Breast cancer remains one of the most prevalent malignancies affecting women worldwide and continues to be a leading cause of cancer-related morbidity and mortality. Patients may present with either localized or advanced disease, with clinical outcomes increasingly influenced by molecular subtype and genetic profile. This review highlights the key genetic factors involved in breast cancer, current diagnostic and therapeutic strategies, and promising emerging approaches that may shape future clinical management. Breast cancer diagnosis typically involves clinical breast examination, imaging techniques such as mammography and ultrasound, and confirmatory biopsies. Genetic mutations in specific genes are strongly linked to the development, progression, and metastasis of the disease. Treatment options for localized breast cancer continue to include surgery (lumpectomy or mastectomy) and radiotherapy, combined with systemic therapies tailored to tumor biology, such as endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and cyclin-dependent kinase (CDK)4/6 inhibitors. For advanced or metastatic breast cancer, recent therapeutic advances include the use of immunotherapy (e.g., immune checkpoint inhibitors), Poly (ADP-ribose) polymerase (PARP) inhibitors for Breast Cancer gene (BRCA)-mutated cancers, antibody-drug conjugates, and novel targeted agents, which have significantly improved patient outcomes in selected populations. Recent findings in breast cancer genetics have highlighted the critical role of germline and somatic mutations, particularly in genes such as BRCA1, BRCA2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and TP53, in driving tumor initiation, progression, and therapeutic response. Molecular profiling and next-generation sequencing technologies have enabled more precise tumor classification and facilitated the development of personalized treatment strategies. Despite these advances, treatment resistance and disease recurrence remain major challenges, particularly in aggressive subtypes such as triple-negative breast cancer. Consequently, ongoing research is exploring alternative and complementary approaches, including nanotechnology-based drug delivery systems, gene editing techniques such as clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9) (CRISPR-Cas9), cancer vaccines, and the integration of traditional and plant-derived compounds. These strategies aim to enhance therapeutic efficacy, reduce systemic toxicity, and overcome resistance mechanisms.
Cancer survivors frequently experience cancer-related cognitive impairment (CRCI), but the contributions of different anti-cancer therapies remain unclear. Patients with breast or gynaecological cancer were recruited before any anti-cancer treatment. Cognitive function was assessed by objective and subjective measures pre-treatment (T0), post-treatment (T1), and 1 year after T1 (T2). Objective measures include Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), Controlled Oral Word Association Test (COWA), and Mnemonic Similarity Task (MST). Subjective measures include Functional Assessment of Cancer Therapy-Cognitive scale (FACT-Cog) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Linear mixed models were performed. Patients (n = 234) were of age 55.4 ± 11.6 years. At T1, chemotherapy was associated with worse visual searching and motor speed (TMT-A: β = 0.36, 95% CI: 0.03-0.69), perceived global function (FACT-Cog Global Function: β = -0.39, 95% CI: -0.67 to -0.11), and cognitive function (EORTC QLQ-C30: β = -0.50, 95% CI: -0.82 to -0.18) compared to endocrine therapy. At T2, endocrine therapy was associated with poorer verbal learning and memory performance (HVLT-R total recall: β = -0.40, 95% CI: -6 to -0.03) and higher perceived cognitive impairments (FACT-Cog PCI: β = 0.34, 95% CI: 0.05-0.63). In conclusion, CRCI may occur during certain types of chemotherapy but appears to ameliorate over time. Ongoing endocrine therapy may have longer-lasting impact on cognitive function. Appropriate counselling for informed decision making and good supportive care is needed.
Hormone receptor-positive (HR+) breast cancer remains a major therapeutic challenge due to endocrine resistance and disease progression. This study investigates the patent landscape of innovative pharmacological strategies for HR+ breast cancer, highlighting emerging targets, technological trends, and their alignment with clinical development. Patent documents were identified through searches of the European Patent Office databases via the keywords "breast cancer and hormone therapy" in the title and/or abstract, along with the International Patent Classification code A61K. The review also examines clinical trials to evaluate the development and approval of new drugs for medical use. A total of 25 patents were selected. Notably, CDK4/6 inhibitors have emerged as promising agents for controlling tumor progression and overcoming endocrine resistance. Another significant innovation involves the use of PIK3CA inhibitors, which are effective in patients with specific mutations in this gene, which are commonly found in HR+ breast cancers. The findings indicate that recent technological developments emphasize targeted mechanisms of action, deeper integration of precision oncology, and a continued shift toward strategies to delay or overcome endocrine resistance. These trends reflect an innovative landscape driving increasingly specific and personalized systemic therapies. This review describes current patent-driven innovations in hormone-sensitive breast cancer, highlighting the focus on precision systemic therapies and combination strategies for advanced disease. However, limited attention to the management of endocrine-related adverse effects reveals a critical unmet need for future research and technological development.
