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The study explored endocrine resistance by leveraging machine learning to establish the prognostic stratification of predicted Circulating tumor cells (CTCs), assessing its integration with circulating tumor DNA (ctDNA) features and contextually evaluate the potential of CTCs-based transcriptomics. 1118 patients with a diagnosis of luminal-like Metastatic Breast Cancer (MBC) were characterized for ctDNA through NGS before treatment start, predicted CTCs were computed through a K nearest neighbor algorithm. Differences across subgroups were analyzed through chi square or Fisher's exact test according to sample size and corrected for False Discovery Rate. Differences in survival were tested by log-rank test and uni- and multivariable Cox regression. CTCs transcriptomics was performed through RNAseq after sorting with DEPArray NxT. Univariable and multivariable analysis adjusted for ctDNA alterations revealed a significant impact of CTCs predictive stratification on both progression-free survival (PFS) and overall survival (OS). Alterations in RTK and ER pathways were significantly correlated with predicted-Stage IV aggressive . The combined impact of CTCs stratification and RTK/ER pathway alterations influenced patient outcomes, with predicted-Stage IV aggressive having a negative impact on PFS regardless of the mutational status. The pilot exploratory CTCs transcriptomics analysis showed transcriptional changes linked to cell proliferation such as under expression of MALAT1 and overexpression of GREM1, GPR85 and OCM. Our data underline the potential of an integration between ctDNA and CTCs, both through quantification and transcriptomic analysis, for a deeper understanding of tumor biology and treatment response in HR-positive, HER2-negative MBC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorenzo Gerratana reports advisory/consultancy fee from AstraZeneca, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Incyte, Novartis, Pfizer, Merck Sharp & Dohme, Menarini Stemline, Abbvie; research funding from Menarini Silicon Biosystems. Massimo Cristofanilli reports advisory/consultancy fee from Novartis, Genentech, Pfizer, Merck, Sanofi, Daiichi Sankyo/Astra Zeneca, Lilly, Gilead Sciences, Menarini, Mersana; research fundings from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, AstraZeneca/Daiichi Sankyo; Aditya Bardia reports research fundings from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/Astra Zeneca, Eli Lilly; advisory/consultancy fee from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi, Pharma/Astra Zeneca, Phillips, Eli Lilly, Foundation Medicine. Fabio Puglisi reports advisory/consultancy fees from AstraZeneca, Roche, Amgen, Lilly, Novartis, Pfizer. Andrew Davis reports payment for lectures from Onclive Lecture and participating on a Data Safety Monitoring Board for Pfizer and Biotheranostics. Carolina Reduzzi reports research fundings from Menarini Silicon Biosystems. Arielle Medford reports consulting fees from Guardant Health, Illumina; payment for lectures from Signatera; Ami N. Shah reports payment for lectures from Gilead. Leslie Bucheit reports to be a shareholder and employee of Guardant Health. Chales Dai reports research funding from National Institute of Health; payment for lectures from Master Class for Breast Cancer (MGH); travel support from Dava Oncology. Amir Behdad reports advisory/cosultancy fees from Leica, Caris; honoraria for lectures from Lily and Foundation Medicine China; travel support from Lily., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: About 15-20 % of patients with metastatic breast cancer (mBC) can experience oligoprogressive disease (OPD) in ≤ 5 sites of disease. Patients with OPD may benefit from metastasis-directed stereotactic radiotherapy (SBRT) to all sites of cancer progression while maintaining the same systemic treatment, aiming to prolong the time to next systemic treatment (NEST). This study aims to assess the outcomes provided by this multimodal strategy., Methods: Prospective-retrospective, single-center, cohort study including consecutive patients who received SBRT to all extracranial OPD sites (≤ 5), from January 2011 to June 2023, without changing systemic therapy, according to the multidisciplinary tumor board's indication. The primary endpoint was post-radiotherapy progression-free survival (pRT-PFS). A sample size of 130 patients was needed to estimate a median pRT-PFS of 8 months with a 95 % confidence interval (95 %CI) ranging from 5.4 (considered clinically significant) to 10.6 months., Results: 129 patients were included: 99 (77 %) had hormone receptor-positive/HER2-negative (HR+/HER2-) disease, 116 (90 %) had ≤ 2 oligoprogressive lesions, 118 (91 %) presented with non-visceral OPD involving bones or lymph nodes. Patients experienced OPD after a median PFS on systemic therapy (pre-OPD PFS) of 11.3 months (95 % CI, 8.7-13.0). Median pRT-PFS was 11.3 months (95 % CI, 9.1-13.5) and median NEST was 13.6 months (95 % CI, 11.5-15.2). Only 19 (15 %) patients experienced a subsequent PD in the OPD sites treated with SBRT., Conclusion: Patients with oligoprogressive mBC, especially with HR+/HER2- disease and non-visceral OPD after a durable pre-OPD PFS, benefit from OPD-directed SBRT while maintaining the same systemic treatment, suggesting its broader implementation in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GC reports financial interests with AstraZeneca, Celcuity, Daiichi Sankyo, Exact Sciences, Lilly, Merck, Novartis, Pfizer, Roche, Veracyte, Ellipsis, Astellas, Blueprint Medicine, BMS, Kymab, Merck, Novartis, Philogen, Relay Therapeutics, Sanofi; and non-financial interests with the Italian National Health Council as Advisor for Ministry of Health ESMO, ESMO as Clinical Practice Guidelines Chair, Europa Donna as Member of the Scientific Council, EUSOMA as member of the Advisory Council, Fondazione Beretta, Lega Italiana Lotta ai Tumori as member of Board of Directors. EM received consulting or advisory fees from Eisai, Exact Sciences, MSD Oncology, Daiichi-Sankyo/AstraZeneca, Pfizer, and Seagen outside the submitted work. All the competing interests were outside the submitted work. All other authors have no potential conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Breast cancer (BC) is the leading cause of cancer death among women worldwide, making the discovery and quantification of new biomarkers essential for improving diagnostic and preventive strategies to limit dissemination and improve prognosis. Essential trace metals such as Fe, Cu, and Zn may play critical roles in the pathophysiology of both benign and malignant breast tumors. However, due to the high metabolic activity and reduced element selectivity of cancer cells, also non-essential elements may be taken up and may even be implicated with disease progression. This study investigates the spatial distribution and concentrations of both essential and non-essential elements in breast tissues, assessing their potential for diagnostic applications. Laser ablation (LA)-inductively coupled plasma-mass spectrometry (ICP-MS) with a time-of-flight (ToF) mass analyzer (LA-ICP-ToF-MS) was used to inquire the distribution of almost all elements across the periodic table and their abundance in metastatic (n = 11), non-metastatic (n = 7), and healthy (n = 4) breast tissues. Quantification was achieved using gelatine-based standards for external calibration to quantitatively map various elements. Overall, the Fe, Cu, Zn, Sr, and Ba levels were significantly increased in tumor samples with Sr and Ba showing strong correlation, likely due to their similar chemistry. Comparison of calibrated LA-ICP-ToF-MS data with a histologic staining demonstrated the possibility to clearly differentiate between various tissue types and structures in breast tissues such as tumor niche and stroma. The levels of the studied elements were significantly higher in the tumor niche areas compared to the stroma, and for Fe, a significant accumulation was observed in the tumor niche areas from the metastatic patient group relative to the levels found in the same areas of the non-metastatic group., Competing Interests: Declarations. Ethical approval: This study was conducted in accordance with national regulations and received approval from the Ethics and Investigation Committee of the Hospital de Jove Foundation (PI02/2018). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: It is unclear whether breast cancer (BC) subtypes or CSF cytology results are associated with overall survival (OS) among patients with BC leptomeningeal disease (LMD). This single-institution retrospective study compares OS among BC patients with LMD across various breast cancer subtypes and CSF cytology results., Methodology: The study enrolled BC patients diagnosed with LMD between 2010 and 2023. Breast cancer subtypes were classified as A. ER+/HER2-, HER2+, or triple-negative BC (TNBC); B. HER2+, HER2-Low, HER2-Zero. CSF cytology subtypes included CSF+, CSF-, or CSF not tested (NT). OS was summarized via Kaplan-Meier analysis and compared using log-rank test. Cox models were used for multivariate analyses., Results: Out of 69 patients registered, median OS (95% CI) for ER+/HER2- (n = 33), HER2+ (n = 12) and TNBC (n = 24) subtypes were 8.0 (3.02, 24.8), 5.71 (1.61, not estimated) and 3.2 (1.11, 4.95) months (P = .17). In multivariate analysis, TNBC was associated with worse OS versus ER+/HER2- [Hazard Ratio (HR), 95% CI: 2.64, 1.23-5.80, P = .04]. HER2 subtypes (HER2-Zero, n = 21; HER2-Low, n = 32; HER2+, n = 12) showed no significant differences in OS. Median OS (95% CI) for CSF+ (n = 16), CSF- (n = 18), and CSF NT (n = 35) groups were 3.54 (1.61, 12.72), 13.41 (4.95, 61.93) and 3.28 (1.44, 6.92) months (P = .04). Multivariate analysis showed both CSF+ and CSF NT were associated with shorter OS compared to CSF- group [HR (95% CI) 4.50 (1.75, 12.11) for CSF+ vs. CSF-; 2.91 (1.45, 6.26) for CSF NT vs. CSF-; P = .002]., Conclusion: TNBC LMD group was associated with worse OS than ER+/HER2- BC LMD when adjusting for other prognostic factors. CSF- LMD patients had better OS than CSF+ or CSF NT LMD., Competing Interests: Disclosure Ruth O'Regan receives or has received research funding from Puma Biotechnology and is an advisor for Pfizer. Carey Anders receives or has received research funding from Puma Biotechnology, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, Pfizer, Astra Zeneca, Elucida, Caris, and Incyclix, honoraria from Genentech, Eisai, IPSEN, Seattle Genetics, Astra Zeneca, Novartis, Immunomedics, Elucida, Athenex, and Roche, and receives royalties from UpToDate and Jones and Bartlett. Ajay Dhakal receives or has received research funding from Celcuity and Puma Biotechnology and honoraria from OncLive/MJH Life Sciences, Gilead Sciences, AstraZeneca, and WebMD/Medscape. All other authors state that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Postoperative radiotherapy (RT) has been shown to effectively reduce disease recurrence and mortality in breast cancer (BC) treatment. A critical step in the planning workflow is the accurate delineation of clinical target volumes (CTV) and organs-at-risk (OAR). This literature review evaluates recent advancements in deep-learning (DL) and atlas-based auto-contouring techniques for CTVs and OARs in BC planning-CT images for RT. It examines their performance regarding geometrical and dosimetric accuracy, inter-observer variability, and time efficiency. Our findings indicate that both DL- and atlas-based methods generally show comparable performance across OARs and CTVs, with DL methods slightly outperforming in consistency and accuracy. Auto-segmentation of breast and most OARs achieved robust results in both segmentation quality and dosimetric planning. However, lymph node levels (LNLs) presented the greatest challenge in auto-segmentation with significant impact on dosimetric planning. The translation of these findings into clinical practice is limited by the geometric performance metrics and the lack of dose evaluation studies. Additionally, auto-contouring algorithms showed diverse structure sets, while training datasets varied in size, origin, patient positioning and imaging protocols, affecting model sensitivity. Guideline inconsistencies and varying definitions of ground truth led to substantial variability, suggesting a need for a reliable consensus training dataset. Finally, our review highlights the popularity of the U-Net architecture. In conclusion, while automated contouring has proven efficient for many OARs and the breast-CTV, further improvements are necessary in LNL delineation, dosimetric analysis, and consensus building., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Radiotherapy plays an essential role in the treatment of breast cancer (BC). Recent advances in treatment technology and radiobiological knowledge have a major impact in BC patients with locoregional disease as the majority are now long-term survivors. Over the last three decades, intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and deep inspiration breath-hold (DIBH) techniques, together with the increasing adoption of moderately hypofractionated and ultra-hypofractionated treatment schedules as well as the possibility to offer partial breast radiotherapy to a well-defined patient subset have significantly changed radiotherapy for BC patients. As dose-volume constraints (DVCs) have to be adapted to these new treatment paradigms we have reviewed available evidence-based data concerning dose-constraints for the main organs at risk (OARs) that apply to the treatment of whole breast/chest wall radiotherapy, whole breast/chest wall radiotherapy including regional nodal irradiation (RNI) and partial breast irradiation (PBI), for the most relevant fractionation schedules that have been introduced recently. This narrative review provides a comprehensive summary that may help to harmonize treatment planning strategies., 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.)

