL and mortality were then evaluated., Methods: The authors identified female breast cancer survivors (n = 2453) from the Sister Study or Two Sister Study who were at least 1 year from breast cancer diagnosis and who had responded to a survivorship survey in 2012. HRQOL was assessed with the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 measures. Multivariable linear regression was used to assess predictors associated with HRQOL. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HRQOL and all-cause mortality., Results: HRQOL, assessed an average of 4.9 years after the cancer diagnosis (standard deviation of 1.9 years), was negatively associated with a higher cancer stage at diagnosis; a higher comorbidity score at the survey; experience of surgical complications; dissatisfaction with breast surgery; and experience of any recent recurrence, metastasis, or secondary malignancy. Since the completion of the survey, there were 85 deaths (3.5%) during a mean follow-up of 4 years (standard deviation of 0.5 years). In multivariate models, decreases in PROMIS physical T scores and mental T scores were associated with increased mortality (HR for physical T scores, 1.08; 95% CI, 1.05-1.11; HR for mental T scores, 1.03; 95% CI, 1.01-1.06)., Conclusions: Prognostic and cancer treatment-related factors affect HRQOL in breast cancer survivors and may inform targeted survivorship care. PROMIS global health measures may offer additional insights into patients' well-being and mortality risk., Lay Summary: Findings from a study suggest that prognostic and cancer treatment-related factors affect health-related quality of life (HRQOL) in breast cancer survivors and that poor HRQOL may increase the mortality risk. The evaluation of HRQOL is important because it may hold potential as a tool for optimizing survivorship care., (© 2020 American Cancer Society.)

Background: The number of elderly cancer survivors is growing because of increasing survival rates. A high comorbidity burden in the elderly can affect their quality of life and survival. The aim of this study was to examine whether breast cancer survivors and population-based controls have a different comorbidity burden after long-term follow-up., Methods: This study used data from a German breast cancer case-control study, which initially comprised 3813 breast cancer cases aged 50 to 74 years who were diagnosed between 2002 and 2005 and 7341 population-based controls. Participants were followed up in 2014/2016. A modified Charlson Comorbidity Index (mCCI) was calculated to quantify severe comorbidities. Negative binomial regression was performed to estimate rate ratios (RRs) with 95% confidence intervals (CIs) for the association between case-control status and mCCI (dependent variable) for the baseline population and for those who participated at follow-up, with adjustments made for relevant lifestyle factors., Results: In total, 1925 cases and 3674 controls participated in the follow-up 12 years after recruitment. In the baseline population 35% had at least 1 comorbid condition.In long-term survivors this proportion was 52%. No difference was found in the mCCI between breast cancer cases and controls at baseline (RR, 1.05; 95% CI, 0.98-1.11) or between long-term survivors of the 2 groups at baseline (RR, 1.07; 95% CI, 0.97-1.18) or at follow-up (RR, 1.00; 95% CI, 0.91-1.10)., Conclusions: The comorbidity burden of long-term breast cancer survivors and controls increased over time; however, it remained similar in both groups after 12 years of follow-up., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The cancer stage at diagnosis, treatment delays, and breast cancer mortality vary with insurance status., Methods: Using the Missouri Cancer Registry, this analysis included 31,485 women diagnosed with invasive breast cancer from January 1, 2007, to December 31, 2015. Odds ratios (ORs) of a late-stage (stage III or IV) diagnosis and a treatment delay (>60 days after the diagnosis) were calculated with logistic regression. The hazard ratio (HR) of breast cancer mortality was calculated with Cox proportional hazards regression. Mediation analysis was used to quantify the individual contributions of each covariate to mortality., Results: The OR of a late-stage diagnosis was higher for patients with Medicaid (OR, 1.72; 95% confidence interval [CI], 1.56-1.91) or no insurance (OR, 2.30; 95% CI, 1.91-2.78) in comparison with privately insured patients. Medicare (OR, 1.21; 95% CI, 1.10-1.37), Medicaid (OR, 1.60; 95% CI, 1.37-1.85), and uninsured patients (OR, 1.58; 95% CI, 1.18-2.12) had higher odds of a treatment delay. The HR of breast cancer-specific mortality was significantly increased in the groups with public insurance or no insurance and decreased after sequential adjustments for sociodemographic factors (HR, 2.39; 95% CI, 1.96-2.91), tumor characteristics (HR, 1.28; 95% CI, 1.05-1.56), and treatment (HR, 1.23; 95% CI, 1.01-1.50). Late-stage diagnoses accounted for 72.5% of breast cancer mortality in the uninsured., Conclusions: Compared with the privately insured, women with public or no insurance had a higher risk for advanced breast cancer, a >60-day treatment delay, and death from breast cancer. Particularly for the uninsured, Medicaid expansion and increased funding for education and screening programs could decrease breast cancer disparities., (© 2020 American Cancer Society.)

