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Background: Metastatic spread is characterized by considerable heterogeneity in most cancers. With increasing treatment options for patients with metastatic disease, there is a need for insight into metastatic patterns of spread in breast cancer patients using large-scale studies. Methods: Records of 2622 metastatic breast cancer patients who underwent autopsy (1974–2010) were retrieved from the nationwide Dutch pathology databank (PALGA). Natural language processing (NLP) and manual information extraction (IE) were applied to identify the tumors, patient characteristics, and locations of metastases. Results: The accuracy (0.90) and recall (0.94) of the NLP model outperformed manual IE (on 132 randomly selected patients). Adenocarcinoma no special type more frequently metastasizes to the lung (55.7%) and liver (51.8%), whereas, invasive lobular carcinoma mostly spread to the bone (54.4%) and liver (43.8%), respectively. Patients with tumor grade III had a higher chance of developing bone metastases (61.6%). In a subgroup of patients, we found that ER+/HER2+ patients were more likely to metastasize to the liver and bone, compared to ER−/HER2+ patients. Conclusion: This is the first large-scale study that demonstrates that artificial intelligence methods are efficient for IE from Dutch databanks. Different histological subtypes show different frequencies and combinations of metastatic sites which may reflect the underlying biology of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

A comprehensive evaluation of the relationship between the densities of various cell types in the breast cancer tumor microenvironment and patient prognosis is currently lacking. Additionally, the absence of a large patch-level whole slide imaging (WSI) dataset of breast cancer with annotated cell types hinders the ability of artificial intelligence to evaluate cell density in breast cancer WSI. We first employed Lasso-Cox regression to build a breast cancer prognosis assessment model based on cell density in a population study. Pathology experts manually annotated a dataset containing over 70,000 patches and used transfer learning based on ResNet152 to develop an artificial intelligence model for identifying different cell types in these patches. The results showed that significant prognostic differences were observed among breast cancer patients stratified by cell density score (P = 0.0018), with the cell density score identified as an independent prognostic factor for breast cancer patients (P < 0.05). In the validation cohort, the predictive performance for overall survival (OS) was satisfactory, with area under the curve (AUC) values of 0.893 (OS) at 1-year, 0.823 (OS) at 3-year, and 0.861 (OS) at 5-year intervals. We trained a robust model based on ResNet152, achieving over 99% classification accuracy for different cell types in patches. These achievements offer new public resources and tools for personalized treatment and prognosis assessment.

Breast cancer is a leading cause of cancer-related mortality among women worldwide, necessitating the identification of reliable prognostic markers to guide treatment and improve patient outcomes. Recent research has highlighted the prognostic significance of tumor-infiltrating lymphocytes (TILs) in breast cancer, with high levels of TILs being associated with improved survival rates and better responses to therapy. This review delves into the mechanisms driving lymphocyte infiltration, its clinical implications, and the potential for TILs to serve as predictive biomarkers in breast cancer management. The presence of TILs within the tumor microenvironment reflects a dynamic interplay between tumor cells and the host immune system. Chemokine signaling, antigen presentation, and immune checkpoint interactions are key mechanisms that facilitate the recruitment and activity of lymphocytes at the tumor site. Clinically, the density of TILs varies across breast cancer subtypes, with the most significant prognostic value observed in triple-negative and HER2-positive breast cancers. High TIL levels correlate with improved overall survival and disease-free survival, underscoring their potential as a valuable prognostic indicator. Therapeutically, the role of TILs has opened new avenues in breast cancer treatment, particularly in the realm of immunotherapy. Immune checkpoint inhibitors, adoptive cell therapy, and combination therapies leveraging TILs are being explored to enhance antitumor responses. As research progresses, the integration of TIL assessment into routine clinical practice could revolutionize personalized treatment strategies, ultimately improving prognostic accuracy and patient outcomes in breast cancer care., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with cardiovascular disease (CVD) comorbidities are often excluded from participating in breast cancer clinical trials. Consequently, data to inform treatment decisions for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and CVD are limited., Objective: We compared the effectiveness of first-line palbociclib plus an aromatase inhibitor (AI) vs an AI alone and evaluated palbociclib treatment patterns in patients with HR+/HER2- mBC and CVD in routine clinical practice., Methods: Data from the Flatiron Health Analytic Database were captured for patients with HR+/HER2- mBC and CVD who initiated first-line treatment with palbociclib plus an AI or an AI alone between February 2015 and March 2020 (data cutoff: September 30, 2020). Overall survival (OS), real-world progression-free survival (PFS), and treatment patterns were evaluated., Results: Of the 469 patients with identifiable CVD, 160 received palbociclib plus an AI, and 309 received an AI alone. After stabilized inverse probability treatment weighting, both median OS (40.7 vs 26.5 months; hazard ratio [HR], 0.732 [95% CI, 0.537-0.997]; P = .048) and median real-world PFS (20.0 vs 12.5 months; HR, 0.679 [95% CI, 0.512-0.900]; P = .007) were significantly prolonged in patients treated with palbociclib plus an AI vs an AI alone. Among patients with a documented palbociclib starting dose, 78.5% started palbociclib at 125 mg/day, and 38.6% experienced dose adjustment., Conclusions: In this real-world analysis, first-line palbociclib plus an AI was associated with improved effectiveness compared with an AI alone in patients with HR+/HER2- mBC and CVD., Trial Registration: NCT05361655 (ClinicalTrials.gov)., (© The Author(s) 2024. Published by Oxford University Press.)

Background: High prevalence of early-onset breast cancer (EOBC) has been reported in Middle Eastern populations. For example, in Oman more than 50% of patients with breast cancer (BC) are under age 45 at diagnosis. Causes for this high incidence are unknown. Germline BRCA gene mutations have been associated with EOBC, however, prevalence of these mutations and how they relate to EOBC in Oman has not been assessed., Patients and Methods: Clinical data were collected for patients with BC treated at Royal Hospital, Oman between 2010 and 2022. Germline BRCA1/2 gene mutations were identified using sequencing and MLPA. Correlation and Kaplan-Meier survival analyses were performed to test relationships among clinico-pathological features, gene mutations, and outcomes., Results: Total of 1336 Middle Eastern patients with BC were included; 611 were aged <45 at diagnosis (45.7%). No significant correlation was found between BRCA1/2 mutation status and EOBC (P = .229), and the majority of EOBC cases had no family history of BC. EOBC tumors did, however, differ in clinicopathological features; EOBCs were significantly larger (P < .0001), of higher grade (P < .0001), and included more HER2-enriched, and triple negative subtypes (P = .018) compared with later onset cases. Accordingly, survival analyses revealed that EOBC had significantly worse disease-free survival (P = .002). BRCA gene variants showed a distinct range of mutations including, in BRCA2, 3 previously unreported mutations and 4 potential founder recurrent mutations., Conclusion: Our findings showed that germline BRCA1/2 mutations were not over-represented in EOBC cases in Oman, and therefore are unlikely to be responsible for high EOBC rates., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The co-occurrence of breast cancer and diabetes presents complex clinical challenges, as each condition may influence the progression and management of the other, potentially worsening patient outcomes. This study aims to examine the association between insulin use and the risks of all-cause mortality, breast cancer-specific mortality, and recurrence in diabetic patients with breast cancer., Methods: A systematic review and meta-analysis were conducted using studies identified from multiple databases, including Web of Science, Scopus, PubMed, Cochrane, Google Scholar, and Embase. The meta-analysis approach was used to estimate the relative risk (RR) of the relationship between insulin use and the risks of all-cause mortality, breast cancer-specific mortality, and recurrence in diabetic patients with breast cancer. Heterogeneity among studies was assessed using statistical tests such as the Chi-square test, I2, and forest plots. Meta-regression and sensitivity analyses were performed to explore sources of heterogeneity. The quality of the included studies was assessed using the Newcastle-Ottawa Scale checklist. Data were analyzed using Stata version 17 (Stata Corp, College Station, Texas)., Results: Data from 22 studies conducted between 2002 and 2023, with a total of 159,674 participants, were analyzed. Nineteen studies were rated as high quality, and three as moderate quality. Diabetic patients with breast cancer who received insulin had a 1.65 (95% CI: 1.36-2.02; P < 0.001; I2 = 89.7%) times higher risk of overall mortality compared to those who did not use insulin. Meta-regression revealed that sample size and study quality were significant contributors to heterogeneity (P ≤ 0.10). Furthermore, insulin use was associated with a 1.22 (95% CI: 1.05-1.42; P = 0.009; I2 = 37.9%) times higher risk of breast cancer-specific mortality. For breast cancer recurrence, insulin use was associated with a 1.45 (95% CI: 1.19-1.77; P < 0.001; I2 = 3.4%) times higher risk. Sensitivity analysis confirmed the stability of the results across all outcomes., Conclusion: This meta-analysis provides strong evidence that insulin use in diabetic patients with breast cancer is associated with increased risks of overall mortality, breast cancer-specific mortality, and recurrence. These findings underscore the need for careful consideration of insulin therapy in this patient population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Loktionova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challenging due to heterogeneity of prior assessments. We examined the association between social vulnerability and breast cancer stage at diagnosis and mortality using a standardized measure of population risk for external stressors on health., Methods: Using institutional cancer registry data, female patients aged 18 or older diagnosed with breast cancer between 2012 and 2019 were assigned a 2018 Social Vulnerability Index (SVI) rank based upon home address census tract. We used multinomial logistic regression and Cox proportional hazards model to examine the relationships between SVI and breast cancer stage at diagnosis and all-cause mortality. Covariates included age and, when assessing mortality, cancer stage, comorbidities, body mass index, insurance type, and treatment regimen., Results: A total of 3,499 women with a median age of 59 (IQR 48-69) were included. 