Background: Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer, with 5-10% of cases progressing into invasive disease. Herein, we investigated the association between HER2-low and clinico-pathological characteristics in DCIS and subsequent ipsilateral loco-regional relapse (LRR)., Materials and Methods: We accessed our prospectively maintained institutional database. HER2 status was determined by immunohistochemistry and classified as null (score 0), over-expressed (3+), and low (1+ or 2+); in situ hybridization was not considered since it is not used for routine DCIS diagnostics., Results: Among 375 patients with DCIS, median age was 54 (27-88) years, with a primary tumor size < 2.5 cm in 63%, grade III in 33%, and positive hormone receptor status (HR) in 81% of cases; 71% underwent breast-conserving surgery, 34% received adjuvant endocrine and 39% radiotherapy. A total of 197 (52%) had tumors with low HER2 expression, which resulted significantly associated with grade I/II (P < .001), Ki67< 20% (P < .001), and HR-positive status (P < .001). HER2-low distribution varied from 19.61% and 50% in ER negative and ER-low (<10%) to 60% and 69% in ER high (50%-95%) and very high tumors (> 95%) (P < .001). After a median 39-month follow-up (IQR 16-65), cumulative incidences of LRR was 0.054. Among 17 patients with paired primary tumor and LRR, 5 had discordant HER2 status, with an even distribution of increased and decreased HER2 expression., Conclusions: Low HER2 expression in DCIS is associated with features of reduced aggressiveness. Importantly, changes in HER2 expression may occur prompting retesting in recurrent cases, in line with observations in invasive breast cancer., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear., Methods: We analyzed a prospective cohort of 66 308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs)., Results: In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI = 1.83, 1.49 to 2.26) and males (2.03, 1.51 to 2.73) as well as early-onset breast cancer in females (3.06, 2.20 to 4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12 to 2.14) and 1.69 (1.11 to 2.57) in the highest genetic risk category and 1.03 (0.64 to 1.67) and 0.81 (0.36 to 1.85) in the lowest., Conclusions: Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer., (Published by Oxford University Press 2024.)

Objectives: Recognizing the limitations of the current pain therapies, the study aimed to explore the unique needs and obstacles related to pain management in Breast Cancer Survivors (BCs) with Chronic Pain (CP)., Methods: 4 focus groups were conducted involving 17 BCs with CP (Mage = 51, SD = 7.99) with varying pain intensities. Thematic analysis was applied to transcribed discussions., Findings: Three key themes emerged: (1) Challenges to pain management, including "Doctor-patients communications barriers" and "Contextual and societal barriers"; (2) Self-management needs, encompassing "Psycho-social support," "Care-related needs," and "Shared decision-making"; (3) Treatment preferences and perceptions of pain management, with subthemes like "Treatment preferences," "Institution preference," and "Decision role perception.", Conclusions: This study emphasizes tailored support systems targeting patient hesitancy, countering pain normalization, and addressing healthcare providers' attitudes. It underscores the importance of integrating caregiver and peer support. Findings advocate refining healthcare provider education, adopting a comprehensive multidisciplinary approach, and strategically incorporating eHealth tools into such care.

Background: Breast cancer among women is the most frequently diagnosed cancer and the leading cause of death worldwide. There many advances in diagnosing and treating this disease, early diagnosis and treatment are still a significant challenge in the early stages. In recent years, microRNAs have attracted much attention in cancer diagnosis and treatment. However, the role of miR-146a in breast cancer is still controversial. We aimed to investigate the roles of miR-146a in apoptosis in breast cancer cells., Methods: A microarray dataset from the GEO database was selected, and using the GEO2R tool, the gene expression profile of this dataset was extracted. Then, the target scan database was used to explore the miR-146a target genes. The link between the signaling pathways was collected. We used miR-146a mimic, which was transfected to the MCF-7 cells to investigate the miR-146a roles in the apoptosis. The expression levels of miR-146a and BAX, BCL-2, and p-21(most essential genes in the apoptosis) were quantified by qPCR and western blot analysis., Results: Our findings indicated that doxorubicin induces miR-146a expression. In addition, overexpression of miR-146a affected MCF-7 cell viability, induced apoptosis, and led to reduced expression levels of BCL-2 and P-21, as well as increased BAX expression levels., Conclusion: Considering the role of doxorubicin in inducing apoptosis and increasing the expression of miR-146a, it can be suggested that this miR is involved in inducing apoptosis in BC cells. In addition, miR-146a can be considered a therapeutic candidate.