Axillary lymph node dissection (ALND) in breast cancer causes substantial arm morbidity and long-term functional impairment. Less extensive axillary surgery, such as targeted axillary dissection (TAD), significantly reduces this risk. Although omission of ALND is standard in clinically node-negative disease with limited sentinel node involvement, this is not the case for patients with clinically node-positive disease undergoing upfront surgery. The aim of the SENOMAC-ULTRA trial is to evaluate whether TAD can safely replace ALND in patients with clinically node-positive breast cancer receiving upfront surgery. SENOMAC-ULTRA is a prospective, international, multicentre, randomized non-inferiority trial. Adults with stage II-III invasive breast cancer and axillary metastases detectable by ultrasound and confirmed by fine needle aspiration or core biopsy are eligible for inclusion. Participants are randomized 1 : 1 to TAD (removal of marked metastatic nodes plus sentinel lymph node biopsy) or standard ALND. The primary endpoint is recurrence-free survival, assessed for non-inferiority using a Cox proportional hazards model. Secondary endpoints include overall survival, locoregional recurrence, regional nodal recurrence, distant relapse-free survival, invasive breast cancer-free survival, patient-reported arm morbidity, and health-related quality of life, as well as performance measures of axillary ultrasound and marking techniques. A sample size of 1380 patients has been calculated to provide 81% power to exclude a hazard ratio > 1.47 for recurrence-free survival at 5 years, adopting a non-inferiority margin of 4.5%. Follow-up is planned for 10 years. The trial protocol has been approved by the Swedish Ethical Review Authority (Dnr 2025-07730-01); each participating country will obtain local ethics approval. It is anticipated that the SENOMAC-ULTRA trial will fill an important knowledge gap guiding the surgical management of patients with clinically node-negative breast cancer. Registration number: NCT06869629 (https://clinicaltrials.gov).
Background and Objectives: Environmental exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a potential contributor to cancer-related biological variability; however, human biomonitoring data in oncology populations remain limited. The present study aimed to assess urinary concentrations of selected phenolic EDCs and their associations with cardiometabolic, hematological, inflammatory, and survival-related parameters in patients with advanced lung cancer. Materials and Methods: A total of 190 patients diagnosed with stage IIIB/IV lung cancer were included in this study. Urinary concentrations of bisphenol A (BPA), bisphenol S (BPS), triclosan (TCS), and resorcinol (RCO) were determined using validated analytical methods. Associations between exposure biomarkers and clinical laboratory parameters were evaluated using sex-stratified statistical analyses and regression models adjusted for age and body mass index. Results: TCS was the most frequently quantified compound (29.47%), followed by BPS (27.37%), RCO (11.58%), and BPA (7.89%). Higher odds of TCS quantification were observed in patients with lung adenocarcinoma and a higher probability of BPA quantification in patients with squamous-cell carcinoma. Sex-specific exposure patterns were observed, with higher BPA and BPS concentrations measured among female patients. Exposure to phenolic EDCs was associated with alterations in kidney function biomarkers, liver enzyme activity, inflammatory cell profiles, and anthropometric indicators. In particular, BPA and BPS showed associations with renal function markers and systemic inflammatory parameters, while TCS exposure was related to reduced leukocyte subpopulations. Survival analysis demonstrates borderline associations for BPA between exposure groups. Conclusions: These findings provide novel human biomonitoring evidence linking exposure to phenolic endocrine-disrupting chemicals with systemic metabolic and inflammatory variability in patients with advanced lung cancer. The observed associations support the biological plausibility that environmental endocrine disruptors may contribute to interindividual heterogeneity in cancer-related physiological responses.