60% were White and 31% were Black. Median SVI was 0.36 (IQR 0.14-0.68) and median follow-up was 58 months (IQR 37.3-83.9). On adjusted analyses, each decile increase in SVI resulted in an 11% (OR 1.11, 95% CI 1.06-1.16, p < .001) and 15% (OR 1.15, 95% CI 1.09-1.21, p < .001) greater odds of presenting with Stage III or IV breast cancer, respectively, compared to DCIS. For patients who underwent surgery (N = 2916), each decile increase in SVI was associated with a 6% increase in all-cause mortality risk (HR 1.06, 95% CI 1.01-1.12, p = .01). Mortality risk was 1.5 times (HR 1.52, 95% CI 1.02-2.26, p = .04) greater for those in the most vulnerable quartile compared to the least vulnerable quartile., Conclusions: Women living in socially vulnerable communities presented with more advanced breast cancers and suffered worse survival. The SVI can be used to identify patients at risk for delayed cancer presentation and increased mortality. This tool can inform geographically targeted resource allocation and interventions aimed at reducing breast cancer care disparities., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the University of Chicago Institutional Review Board (IRB 2022 − 1049) and a waiver for consent was obtained. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Breast cancer is one of the most prevalent cancers with an increasing trend in both incidence and mortality rates in Iran. Survival analysis is a pivotal measure in setting appropriate care plans.  To the best of our knowledge, this study is pioneering in Iran, introducing a multi-method approach using a Deep Neural Network (DNN) and 11 conventional machine learning (ML) methods to predict the 5 year survival of women with breast cancer. Supplying data from two centers comprising a total of 2644 records and incorporating external validation further distinguishes the study. Thirty-four features were selected based on a literature review and common variables in both datasets. Feature selection was also performed using a p value criterion (< 0.05) and a survey involving oncologists. A total of 108 models were trained. According to external validation, the DNN model trained with the Shiraz dataset, considering all features, exhibited the highest accuracy (85.56%). While the DNN model showed superior accuracy in external validation, it did not consistently achieve the highest performance across all evaluation metrics. Notably, models trained with the Shiraz dataset outperformed those trained with the Tehran dataset, possibly due to the lower number of missing values in the Shiraz dataset., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All experimental protocols were approved by the Institutional Review Board of Shahid Beheshti University of Medical Sciences, with the approval code IR.SBMU.RETECH.REC.1401.823, and informed consent was obtained from all subjects and/or their legal guardians. In addition, all methods were performed in accordance with the relevant guidelines and regulations., (© 2024. The Author(s).)

Importance: Young Black women bear a disproportionate burden of breast cancer deaths compared with White women, yet they remain underrepresented in genomic studies., Objective: To evaluate the association of biological factors, including West African genetic ancestry, and nonbiological factors with disease-free survival (DFS) among young Black women with breast cancer., Design, Setting, and Participants: This observational cohort study included Black women diagnosed with invasive breast cancer between January 1, 2005, and December 31, 2016. Participants diagnosed with breast cancer at age 50 years or younger were recruited through the Florida and Tennessee state cancer registries. The final analysis was completed between June and September 2024., Exposure: West African genetic ancestry., Main Outcomes and Measures: A multivariable model was developed to evaluate the association between West African genetic ancestry and breast cancer DFS, adjusting for immunohistochemistry subtype, lymph node (LN) status, and full-time employment., Results: This study included 687 Black women with early-stage invasive breast cancer. Their median age at diagnosis was 44 years (IQR, 38-47 years), and the median follow-up was 10 years (IQR, 7-11 years). In multivariable analysis, triple-negative breast cancer (TNBC) and LN involvement were associated with shorter breast cancer DFS (hazard ratio, 1.81 [95% CI, 1.20-2.73] and 1.77 [95% CI, 1.30-2.41], respectively), whereas full-time employment was associated with improved outcomes (hazard ratio, 0.44 [95% CI, 0.30-0.63]). Among the 551 participants for whom global genetic ancestry could be assessed, having a higher percentage of West African genetic ancestry was associated with shorter breast cancer DFS among 246 participants in the hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-negative subgroup (hazard ratio, 1.45 [95% CI, 1.04-2.04]). Of the 369 participants (53.7%) with PAM50 data available, basal (133 [36.0%]) and luminal B (107 [29.0%]) subtypes were the most common. Among the 179 patients with HR-positive/ERBB2-negative disease and PAM50 data available, luminal B and basal subtypes combined were also overrepresented (81 [45.3%] and 24 [13.4%], respectively) compared with luminal A (70 [39.1%])., Conclusions and Relevance: In this study of young Black women with breast cancer, having a higher percentage of West African genetic ancestry, TNBC, and LN involvement were associated with shorter breast cancer DFS. Interestingly, full-time employment was associated with improved breast cancer DFS. These findings highlight the importance of considering genetic ancestry beyond self-reported race and accounting for social determinants of health, in efforts to improve survival outcomes among Black women with breast cancer.

The striking ethnic and racial disparities in breast cancer mortality are not explained fully by pathologic or clinical features. Structural racism contributes to adverse conditions that promote cancer inequities, but the pathways by which this occurs are not fully understood. Social determinants of health, such as economic status and access to care, account for a portion of this variability, yet interventions designed to mitigate these barriers have not consistently led to improved outcomes. Based on the current evidence from multiple disciplines, we describe a conceptual model in which structural racism and racial discrimination contribute to increased mortality risk in diverse groups of patients by promoting adverse social determinants of health that elevate exposure to environmental hazards and stress; these exposures in turn contribute to epigenetic and immune dysregulation, thereby altering breast cancer outcomes. Based on this model, opportunities and challenges arise for interventions to reduce racial and ethnic disparities in breast cancer mortality., (©2024 American Association for Cancer Research.)

Background: It remains unclear whether residential segregation impacts on clinical treatment and outcomes for ductal carcinoma in situ (DCIS), a nonobligate precursor to invasive breast cancer (IBC)., Methods: This population-based retrospective cohort study included adult non-Hispanic White and Black women diagnosed with unilateral DCIS between January 1990 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results dataset. County-level racialized economic segregation was measured using the Index of Concentration at the Extremes. Multilevel logistic regression and Cox proportional hazards regression accounting for county-level clustering were used to estimate the ORs of local treatment and HRs of subsequent IBC and mortality., Results: Of 103,898 cases, mean age was 59.5 years, 12.5% were non-Hispanic Black, 87.5% were non-Hispanic White, 97.5% underwent surgery, 64.5% received radiotherapy following breast-conserving surgery (BCS), 7.1% developed IBC, and 18.6% died from all causes. Among women living in the least versus most privileged counties, we observed higher odds of receiving mastectomy [vs. BCS; OR = 1.51; 95% confidence interval (CI), 1.35-1.69; Ptrend < 0.001] and radiotherapy following BCS(OR = 1.27; 95% CI, 1.07-1.51; Ptrend < 0.01); the risk was higher in subsequent ipsilateral IBC (HR = 1.16; 95% CI, 1.02-1.32; Ptrend = 0.04), not in breast cancer-specific mortality (HR = 1.04; 95% CI, 0.88-1.23; Ptrend = 0.56)., Conclusions: The results provide evidence for disparities in clinical treatment for DCIS and prognostic outcomes among women in racially and economically segregated counties., Impact: Our findings may inform geographically targeted multilevel interventions to reduce breast cancer burden and improve breast cancer care and equity., (©2024 American Association for Cancer Research.)