Introduction: Breast cancer is the leading cause of cancer amongst women in the United Kingdom, with implant-based reconstruction (IBR) using Acellular Dermal Matrices (ADM) gaining popularity for post-mastectomy procedures. This study compares outcomes of different ADMs that are commonly used in women undergoing IBR, this was short and long-term complications., Methods: A systematic search of MEDLINE, Embase, CENTRAL, and CDSR databases was performed according to the PRISMA guidelines, focusing on women undergoing IBR with FlexHD, AlloDerm, Bovine, or Porcine ADMs. A network meta-analysis (NMA) was also conducted., Results: A total of 51 studies were captured by the search, of which 27 were included in the network meta-analysis. Alloderm was the most used ADM (54%), followed by Porcine (17%), Bovine (11%), DermAcell (11%), and FlexHD (7%). The mean follow-up was 27.8 months. The complication rates varied. Porcine ADMs had the highest rate of seroma formation (10.3%) and of haematoma formation (2.7%). AlloDerm FD had the highest rate of wound dehiscence (3.1%). Implant failure was highest in AlloDerm FD ADMs (11.8%), followed by Porcine ADMs (11.2%). Infections were most common in Porcine (11.2%) and AlloDerm FD ADMs (11.0%). Capsular contracture was rare across all ADM types, with no significant differences observed. In the NMA, AlloDerm FD showed significantly higher risks of infection, explantation, and wound dehiscence compared to AlloDerm RTU., Conclusion: The overall complication profiles of ADMs used in IBR are similar, except for the higher risks associated with AlloDerm FD compared to RTU. These findings suggest that the choice of ADM may not significantly impact overall outcomes, except in specific cases like AlloDerm FD. Further high-quality, long-term, double-arm studies are necessary to confirm comparative profile of specific ADM types and to account for potential confounding variables through multivariable regression analysis., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Breast cancer (BCa) is a highly prevalent pathological condition (̴30% in women) with limited and subtype-dependent prognosis and therapeutic options. Therefore, BCa management might benefit from the identification of novel molecular elements with clinical potential. Since splicing process is gaining a great relevance in cancer, this work analysed the expression of multiple Spliceosome Components (SCs = 17) and Splicing Factors (SFs = 26) and found a drastic dysregulation in BCa (n = 69) vs. control (negative biopsies; n = 50) samples. Among all the components analysed, we highlight the upregulation of ESRP1 and down-regulation of PRPF8 and NOVA1 in BCa vs. control samples. Indeed, ESRP1 was specially overexpressed in triple-negative BCa (TNBCa) and associated with worse prognosis (i.e., higher BCa grade and lower overall survival), suggesting an association of ESRP1 with BCa aggressiveness. On the other hand, PRPF8 expression was generally downregulated in BCa with no associations to clinical characteristics, while NOVA1 expression was lower in TNBCa patients and highly aggressive tumours. Consistently, NOVA1 overexpression in vitro reduced functional parameters of aggressiveness in ER-/PR- cell lines (MDA-MB-231 and BT-549) but not in ER+/PR+ cells (MCF7), suggesting a critical role of NOVA1 in subtype-specific BCa. Finally, the in vitro pharmacological inhibition of splicing machinery using pladienolide B decreased aggressiveness features in all the BCa cell lines, showing a subtype-independent inhibitory potential, but being relatively innocuous in normal-like breast cells. These results demonstrate the profound dysregulation of the splicing machinery in BCa and their potential as source of promising diagnosis/prognosis markers, as well as valuable therapeutic targets for BCa., Competing Interests: Declarations. Conflict of interest: Authors declare no conflict of interest., (© 2024. The Author(s).)

Background: To find support for risk-modifying genes in breast cancer, a haplotype GWAS in sporadic breast cancer cases was undertaken. The results were compared with the results from previous analyses in familial cases and all cases from the same Swedish cohort. Methods: In total, 2550 women with sporadic invasive breast cancer and 5021 healthy controls were included in a sliding-window haplotype GWAS using PLINK 1.07. Results: The analysis of sporadic cases confirmed the loci on chromosomes 10q26.13, 11q13.3, and 16q12.1 and suggested one novel locus on chromosome 12p11.21 (OR = 1.42 p = 4.55 × 10 -8 ). A comparison between these loci and the same loci in the analyses of familial cases and all breast cancer cases was undertaken. Conclusions: Haplotype GWAS in sporadic cases of Swedish breast cancer cases supported known risk loci and suggested another risk locus. The loci identified in the analysis of sporadic and all breast cancer cases were suggested to act as modifiers of the risk of breast cancer. Haplotype analysis identified other loci with higher odds ratios than single-variant analysis. Further studies are needed to find out how to best include the findings in breast cancer prevention.

Purpose: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC)., Patients and Methods: Part 1 determined the recommended dose for expansion of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate by independent central review., Results: In part 1, seven patients with mBC were enrolled and received T-DXd 3.2 mg/kg (four patients) or 5.4 mg/kg (three patients) plus nivolumab. The recommended dose for expansion for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously every 3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of three administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and four with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the confirmed objective response rates (95% confidence interval) for cohorts 1 to 4 were 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. The median treatment duration (range) with T-DXd in cohorts 1 to 4 was 8.9 (1-23) months, 6.9 (1-21) months, 3.9 (1-21) months, and not assessed, respectively; the most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, and 75.0%, respectively). Adjudicated drug-related interstitial lung disease/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0%, respectively (one grade 5 each, cohorts 1 and 3)., Conclusions: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T-DXd. Interstitial lung disease/pneumonitis is an important risk and requires careful monitoring and prompt intervention., (©2024 The Authors; Published by the American Association for Cancer Research.)

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER)-positive breast cancer, and most relapsed patients die with ET-resistant disease. Although genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders, such as fulvestrant, promote expression of vestigial-like 1 (VGLL1), a coactivator for TEF-1 and AbaA domain (TEAD) transcription factors. VGLL1, acting via TEADs, promoted the expression of genes that drive the growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1-TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent the growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients. Significance: Transcriptional reprogramming mediated by the upregulation of the TEAD coactivator VGLL1 confers resistance to estrogen receptor degraders in breast cancer but provides alternative therapeutic options for this clinically important patient group., (©2024 American Association for Cancer Research.)

Background: Toll-like receptor 9 (TLR9) is a DNA recognizing receptor expressed also in several cancers. Decreased TLR9 expression is associated with poor prognosis in triple negative breast cancer (TNBC), but the role of TLR9 in breast cancer pathophysiology is currently unclear. Regulation of TLR9 expression in breast cancer is poorly understood. Human papillomavirus (HPV) infections suppress TLR9 expression in cervical cancers but the association between HPV and breast cancer has remained controversial. The aim of this study was to test if HPV16 can suppress TLR9 expression in breast cancer cells and affect cell behavior., Methods and Results: Human T-47D and MDA-MB-231 breast cancer cells were transduced with lentivirus encoding HPV16 E6 oncoprotein. The effects of E6 on TLR9 mRNA and protein expression, and cell proliferation, migration, invasion and sensitivity to chemotherapy were studied in vitro. Breast cancer tissue samples (n = 37) were analyzed for the presence of HPV DNA. E6 expression decreased TLR9 mRNA expression in MDA-MB-231 and T-47D cells in hypoxia. E6 expression altered breast cancer cell proliferation and made cells significantly less sensitive to the growth inhibitory effects of chemotherapeutic agents. HPV L1 gene was not detected in a small pilot cohort of clinical breast cancer specimens., Conclusion: HPV16 may influence breast cancer cell TLR9 transcription and chemotherapy responses and could thereby affect breast cancer prognosis. These results suggest that HPV may have a previously unrecognized role in breast cancer pathophysiology and warrant further studies on the topic., Competing Interests: Declarations. Ethical approval: The study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Regional Medical Research Ethics Committee of the Wellbeing Services County of North Ostrobothnia (EETTMK 50/2021). Consent to participate: Written informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

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.)

Purpose: Oral adjuvant endocrine therapy (AET) reduces the risk of cancer recurrence and death for women with hormone receptor-positive (HR+) breast cancer. Because of adverse symptoms and socioecologic barriers, AET adherence rates are low. We conducted post hoc analyses of a randomized trial of a remote symptom and adherence monitoring app to evaluate characteristics associated with higher app use, satisfaction, and how app use was associated with AET adherence., Methods: Patients prescribed AET were randomly assigned to receive one of three intervention conditions: app, app + feedback, or enhanced usual care. Baseline and 6-month follow-up surveys, app use, and pillbox-monitored AET adherence data for app and app + feedback participants were used. Logistic regression evaluated the association between sociodemographic/clinical characteristics and app utilization and satisfaction, and how app use was associated with AET adherence (>80%)., Results: Overall, 163 women with early-stage HR+ breast cancer were included; 35.0% had high app use (≥75% of weeks enrolled). No sociodemographic characteristics were associated with app use. Satisfaction with the app was higher among those who were younger (88.9% for age 31-49 years v 54.9% for age 65+ years, P < .001), identified as White (76.8% v 60.1% for Black, P = .045), had lower health literacy (85.4% v 68.2% with higher health literacy, P = .017), or were nonurban residents (85.7% v 68.6% for urban, P = .021). Most participants (90.3%) with high app use were AET-adherent compared with 66.8% for those with lower app use ( P < .001)., Conclusion: Use of a remote monitoring app was similar across sociodemographic characteristics, and more frequent app use was associated with a higher likelihood of 6-month AET adherence. Encouraging women to monitor medication adherence and communicate adverse symptoms could improve AET adherence.