Background: Louisiana is one of the few Southern states that enacted the Medicaid expansion of the Patient Protection and Affordable Care Act (ACA). To the authors' knowledge, the issue of how this has affected the breast cancer landscape in Louisiana is unknown. The authors have postulated that ACA expansion had a positive impact for Louisiana women diagnosed with breast cancer., Methods: Data from the Louisiana Tumor Registry regarding 14,640 women aged 20 to 64 years who resided in Louisiana and were diagnosed with American Joint Committee on Cancer stage 0 to stage IV breast cancer between 2012 and 2018 were analyzed. The study period was divided into 2 groups: 1) before ACA expansion (January 1, 2012-May 31, 2016); and 2) after ACA expansion (June 1, 2016-December 31, 2018). The chi-square test and multivariable logistic regression models were used to assess the impact of ACA expansion. A P value <.05 was considered statistically significant., Results: After ACA expansion, the rate of uninsured patients decreased from 5.4% to 3.0% (P < .0001), and the rate of Medicaid recipients increased from 11.6% to 17.7% (P < .0001). The diagnosis of stage I breast cancer increased from 36.8% to 44.7% (P < .0001), whereas the diagnosis of stage III breast cancer decreased from 10.7% to 8.5% (P < .0001). The receipt of radiotherapy after breast-conserving surgery increased from 81.2% to 84.0% (P = .0035), and the receipt of radiotherapy within 90 days increased from 57.2% to 61.7% (P = .0012). After adjustment for sociodemographic and clinical variables, the models demonstrated that ACA expansion decreased the uninsured rate by 48% (odds ratio [OR], 0.52; 95% CI, 0.43-0.63), increased the diagnosis of early-stage disease (stage0 to stage II) by 27% (OR, 1.27; 95% CI, 1.15-1.41), increased receipt of radiotherapy after breast-conserving surgery by 19% (OR, 1.19; 95% CI, 1.03-1.37), and reduced the delay of receipt of radiotherapy by 16% (OR, 0.84; 95% CI, 0.74-0.95)., Conclusions: ACA expansion in Louisiana reduced the uninsured rate, increased the diagnosis of early-stage disease, and increased access to treatment., (© 2020 American Cancer Society.)

Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor-positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1-98 trial., Methods: BIG 1-98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow-up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post-DR survival., Results: The median follow-up time after DR was 59 months (interquartile range, 29-88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post-DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P = .21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15-1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00-1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05-1.64), progesterone receptor (PR)-negative tumors (HR, 1.25; 95% CI, 1.02-1.52), or shorter disease-free survival (DFS) had significantly worse post-DR survival., Conclusions: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high-risk features remain prognostic in the metastatic setting., (© 2020 American Cancer Society.)

Background: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer., Methods: This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival., Results: After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42)., Conclusions: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation., Lay Summary: This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer., (© 2020 American Cancer Society.)

Background: As circular RNAs (circRNAs) have been found to significantly involve in the onset and progression of multiple malignant tumors including breast cancer (BC), this study aims at evaluating the diagnostic and prognostic values of circRNAs in this malady., Methods: Available databases were thoroughly searched to collect studies on the diagnosis and/or prognosis of BC using circRNA profiling. The updated Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool and the Newcastle Ottawa Scale (NOS) were used to assess the underlying bias of included studies. Clinical characteristics of the studies were merged by the quantitative-weighted integral method to obtain the combined effects., Results: Sixteen studies were included, comprising 2438 BC cases and 271 noncancerous controls. The expression signature covered 24 circRNAs (down-regulated: circ-VRK1, hsa&#95;circ&#95;0068033, hsa&#95;circ&#95;103110, hsa&#95;circ&#95;104689, and hsa&#95;circ&#95;104821; up-regulated: circAGFG1, hsa&#95;circ&#95;0001785, hsa&#95;circ&#95;0108942, hsa&#95;circ&#95;0001785, hsa&#95;circ&#95;006054, hsa&#95;circ&#95;100219, hsa&#95;circ&#95;406697, circEPSTI1, circANKS1B, circGFRA1, circ&#95;0103552, CDR1-AS, has&#95;circ&#95;001569, hsa&#95;circ&#95;001783, circFBXL5, circ&#95;0005230, circAGFG1, circ-UBAP2, and circ&#95;0006528). The sensitivity and specificity of circRNAs in distinguishing BC patients from noncancerous controls were 0.65 and 0.68, and the corresponding area under the curve was 0.66. Survival analysis revealed that patients showing highly expressed oncogenic circRNAs were associated with increased mortality risks of BC in overall survival (univariate analysis: hazard ratio [HR] = 3.30, P = .000; multivariate analysis: HR = 3.07, P = .000), and disease-free survival (HR = 8.26, P = .000). Stratified analysis based on circRNA expression status and control type also showed robust results., Conclusions: Circular RNA profiling presents prominent diagnostic and prognostic values in BC, and can be rated as a promising tool facilitating its early diagnosis and survival., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, LLC.)