Background: Annual or biennial breast cancer screenings are recommended for women 40 and older. Women residing in rural areas have worse breast cancer survival rates than urban women, but no study has focused on rural versus urban residence in Utah regarding breast cancer screening and mortality., Methods: Cases (n = 14,516) were women aged > 39 diagnosed with a first primary invasive breast cancer between 1998 and 2017 in Utah. Controls (n = 63,117) without a history of breast cancer were matched to cases by birth year and birth state. Mammography screening status was identified by Current Procedural Terminology (CPT) codes. Logistic regression was used to assess the odds of breast cancer diagnosis. The Cox proportional hazards model was used to assess survival outcomes for rural and urban breast cancer patients based on screening status., Results: Screening mammography usage among rural patients diagnosed with breast cancer was lower (17.7%) than urban usage (20.7%). Usage of screening mammograms resulted in higher odds of breast cancer diagnosis at localized stage rather than at a regional and distant stage. Rural breast cancer cases had a higher proportion of deaths, and a lower proportion screened, than urban breast cancer cases. Hazard ratios showed that screening mammography usage was associated with better survival among both rural (HR = 0.50, 95% CI = 0.44-0.57) and urban (HR = 0.56, 95% CI = 0.39-0.82) breast cancer cases., Conclusion: Screening mammography usage was associated with better overall survival regardless of place of residence. Removing barriers and improving information regarding breast cancer screenings are needed in both rural and urban settings in Utah to increase mammography usage, with the overall goal of increasing early detection and outcomes of breast cancer., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Carbonic anhydrase IX (CAIX) is a well-established prognostic marker in breast cancer (BC). Nevertheless, this prognostic value is yet to be confirmed in BC subtypes. This study aims to investigate the prognostic effects of CAIX in oestrogen receptor (ER)-negative (ER-) BCs and to establish pathways related to cytoplasmic CAIX expression in ER- and lymph node-negative BCs., Methods: Immunohistochemistry was performed to identify the prognostic role of CAIX protein expression in ER- tissue microarrays (TMAs) (n = 191). CAIX-positive samples (n = 37) were transcriptionally profiled by TempO-Seq and analysed by STRING. Real-time quantitative PCR (RT-qPCR) analysis was used to validate differentially expressed genes., Results: Overexpression of cytoplasmic CAIX was an independent predictor of recurrence free survival, disease-free survival and overall survival in ER- cohort. RNA transcriptomic analysis identified 10 significant genes in ER- cohort and 3 genes in the node-negative group. The STRING database demonstrated a significant interaction between MUCL1 and GALNT6, which were linked with extracellular matrix organisation, degradation of the extracellular matrix and disease of glycosylation pathways. In the node-negative group, SPNS2 is mainly involved in the sphingolipid de novo biosynthesis pathway. A significant correlation between cytoplasmic SphK1 and cytoplasmic hypoxia-inducible factor-1α was observed. Among the 10 genes, 7 genes (SERHL2, GALNT6, MUCL1, MMP7, PITX2, CEACAM6 and SPNS2) were selected, and their expression was quantitatively assessed by RT-qPCR. The PCR data of these genes showed that SERHL2, GALNT6, MUCL1, PITX2, and SPNS2 mRNA levels were expressed in MDA-MB-231 BC cell lines at variable levels of hypoxic exposure., Conclusion: Cytoplasmic CAIX was independently associated with poor prognosis in ER- BC. Gene expression profiles shed light on the pathways and genes associated with hypoxia in ER- BC. In node-negative patients, SPNS2 was of particular interest., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Breast cancer is the leading cause of cancer-related mortality among women worldwide. The connexin (Cx) family, including GJB1 (Cx32), plays complex roles in tumor progression depending on cellular context and cancer subtype. While Cx32 overexpression has been linked to lymph node metastasis, its effects on survival and molecular processes remain unclear. Herein, we aimed to investigate the role of GJB1 in breast cancer by examining its impact on survival and cellular processes in addition to its expression pattern in tumor subtypes, using public datasets., Materials and Methods: We conducted a comprehensive analysis of GJB1 in breast cancer using METABRIC patient dataset, Cancer Cell Line Encylopedia, and other publicly available databases. We examined the association between GJB1 expression and patient survival, performed differential gene expression analysis, and explored gene set enrichment to identify biological processes associated with high GJB1 expression., Results: GJB1 was significantly down-regulated in breast cancer tissues compared to normal tissues. However, patients with high GJB1 expression had significantly poorer survival compared to those with low expression, with the median survival reduced by over 25 months. Gene ontology (GO) analysis revealed that down-regulated genes in the GJB1-high group were enriched in extracellular matrix components and membrane junctions, while up-regulated genes were associated with mitochondrial function and cellular respiration., Conclusion: Our findings suggest a dual role for GJB1 in breast cancer. Although it is generally down-regulated, high GJB1 expression is associated with poorer survival, implying a potential oncogenic role. Further studies are needed to clarify the role of GJB1 in breast cancer and explore its therapeutic implications., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Opinion Statement: Antibody-drug conjugates (ADCs) are a novel class of anti-cancer agents that have changed the standard of care for patients with breast cancer. Their targeted approach delivers potent anti-cancer drugs to cancer cells bearing specific surface antigens, thereby maximizing anti-cancer effects and minimizing systemic toxicity. Currently, there are three ADCs available for use in breast cancer: trastuzumab emtansine for HER2 positive breast cancer (early stage and metastatic), trastuzumab deruxtecan for HER2 positive and HER2 low breast cancer (metastatic) and sacituzumab govitecan for triple negative and hormone receptor positive (HR +), HER2 negative breast cancer(metastatic). Trials have shown that these drugs have improved both progression free survival and overall survival in the metastatic setting, and trastuzumab emtansine has improved overall survival in early-stage breast cancer as well. The future of this class of compounds is very exciting. This field is rapidly evolving with new ADCs being investigated and clinical trials looking at the use of known ADCs in earlier stage disease., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The aim of this study was to evaluate the effectiveness of CDK 4/6 inhibitors (CDK 4-6i) according to HER2 status (low/zero), and endocrine resistance/sensitivity, as well as the efficacy of second-line treatments, in a large real-world cohort., Methods: The GIM14/BIOMETA study (NCT02284581) is a retrospective/prospective study of the Gruppo Italiano Mammella evaluating treatment patterns and survival outcomes in patients with metastatic breast cancer (MBC). We retrieved data on patients with hormone receptor-positive/HER2-negative MBC receiving first-line CDK 4/6i., Results: Among 3832 patients enrolled in the GIM14-BIOMETA study, 701 were eligible. At a median follow-up of 24.80 months, no significant differences were found between HER2-zero and HER2-low subgroups in terms of first-line time to treatment discontinuation (TTD) (26.16 months [IQR 12.84-NR] vs. 27.60 months [IQR 12.12-64.44], p = 0.972) or overall survival (OS) (mOS>60 months for both groups, p = 0.398). Median TTD was 33.24 months (IQR 16.32-NR) for the endocrine sensitive subgroup, 19.92 months (IQR 8.88-51.24) for the secondary endocrine resistant subgroup and 17.40 months (IQR 7.44-24.72) for the primary endocrine resistant subset, respectively (p < 0.001). Among 239 patients receiving second-line treatment, no significant difference (p = 0.188) was found in terms of second-line TTD between those treated with capecitabine (6.11 months, IQR 2.96-11.47), taxane-based chemotherapy (5.06 months, IQR 2.99-9.99), everolimus plus exemestane (5.39 months, IQR 2.53-9.03) or fulvestrant (6.44 months, IQR 3.38-NR)., Conclusions: Endocrine therapy plus CDK 4/6i represents an effective treatment, regardless of HER2 status (low/zero). Second-line agents did not differ significantly in terms of TTD. Endocrine resistant cancers exhibit poor response to CDK 4/6i., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chiara Molinelli reports honoraria for consultancy and consulting fees from Daiichi Sankyo, travel support to attend conferences from Gilead, Menarini and fees for medical writing from Lilly and Seagen. Eva Blondeaux reports honoraria from Eli Lilly and research funding (to institution) from Gilead. Michelino De Laurentiis reports honoraria or consultation fees for speaker, consultancy or advisory roles from Eli Lilly, Seagen, Therapeutics, GSK, Roche, Novartis, Genetic, Pfizer, Pierre Fabre, MSD, Menarini Stemline, Sophos Biotech, Max Farma, Celltrion Healthcare, Gilead, Daiichi Sankyo; institutional financial interests, financial support for clinical trials or contracted research, from: Novartis, Pierre Fabre, Pfizer, Roche, Stemline Therapeutics. Alessandra Fabi reports consulting fees and honoraria from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Daiichi Sankyo. Support for attending meetings and/or travel from Novartis, Lilly, Pfizer, MSD. Grazia Arpino reports research and medical writing from AstraZeneca; advisory boards, travel grants, activities as a speaker, consultancy from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Exact Science, Novartis, Roche, Seagen, Viatris. Andrea Fontana reports advisory boards from Roche, Novartis, Eli Lilly, Pfizer, MSD, Pierre Fabre, Eisai, Gilead, Seagen, Astra Zeneca, Exact Sciences; consulting fees from Dompé Farmaceutici S.p.A. D.G. Research funding from Menarini, Seagen, Novartis, AstraZeneca; advisory boards, activities as a speaker, consultancy from Seagen, Novartis, Eli Lilly, Roche, Gilead, Pfizer, Eisai, Exact Sciences. Fabio Puglisi reports advisory role for and receiving speaker honoraria from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris. Travel grants from AstraZeneca, Daichii Sankyo, Novartis, Roche. Research grants (to his institution) from Astrazeneca, Eisai, Roche. Claudia Bighin reports personal fees from Roche, Novartis, Lilly, Gilead, and Daiichi. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, Menarini; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Menarini, AstraZeneca; travel Grants from Gilead, Daiichi Sankyo, Roche; research funding (to the Institution) from Gilead all outside the submitted work. Lucia Del Mastro reports grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead, and Pierre Fabre; receiving consulting fees from Eli Lilly, Gilead, and Daiichi Sankyo; receiving speaker honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, and Agendia-Stemline; receiving travel grants from Roche, Pfizer, Eisai, Daiichi Sankyo, and AstraZeneca; and having an advisory role for Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, AstraZeneca, Agendia, GSK, and Seagen. All the other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Opinion Statement: The therapeutic landscape for HER2-positive metastatic breast cancer has exploded in the last two decades following the initial advent of trastuzumab, a monoclonal antibody. While the first line treatment has remained a combination of dual HER2 blockade with taxane chemotherapy, we now have several exciting options in the second line and beyond. The introduction of antibody-drug conjugates, in specific trastuzumab deruxtecan, has resulted in the best progression-free survival among patients with this subtype of breast cancer. Given the excellent outcomes of these drugs, clinical trials are now evaluating the role of ADCs in the front-line setting in previously untreated patients. In addition, there are also clinical trials evaluating the role of other targets in patients with HER2-positive cancers, including PI3KCA mutations, PD-L1 and CDK4/6. Given the predilection for brain metastases in this population, there is enthusiasm to identify the optimal combination of effective treatments. Tucatinib, capecitabine, and trastuzumab combination represent one such promising strategy. With the increasing longevity of these patients, important clinical questions include optimal treatment sequencing, the role of de-escalation of treatment in excellent responders, and the associated financial toxicity. Despite the aggressive nature of this subtype of breast cancer, the outcomes continue to improve for these patients with the evolving treatments., Competing Interests: Declarations. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Conflict of Interest: PVB has received stock options with Doximity. None of the other authors have any conflicts of interest to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The efficacy of adjuvant denosumab in combination with hormonotherapy in breast cancer patients was investigated in two randomized trials, ABCSG-18 and D-Care, but the results were mixed with respect to the impact of this drug on disease-free survival. However, the ABCSG-18 study has achieved its primary goal: prevention of clinical fractures. Therefore, the protective role of Denosumab on bone fragility induced by estrogen deprivation, already demonstrated in post-menopausal women, has been validated in the breast cancer setting., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neoadjuvant chemotherapy (NACT) for early-stage breast cancer is associated with an increased risk of locoregional recurrence (LRR). We investigated whether the risk of LRR after NACT varies across tumor subtypes., Methods: We retrospectively reviewed the medical records of women who underwent breast-conserving surgery for breast cancer at three institutions between January 1, 2004, and December 31, 2018. Patients received either NACT or adjuvant chemotherapy (ACT), followed by radiotherapy. LRR was analyzed according to the hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status using propensity score matching, log-rank test, and Cox regression analysis., Results: Among 10,328 patients, 2479 (24.0 %) received NACT. Within the median follow-up of 84.5 (IQR, 35.1-118.5) months, the 10-year LRR-free survival rates were 94.5 % and 90.7 % for the ACT and NACT groups, respectively (hazard ratio: 2.04, 95 % confidence interval [CI]: 1.68-2.46, p < 0.0001). NACT was significantly associated with higher LRR in the HR+/HER2- (hazard ratio: 2.52, 95 % CI: 1.83-3.46, p < 0.0001) and HR-/HER2- (hazard ratio: 1.85, 95 % CI: 1.37-2.50, p < 0.0001) subtypes. In the HR+/HER2- subtype, the elevated risk remained significant after propensity-score matching and Cox-regression analysis. However, NACT was not associated with LRR in the HR-/HER2- subtype after adjusting for other variables. Annual LRR pattern among the HR+/HER2- subtype showed the highest incidence in the early period of treatment., Conclusion: Patients with the HR+/HER2- subtype showed an increased risk of LRR after NACT, while those with other subtypes showed comparable LRR-free survival., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer has become the most prevalent malignant tumor worldwide and remains one of the leading causes of cancer-related mortality among women globally. The prognosis for patients with metastatic breast cancer remains poor, necessitating the exploration of novel therapeutic strategies to improve survival rates. In the era of precision medicine, antibody-drug conjugates (ADCs) have gained significant attention as a targeted therapeutic strategy in breast cancer treatment. ADCs, a relatively new treatment for breast cancer, deliver cytotoxic drugs (payloads), directly into the tumor space, turning chemotherapy into a targeted agent, which enables patients to experience significant improvements with manageable drug toxicity. For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. Recent clinical studies have demonstrated that the benefits of ADC therapies extend beyond HER2-positive breast cancer toinclude hormone receptor (HR)-positive breast cancer, triple-negative breast cancer (TNBC), and HER2-low expressing breast cancer. Notably, the DESTINY-Breast series of studies, particularly focusing on T-Dxd, encompass neoadjuvant, adjuvant, and multiple lines of therapy for advanced breast cancer. This marks the advent of a comprehensive ADC era in breast cancer treatment. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Oligometastatic breast cancer (OMBC) is a clinical entity with a prospect of long-term survival, but uncertainty remains on its optimal treatment. We studied whether intensified alkylating chemotherapy (IACT) improves long-term outcome compared to conventional-dose chemotherapy (CDCT) as part of a multimodality approach for patients with OMBC harboring homologous recombination deficiency (HRD)., Patients and Methods: Eligible patients had HER2-negative OMBC, harboring HRD, with ≤ 3 distant metastases, pathologic proof of distant disease and a favorable response to three cycles CDCT. Participants were randomized 1:1 to continue with either CDCT or IACT. IACT consisted of one mobilization course followed by two cycles of mini-CTC (carboplatin, thiotepa and cyclophosphamide) supported by peripheral blood progenitor cell reinfusion. Primary outcome was event-free survival (EFS). Secondary endpoints included overall survival (OS), quality of life and safety., Results: Seventy-five patients were randomized to either IACT (n = 36) or CDCT (n = 39). Twenty-three (31 %) patients had hormone receptor-positive disease and 52 (69 %) had triple-negative disease. Median EFS in the IACT-group was 28 months (95 % confidence interval [CI] 21-not reached [NR]) versus 25 months (95 %CI 14-NR) in the CDCT-group (hazard ratio [HR] for recurrence or death 0.78, 95 %CI 0.42-1.42). Median OS was 67 months (95 %CI 37-NR) in the IACT-group and 36 (95 %CI 26-NR) in the CDCT-group (HR 0.74, 95 %CI 0.37-1.48)., Conclusions: The entire study population experienced long-term survival, with median OS well over five years. IACT compared to CDCT did not improve outcome in patients with OMBC harboring study-defined HRD. The optimal therapy for patients with OMBC requires further study., Trial Registration: ClinicalTrials.gov: NCT01646034., Competing Interests: Declaration of Competing Interest TS reports the receipt of honoraria from Gilead Sciences outside the submitted work. SL reports grants from ZonMw and A Sister’s Hope; has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Sanofi and Roche; and received institutional research grants from Agendia, AstraZeneca, Eurocept-pharmaceuticals and Merck and Pfizer. In addition, SL received institutional research grants and institutional non-financial support from Agendia, Genentech, Novartis, Roche, Tesaro and Immunomedics and other institutional support from AstraZeneca, Pfizer, Cergentis, Daiichi Sankyo, IBM and Bayer outside the submitted work. GS reports institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen and consultancy for Biovica, Novartis, and Seagen. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Demonstration of trial emulation ability to benchmark randomised controlled trials (RCTs) from real-world data (RWD) is required to increase confidence in the use of routinely collected data for decision making in oncology., Methods: To assess the frequency with which emulation findings align with RCTs regarding effect size on overall survival (OS) in metastatic breast cancer (MBC), 8 of 13 pre-selected pivotal RCTs in MBC were emulated using data from 32,598 patients enrolled in the French ESME-MBC cohort between January 1, 2008 and December 31, 2021. Adjustment methods and confounders were selected a priori for each emulation; stabilized weight was the reference method to mitigate confounding. Concordance in OS hazard ratios with associated 95 % confidence intervals between RCTs and emulations were assessed used predefined metrics based on statistical significance, estimates, and standardized differences., Results: The effect sizes were consistent with RCT results in 7 out of the 8 emulations; 4 emulations achieved full statistical significance agreement; 5 emulations had a point estimate included in the RCT CI (estimate agreement); 6 emulations reported no significant differences between RCT and emulation (standardized difference agreement). Discrepancies related to residual confounders and significant shifts in prescription practices post-drug approval may arise in some cases., Conclusion: Target trial emulation from RWD combined with appropriate adjustment can provide conclusions similar to RCTs in MBC. In oncology, this methodology offers opportunities for confirming the impact on long-term survival, for expanding indications in patients excluded from RCTs and for comparative effectiveness in single-arm trials using external control arms., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alison Antoine received a grant from the National French Agency for Research and Technology (ANRT) and Roche (France) via CIFRE (“Industrial Agreements for Training through Research”) doctoral fellowship no. 2020/1054. Rémy Choquet and Béchir Ben Hadj Yahia are employed by Roche. Suzette Delaloge is an Associate Editor for [European Journal of Cancer] and was not involved in the editorial review or the decision to publish this article. All remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Radiation associated angiosarcoma (RAAS) of the breast is a rare malignancy with poor survival. Optimal treatment strategies remain uncertain due to a lack of data, and vary between surgery alone and a combination of surgery with (neo)adjuvant chemotherapy (NACT) and/or re-irradiation. The aim of this study was to evaluate the potential benefit of taxane based NACT., Methods: In this retrospective single center study, all patients with RAAS of the breast treated between 1994 and 2024 are included. Since 2018, NACT is considered a treatment option for this patient population in our institute. The difference in oncological outcomes of patients with and without NACT were compared., Results: Thirty-five women were included. Thirteen (37 %) received NACT of which five (39 %) also had neoadjuvant re-irradiation with hyperthermia. Eleven patients (85 %) received paclitaxel, the other two (15 %) had doxorubicine/docetaxel. Complete pathological