Background: Data published in 2015 showed that patients with early breast cancer (EBC) and a low-risk (LR) Recurrence Score® (RS) result by the 21-gene Oncotype DX® assay ("the test") did not derive benefit from adding chemotherapy (CT) to endocrine therapy (HT), while those with a high-risk (HR) RS result did. However, the role of CT remained uncertain in patients with intermediate-risk (IR) cancers. We designed a study to assess the test's ability to categorize patients with EBC with uncertain biological behavior into the groups (LR and HR) for which the value of additional chemotherapy was defined., Methods: The POST trial was a multicenter, prospective cohort study conducted in 14 Breast Centers of the Tuscany region of Italy. Consecutive patients with pT1-2 pN0-N1mi hormone receptor-positive/HER2-negative EBC and uncertain biological behavior based on standard parameters were enrolled. Patients were categorized based on RS results into LR, IR, and HR groups if RS result was < 11, 11-25, and > 25, respectively. Treatment recommendations by multidisciplinary meeting assessed before and after RS results were available., Results: Of 246 tested samples, 78 were classified as LR or HR, with most of the patients (65.4 %) being at IR. Following test results, the recommendation changed in 15.9 % of cases. Among patients initially recommended for CT or for discussion about the role of CT, respectively 64.3 % and 75.9 % ultimately received recommendation for HT alone., Conclusions: Our study suggests that RS results can refine treatment decisions for patients with EBC exhibiting uncertain biological behavior initially recommended or considered for CT. (250/250)., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with breast cancer experience various types of adverse events (AEs) during their treatment journey. We aimed to evaluate the incidence, characteristics, and impact of serious AEs in breast cancer patients receiving antineoplastic treatment in the ambulatory setting. A 4-month prospective observational study that included patients with breast cancer treated in the chemotherapy infusion clinics. Patients were assessed for serious AEs, defined as any AE that resulted in a visit to the emergency department (ED) with or without hospital admission, or required any clinical intervention, which were considered as the addition of supportive medications or modifications to the treatment protocol. Characteristics of the patients and antineoplastic regimens as well as the type of AEs were recorded. During the study period, 1168 patients received 2547 cycles. The mean age was 50 ± 11.6 (SD) years and patients had received a median (IQR) of 3 (1-5) treatment cycles prior to enrollment. Among the study cohort, 465 patients(40%) developed at least one serious AE. A total of 660 (26%) cycles were associated with 757 AEs, which required ED visits, addition of supportive medications, and modifications to the treatment protocol in 58%, 29%, and 17% of the cycles, respectively. Most common AEs were musculoskeletal (n = 132, 17%) and gastrointestinal (n = 125, 16.5%). Taxane-based regimens were associated with the most AEs (n = 286, 38%). In a cohort of patients with breast cancer treated in the ambulatory setting, 4 out of 10 patients developed at least one serious AE during the study period. Future research should identify measures to reduce the incidence and severity of such complications., (© 2024 The Author(s). Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Objective: To identify patients with atypical ductal hyperplasia (ADH) at low risk of upgrading to carcinoma. This study aims to assess the performance of radiomics combined with clinical factors to predict occult breast cancer among women diagnosed with ADH., Methods: This study retrospectively included microcalcification clusters of patients who underwent Mx and VABB with a diagnosis of ADH at a tertiary center from January 2015 to May 2023. Clinical and radiological data (age, cluster size, BI-RADS classification, mammographic density, breast cancer history, residual microcalcifications) were collected. Surgical outcomes were used to determine upgrade. Four logistic regression models were developed to predict the risk of upgrade. The performance was evaluated using the area under the receiver operating characteristic curve (AUC) and performance scores., Results: A total of 143 patients with 153 clusters were included. Twelve radiomic features and six clinical factors were selected for model development. The sample was split into 107 training and 46 test cases. Clinical features achieved an AUC of 0.72 (0.60-0.84), radiomic features an AUC of 0.73 (0.61-0.85). Radiomic features with "cluster size" and "age" improved the AUC to 0.79 (0.67-0.91). The best model, incorporating all data, achieved an AUC of 0.82 (0.71-0.92), a specificity of 0.89 (0.75, 0.97), and NPV of 0.92 (0.78-0.98)., Conclusion: This study demonstrates the potential of radiomic as a valuable tool for reducing unnecessary treatments for patient classified as "low risk of ADH upgrade". Combining radiomic information with clinical data improved the accuracy of risk prediction., 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.)

Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity and unravel the molecular mechanisms driving tumor progression and drug resistance, we established a comprehensive patient-derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) and young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 established PDX lines out of 151 total attempts), specifically 15% in luminal, 12% in human epidermal growth factor receptor 2 positive (HER2+) and 35% in triple negative BC. These PDX mirrored morphologic and genetic features of BC from which they originated, serving as a reliable tool to investigate drug resistance and test therapeutic strategies. We focused on understanding resistance to CDK4/6 inhibitors (CDK4/6i), which are crucial in the treatment of patients with advanced luminal BC. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumor shrinkage, some tumors might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that these PDXs have become refractory to CDK4/6i, both at biological and molecular levels, displaying significant enrichment in proliferation pathways, such as MTORC1, E2F and MYC. Using organoids derived from these PDX (PDxO), we observed that acquisition of CDK4/6i resistance conferred cross-resistance to endocrine therapy and that targeting MTORC1 was a successful strategy to overcome CDK4/6i resistance. Considered together, these results indicate that our PDX models may serve as robust tools to elucidate the molecular basis of BC disease progression and, by providing the possibility to simultaneously test different therapies on the same tumor, to surmount treatment resistance. While this approach is of course not feasible in the clinic, its exploitation in PDX may expedite the identification and development of more successful therapies for patients with advanced luminal BC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Breast cancer stands as the most frequently diagnosed cancer and the primary cause of cancer-related mortality among women worldwide, including Italy. With the increasing number of survivors, many are enrolled in regular follow-up programs. However, adherence to recommendations from scientific societies (such as ASCO, ESMO, AIOM) for breast cancer follow-up management varies in daily clinical practice across different cancer centers, potentially resulting in unequal management and escalating costs. To address these concerns, the Italian Association of Multidisciplinary Oncology Groups (AIGOM) orchestrated a Consensus on early Breast Cancer follow-up utilizing the Estimate-Talk-Estimate methodology. Following the identification of 18 Items and 38 statements by a select Board, 46 out of 54 (85.1%) experts comprising a multidisciplinary and multiprofessional panel expressed their degree of consensus (Expert Panel). The Expert Panel underscores the potential for the multidisciplinary team to tailor follow-up intensity based on the individual risk of recurrence. In selected cases, the general practitioner may be recommended as the clinical lead for breast cancer follow-up, both after completion of adjuvant treatment and at early initiation of endocrine therapy in low-risk patients. Throughout follow-up, and alongside oncologic surveillance, the expert panel advises osteometabolic, cardiologic, and gynecologic surveillance for the early detection and management of early and late treatment toxicities. Moreover, preserving quality of life is emphasized, with provisions for psycho-oncologic support and encouragement to adopt protective lifestyle behaviors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None of the authors has any interests to report directly related to this manuscript. Outside the scope of this manuscript: Stefania Gori, Fiorenza De Rose, no conflict of interests to declare. Antonella Ferro, honoraria from Novartis, MDS, Daiichi Sankyo, Astra Zeneca, Ely Lilly, Gentili. Alessandra Fabi grants from Astra Zeneca (steering committee); consulting fees from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; honoraria from Astra Zeneca, Roche, Lilly, Novartis, Gilead, Pfizer, Daiichi Sankyo Exact Sciences; travel grants from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; advisory board from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini. Catia Angiolini, Giuseppe Azzarello, Maurizio Cancian, Michela Cinquini, Luca Arecco no conflict of interests to declare. Cynthia Aristei, grants from PRIN 2023, from the Ministry of University and Research. Project title “The microbiome in breast cancer therapy and its potential for pRobIOtics to improve treatment outcome. Acronym: BARRIO”. Daniela Bernardi, Laura Biganzoli, Anna Cariello no conflict of interests to declare. Laura Cortesi, report grants from Astra Zeneca, MSD, Pfizer; consulting fees and honoraria from Astra Zeneca, Gilead, MSD, Roche, Pfizer, Daijchii Sanchio, Novartis; travel grants from Gilead, Pfizer, Daijchi Sanchio; Advisory Board from Astra Zeneca, MSD, Novartis. Elisabetta Cretella no conflict of interests to declare. Carmen Criscitiello, grants from Seagen, Gilead; consulting fees and honoraria from Pfizer, Novartis, Lilly, MSD; Seagen, Daiichi Sankyo, Gilead, AstraZeneca, Roche. Ugo De Giorgi consulting fees from Amgen, Astellas Pharma, Astrazeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer; travel grants from Pfizer, Ipsen, Astrazeneca. Maria Carmen De Santis, Giuseppe Deledda, Massimo Dessena, Sara Donati, Arianna Dri, Gianluigi Ferretti no conflict of interests to declare. Jennifer Foglietta, honoraria from Novartis; travel grants from Roche, Sophos, Pfizer; Advisory Board from Menarini Stem Line. Davide Franceschini, Pierfrancesco Franco, Alessio Schirone no conflict of interests to declare. Daniele Generali, grants from LILT, University of Trieste, Novartis, Roche; consulting fees from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo; honoraria from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo, Astrazeneca, Istituto Gentili; travel grants from Roche, Menarini; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Mednote. Lorenzo Gianni, travel grants from Novartis, Lilly, Pfizer; Advisory Board from Astra Zeneca, Novartis, Seagen. Stefano Giordani, Giovanni Grandi, Maria Cristina Leonardi, Stefano Magno, no conflict of interests to declare. Luca Malorni, consulting fees from Menarini, Pfizer, Lilly, Novartis, Roche; travel grants from Roche, Menarini, Celgene, IT Health Fusion; Advisory Board from Novartis. Carlotta Mantoan no conflict of interests to declare. Federica Martorana honoraria from Lilly, Daychii-Sankyo, Pfizer, Astra-Zeneca, Novartis; travel grants from Gilead, Roche, Pfizer, Lilly; advisory board from Amgen. Icro Meattini consulting fees from Pfizer, Astra Zeneca, Daiichi Sankyo, Novartis, Eli Lilly, Seagen, Gilead, Menarini StemLine. Bruno Meduri, Laura Merlini, Federica Miglietta, Alessandra Modena, Fabrizio Nicolis, Isabella Palumbo, no conflict of interests to declare. Pietro Panizza honoraria and travel grants from Bayer AG. Francesca Angela Rovera, Piermario Salvini, Armando Santoro, Mario Taffurelli, no conflict of interests to declare. Angela Toss consulting fees and grants from Lilly, Pfizer, Novartis, MSD, Astrazeneca, Gilead, Seagen, Daiichi Sankyo; travel grants from Gilead, Daiichi Sankyo, Menarini, Astrazeneca. Paolo Tralongo, Monica Turazza, Matteo Valerio, Matteo Verzè no conflict of interests to declare. Patrizia Vici consulting fees from Lilly, Daiichi-Sankyo, Pfizer, MSD, Novartis; honoraria from EISAI, Daiichi-Sankyo, Lilly, Novartis, Pfizer; travel grants from Roche, Pfizer, Daiichi-Sankyo, Novartis, IPSEN; advisory board from Pfizer, Novartis. Claudio Zamagni no conflict of interests to declare. Giuseppe Curigliano advisory board from Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daichii Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, Menarini. Giovanni Pappagallo no conflict of interests to declare. Alberto Zambelli consulting fees Pfizer, Lilly, Novartis, Roche, AstraZeneca, DaiichiSankyo, Seagen, ExactSciences, MSD, Gentili, Gilead; travel grants from Roche, DaiichiSankyo, AstraZeneca, Novartis; advisory board from Roche., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This meta-analysis compares the efficacy, limitations, and clinical implications of abbreviated breast MRI (AB-MRI) and full protocol MRI (FP-MRI), focusing on diagnostic accuracy across diverse populations. It extends previous analyses by including studies conducted after 2019 in both screening and diagnostic contexts., Methods: We conducted a systematic review (November 2019 to December 2022), using a bivariate model to calculate summary estimates of sensitivity and specificity. Random effect models were applied for summary area under the curve (AUC), and probability distributions for negative and positive predictive values were obtained. Subgroup analyses explored differences in sensitivity, specificity, and AUC between AB-MRI and FP-MRI., Results: From 11 eligible studies (1 prospective, 10 retrospective), statistical analysis revealed a significant difference in sensitivity between FP-MRI (95%) and AB-MRI (86%, P = .005), with no significant difference in specificity (P = .50). AB-MRI's shorter acquisition time suggests potential for higher patient throughput, but challenges remain in detecting small lesions and nonmass enhancements. Some studies recommend additional sequences, like diffusion-weighted imaging, to improve diagnostic performance., Conclusions: While FP-MRI remains the gold standard in breast cancer detection, AB-MRI offers a quicker alternative, especially in high-risk screening. However, its lower sensitivity limits its use as a standalone diagnostic tool. Future research should optimize AB-MRI protocols and consider patient-specific factors to enhance breast cancer screening and diagnostic strategies., Advances in Knowledge: This meta-analysis expands understanding of AB-MRI's role in breast cancer detection, highlighting its benefits and limitations compared to FP-MRI, particularly in terms of sensitivity and screening efficiency., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Importance: In patients with clinically node-negative (cN0) breast cancer and 1 or 2 sentinel lymph node (SLN) macrometastases, omitting completion axillary lymph node dissection (CALND) is standard. High nodal burden (≥4 axillary nodal metastases) is an indication for intensified treatment in luminal breast cancer; hence, abstaining from CALND may result in undertreatment., Objective: To develop a prediction model for high nodal burden in luminal ERBB2-negative breast cancer (all histologic types and lobular breast cancer separately) without CALND., Design, Setting, and Participants: The prospective Sentinel Node Biopsy in Breast Cancer: Omission of Axillary Clearance After Macrometastases (SENOMAC) trial randomized patients 1:1 to CALND or its omission from January 2015 to December 2021 among adult patients with cN0 T1-T3 breast cancer and 1 or 2 SLN macrometastases across 5 European countries. The cohort was randomly split into training (80%) and test (20%) sets, with equal proportions of high nodal burden. Prediction models were developed by multivariable logistic regression in the complete luminal ERBB2-negative cohort and a lobular breast cancer subgroup. Nomograms were constructed. The present diagnostic/prognostic study presents the results of a prespecified secondary analysis of the SENOMAC trial. Herein, only patients with luminal ERBB2-negative tumors assigned to CALND were selected. Data analysis for this article took place from June 2023 to April 2024., Exposure: Predictors of high nodal burden., Main Outcomes and Measures: High nodal burden was defined as ≥4 axillary nodal metastases. The luminal prediction model was evaluated regarding discrimination and calibration., Results: Of 1010 patients (median [range] age, 61 [34-90] years; 1006 [99.6%] female and 4 [0.4%] male), 138 (13.7%) had a high nodal burden and 212 (21.0%) had lobular breast cancer. The model in the training set (n = 804) included number of SLN macrometastases, presence of SLN micrometastases, SLN ratio, presence of SLN extracapsular extension, and tumor size (not included in lobular subgroup). Upon validation in the test set (n = 201), the area under the receiver operating characteristic curve (AUC) was 0.74 (95% CI, 0.62-0.85) and the calibration was satisfactory. At a sensitivity threshold of ≥80%, all but 5 low-risk patients were correctly classified corresponding to a negative predictive value of 94%. The prediction model for the lobular subgroup reached an AUC of 0.74 (95% CI, 0.66-0.83)., Conclusions and Relevance: The predictive models and nomograms may facilitate systemic treatment decisions without exposing patients to the risk of arm morbidity due to CALND. External validation is needed., Trial Registration: ClinicalTrials.gov Identifier: NCT02240472.