Background: Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer., Objectives: To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events., Search Methods: We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies., Selection Criteria: We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods., Main Results: We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 μg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Invasive lobular breast cancer (BC) is the second most common BC subtype. Prognostic parameters (tumor classification, lymph node status, histologic grade, Oncotype DX recurrence score [RS], progesterone receptor status, and Ki67 index) were retrospectively studied in a large, prospective clinical trial encompassing 2585 patients who had hormone receptor-positive early BC (the West German Study Group PlanB trial)., Methods: BCs were centrally reviewed and classified as lobular (n = 353; 14%) or nonlobular (n = 2232; 86%). The median follow-up was 60 months. Five-year disease-free survival (DFS) estimates were obtained using the Kaplan-Meier method. Prognostic parameters were evaluated using Cox proportional hazard models., Results: Lobular BC was associated with higher tumor classification, higher lymph node status, lower histologic grade, lower Ki67 index, and low or intermediate RS. The prevalence of high RS (RS range, 26-100) was 3-fold lower in patients who had lobular BC compared with those who had nonlobular BC (8% vs 24%; P < .001). However, 5-year DFS estimates for lobular and nonlobular BC were similar (92.1% and 92.3%, respectively; P = .673). In multivariate analyses, prognostic parameters for DFS in lobular BC included grade 3 (hazard ratio, 5.06; 95% CI, 1.91-13.39) and a pathologic lymph node status (pN) of pN3 (hazard ratio, 12.16; 95% CI, 3.87-38.24), but not RS. By contrast, prognostic parameters in nonlobular BC included grade 3 (hazard ratio, 1.65; 95% CI, 1.11-2.44), pN3 (hazard ratio, 3.68; 95% CI, 1.60-8.46), and high RS (hazard ratio, 2.49; 95% CI, 1.69-3.68)., Conclusions: Lobular BC is associated with low and intermediate RS, although 5-year DFS is similar to that of nonlobular BC. The effect of the RS in lobular BC appears to be distinct from that in nonlobular BC. For risk assessment, the RS needs to be complemented by clinicopathologic parameters for therapy decision making., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Assuming the proportional hazards model and non-informative censoring, the full likelihood approach is used to obtain two new residuals. The first residual is based on the ideas used in obtaining score-type residuals similar to the partial likelihood approach. The second type of residual is based on the concept of deviance residuals. Extensive simulations are conducted to compare the performance of the residuals from the full likelihood-based approach with those of the partial likelihood method. We demonstrate through simulation studies that the full likelihood-based residuals are more efficient than their partial likelihood counterpart in identifying potential outliers when the censoring proportion is high. The graphical techniques are used to illustrate the applications of these residuals using some examples., (© 2020 John Wiley & Sons Ltd.)

Background: Insulin resistance is associated with higher all-cause and cancer-specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants., Methods: A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage-enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause)., Results: During a median of 19.8 years of follow-up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA-IR quartile (HR, 1.34; 95% CI, 1.12-1.61 [P for trend = .003]). Although HOMA-IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60-1.79), women in the highest versus those in the lowest HOMA-IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32-2.39 [P for trend <.001])., Conclusions: Higher levels of insulin resistance in postmenopausal women are associated with higher breast cancer incidence and higher all-cause mortality after breast cancer., (© 2020 American Cancer Society.)