response was found in 69 % (n = 9). Median follow up was 41 months (range 24-56) for patients with NACT and 44 (range 20-108) for patients without NACT. In the NACT group, only one patient developed a recurrence after 6.5 years. Patients with NACT had improved oncological outcomes compared to patients without NACT in terms of 3-year local recurrence free survival (100% vs. 63.9 %, p = 0.14), distant metastasis free survival (100 % vs. 47.5 %, p = 0.005), and overall survival (100% vs. 56.1 %, p = 0.016)., Conclusion: In this study, neoadjuvant taxanes for RAAS of the breast leads to improved distant metastasis free survival and overal survival in patients treated with NACT compared to no NACT., Competing Interests: Declaration of competing interest N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, Luszana. N Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & DohmeMerck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. W. van der Graaf: Advisory boards SpringworkTx, Agenus and PTC Therapeutics (all to the institute) and research grants from Eli Lilly (to the Institute). W. van Houdt: advisory boards of Amgen, Boehringer Ingelheim, Sanofi, Novartis, Sirius Pintuition, Belpharma. All payment to the Netherlands Cancer Institute., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: There is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established., Methods: The main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive., Results: Among 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor., Conclusions: This study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Cyclin Dependent Kinase (CDK) 4-6 inhibitors are the recommended first-line treatment option for hormone-positive metastatic breast cancer (MBC). They show their effects by causing cell cycle arrest in G1-S phase. Neutropenia is the most common haematological side effect. In the literature, data on the association between CDK 4-6 inhibitors and macrocytosis are limited. We aimed to investigate the effect of macrocytosis on survival., Methods: We retrospectively analysed 133 patients with de novo hormone positive MBC using CDK 4-6 inhibitors in first line treatment. Mean Corpuscular Volume (MCV) > 100 was considered macrocytosis and patients were divided into two groups; MCV<100 and MCV >100. The association of macrocytosis with clinicopathological features, Progression Free Survival (PFS) and Overall Survival (OS) were evaluated., Results: 42 patients were receiving palbociclib and 81 patients were receiving ribociclib. Median OS was determined as 33 months and median PFS was determined as 22 months. Macrocytosis ever rate was 45.8 % during follow-up. Macrocytosis was observed in 4.2 % of the patients in the first month, 16.7 % in the third month, 41.6 % in the sixth month and 42.2 % in the twelfth month. ER receptor level, ki-67, macrocytosis at 6-12 months and macrocytosis-ever which were found to affect OS as a result of univariate Cox regression analysis, were evaluated with multivariate Cox regression models and it was observed that they had significant effect on PFS and OS., Conclusion: Macrocytosis may be a useful biomarker for the prediction of PFS and OS in MBC patients receiving CDK 4-6 inhibitors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The incidence of breast cancer increases with age. Particularly in ageing societies, breast cancer has a significant impact on both the older patient and the healthcare system. In older patients with early breast cancer, there is a complex interplay between (i) tumor biology, (ii) risk of recurrence, (iii) comorbidities, (iv) frailty, (v) life expectancy and (vi) patient expectations and preferences. Our treatment guidelines are often based on large meta-analyses that have shown that (neo)adjuvant chemotherapy improves the survival rate in early breast cancer in general. This is particularly important in triple-negative and HER2-positive breast cancer, but hormone receptor (HR)-positive, HER2-negative patients with a higher risk of recurrence also benefit from chemotherapy. However, most studies included younger and carefully selected patients. Since there is a positive correlation between age and estrogen receptor status, as well as between age and the number of concomitant diseases and the tolerability of chemotherapy, it is of great importance to evaluate the effects of additional (neo)adjuvant chemotherapy, especially in older patients with early-stage breast cancer. There are only a few studies in which only older patients with early breast cancer were included. On the whole, they show that older patients with HR-positive, HER2-negative tumors hardly benefit from chemotherapy in addition to endocrine therapy. In these patients, additional chemotherapy should be considered critically when weighing up the potential benefits and harms. However, this critical evaluation should not be confused with abandoning standard chemotherapy when it is feasible and clinically indicated based on geriatric assessment, risk assessment, and patient preference. The aim of our narrative review is to provide a concise overview of the evidence on chemotherapy in older women with breast cancer and place it in the context of geriatric assessment and risk evaluation in older HR-positive, HER2-negative patients with early breast cancer. This in turn should help to critically weigh up the risks and benefits of chemotherapy for the individual older patient with early-stage breast cancer, which should ultimately lead to more individualized and at the same time more evidence-based treatment recommendations that take into account the complex interplay of different and sometimes contradictory patient- and tumor-specific factors., Competing Interests: Declaration of competing interest MS reports grants and personal fees from Pierre-Fabre, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Pfizer, grants and personal fees from Novartis, grants and personal fees from Astra-Zeneca, grants and personal fees from Eisai, personal fees from Amgen, grants, personal fees and non-financial support from Pantarhei Bioscience, grants, personal fees and non-financial support from BioNTech, grants from Genentech, personal fees from SeaGen, personal fees from Lilly, personal fees from Gilead, personal fees from Daiichi Sankyo, personal fees from Menarini Stemline, outside the submitted work; In addition, Dr. Schmidt has a patent EP: 2951317 Method for predicting the benefit from inclusion a taxane in a chemotherapy regimen in patients with breast cancer issued, and a patent EP2390370 A method for predicting the response of a tumor in a patient suffering from or at risk of developing recurrent gynecologic cancer towards a chemotherapeutic agent issued. SL reports employment as Chief Executive Officer (CEO) at German Breast Group (GBG) Forschungs GmbH; institutional fees for advisory board membership for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb (BMS), Celgene, DSI, EirGenix, Gilead, GSK, Lilly, Merck, Novartis, Olema, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi and Seagen; institutional fees as an invited speaker for AstraZeneca, DSI, Gilead, Medscape, Novartis, Pfizer, Roche, Seagen and Stemline-Menarini; institutional research grants from AstraZeneca, Celgene, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer and Roche; institutional funding from AbbVie, Greenwich Life Sciences and Molecular Health; institutional licensing fees from VMscope GmbH; a role as a steering committee member (non-financial interest) for AstraZeneca, Daiichi Sankyo, Immunomedics/Gilead, Novartis, Pfizer, Roche and SeaGen; a role as a principal investigator (PI) for Pfizer (non-financial interest); a non-remunerated advisory role for Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Kommission Mamma; a non-remunerated role as PI for PI Aphinity; non-remunerated membership of Die AGO, the American Society of Clinical Oncology (ASCO), German Cancer Society (DKG), ESMO and the ESMO Guidelines Committee; non-remunerated role as Chair of ESMO Breast; institutional patents for EP19808852.8, EP14153692.0, EP21152186.9 and EP15702464.7 (non-financial interest)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Germline pathogenic mutation of the BRCA gene increases the prevalence of breast cancer. Reports on the benign variants of BRCA genes are limited. However, the definition of these variants might be altered with the accumulation of clinical evidence. Therefore, in the present study, we focused on benign single nucleotide polymorphisms (SNPs) of BRCA genes. Linkage disequilibrium was calculated from whole genome sequencing of the BRCA genes obtained from 500 healthy controls and 49 breast cancer patients. Sanger sequencing was used to confirm the mutation. The linkage disequilibrium was noted for seven and three SNPs in the BRCA1 and BRCA2 genes, respectively. Breast cancer with BRCA1/2 linkage disequilibrium was not correlated with a personal history of benign diseases or family history of cancer. Nevertheless, breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor-infiltrating lymphocytes and positive extensive intraductal components. The patients with BRCA1 linkage disequilibrium tended to have worse disease-specific survival. Cancers with BRCA2 linkage disequilibrium are associated with a lower ratio of grade III cancer. Moreover, patients with BRCA2 linkage disequilibrium tended to have better overall survival. In conclusion, linkage disequilibrium from benign SNPs of the BRCA genes potentially affects cancer characteristics., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Temporal heterogeneity in human epidermal growth factor receptor 2 (HER2) status may be associated with the prognosis of breast cancer. We aimed to clarify the relationship of HER2-low transition during neoadjuvant therapy with survival outcomes under the new classification of HER2 status., Methods: This retrospective study was conducted based on the prospective database of breast cancer patients treated with neoadjuvant therapy from September 2013 to August 2020., Results: This analysis enrolled 185 patients, including 44 patients with HER2-zero tumours, 93 patients with HER2-low tumours and 48 patients with HER2-positive tumours after neoadjuvant therapy. Nearly, 57.6% of HER2-zero tumours turned into HER2-low tumours after neoadjuvant therapy, while 25.0% of HER2-low patients changed to HER2-zero or HER2-positive tumours. We found that at least once diagnosis as HER2-low breast cancer was related to hormone receptor status ( p  < .001) and Ki-67 expression ( p  = .036). Patients ever diagnosed as HER2-low tumours had favourable clinicopathological features (less Ki-67 expression, lower pathological staging, etc.) as well as significantly better locoregional relapse-free survival (LRFS; p  = .007) and overall survival (OS; p  = .026) compared with those never exhibiting HER2-low expression. Furthermore, the 6-year OS rates were 94.2% (95% confidence interval (CI) 83.1-98.1), 88.7% (74.4-95.2) and 78.1% (65.4-86.6) for patients with stable, once and none HER2-low expression, respectively (adjusted HR, 0.514 [95%CI, 0.294-0.897], p  = .019)., Conclusions: Our study first indicated in patients across all expression levels of HER2 that stable or at least once HER2-low status may confer favourable attributes including less malignant biological behaviour and long-term survival benefit for breast cancer receiving neoadjuvant therapy.