Purpose: The impact of dietary counseling on body composition in early breast cancer patients (EBC) treated with aromatase inhibitors (AIs) is uncertain. The aim of this study was to assess the effects of a diet counseling program on weight, BMI, total and regional body composition in patients treated with AIs., Methods: This observational study involved 194 EBC patients, of which 97 attended a 6-month personalized counseling program, based on Mediterranean diet principles (cohort A) and 97 did not (cohort B). Dual-energy X-ray absorptiometry (DXA) scan was used to measure the total and regional fat and lean body mass, before (baseline) and after at least 18 months of AI-therapy., Results: Weight and BMI increased significantly, on the average, in cohort B, but not in cohort A. In the cohorts A and B, fat mass increased by 10 % and 7.7 % respectively, while lean mass decreased by 3.3 % and 2.6 % from before to after AI therapy, without statistically significant differences between them using the Mann-Whitney test. The changes in body composition were greater in premenopausal than in postmenopausal women at cancer diagnosis. The proportion of patients with sarcopenia, obesity and sarcopenic obesity increased from before to after AI therapy, similarly in both cohorts., Conclusions: Patients treated with AIs reported an increase in fat mass and a decrease in lean mass, and consequently an increase in sarcopenia and obesity, regardless of the participation in a dietary counseling program. A combined dietary counseling and physical exercise program may be necessary for preventing these unfavourable changes in these patients., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The drug's activity at the target tissue could help to define the minimal effective dose to promote cancer preventive therapy. Here we present exemestane and sex hormone concentrations within breast tissue from a presurgical study of alternative exemestane schedules. Postmenopausal women candidates for breast surgery for estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg once daily (QD), 25 mg 3 times/week (TIW), or 25 mg per week (QW) for 4-6 weeks before surgery. Drug and sex hormones were analyzed from homogenized frozen tissue using a QTRAP 6500+ LC-MS/MS System. Tissue drug concentrations were detectable only in the QD arm with higher concentrations in nonmalignant tissue. Estradiol was nearly suppressed in all groups in the nonmalignant tissue (QD vs TIW P = .364 and QD vs QW P = .693). In contrast, a dose-response trend was observed in cancer tissue. Based on estradiol suppression in nonmalignant tissue, lower exemestane schedules should be explored for breast cancer preventive therapy. Trial Registration: Clinical Trials.gov NCT02598557 and EudraCT 2015-005063-1., (© The Author(s) 2024. Published by Oxford University Press.)

This systematic review aims to evaluate the role of ultrasound (US) radiomics in assessing lymphadenopathy in patients with cancer and the ability of radiomics to predict metastatic lymph node involvement. A systematic literature search was performed in the PubMed (MEDLINE), Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE (Ovid) databases up to June 13, 2023. 42 articles were included in which the lymph node mass was assessed with a US exam, and the analysis was performed using radiomics methods. From the survey of the selected articles, experimental evidence suggests that radiomics features extracted from US images can be a useful tool for predicting and characterizing lymphadenopathy in patients with breast, head and neck, and cervical cancer. This noninvasive and effective method allows the extraction of important information beyond mere morphological characteristics, extracting features that may be related to lymph node involvement. Future studies are needed to investigate the role of US-radiomics in other types of cancers, such as melanoma., Competing Interests: The authors declare that Dr. Cantisani is a member of the Editorial Board of the journal., (Thieme. All rights reserved.)