Background: It is of paramount importance to evaluate the impact of participation in organized mammography service screening independently from changes in breast cancer treatment. This can be done by measuring the incidence of fatal breast cancer, which is based on the date of diagnosis and not on the date of death., Methods: Among 549,091 women, covering approximately 30% of the Swedish screening-eligible population, the authors calculated the incidence rates of 2473 breast cancers that were fatal within 10 years after diagnosis and the incidence rates of 9737 advanced breast cancers. Data regarding each breast cancer diagnosis and the cause and date of death of each breast cancer case were gathered from national Swedish registries. Tumor characteristics were collected from regional cancer centers. Aggregated data concerning invitation and participation were provided by Sectra Medical Systems AB. Incidence rates were analyzed using Poisson regression., Results: Women who participated in mammography screening had a statistically significant 41% reduction in their risk of dying of breast cancer within 10 years (relative risk, 0.59; 95% CI, 0.51-0.68 [P < .001]) and a 25% reduction in the rate of advanced breast cancers (relative risk, 0.75; 95% CI, 0.66-0.84 [P < .001])., Conclusions: Substantial reductions in the incidence rate of breast cancers that were fatal within 10 years after diagnosis and in the advanced breast cancer rate were found in this contemporaneous comparison of women participating versus those not participating in screening. These benefits appeared to be independent of recent changes in treatment regimens., (© 2020 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Objective: We aimed to evaluate the correlation of circular RNA La-related RNA-binding protein 4 (circ-LARP4) with tumor characteristics and prognosis, and its effect on chemosensitivity in breast cancer., Methods: Circ-LARP4 from tumor and adjacent tissues of 283 female breast cancer patients underwent resection was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor features, disease-free survival (DFS), and overall survival (OS) were recorded. In vitro, circ-LARP4 in human normal mammary epithelial cells (HMEC) and breast cancer cell lines was detected by RT-qPCR. MCF-7 and MDA-MB-231 cells were transfected with circ-LARP4 overexpression plasmid (as OE-Circ group) and control overexpression plasmid (as OE-Control group). Relative cell viability under different concentrations of doxorubicin was measured., Results: Circ-LARP4 was decreased in tumor tissues than adjacent tissues (P < .001). Tumor circ-LARP4 negatively correlated with tumor size (P = .001), T stage (P = .009), N stage (P = .006), and TNM stage (P < .001), whereas positively correlated with DFS (P = .004) and OS (P < .001). In vitro, circ-LARP4 was decreased MCF-7, BT474, MDA-MB-231, and MDA-MB-468 cell lines than HMEC (all P < .001). Relatively cell viability of MCF-7 cells (at 20 nmol/L [P < .05], 40 nmol/L [P < .01], 80 nmol/L [P < .05] of doxorubicin) and MDA-MB-231 cells (at 120 nmol/L [P < .05], 240 nmol/L [P < .05] of doxorubicin) was decreased in OE-Circ group than OE-Control group. IC 50 value of doxorubicin was decreased in OE-Circ group than OE-Control group in MCF-7 and MDA-MB-231 cell lines (both P < .01)., Conclusion: Circ-LARP4 was a potential prognostic biomarker, which might improve the management of breast cancer., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: Among Latinas with breast cancer, residence in an ethnic enclave may be associated with survival. However, findings from prior studies are inconsistent., Methods: The authors conducted parallel analyses of California and Texas cancer registry data for adult (aged ≥18 years) Latinas who were diagnosed with invasive breast cancer from 1996 to 2005, with follow-up through 2014. Existing indices applied to tract-level 2000 US Census data were used to measure Latinx enclaves and neighborhood socioeconomic status (nSES). Multivariable Cox proportional hazard models were fit for all-cause and breast cancer-specific survival adjusted for year of diagnosis, patient age, nativity (with multiple imputation), tumor stage, histology, grade, size, and clustering by census tract., Results: Among 38,858 Latinas, the majority (61.3% in California and 70.5% in Texas) lived in enclaves. In fully adjusted models for both states, foreign-born women were found to be more likely to die of breast cancer and all causes when compared with US-born women. Living in enclaves and in neighborhoods with higher SES were found to be independently associated with improved survival from both causes. When combined into a 4-level variable, those in low nSES nonenclaves had worse survival for both causes compared with those living in low nSES enclaves and, in the all-cause but not breast cancer-specific models, those in high nSES neighborhoods, regardless of enclave status, had improved survival from all causes., Conclusions: Applying the same methods across 2 states eliminated previously published inconsistent associations between enclave residence and breast cancer survival. Future studies should identify specific protective effects of enclave residence to inform interventions., (© 2020 American Cancer Society.)