Background: Older patients with breast cancer are often underrepresented in clinical trials, leading to a lack of evidence-based guidelines for surgical treatment in this cohort. Consequently, synthesizing real-world data is crucial for determining the optimal surgical management of geriatric patients with breast cancer., Methods: A comprehensive search was conducted of the PubMed, Embase, and Cochrane Library databases. The review included clinical studies evaluating treatments in patients aged ≥65 years with breast cancer. Comparisons were made between primary surgical treatment and endocrine therapy alone, breast-conserving surgery without radiotherapy versus mastectomy, sentinel lymph node biopsy versus omission of sentinel lymph node biopsy, and surgery plus axillary lymph node dissection versus omission of axillary lymph node dissection., Results: A total of 44 studies were analyzed. Surgery significantly increased overall survival, breast cancer-specific survival, and recurrence-free survival compared with endocrine therapy alone. Pooled estimates revealed that mastectomy yielded significantly better prognoses than breast-conserving surgery without radiotherapy in terms of both overall survival and breast cancer-specific survival. Omitting sentinel lymph node biopsy and axillary lymph node dissection did not significantly reduce overall survival., Conclusions: For older patients with breast cancer, primary surgical treatment significantly enhances survival and regional control compared with endocrine therapy alone without compromising quality of life. Frail patients with nonmetastatic breast cancer who are unwilling to undergo radiotherapy benefit from mastectomy, with no notable psychosocial decline compared with breast-conserving surgery alone. Sentinel lymph node biopsy omission does not increase recurrence rates or mortality, and avoiding axillary lymph node dissection may be viable for node-positive older patients due to its comparable survival outcomes., Competing Interests: Conflict of Interest/Disclosure All authors have no conflicts of interest or financial ties to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Breast cancer is the most commonly diagnosed cancer among women worldwide. While previous studies have reported urban and rural differences in breast cancer outcomes, the level of heterogeneity within these broad regions is currently unknown., Methods: Population-level data from Queensland Cancer Register including 58,679 women aged at least 20 years who were diagnosed with breast cancer in Queensland, Australia, 2000-2019 were linked to BreastScreen Queensland and Queensland Hospital Admitted Patients Data Collection to estimate five breast cancer outcomes: incidence, proportion of localised disease and screen-detected cases (via public-funded program), surgical rates, and 5-year survival. Bayesian spatial models were used to smooth outcomes across 512-517 small areas in Queensland., Results: The incidence of breast cancer was not proportionally distributed, with urban regions having higher rates. Less than half (47 %) of women were diagnosed with localised disease, 91 % had surgery, with five-year relative survival of 92 %. There was no evidence of geographic variation in the proportion of localised disease, surgical rates, or survival over Queensland. Publicly-funded screening detected 38 % of cases, with lower proportion of screen-detected cases observed in Queensland's urbanised south-east corner., Conclusion: Although the disparities in health outcomes faced by Australians living in rural areas have received increased attention, this study found limited evidence for spatial variation in breast cancer outcomes along the continuum of care across Queensland. These results suggest the detection and management practices for breast cancer may provide an achievable benchmark for other cancer types in reducing the geographical disparity in cancer outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial., Material/methods: Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided., Results: Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy., Conclusion: Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Breast cancer is a disease with high global prevalence. Clinical inflammatory biomarkers have been proposed as prognostic indicators in oncology. This research aims to determine the relationship between inflammatory markers and overall survival in breast cancer patients from four representative hospitals in Lima, Peru., Methods: This is a multicentric, analytical, longitudinal retrospective cohort study with survival analysis in female patients with breast cancer, from 2015 to 2020, who had received at least one complete treatment regimen. The dependent variable was overall survival, and the independent variables were inflammatory markers neutrophil lymphocyte ratio, platelet lymphocyte ratio (PLR), albumin, and red cell distribution width; intervening variables included age, clinical stage, molecular subtype, and other known prognostic factors. The Kaplan-Meier method was applied to generate survival curves with the Log-Rank test, and finally, Cox regression, to find crude and adjusted hazard ratios (HR)., Results: Of 705 evaluated patients, 618 were analyzed. The mean age was 56.6 ± 12.3 years, 18.0% of patients were pure HER2 positive, 39.3% luminal A, 29.9% luminal B, 11.0% triple-negative, and 81.4% showed overweight and obesity. The average overall survival was 51.1 months. In the multivariate analysis, factors significantly related to lower overall survival were PLR > 150 (adjusted HR: 2.33; 95% confidence interval (CI): 1.22, 4.44) and stage III (adjusted HR: 4.15; 95% CI: 1.35, 12.83)., Conclusions: The Elevated Platelet-Lymphocyte Index and advanced clinical stage were associated with lower overall survival in breast cancer patients. Furthermore, PLR >150 proved to be an independent prognostic factor for mortality., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Renal cell carcinoma (RCC) and breast carcinoma (BC) are frequent tumours, yet their co-occurrence in the same patient is a unique scenario. Few studies explored the characteristics of such patients without specific focus on pathological data. In this retrospective study, we aimed to describe the clinico-pathological features of RCC patients with a history of BC and compare them to a control cohort of RCC women free of previous BC., Methods: All adult women treated for BC at a high-volume cancer institution between 2007 and 2020 and who subsequently developed a RCC were retrospectively included. Their clinical and pathological characteristics were compared to an independent cohort of consecutive women undergoing percutaneous kidney tumour biopsy for localized kidney cancer in a second high-volume cancer institution., Results: A total of 113 patients were identified from 2 different institutions. We observed a lower rate of clear cell RCC in the Kidney-breast (KB) group compared to the Kidney-only (KO) group, suggesting a potential association between breast cancer and non-ccRCC. The KB group had a higher proportion of locally advanced tumours and high-grade lesions. Although recurrence-free survival favored the KO cohort, no significant difference was found in cancer-specific survival and overall survival rates between the groups. Noteworthy, patients in the KB group had a higher prevalence of family history of cancer., Conclusion: Our findings highlight the need for further research to elucidate the underlying mechanisms and clinical implications of RCC coexisting with breast carcinoma. Understanding the characteristics of this unique population can guide clinical strategies and improve patient outcomes., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: This study aimed to analyze the association between the primary tumor site and clinicopathological characteristics and survival prognosis of breast cancer (BC) patients using a large population database., Methods: BC patients screened in the Surveillance, Epidemiology, and End Results (SEER) database were categorized into 6 groups based on primary sites. Descriptive statistics, Kaplan-Meier curves, Cox regression models, forest plots were used to assess the effect of primary sites on overall survival (OS) and breast cancer-specific survival (BCSS). Multivariate Cox proportional analyses were conducted to calculate hazard ratios (HRs) and adjusted subgroups' hazard ratios (AHRs). Nomograms were utilized to predict OS and BCSS., Results: Among 193,043 BC patients, the highest incidence was found in the upper outer quadrant (52.60%). Central portion patients are associated with more clinical features indicating a poor prognosis, and had worse OS and BCSS than other sites. Univariate and multifactorial Cox analyses showed associations between OS/BCSS and various factors. Subgroup analyses revealed differences in OS and BCSS between central portion and upper outer quadrant varied among age, T and N stage. The nomogram was established to predict the survival of central portion BC patients., Conclusions: Primary tumor site is associated with clinicopathological features and prognosis of BC, may be influenced by age at diagnosis and T and N stage. Central portion BC patients have worse prognosis due to older age at diagnosis, higher T stage and higher likelihood of lymph node metastasis. Early diagnosis and treatment may help to improve survival of central portion BC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), at the end of treatment (EOT) with CDK4/6 inhibitors abemaciclib and palbociclib in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer., Methods: We included 67 patients treated with fulvestrant plus abemaciclib or palbociclib. Overall survival (OS) since the EOT with CDK/4/6 inhibitors was compared in relation to the levels of ALC and NLR. The cut-off values of ALC and NLR were set at 1000/μL and 3, respectively., Results: Patients with a high ALC at EOT showed significantly longer OS than those with a low ALC (p = 0.0358). Moreover, patients with a low NLR at EOT showed significantly longer OS than those with a high NLR at EOT (p = 0.0044). Looking at the changes of ALC and NLR between