Background: The timing of a breast cancer (BC) diagnosis has a significant psychological impact on patients. However, it reported that those eligible for treatment regimens based on neoadjuvant chemotherapy may experience high levels of depression, anxiety and distress. To cope with this situation, patients deploy psychological coping strategies. The aim of this study is to explore effective and ineffective psychological adjustment mobilized by Moroccan patients newly diagnosed with BC and before receiving neoadjuvant chemotherapy, as well as to identify their associations to socio-demographic and clinical determinants., Materials and Methods: A total of 209 patients were recruited in outpatient in oncology department in the public oncology hospital of Fez city, between 2021 and 2023. Ethics approval was obtained for this study and patients has signed an informed consent form. The questionnaire interview included socio-economic and clinical variables and the Arabic version of Mini-Mental Adjustment to Cancer (Mini-MAC) scale, which measures the strategies of mental adjustment to disease, as fighting spirit (FS), hopelessness/helplessness (HH), anxious preoccupations (AP), cognitive avoidance (CA), fatalism (FA), "maladaptive coping" and "adaptive coping". Bivariate analysis of psychological adjustment strategies and sociodemographic and clinical variables was carried out using statistical tests according to the nature of the variables, to their normality and the homogeneity of their variances. Univariate and multivariate linear regression modelling was carried out using a forward "enter" regression procedure., Results: A mean age of 47.43 ± 9.45 was found among participants. Assessment of mental adjustment to cancer using Mini-MAC scores revealed that psychological adjustment strategies with a higher mean score were FA, FS and "adaptive coping" strategies. Based mainly on multiple linear Regression, monthly family income was negatively associated with HH, and FS and positively linked to FA and "adaptive coping" strategies. Moreover, the left side as BC laterality was negatively associated with AP and "maladaptive coping" strategies. Furthermore, positive ER status was negatively associated with HH and "maladaptive coping" strategies and high Ki-67 levels were positively linked to AP., Conclusion: Programs to strengthen psychological adjustment in patients with BC candidates for NACT, taking into consideration the determinants found associated in this study, are of great importance since the first oncology consultation., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki and the ethical approval was obtained from the hospital-university ethics committee of Sidi Mohamed Ben Abdellah University (N°24/18). Informed consent was taken from all the participants. All the participants were notified about the aim of the study and had provided written consent before starting the investigation. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Patients with cancer often face depression and anxiety, and mindfulness-based interventions, including internet-based versions, can effectively reduce these symptoms and improve their quality of life. This study aims to investigate the impact of internet-based mindfulness-based interventions (e-MBIs) on anxiety, depression, and stress symptoms in patients with prostate or breast cancer., Objective: The primary aims are to assess the association between the amount and variety of e-MBI practices and symptom reduction. Second, this study aims to examine how baseline information such as sociodemographic characteristics, dispositional mindfulness (DM), and dispositional self-compassion (DSC) correlate with both app usage and symptom reduction., Methods: Participants included 107 patients with cancer (68 women with breast cancer and 38 men with prostate cancer) enrolled in a hospital setting. They were assigned to the intervention group of the NEVERMIND project, using the e-BMI module via the NEVERMIND app. A longitudinal design involved Pearson correlation analysis to determine the relationship between the amount and duration of e-MBI practices. Linear regression analysis was conducted to gauge the dose-response effect, evaluating the impact of DM and DSC on depression, anxiety, and stress. Negative binomial regression was conudcted to study sociodemographic factors' influence on the amount of practice in e-MBIs., Results: The participants with more diverse and sustained mindfulness practices experienced significant reductions in depression, anxiety, and stress. A high correlation (0.94) between e-MBI practices and symptom reduction was also highlighted. Male, married, and highly educated patients were more likely to engage in mindfulness. Even if DM and DSC did not impact the amount or variety of practices correlated, they were correlated with symptom reduction, showing that higher levels were associated with significant reductions in depression, anxiety, and stress., Conclusions: While more e-MBI practice is linked to reduced anxiety, depression, and stress, this study emphasizes the crucial role of variety of practice over amount. DM and DSC are key in shaping intervention effectiveness and may act as protectors against psychological distress. Using app log data, our research provides a unique perspective on e-MBI impact, contributing to cancer care understanding and guiding future studies., (© Francesca Malandrone, Sara Urru, Paola Berchialla, Pierre Gilbert Rossini, Francesco Oliva, Silvia Bianchi, Manuel Ottaviano, Sergio Gonzalez-Martinez, Vladimir Carli, Gaetano Valenza, Enzo Pasquale Scilingo, Sara Carletto, Luca Ostacoli. Originally published in JMIR Mental Health (https://mental.jmir.org).)

Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps., Competing Interests: Competing interests A. Regev, J.K. and D.L.A. are co-inventors on patent application number 17/156,392, filed by the Broad Institute, for inventions relating to work in this manuscript. A. Regev is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas and, until 31 July 2020, a scientific advisory board (SAB) member of Thermo Fisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov. From 1 August 2020, A. Regev is an employee of Genentech and has equity in Roche. A. Rotem is an employee of AstraZeneca since September 2020 and has equity in AstraZeneca. E.S.B. co-founded a company that is exploring commercial applications of expansion microscopy. G.N. holds equity in and consults for Akoya Biosciences. J.G.T.Z. owns stocks in the biotechnology exchange-traded funds CNCR, IDNA, IBB and XBI, owns stock in Novo Nordisk and owns stock in Adaptive Biotechnologies, 2seventy bio and bluebird bio. J.J-V. is a contractor at Genentech since 2021. M.S. is a contractor at Genentech since November 2020. O.R.-R. is a co-inventor on patent applications filed by the Broad Institute for inventions related to single-cell genomics. She has given numerous lectures on the subject of single-cell genomics to a wide variety of audiences and, in some cases, has received remuneration to cover time and costs. O.R.-R. is an employee of Genentech since 19 October 2020 and has equity in Roche. S.J.R. is a member of the SAB of Immunitas Therapeutics and receives research funding from Bristol Myers Squibb and Kite/Gilead. X.Z. is a co-founder of and consultant for Vizgen. The other authors declare no competing interests., (© 2024. The Author(s).)

Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited., Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium., Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population., Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification., Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts., (©2024 American Association for Cancer Research.)

Background: Rates of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for breast cancer have improved, especially among human epidermal growth factor 2-positive (HER2+) and triple-negative subtypes. The frequency and significance of biomarker profile change in residual disease are unclear. This study aimed to determine the rate of biomarker profile changes after NAC and the impact on clinical outcomes in a contemporary cohort., Methods: Upon institutional review board approval, the study identified 634 consecutive patients treated with NAC between 2010 and 2022 at two academic institutions. The study cohort was focused on patients with residual disease who underwent biomarker profile retesting. Biomarker profile change for each subtype was compared across groups using Fisher-Irwin tests. Cox Proportional Hazards Model and Kaplan-Meier plots were performed to evaluate the association of changed versus unchanged biomarker profile with event-free survival., Results: Biomarker retesting was performed for 259 (61.4 %) of 422 patients with residual disease. Biomarker profile change occurred in 18.1 % overall and was significantly higher among those with pre-NAC HER2+ disease (32.7 %, 17/52) than among those with HER2-disease (14.5 %, 30/207) (p = 0.004). Conversion of pre-NAC biomarker profiles of HR+HER2- and HR+HER2+ to triple-negative breast cancer (TNBC) post-NAC may be associated with worse event-free survival, hazard ratios of 2.23 (95 % confidence interval [CI], 0.90-5.53; p = 0.08), trending toward significance, and 36.7 (95 % CI, 2.2-610.8; p = 0.01), respectively., Conclusions: The results from one of the largest contemporary cohorts demonstrated that biomarker profile change in patients with residual disease after NAC was common. Furthermore, specific biomarker profile change in residual disease may have prognostic value. These findings strengthen the rationale for routine re-testing of biomarkers in residual disease after NAC., (© 2024. The Author(s).)

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression., (© 2024 UICC.)

Purpose: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time., Methods: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time., Results: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination., Conclusion: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials., Methods and Materials: We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes., Results: Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART., Conclusions: This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The increasing incidence of breast cancer and disease burden is a significant public health concern. While 30% of breast cancers could be prevented through addressing modifiable risk factors, misconceptions among women about breast cancer risks hamper primary prevention. In the absence of primary prevention, secondary prevention such as mammography increases the early detection of breast cancer and improves health outcomes. However, current population-level screening rates indicate secondary prevention is suboptimal. More effective public health efforts to improve breast cancer prevention are required. Given breast cancer is socially patterned, this work explores how social class impacts women's breast cancer prevention practices. This study uses the concepts of lay epidemiology and candidacy as a mechanism to understand women's breast cancer risk perspectives. It engages Bourdieu's relational social class theory to unpack how women's social, cultural, and structured life contexts shape these perspectives and their considerations regarding primary and secondary prevention., Methods: In this qualitative study 43 Australian midlife women (aged 45-64 years), were interviewed to explore their understandings of breast cancer risks, how they perceived their own risk, and how this shaped their prevention behaviours. A theory-informed thematic analysis applying Bourdieu's concepts of habitus, capital, and fields to understand how women's social class positions shapes risk perspectives and prevention practices was conducted., Results: This social class analysis showed differences in how women engage in breast cancer discourse, consider risks, and participate in breast cancer prevention. Middle-class women prioritise health promoting practices and were more likely than working-class and affluent women to attend mammography screening. Working-class women experience structural factors, like low income, stress and difficult life circumstances, which hamper primary prevention practices and for some screening is not considered or prioritised, and their decisions not to screen are less active. Affluent women often do not consider themselves at-risk due to their healthier 'lifestyles. 'They suggest that this, and their knowledge of screening benefits and harms allows them to make informed decisions not to screen., Conclusions: Women interpret and understand breast cancer risks differently and enact prevention practices within the parameters afforded by their social class positions. These findings are useful to inform improved public health approaches regarding both modifiable breast cancer risks and increasing mammography screening. To improve equity in breast cancer prevention efforts, such approaches must respond to limitations based on social class and address structural factors that impact prevention practices., (© 2024. The Author(s).)