Objective: Sex-determining region Y-box 30 (SOX30) suppresses progression of several cancers, whereas its role in breast cancer is unclear. Therefore, we aimed to determine the correlation of SOX30 with tumor characteristics and prognosis in breast cancer patients., Methods: The tumor samples of 510 breast cancer patients who underwent resection were obtained, and SOX30 expression was analyzed by immunohistochemistry. Clinical characteristics, disease-free survival (DFS), and overall survival (OS) of breast cancer patients were recorded., Results: There were 368 breast cancer patients in SOX30 low-expression group and 142 in SOX30 high-expression group. SOX30 was negatively correlated with tumor size (P = .010), tumor (T) stage (P < .001), node (N) stage (P = .001), and tumor, node, metastasis (TNM) stage (P < .001) in breast cancer patients. For prognosis, patients in SOX30 high-expression group had prolonged DFS (P = .011) and OS (P = .002); moreover, increased SOX30 grade (assessed by semi-quantitative scoring method assessment) was correlated with better DFS (P = .015) and OS (P = .014). Univariate Cox's regression analysis disclosed that SOX30 high expression was correlated with enhanced DFS (P = .012, hazard ratio (HR) = 0.582) and OS (P = .002, HR = 0.389); however, multivariate Cox's regression analysis revealed that SOX30 could not independently predict DFS (P = .224, HR = 0.766) or OS (P = .087, HR = 0.582) in breast cancer patients, indicating it might interact with other independent predictive factors (such as pathological differentiation, T stage, and N stage) to influence DFS and OS in breast cancer patients., Conclusion: Sex-determining region Y-box 30 is a potential prognostic biomarker in breast cancer, which might contribute to the better outcome of breast cancer patients., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Background: The Centers for Disease Control and Prevention, the American Cancer Society, the National Cancer Institute, and the North American Association of Central Cancer Registries collaborate to provide annual updates on cancer occurrence and trends in the United States and to address a special topic of interest. Part I of this report focuses on national cancer statistics, and part 2 characterizes progress in achieving select Healthy People 2020 cancer objectives., Methods: For this report, the authors selected objectives-including death rates, cancer screening, and major risk factors-related to 4 common cancers (lung, colorectal, female breast, and prostate). Baseline values, recent values, and the percentage change from baseline to recent values were examined overall and by select sociodemographic characteristics. Data from national surveillance systems were obtained from the Healthy People 2020 website., Results: Targets for death rates were met overall and in most sociodemographic groups, but not among males, blacks, or individuals in rural areas, although these groups did experience larger decreases in rates compared with other groups. During 2007 through 2017, cancer death rates decreased 15% overall, ranging from -4% (rural) to -22% (metropolitan). Targets for breast and colorectal cancer screening were not yet met overall or in any sociodemographic groups except those with the highest educational attainment, whereas lung cancer screening was generally low (<10%). Targets were not yet met overall for cigarette smoking, recent smoking cessation, excessive alcohol use, or obesity but were met for secondhand smoke exposure and physical activity. Some sociodemographic groups did not meet targets or had less improvement than others toward reaching objectives., Conclusions: Monitoring trends in cancer risk factors, screening test use, and mortality can help assess the progress made toward decreasing the cancer burden in the United States. Although many interventions to reduce cancer risk factors and promote healthy behaviors are proven to work, they may not be equitably applied or work well in every community. Implementing cancer prevention and control interventions that are sustainable, focused, and culturally appropriate may boost success in communities with the greatest need, ensuring that all Americans can access a path to long, healthy, cancer-free lives., (© 2020 American Cancer Society.)

Background: In previous research, we found diabetes rather than obesity was an independent risk factor of breast cancer. However, why diabetes could lead to increased risk of breast cancer patients remains elusive. Long non-coding RNAE330013P06 has been shown to be upregulated in diabetes, and long non-coding RNAs generally promote progression of cancer., Methods: About 200 specimens of breast patients were obtained in previous clinical trial; 34 samples diagnosed as type 2 diabetes in breast cancer patient were enrolled in this research. Blood samples from 36 patients diagnosed as breast cancer without diabetes; 35 diabetic patients and 35 healthy peoples were obtained as control. All blood samples were measured by quantitative real-time PCR (qRT-PCR). Invasion and migration were tested by Transwell assay. Cell proliferation assay was tested by CCK-8. Protein analysis was determined by Western blot., Results: Compared with breast cancer patients without diabetes, diabetic patients without breast cancer and healthy peoples, LncRNAE330013P06 was upregulated in breast cancer patient with diabetes. Furthermore, of 34 breast patients, high LncRNAE330013P06 expression was significantly associated with family history, tumor-node-metastasis stage and lymph node metastasis. E33 promoted cancer cell growth in vitro via downregulation of P53., Conclusion: Upregulation of LncRNAE330013P06 driven by type 2 diabetes is one of the factors which promoted progression of breast cancer., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Purpose: Clinical trials have clearly documented the survival benefit of aromatase inhibitors (AIs); however, many women fail to initiate (primary nonadherence) or remain adherent to AIs (secondary nonadherence). Prior studies have found that costs impact secondary nonadherence to medications but have failed to examine primary nonadherence. The purpose of this study is to examine primary and secondary adherence following the reduction in copays due to the introduction of generic AIs., Methods: Using Surveillance, Epidemiology, and End Results-Medicare data, we identified 50 054 women diagnosed with incident breast cancer between 2008 and 2013. We compare women whose copays would change and those whose would not, due to the receipt of cost-sharing subsidies before and after generics were introduced using a difference-in-difference (DinD) analysis. To examine primary and secondary nonadherence, we rely on a multistate model with four states (Not yet initiated, User, Not Using, and Death). We adjusted for baseline factors using inverse probability treatment weights and then simulated adherence for 36 months following diagnosis., Results: The generic introduction of AIs resulted in patients initiating AIs faster (DinD = -4.7%, 95%CI = -7.0, -2.3; patients not yet initiating treatment at 6-months), being more adherent (DinD ranging in absolute increase of 8.1%-10.4%) and being less likely to not be using the therapy (DinD range in absolute decrease of 1.2% at 6 months to 8.8% at 24 months) for women that do not receive a subsidy after generics were available., Conclusions: Introduction of generic alternatives to AIs significantly reduced primary and secondary nonadherence., (© 2020 John Wiley & Sons Ltd.)