baseline and the EOT, patients with a high ALC both at baseline and at the EOT showed significantly longer OS than others (p = 0.0201). Similarly, patients with a low NLR both at baseline and at the EOT showed significantly longer OS after EOT than others (p = 0.0136). Multivariable analysis revealed that the NLR at EOT (low vs. high) and changes in NLR (low at baseline to low at EOT vs. others) were significant and independent prognostic factors for OS after EOT (p = 0.0337, p = 0.0039, respectively)., Conclusion: NLR at EOT with CDK4/6 inhibitors is a significant and independent prognostic marker for patients with ER-positive HER2-negative advanced breast cancer., Competing Interests: Declarations. Conflict of interest: M Nagahashi received honoraria from Chugai, AstraZeneca, Eli Lilly, Pfizer, Novartis, Taiho, Daiichi Sankyo, Esai, Kyowa-Kirin, and Denka. Y Miyoshi received research funding and honoraria from Esai, Chugai, AstraZeneca, Eli Lilly, Pfizer, MSD, Kyowa-Kirin, Daiichi-Sankyo, and Taiho. A Mitsuyoshi, H Kanaoka, A Oshiro, Y Togashi, A Hattori, T Higuchi, A Nishimukai, K Murase, Y Takatsuka have no conflict of interest., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Breast cancer (BC) is the most common neoplasm, and its global burden has become one of the most important factors jeopardizing the health of the world population, especially women. The aim of this study was to analyze mortality trends and the spatial distribution of BC in women in the capital and state of Sergipe, aiming to contribute to the implementation and improvement of strategies for the prevention and health promotion of women with BC. Trends were calculated using the Joinpoint Regression Program 5.0.2. Spatial analyses were performed using the empirical Bayesian model, thematic maps were created using QGIS 3.10.7 and Moran's I indices were calculated using TerraView 4.2.2. Between 1996 and 2022, 1384 and 3128 BC deaths were recorded in the capital and state of Sergipe, respectively. The mortality trend increased in the age groups of 45-75+ for the state of Sergipe, while in the capital, we observed stability in all age groups. The highest AAPC was 4.6213, with a 95 % confidence interval (2.16; 7.14). Univariate global Moran's I analysis indicated spatial autocorrelation during the study period. A direct relationship was found between mortality rates and the more economically developed regions., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Breast conserving surgery (BCS) is well established for the management of ductal carcinoma in situ (DCIS), but neither randomized trials nor guidelines address management of ipsilateral breast tumor recurrence (IBTR) after BCS for DCIS., Patients and Methods: We identified women treated with BCS for DCIS who developed IBTR as a first event. Between those treated with mastectomy versus re-BCS, we compare the clinicopathologic characteristics, the use of adjuvant radiotherapy (RT) both upfront ("primary RT") and post IBTR ("secondary RT"), of tamoxifen, the rate of third events (local, regional, distant), and both breast cancer specific (BCSS) and overall survival (OS)., Results: Of 3001 women treated with BCS for DCIS (1978-2010), 383 developed an IBTR as a first event (1983-2023) and were treated by mastectomy (51%) versus re-BCS (49%). Compared with re-BCS, mastectomy patients at initial treatment were higher grade (74% versus 59%, p = 0.004), with more frequent primary RT (61% versus 21%, p < 0.001). Third local events were more frequent for re-BCS than mastectomy (16% versus 3%, p = 0.001), but there were no differences in breast cancer specific or overall survival., Conclusions: For isolated IBTR following BCS for DCIS and treated by mastectomy versus re-BCS (1) mastectomy was associated with less favorable initial pathology and more frequent use of primary RT, (2) re- recurrence was more frequent with re-BCS, and (3) BCSS and OS were comparable. Our data suggest a wider role for re-BCS and further study of the relationship between secondary RT and the rate of third breast events., (© 2024. Society of Surgical Oncology.)

Background: Most patients with breast cancer treated with neoadjuvant chemotherapy (NAC) experience clinical benefit, however, a small proportion progress. We aimed to characterize factors predicting in-breast tumor progression and impact on distant recurrence., Patients and Methods: We reviewed all patients with clinical stage I-III breast cancer treated with NAC in 2006-2021 at our institution. We compared in-breast progressive disease (PD), defined as ≥ 20% increase in tumor size, with stable disease (SD) or response. Distant recurrence-free survival (DRFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards regression., Results: Of 1403 patients, 70 (5%) experienced in-breast PD, 243 (17%) SD, 560 (40%) partial response (PR), and 530 (38%) breast pathologic complete response (breast pCR, ypT0/Tis). The rate of PD varied by tumor subtype (8% in HR+/HER2-, 5% TNBC, 2% HER2+, p < 0.001). With median 48 months follow-up, the rates of DRFS were significantly different according to clinical breast response as follows: PD 56%, SD 68%, PR 82%, or breast pCR 93%, p < 0.001. In patients with PD on multivariable analysis, post-NAC grade (adjusted HR 2.9, p = 0.002) and ypT3-4 category (adjusted HR 2.4, p = 0.03) were the strongest predictors of DRFS. Combining these factors, 23% had neither, 44% had one, and 33% had both, which stratified outcome in PD with 3-year DRFS of 100%, 77%, and 30%, respectively (p < 0.001)., Conclusions: While in-breast PD during NAC is uncommon (5%), it predicts poor survival. Among patients with in-breast PD, post-NAC tumor grade and T category predict outcomes and may be useful to guide treatment escalation., (© 2024. Society of Surgical Oncology.)

Background: The evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection., Methods: We enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival., Results: Between 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100)., Conclusions: PC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer., Competing Interests: Disclosures No conflicts of interest to be declared., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Breast cancer (BC) is the most common malignant tumor in women. Between 20 % and 30 % of patients develop metastases from BC, 50 % of them in the liver. The mean survival rate reported in patients with liver metastases from BC (LMBC) ranges from 3 to 29 months. The role of surgery in LMBC is not clearly defined. The objective of the present study was to determine the long-term survival and disease-free survival of patients undergoing surgery for LMBC and to identify the patients who most likely benefit from surgery., Material and Methods: This retrospective multicenter cohort study included all consecutive patients undergoing LMBC surgery at the participating European centers from January 1, 2010, to December 31, 2015. The ClinicalTrials.gov ID is NCT04817813., Results: A hundred women (mean age 52.6 years) undergoing LMBC surgery were included. Five-year disease-free survival was 29 %, and 5-year overall survival was 60 %. Median survival after BC surgery was 12.4 years, and after LMBC surgery, 7 years. Patients with ECOG 1, ASA score I-II, metachronous LMBC, positive hormone receptors, and who had received neoadjuvant and adjuvant hormone treatment obtained the best overall and disease-free survival results., Conclusions: In cases of correct patient selection and as part of a comprehensive onco-surgical strategy, surgery for LMBC improves overall long-term survival. In our series, certain factors were linked to better disease-free and overall survival; consideration of these factors could improve the selection of the best candidates for LMBC surgery., Gov Id: NCT04817813., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: This study aimed to examine the impact of the level of HER2 overexpression on pathologic and clinical outcomes in HER2-positive breast cancer (BC) patients treated with neoadjuvant therapy (NAT)., Methods: Women with Stage II or III HER2-positive BC who received anthracycline-taxane-trastuzumab NAT regimens followed by curative-intent surgery were included. Patients were classified according to tumor HER2 expression into HER2-high (immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) HER2/CEP17 ratio ≥5 or HER2 copy number ≥10) and HER2-intermediate (IHC 2+ with HER2/CEP17 ratio ≥2 to <5 or copy number ≥4 to <10). Univariate and multivariate logistic regression analyses were performed using HER2 expression as a categorical variable. The primary outcome was pathological complete response (pCR). Estimated 3-year disease-free survival (DFS) and Overall Survival (OS) were secondary outcomes., Results: Among 161 patients with HER2-positive BC, 139 (86%) and 22 (14%) were classified as HER2-high and HER2-intermediate, respectively; 105 (65.2%) had hormone receptor (HR)-positive tumors; 72 (45%) achieved a pCR. In the overall population, pCR rates of 18% and 49% were achieved in HER2-intermediate and HER2-high cases, respectively (odds ratio [OR] = 0.23 95% CI 0.07-0.72; P = .007). No pCRs were observed among HR-positive, HER2-intermediate cases. Estimated 3-year DFS was 97.1% versus 89.3% for patients achieving a pCR versus those with residual disease, respectively (P = .0011)., Conclusion: We found that patients with HER2-high disease were more likely to achieve pCR after NAT compared to patients with HER2-intermediate BC, a subgroup of patients that may benefit from more personalized NAT strategies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The results of the OlympiA study led to the approval of a PARP inhibitor (olaparib) as adjuvant treatment for early breast cancer (eBC) at high risk of relapse in patients with a germline BRCA1/2 mutation (gBRCAm). However, the proportion of patients in routine practice who meet the "high-risk" criteria applied in the OlympiA study, and for whom gBRCAm testing would now be mandatory, remains unknown., Patients and Methods: In this population-based study, we use unique data from the French specialized Côte d'Or Breast and Gynecological Cancer Registry, to