Introduction: Breast cancer is the most diagnosed tumor and a leading cause of cancer death in women worldwide. Taxanes are the most used chemotherapeutic agents and are strictly connected to neurotoxicity. Taxane-induced neuropathy (TIN) significantly impacts patients' quality of life (QOL). Early identification and management of TIN could improve preventive strategies to preserve patients' QOL during and after breast cancer treatment., Objective: This prospective, observational study aimed to evaluate the taxane-induced neuropathy (TIN) in early breast cancer patients treated with weekly paclitaxel at an earlier stage and identify any correlation between TIN and QOL., Methods: Data from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 were collected at the Medical Oncology Unit of the University Hospital of Cagliari. Peripheral neuropathy was evaluated using the NCI-CTCAE scale (National Cancer Institute, Common Terminology Criteria for Adverse Events) at every drug administration. In contrast, QOL was assessed using EORTC QLC-CIPN20 and FACT-Taxane questionnaire at baseline (T0), after 4 weeks (T1) and 12 (T2) weeks of treatment. Statistical analysis was performed to evaluate the correlation between neurotoxicity and QOL., Results: Neurotoxicity incidence peaked at the third, fourth, and sixth week of treatment, with patients reporting grade 1 and 2 neurotoxicity. Simultaneously with increasing doses of paclitaxel, significant differences in QOL were observed in early treatment cycles relating to TIN presentation. Patients with higher neurotoxicity grades reported lower QOL scores., Conclusions: Despite the absence of effective treatments to prevent paclitaxel-induced neurotoxicity, symptoms are managed through dosage reduction, delay, or treatment interruption. Future research should focus on identifying neuroprotective measures to avoid an irreversible decline in the quality of life for breast cancer survivors., (© 2024. The Author(s).)

Background: Guidelines informing chemotherapy regimen selection are based on clinical trials with participants who do not necessarily represent general populations with breast cancer. Understanding who receives nonguideline regimens is important for understanding real-world chemotherapy administration and how it relates to patient outcomes., Methods: Using data from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study, based at Kaiser Permanente Northern California (2006-2019) and Kaiser Permanente Washington (2004-2015), we use logistic regression to examine the associations between patient characteristics and receipt of nonguideline chemotherapy regimens among 11,293 women with primary stage I to IIIA breast cancer receiving chemotherapy., Results: The use of nonguideline regimens was strongly associated with several factors, including older age [≥80 vs. 18-39 years: OR, 5.25; 95% confidence interval (CI), 3.06-9.00; P-trend = 0.002] and HER2 status (HER2+ vs. HER2-: OR, 3.44; 95% CI, 3.06-3.87) and was less likely in women with larger tumor size (>5 cm vs. 0.1 to ≤0.5 cm: OR, 0.56; 95% CI, 0.36-0.87; P-trend = 0.01) and diagnosed in later years (2012-2019 vs. 2005-2011: OR, 0.80; 95% CI, 0.71-0.90). Factors associated varied by type of nonguideline regimens. For example, women with comorbidity and older age were more likely to receive nonguideline drug combinations in particular, whereas women with larger tumor size were less likely to receive nonguideline administration schedules., Conclusions: Nonguideline chemotherapy regimens are more likely in certain patient populations., Impact: These associations highlight that vulnerable patient populations may be less likely to receive guideline care, and thus, real-world studies are essential for understanding how the use of nonguideline regimens impacts patient outcomes in these groups., (©2024 American Association for Cancer Research.)

Background: Despite advancements in breast cancer (BC) diagnosis and treatment, it continues to be a serious health concern among women due to its high incidence rate. Thus, prevention strategies in BC are essential. Some nutrients such as vitamin D may play a preventive role against BC through different genes which have a vital role in several pathways. These pathways include autophagy, tumorigenesis, apoptosis, immunity, and genome stability. This study aimed to review the role of vitamin D in BC via the network of vitamin D-regulated pathways., Methods: This systematic review was conducted following PRISMA guidelines. PubMed, ScienceDirect, and Scopus were searched using a combination of MeSH terms and keywords related to molecular and cellular mechanisms of the effects of vitamin D on breast cancer. A total of 200 articles were initially found, from which 14 relevant studies were selected based on specific inclusion and exclusion criteria., Results: Experimental studies have shown possible anti-carcinogenic effects of vitamin D-related genes due to their participation in regulating autophagy, tumorigenesis, apoptosis, immunity, and genome stability in normal and malignant breast cells. Moreover, vitamin D deficiency has the potential to create a supportive environment that promotes proangiogenic processes, tumor cell dissemination, metastasis, and establishment at secondary sites., Conclusion: Vitamin D may have systematic roles against BC in humans through various interactions with different genes, which have roles in different and important pathways as underlying mechanisms in the pathophysiology of BC. More broadly, research is also needed to determine the exact protective effect of vitamin D on BC risk.

Background: Due to the establishment of screening mammography for breast cancer detection, the number of non-palpable lesions has increased. Thus, an optimal localization system is mandatory for the excision of non-palpable breast tumors., Objective: The aim of the study is to report the feasibility Surgical Marker Navigation (SMN) system Sirius Pintuition® for the excision of non-palpable breast tumors and non-palpable axillary lymph nodes., Methods: A retrospective observational study of patients undergoing breast-conserving surgery and lymph node excision guided by SMN between December 2022 and May 2023 was performed., Results: A total of 84 patients underwent excision of non-palpable breast tumors (77; 91.7%) or non-palpable axillary lymph-nodes (7; 8.3%) using SMN. In total, 94 markers were placed, in 74 patients (88.1%) only one marker was placed, whereas in 10 patients (11.9%) two markers were placed to correctly localize the lesion in the operating room. Most markers were placed using ultrasonographic guidance (69; 82.1%). Seventy-seven patients underwent breast-conserving surgery (91.7%) and 7 (8.3%) lymph node excision. In 10 cases (11.9%), the marker was accidentally displaced during surgery due to the use of magnetized instruments, although the specimen could be removed. In sum, all the markers were removed from the patients, although the marker retrieval rate, as we defined it (percentage of patients in whom the initial excised specimen contained the marker divided by the total number of patients), was 88.1%., Conclusion: The use of Sirius Pintuition® SMN for non-palpable breast tumors and non-palpable lymph nodes is feasible, with a retrieval rate of 88.1%., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Oral capecitabine improves convenience compared to intravenous therapies but presents monitoring challenges. We conducted a randomized pilot trial to evaluate a mobile health intervention to remotely monitor capecitabine adherence and patient-reported outcomes (PROs) among women with breast cancer., Methods: Patients with breast cancer prescribed capecitabine, an oral chemotherapy with a complex, cyclical regimen, were randomly assigned to enhanced usual care (EUC) or PRO arm. Participants were asked to use a smart pill bottle to measure adherence (timing and dose) and complete baseline and 90-day follow-up surveys. PRO participants received text messages for missed or incorrect doses and weekly text-based symptom assessments, and their oncologists received alerts for severe symptoms or missed doses. We compared nonadherence (<80%) and changes from enrollment to follow-up on reported physical and mental health quality-of-life scores and number of severe symptoms by study arm., Results: Overall, 32 women were randomly assigned (17 EUC and 15 PRO): 28 (87.5%) received the intervention and 24 (78.1%) completed the follow-up survey. Among participants who received the intervention, PRO participants responded to 83.3% of symptom questions; 7.7% of PRO participants were nonadherent compared with 40.0% of EUC participants ( P = .049). Among those who completed the follow-up survey, 12.5% of PRO participants had reductions in their mental health composite scores compared with 69.2% of EUC participants ( P = .011); 10% of PRO participants had more severe symptoms at follow-up compared with 57.1% of EUC participants ( P = .019)., Conclusion: A mobile health intervention using text message reminders and symptom assessments improved medication adherence and mental health quality-of-life scores and lowered symptom burden of patients with breast cancer prescribed capecitabine. Future work should evaluate the longer-term impacts of this intervention.