Background: The focus on noncancer causes of death in patients with breast cancer (BC) remains superficial. The objective of the current study was to assess and quantify causes of death after BC diagnosis., Methods: In total, 754,270 women with BC in the United States who were diagnosed during 2000 through 2015 and retrieved from the Surveillance, Epidemiology, and End Results (SEER) program were studied. Standardized mortality ratios (SMRs) for causes of death were calculated., Results: Of the included patients, 183,002 (24.3%) died during the follow-up period. The greatest proportion of deaths (46.2%) occurred within 1 to 5 years after diagnosis. Most deaths occurred from BC itself or from other cancers, and the number of BC deaths decreased as more years passed after diagnosis. The most common noncancer causes of death within <10 years after diagnosis were heart diseases followed by cerebrovascular diseases. However, >10 years after diagnosis, the most common noncancer causes of death were heart diseases followed by Alzheimer disease. Patients had a statistically significant higher risk of death from chronic liver diseases within 5 to 10 years after diagnosis compared with the general population (SMR, 1.23; 95% CI, 1.09-1.38) and had statistically significant higher risks of death from Alzheimer disease (SMR, 1.21; 95% CI, 1.14-1.29) and from diseases of the heart (SMR, 1.06; 95% CI, 1.02-1.09) >10 years after diagnosis., Conclusions: Although BC remains the most common cause of death after BC diagnosis, other non-BC causes of death (mainly heart and cerebrovascular diseases) represent a significant number of deaths among patients with BC. These findings provide important insight into how BC survivors should be counselled regarding future health risks., (© 2019 American Cancer Society.)

Background: Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment., Objectives: To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer., Search Methods: For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions., Selection Criteria: We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided., Main Results: This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS. High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively). Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence). Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence). Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups., Authors' Conclusions: This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time., Methods: Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts., Results: Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years)., Conclusions: Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade., (© 2019 American Cancer Society.)

The data supporting hypofractionated post-mastectomy radiotherapy is limited. The purpose of this study is to present the experience from Tarnów of hypofractionated PMRT over 20 fractions with respect to toxicity and effectiveness. We delivered post-mastectomy radiotherapy at the dose of 45 Gy in 20 fractions to the chest wall and the draining regional lymph nodes. The primary outcome of interest was to ensure that the rate of grade 3 or greater toxicity from the hypofractionation, at any time point, was non-inferior to standard post-mastectomy radiotherapy. We conducted a retrospective analysis of 211 women with stages I-IV breast cancer. After a median follow-up of 30 months, there were four reported grade 3 toxicities, with grade 3 lymphedema being the most frequent (1.5%). There were 134 reported grade 2 toxicities, with grade 2 fatigue being the most frequent (18%). There were six instances of isolated locoregional (6 of 211; 2.8%). Three-year estimated local recurrence-free survival was 96.4% (95% CI 0.921-0.984). The 3-year estimated distant recurrence-free survival was 77.8% (95% CI 0.699-0.838). To our knowledge, the results presented here are the largest single institution experience of hypofractionated post-mastectomy radiotherapy published in the literature to date. Our fractionation scheme, 45 Gy in 20 fractions, seems to be safe and effective with low toxicity., (© 2019 Wiley Periodicals, Inc.)

To assess the efficacy, and the acute and late toxicity of hypofractionated radiotherapy (Hypo-RT), and the impact of age and comorbidities on disease progression and death in elderly breast cancer (BC) patients. Women aged ≥65 years who received Hypo-RT (42.4 Gy in 16 fractions, plus a boost for high-risk patients) were considered for the present analysis. Competing risk analysis was used to estimate the 5-year cumulative incidence of BC progression and BC-related death, calculating the adjusted subhazard ratios (SHR) with 95% confidence intervals (95%CI) in relation to age, hypertension-augmented Charlson Comorbidity Index (hCCI), tumor characteristics, and chemotherapy. The sample included 794 patients with a median age of 74 years (range 65-91 years). At the baseline, 70% of these patients had at least one comorbidity. With a median follow-up of 48.3 months, the 5-year cumulative incidence of BC progression and BC-related death was 6.7% (95%CI 4.8%-9.2%) and 2.3% (95%CI 1.2%-3.9%), respectively. Old age (≥80 years) and a high burden of comorbidity (hCCI ≥ 2) were independently associated with BC progression. Hypo-RT is safe in elderly BC patients, but age and comorbidities influence BC progression. Further studies are warranted., (© 2019 Wiley Periodicals, Inc.)