assess the real-life proportion, and long-term prognosis of patients treated for eBC between 2005 and 2015 with standard treatment, and at "high risk" of relapse according to the OlympiA trial criteria., Results: We included 3483 patients treated for HER2-negative eBC (N = 380 with ER-, and N = 3103 with ER + tumor). We found N = 62 (1.8 %) patients with gBRCA1/2 mutations. A total of 494 patients (14.2 %) were classified as "high risk" according to the Olympia criteria; 55 % with ER-tumors, and 9.1 % with ER + tumors, respectively. Despite more intensive systemic treatments in "high risk" patients, 10-year overall survival was much worse in these "high risk" patients compared to the others: 60.1 % vs 83.8 % in ER-tumors, and 55.4 % vs 84.1 % in ER + tumors. Our estimates of net survival show an even greater difference., Conclusion: This study provides real-life insights into the prevalence and prognosis of patients with high-risk eBC, in a context where the approval of adjuvant olaparib requires careful reorganization of care, so as not to overlook a patient with gBRCAm who could benefit from adjuvant olaparib., Competing Interests: Declaration of competing interest SL, ID, DM, CC, LA, and MR report travel accommodations and expenses from AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment., Patients and Methods: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety., Results: A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd., Conclusions: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy., Methods: We analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3-5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS., Results: From January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller-Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26-0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51-9.84; P = 0.28)., Conclusion: MPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Axillary management after neoadjuvant chemotherapy (NAC) is evolving but axillary lymph node dissection (ALND) remains the standard of care for patients with residual nodal disease. The results of the Alliance A011202 trial evaluating the oncologic safety of ALND omission in this cohort are pending but we hypothesize that ALND omission is already increasing., Methods: The National Cancer Database was queried to identify patients diagnosed with cT1-3N1M0 breast cancer who underwent NAC and had residual nodal disease (ypN1mi-2) from 2012 to 2021. Temporal trends in omission of completion ALND were assessed annually. Multivariable logistic and Cox regression models were used to identify factors associated with ALND omission and overall survival (OS), respectively., Results: A total of 6101 patients were included; the majority presented with cT2 disease (57%), with 69% HER2+, 23% triple-negative, and 8% hormone receptor-positive/HER2-. Overall, 34% underwent sentinel lymph node biopsy (SLNB) alone. Rates of ALND were the lowest in the last 4 years of observation. After adjustment, treatment at community centers (vs. academic) and lower pathologic nodal burden were associated with omission of ALND. ALND omission was associated with a higher unadjusted OS (5-year OS: 86% SLNB alone vs. 84% ALND; log-rank p = 0.03), however this association was not maintained after adjustment., Conclusions: Despite the impending release of the Alliance A011202 results, omission of ALND in patients with residual nodal disease after NAC is increasing. This practice appears more prominent in community centers and in patients with a lower burden of residual nodal disease. No association with OS was noted., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown., Patients and Methods: This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m 2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status., Results: Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m 2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation., Conclusion: This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study., Competing Interests: Disclosure YA reports consulting income from Exact Sciences, AstraZeneca and Pfizer. C.K.A. reports research funding provided by PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Astra Zeneca, Elucida, Caris, Incyclix; consulting for Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex, Roche; royalties from UpToDate, Jones and Bartlett. L.A.C. reports research funding from Genentech/Roche, AstraZeneca, Lilly, Novartis, Veracyte, Nanostring. C.M.P. is an equity stockholder and board of director member of BioClassifer LLC and is listed as inventor on patent applications for the Breast PAM50 assay. E.C.D. reports consulting income from Sanofi, research funding from Novartis, Genentech, Bayer, Pfizer, and Merck and a family member who received past consulting income from Novartis. L.A.C reports research funding from AstraZeneca, Genentech/Roche, Lilly, Merck, Nanostring, Novartis, SeaGen, and Veracyte. P.K.M. is a full-time employee and equity stockholder with Veracyte., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The purpose of this study was to compare characteristics and outcomes of patients with breast cancer with liver metastasis who had and had not undergone radioembolization. Medical records of patients with breast cancer with liver metastases (4,332 patients who had not undergone radioembolization and 166 patients who had) seen between January 1, 2009, and October 31, 2021, were assessed. Propensity score matching was performed. Patients who underwent radioembolization were significantly younger (47.7 years [SD ± 10.1] vs 52.3 years [SD ± 12.5]; P < .001) and underwent more systemic treatment regimens (8.6 [SD ± 4.1] vs 5.2 [SD ± 3.2]; P < .001). Median survival was longer, in unmatched (67.1 vs 40.7 months; P = .001) and matched (67.1 vs 38.0 months, P = .001) cohorts. Radioembolization was associated with superior survival (P = .002). In conclusion, patients with breast cancer with liver metastases who underwent radioembolization were significantly younger and underwent more treatment regimens. Radioembolization was associated with longer median survival., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Cancer caused an estimated 2.2 million deaths across Europe in 2020. This analysis estimated the cost of lost productivity due to premature deaths associated with lung, breast and melanoma cancer and investigated the temporal trends across European regions across 2010, 2015 and 2019., Method: The human capital approach was used to estimate the indirect costs from lung, melanoma, and breast cancers (ICD-10 code: C33-34, C43, and C50, respectively) in Northern, Eastern, Southern, and Western Europe. Age-specific mortality, and country-specific wages and employment rates were used to calculate years of productive life lost (YPLL), YPLL/death and present value of future lost productivity (PVFLP). Data were sourced from the World Health Organization, Eurostat, and the World Bank., Results: The number of cancer deaths remained relatively stable from 2010 to 2019. YPLL/death decreased across all European regions and for all cancers between 2010 and 2019 (reported ranges across European regions; lung cancer: 25-42 %; breast cancer: 18-21 %; melanoma: 31-37 %). In Europe, the decrease in PVFLP in 2019 compared to 2010 was €2995M for lung cancer, €295M for melanoma, and €466M for breast cancer, with an overall reduction of productivity cost of €3756M in these cancer types., Conclusion: The results from this study illustrate a decreased trend in productivity costs from 2010 to 2019 which could be driven by deaths occurring at an older age, suggesting that advances in cancer prevention and the treatment landscape have extended the life of cancer patients, yielding less productivity losses., Policy Summary: The indirect economic costs modelled show the impact of past effective health policies and new treatments. Continued efforts to improve public health policies in supporting public awareness of risk factors and value of early diagnosis could lead to further reduction in these losses. Prevention, early diagnosis, and activation of early treatment pathways could serve to reduce loss of life and improve productivity., Competing Interests: Declaration of Competing Interest AB and GB are employees of MSD subsidiaries of Merck & Co., Inc., Rahway, NJ, USA and may own stocks and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. EO, AM, RH and GW are employees of Adelphi Values (PROVE), paid consultants to MSD. PMGC declares no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences., Method: The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series., Results: One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40 years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival., Conclusion: This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Thrombosis may be included in the profile of side effects associated with CDK4/6 inhibitors. Its significance might be greater than reported in randomized clinical trials. To investigate this, a retrospective, multicenter study was conducted. The primary objective was to calculate the incidence of thrombosis associated with CDK4/6 inhibitors. Secondary objectives included examining the impact of thrombosis on survival and identifying predictor variables for the development of venous thromboembolism (VTE) or arterial thrombosis (AT). A total of 986 patients were recruited. The incidence of VTE/AT associated with CDK4/6 inhibitor treatment during the follow-up period was 5.48 %. Survival analysis did not indicate that the development of VTE/AT during CDK4/6 inhibitor treatment significantly impacted patient survival (p = 0.133). In our analysis, two variables were found to be statistically significant (p < 0.05) as predictors of VTE/AT in breast cancer patients receiving CDK4/6 inhibitor therapy. These variables were the presence of central nervous system (CNS) metastasis with an odds ratio (OR) of 3.68 (95 % CI 1.18 - 11.49) and the use of abemaciclib with an OR of 2.3 (95 % CI 1.16 - 4.57)., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this article., (Copyright © 2024. Published by Elsevier B.V.)