Patients' self-reporting is increasingly considered essential to measure quality-of-life and treatment-related side-effects. However, if multiple patient-reported instruments are used, redundancy may represent an overload for patients. Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) are a tool allowing direct patients' reporting of side-effects. We tested psychometric properties of a selected list of PRO-CTCAE items, in a cohort of 303 breast cancer patients, using validated instruments for quality of life assessment as anchors. The analysis of convergent validity with HADS (Hospital Anxiety and Depression Scale) and EORTC BR-23 sub-scales, and the analysis of responsiveness with the PGIC (Patients Global Impression of Change) score supported that a selected list of PRO-CTCAE symptoms might represent a standardized, agile tool for both research and practice settings to reduce patient burden without missing relevant information on patient perceptions. Among patients using digital devices, those with a higher education levels required shorter time to fulfil questionnaires. In conclusion, a selected list of PRO-CTCAE items can be considered as a standardized, agile tool for capturing crucial domains of side-effects and quality of life in patients with breast cancer. The study is registered on clinicaltrials.gov (NCT04416672)., Competing Interests: Declaration of competing interest Michelino De Laurentiis declares: 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. Fortunato Ciardiello declares: honoraria or consultation fees for speaker, consultancy or advisory roles from Amgen, Merck KGaA, MSD, Pierre Fabre, Pfizer, Roche, Servier; institutional financial interests, financial support for clinical trials or contracted research, from: Amgen, Merck KGaA, MSD, Pierre Fabre, Pfizer, Roche, Servier. Lugi Cavanna declares honoraria from Roche and Pfizer. Filippo Giovanardi declares honoraria from Eli Lilly, AstraZeneca, Roche, Seagen, Novartis. Maria Carmela Piccirillo declares: honoraria for speaker activities from Astellas, Pfizer, Ipsen, Astrazeneca; financial support to institutional research activities from AstraZeneca, Bayer, Roche. Francesco Perrone declares: institutional grants or contracts from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, Merck; consulting fees from Bayer, Pierre Fabre, Astra Zeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; leadership in scientific society: President of AIOM 2023–2025. All the other authors declares no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Barrier films or dressings were reported to be effective in preventing radiation dermatitis (RD) in breast cancer patients, but their comparative efficacy is unknown., Methods: A systematic literature search was performed on Embase, MEDLINE and Cochrane CENTRAL Registry of Clinical Trials from inception to October 20, 2023. Randomised controlled trials (RCTs) comparing barrier films or dressings to the standard of care (SOC) or other interventions were included. We estimated summary odds ratios and mean differences using network meta-analysis with random effects. This study was registered with PROSPERO (ID: CRD42023475021)., Results: Fourteen RCTs met inclusion criteria. Six interventions were analysed: 3M™ Moisturizing Double Barrier Cream (MDBC), 3M™ No Sting Barrier Film (BF), Hydrofilm® (HF), Mepitel® Film (MF), Silver Leaf Nylon Dressing and StrataXRT®. HF, MF and StrataXRT® reduced the incidence of moist desquamation compared to SOC (HF: OR = 0.08; p = 0.02; MF: OR = 0.31 p < 0.01; StrataXRT®: OR = 0.22, p = 0.04). The ranking of agents from most to least effective in preventing moist desquamation according to P-scores was HF (92.5%), MF (78.5%), StrataXRT® (70.1%), BF (46.4%), Silver Leaf Nylon Dressing (24.9%), MDBC (22.9%) and SOC (14.7%). Only four RCTs on HF and MF included patient-reported outcome (PRO) assessments that allowed pooling for analysis. HF and MF were more effective in reducing pain, itchiness and burning sensation compared to SOC (p < 0.01 for all symptoms)., Conclusion: HF and MF were effective in preventing RD in breast cancer. Future RCTs should compare these interventions to effective cream preparations, such as topical corticosteroids., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Wnt family member 9b (Wnt9b) has been demonstrated as a valuable marker for breast cancer diagnosis in surgical pathology. In this study, we examined the utility of Wnt9b in diagnosing metastatic breast carcinoma in cytology samples. Cell blocks from fine needle aspirations (FNA) and fluid specimens of 96 metastatic breast carcinomas and 123 primary and metastatic non-breast neoplasms from various organ systems were evaluated by Wnt9b and GATA3 immunohistochemistry (IHC). Wnt9b and GATA3 were positive in 81.3% and 92.7% of metastatic breast carcinomas, respectively. Conversely, 93.5% and 90.0% of non-breast, non-urothelial carcinomas were negative for Wnt9b and GATA3, respectively. Wnt9b expression was positive in rare gastrointestinal, gynecological, lung, pancreas, and salivary gland tumors. All twenty-eight urothelial carcinomas were negative for Wnt9b, while twenty-six (92.9%) were positive for GATA3. Wnt9b was slightly less sensitive but more specific than GATA3 in diagnosing metastatic breast cancer in cytology samples. Particularly, Wnt9b shows higher specificity in differentiating breast and urothelial primaries. The combined use of Wnt9b and GATA3 may increase diagnostic accuracy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Most premenopausal patients with early breast cancer (eBC) are diagnosed with hormone receptor-positive disease and therefore candidate for adjuvant endocrine therapy (ET)., Patients and Methods: The Gruppo Italiano Mammella (GIM) 23-POSTER (GIM23) is a multicenter, prospective, observational study conducted in 26 Italian institutions, aiming to evaluate ET choices for premenopausal patients affected by hormone receptor-positive eBC in a real-world setting. Here we report also the results in terms of type of ET prescribed according to the definition of high-risk patients by monarchE and NATALEE trials., Results: Between October 2019 and June 2022, 600 premenopausal patients were included, with a median age of 46 years. Almost half (271, 45.2 %) of the patients had stage I disease, while 254 (42.3 %) and 60 (10.0 %) patients had stage II and III, respectively. Overall, 149 (25.1 %) patients received tamoxifen alone, 83 (14.0 %) tamoxifen with ovarian function suppression (OFS), while 361 (60.9 %) received aromatase inhibitor (AI) with OFS. Patients treated with AI and OFS had higher number of metastatic axillary nodes, higher grade and more often received chemotherapy (all p < 0.001). According to the inclusion criteria of the monarchE and NATALEE trials, 81 patients (15.6 %) were considered high-risk for the monarchE and received AI with OFS in 88.9 % of the cases, while 231 patients (44.4 %) were considered high-risk for the NATALEE trial and received AI with OFS in 74.5 % of cases., Conclusions: AI with OFS is the most prescribed adjuvant ET among premenopausal patients, especially in the presence of high-risk features., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eva Blondeaux: speaker fee from Eli Lilly and research support from Gilead Science (to the institution). Valentina Guarneri: personal fees from EliLilly, Exact Sciences, Novartis, Pfizer, Gilead, MSD, Amgen, Sanofi, Merck Serono, and Eisai outside the submitted work. Eleonora Mioranza: personal fee from Novartis e Lilly. Fabio Puglisi: 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. Antonella Ferro: support for attending meeting from Gilead, MSD and Pfizer; honoraria from Pfizer, Novartis, Daiichi Sankyo, Ely Lilly, Seagen, Gilead, Astra Zeneca, MSD. Vincenzo Adamo: consultancy/advisory role/speaker bureau from Amgen, Astra Zeneca, BMS, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sevier, Takeda. Laura Biganzoli: Personal financial interests (Honoraria, consultancy or advisory role): Amgen, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Menarini, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, SeaGen. Institutional financial interests: Celgene, Genomic Health, Novartis. Travel grant: AstraZeneca, Daiichi-Sankyo. Evandro de Azambuja: honoraria from or participation in advisory boards for Roche, Genentech, Novartis, SeaGen, Zodiac, Libbs, Pierre Fabre, Eli Lilly, and AstraZeneca. Francesca Poggio: fees and other support from AstraZeneca and personal fees from Eli Lilly, Novartis, Daichii Sankyo, and Gilead outside the submitted work. Matteo Lambertini: advisory role for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, and Exact Sciences; receiving speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Knight, Ipsen, and AstraZeneca; receiving travel grants from Gilead and Daiichi Sankyo; receiving research funding (to his institution) from Gilead. Lucia Del Mastro: 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.)

Background: Breast cancer is the most common malignancy among women in the UK. Reconstruction - of which implant-based breast reconstruction (IBBR) is the most common - forms a core part of surgical management of breast cancer. More recently, pre-pectoral IBBR has become common as technology and operative techniques have evolved. Many surgeons use acellular dermal matrix (ADM) in reconstruction however there is little evidence in literature that this improves surgical outcomes. This review will assess available evidence for surgical outcomes for breast reconstructions using ADM versus non-use of ADM., Methods: A database search was performed of Ovid Medline, Embase, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (2012-2022). Studies were screened using inclusion and exclusion criteria. Risk of Bias was assessed using the Newcastle Ottawa scale and ROBIS tools. Analysis and meta-analysis were performed., Results: This review included 22 studies (3822 breast reconstructions). No significant difference between overall complications and failure rates between ADM and non-ADM use was demonstrated. Capsular contracture, wound dehiscence and implant rippling had significant differences however these results demonstrated high heterogeneity thus wider generalisation may be inaccurate. Patient quality of life scores were not recorded consistently or comparably between papers., Conclusions: This review suggests a lack of significant differences in most complications between ADM use and non-use for pre-pectoral IBBR. If no increase in complications exists between groups, this has significant implications for surgical and legislative decision-making. There is, however, inadequate evidence available on the topic and further research is required., (© 2024. The Author(s).)

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Breast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC., Methods: A randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls., Discussion: The aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms., Trial Registration: EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guerrieri-Gonzaga 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: Invadopodia facilitate cancer cell extravasation, but the molecular mechanism whereby invadopodia-specific proteases such as MT1-MMP are called to invadopodia is unclear., Methods: Mass spectrometry and immunoprecipitation were used to identify interactors of MT1-MMP in metastatic breast cancer cells. After identification, siRNA and small molecule inhibitors were used to assess the effect these interactors had on cellular invasiveness. The chicken embryo chorioallantoic membrane (CAM) model was used to assess extravasation and invadopodia formation in vivo., Results: In metastatic breast cancer cells, MT1-MMP was found to associate with plectin, a cytolinker and scaffolding protein. Complex formation between plectin and MT1-MMP launches invadopodia formation, a subtype we termed i plectin ( i  = invadopodial). i Plectin delivers MT1-MMP to invadopodia and is indispensable for regulating cell surface levels of the enzyme. Genetic depletion of plectin with siRNA reduced invadopodia formation and cell invasion in vitro. In vivo extravasation efficiency assays and intravital imaging revealed i plectin to be a key contributor to invadopodia ultrastructure and essential for extravasation. Pharmacologic inhibition of plectin using the small molecule Plecstatin-1 (PST-1) abrogated MT1-MMP delivery to invadopodia and extravasation efficiency., Conclusions: Anti-metastasis therapeutic approaches that target invadopodia are possible by disrupting interactions between MT1-MMP and i plectin., Clinical Trial Registration Number: NCT04608357., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)