Background: Breast cancer subtypes are associated with distinct metastatic patterns. Whether germline BRCA1/BRCA2 mutation status is independently associated with central nervous system (CNS) relapse, controlling for tumor subtype, is unknown., Methods: Patients who were treated at Dana-Farber Cancer Institute and diagnosed with a first locoregional recurrence (LRR) or metastasis between 1981 and 2014 were identified using 2 institutional registries: 1) patients treated for recurrent breast cancer and 2) patients who underwent BRCA testing. The frequencies of LRR, sites of metastasis, and breast cancer-specific survival from LRR or metastasis were calculated, and the factors associated with CNS recurrence were evaluated using multivariable logistic regression models., Results: The final study cohort included 30 BRCA1 mutation carriers, 32 BRCA2 mutation carriers, and 270 noncarriers. Most BRCA1 carriers (73%) had triple-negative breast cancer; whereas most BRCA2 carriers (72%) had hormone receptor-positive tumors. BRCA1 carriers frequently experienced lung and distant lymph node metastasis, whereas BRCA2 carriers and noncarriers most often experienced bone metastasis. Although CNS disease occurred frequently in both BRCA1 and BRCA2 carriers (53% BRCA1, 50% BRCA2, 25% noncarriers; P < .001), only BRCA2 mutation (P = .006) was significantly associated with CNS metastasis in multivariable analysis controlling for tumor subtype. BRCA2 mutation (P = .01), triple-negative subtype (P < .001), and the involvement of CNS (P < .001) and other non-CNS distant sites (relative to locoregional recurrence or contralateral disease; P < .001) at presentation of recurrent breast cancer were associated with risk for mortality., Conclusions: CNS involvement is frequent in women with germline BRCA1/BRCA2 mutations who have metastatic breast cancer. BRCA2 mutation carriers had a significantly higher frequency of CNS metastasis than noncarriers when controlling for breast cancer subtype., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: The extent of breast cancer outcome disparity can be measured by comparing Surveillance, Epidemiology, and End Results (SEER) breast cancer-specific survival (BCSS) by region and with institutional cohort (IC) rates., Methods: Patients who were diagnosed with a first primary, de novo, stage IV breast cancer at ages 25 to 84 years from 1990 to 2011 were studied. The change in 5-year BCSS over time from 1990 to 2011 was compared using the SEER 9 registries (SEER 9) without the Seattle-Puget Sound (S-PS) region (n = 12,121), the S-PS region alone (n = 1931), and the S-PS region IC (n = 261). The IC BCSS endpoint was breast cancer death confirmed from chart and/or death certificate and cause-specific survival for SEER registries. BCSS was estimated using the Kaplan-Meier method. Hazard ratios (HzR) were calculated using Cox proportional-hazards models., Results: For SEER 9 without the S-PS region, 5-year BCSS improved 7% (from 19% to 26%) over time, it improved 14% for the S-PS region (21% to 35%), and it improved 27% for the S-PS IC (29% to 56%). In the IC Cox proportional-hazards model, recent diagnosis year, chemotherapy, surgery, and age <70 years were associated with better survival. For SEER 9, additional significant factors were white race and positive hormone receptor status and S-PS region was associated with better survival (HzR, 0.87; 95% CI, 0.84-0.90). In an adjusted model, hazard of BC death decreased in the most recent time period (2005-2011) by 28% in SEER 9 without S-PS, 43% in the S-PS region and 45% in the IC (HzR, 0.72 [95% CI, 0.67-0.76], 0.57 [95% CI, 0.49-0.66], and 0.55 [95% CI, 0.39-0.78], respectively)., Conclusions: Over 2 decades, the survival of patients with metastatic breast cancer improved nationally, but with regional survival disparity and differential improvement. To achieve equitable outcomes, access and treatment approaches will need to be identified and adopted., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Pathology is the study of human illness. Throughout centuries of scientific discoveries, pathologic examination of tissue samples has been the gold standard for diagnosis and pathologists have been involved in the elucidation of aetiology, assessment of the biology, clinicopathologic correlation and prediction of prognosis. The advances in science and technology and focused interest in breast cancer research have provided ample opportunities for pathologists to participate in better understanding of the basic fundamental cascade of events leading to tumorigenesis in breast cancer. They also partnered with their clinical colleagues and scientists to find more effective therapeutic options. This change has been possible with recognition of the fact that morphology alone may not be sufficient to tell the entire story of clinical behaviour of all breast cancer patients. In addition, the realization of heterogeneity of breast cancer and the differences in the expression of various biomarkers and the observed differences in response to therapy have resulted in extensive efforts to better define the characters of each breast cancer subtype. It is now generally agreed that breast cancer is not a single disease and not all patients with breast cancer can benefit from the same therapy. These changes have brought new challenges for pathologists. Pathologist are now required to not only provide diagnosis, but also study the precise molecular characterization of each individual breast cancer case and play a significant role in the treatment planning of breast cancer patients. This remarkable change in the role of the pathologist require his/her involvement in the modern taxonomy of this disease and to rise to the challenge of genomic medicine and molecular diagnostics, which are the fastest growing areas of medicine. Emphasis should also been placed to create a new morphomolecular pathology and train our young pathologist to expand beyond morphology and to embrace the power of molecular diagnostics, in order to be able to effectively practise in the era of precision medicine., (© 2019 Wiley Periodicals, Inc.)

Axillary dissection has been the standard of care for any patient with clinically positive lymph nodes at initial breast cancer presentation. However, modern neo-adjuvant therapies can convert positive nodes to negative nodes, especially in the setting of HER2-positive disease. Accurate axillary staging can be achieved after neo-adjuvant therapy in initially node-positive patients using dual tracer lymphatic mapping, removal of three or more lymph nodes, and confirmation of excision of the previously biopsied and clipped lymph node. Currently accruing clinical trials are designed to determine which patients can safely avoid axillary dissection and/or axillary radiation., (© 2019 Wiley Periodicals, Inc.)

Background: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses., Methods: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted., Results: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm., Conclusions: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

To investigate adverse events (AEs, CTCAE v4.0) and clinical outcomes for proton beam therapy (PBT) reirradiation (reRT) for breast cancer. From 2011 to 2016, 50 patients received PBT reRT for breast cancer in the prospective Proton Collaborative Group (PCG) registry. Acute AEs occurred within 180 days from start of reRT. Late AEs began or persisted beyond 180 days. Fisher's exact and Mann-Whitney rank-sum tests were utilized. Kaplan-Meier methods were used to estimate overall survival (OS) and local recurrence-free survival (LFRS). Median follow-up was 12.7 months (0-41.8). Median prior RT dose was 60 Gy (10-96.7). Median reRT dose was 55.1 Gy (45.1-76.3). Median cumulative dose was 110.6 Gy (70.6-156.8). Median interval between RT courses was 103.8 months (5.5-430.8). ReRT included regional nodes in 84% (66% internal mammary node [IMN]). Surgery included the following: 44% mastectomy, 22% wide local excision, 6% lumpectomy, 2% reduction mammoplasty, and 26% no surgery. Grade 3 AEs were experienced by 16% of patients (10% acute, 8% late) and were associated with body mass index (BMI) > 30 kg/m 2 (P = 0.04), bilateral recurrence (P = 0.02), and bilateral reRT (P = 0.004). All grade 3 AEs occurred in patients receiving IMN reRT (P = 0.08). At 1 year, LRFS was 93%, and OS was 97%. Patients with gross disease at time of PBT trended toward worse 1-year LRFS (100% without vs. 84% with, P = 0.06). PBT reRT is well tolerated with favorable local control. BMI > 30, bilateral disease, and IMN reRT were associated with grade 3 AEs. Toxicity was acceptable despite median cumulative dose > 110 Gy., (© 2019 Wiley Periodicals, Inc.)

Background: The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer., Methods: Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions., Results: All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null., Conclusions: The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer., (© 2019 American Cancer Society.)

We queried the National Cancer Database for nonmetastatic breast angiosarcoma, yielding 808 patients (202 de novo, 606 secondary). The median survival was 53.7 months. Secondary tumors were more likely to undergo mastectomy than de novo lesions (OR = 3.99, P < 0.001). Treatments included lumpectomy (10%), lumpectomy/radiation (3%), mastectomy alone (73%), or mastectomy/radiation (14%), with no difference in survival (P = 0.68). Lumpectomy correlated with positive margin rate (OR 3.29), which was a predictor for death (HR = 2.37, P < 0.01), along with older age, higher comorbidity scores, size >5 cm, and high-grade disease (P < 0.05). While breast angiosarcoma is usually treated with mastectomy, lumpectomy may be feasible for well-selected tumors., (© 2019 Wiley Periodicals, Inc.)