Background/Objectives: Non-small cell lung cancer (NSCLC) remains associated with high mortality, frequent late-stage diagnosis, biological heterogeneity, and recurrence after treatment. Although molecular and immunohistochemical biomarkers have transformed treatment selection, there remains a need for accessible, repeatable, and clinically practical circulating biomarkers that may support prognosis and post-treatment monitoring. This review discusses prolactin (PRL) as a candidate supplementary biomarker in NSCLC, with particular emphasis on its biological rationale, potential prognostic relevance, and possible role in personalized risk stratification after systemic therapy. Methods: This narrative review summarizes current evidence on established biomarkers in NSCLC, the physiology and regulation of PRL, PRL/PRLR signaling in cancer biology, mechanisms of PRL dysregulation in lung cancer, and available clinical observations concerning PRL alterations in NSCLC. Particular attention is given to the distinction between prognostic and predictive biomarkers, longitudinal monitoring, pituitary involvement, immune checkpoint inhibitor-related endocrine effects, and biological, pharmacological, and analytical confounders affecting PRL interpretation. Results: Current evidence suggests that PRL may be biologically relevant in NSCLC through its involvement in pathways related to cell proliferation, survival, angiogenesis, invasion, epithelial-mesenchymal transition, immune modulation, and possible therapy resistance. Clinical observations indicate that altered PRL levels may occur in advanced disease, pituitary involvement, systemic inflammation, stress, or during anticancer and supportive treatment. However, PRL lacks cancer specificity and is influenced by multiple confounders, including circadian rhythm, stress, endocrine disorders, macroprolactin, cachexia, medications, and assay variability. Available clinical data remain limited and are largely derived from small studies or case-based evidence. Conclusions: PRL should not currently be considered a standalone diagnostic, predictive, or treatment-selective biomarker in NSCLC. Its most realistic potential role is as a supplementary circulating marker within multimarker prognostic and monitoring models. Prospective validation with standardized sampling, assay procedures, and confounder adjustment is required before clinical implementation.
Invasive lobular carcinoma (ILC) of the breast typically affects older women. As a result, there is limited research on prognosis and prognostic factors in young women with ILC. Here we set out to determine the long-term outcome and prognostic factors of women under 40 years of age with lymph node-negative (N0), hormone-receptor positive (HR+)/human epidermal growth-factor receptor 2 negative (HER2-) ILC who did not receive adjuvant systemic treatment (chemo- and/or endocrine therapy). Through the Netherlands Cancer Registry we selected all systemically untreated patients younger than 40 years with HR+/HER2-, N0, early breast cancer diagnosed in the Netherlands from 1989-2000. At the time, node-negativity was considered a favorable prognostic marker and guidelines recommended no adjuvant systemic therapy for this subgroup. Distant recurrence-free survival (DRFS), recurrence-free survival (RFS) and overall survival (OS) were assessed according to the STEEP criteria. Uni- and multivariable Cox proportional hazard models were used to assess prognosis, calculating hazard ratios (HR) with confidence interval (CI). Of the n = 1138 selected patients, n = 95 were histologically classified as ILC and n = 805 as invasive breast cancer of no special type (BC-NST), n = 238 were classified as other breast cancer subtype. In ILC, tumor grade was not associated with DRFS/RFS or OS (HR for DRFS 1.40, 95%CI 0.42-4.63). However, the presence of lymphovascular invasion (LVI) (adjusted HR DRFS 2.81, 95%CI 1.14-6.94, p < 0.05) and multifocality (adjusted HR DRFS 3.28, 95%CI 1.49-7.22, p < 0.01) were. When comparing DRFS, RFS and OS in matched low-risk luminal A-like ILC vs. BC-NST, we observed a trend for worse 15-year survival in ILC (15-year DRFS 63% in ILC vs. 74% in BC-NST; HR 1.50, 95%CI 0.98-2.29, p = 0.06). In these young patients with systemically untreated N0 ILC we show that grade was not prognostic at 15 years follow-up, whereas LVI and multifocality were. Furthermore, ILC had a numerically worse 15-year survival than matched luminal A-like BC-NST.
Ovarian cancer is a heterogeneous solid tumor, whereas polycystic ovary syndrome (PCOS) is a distinct endocrine-metabolic ovarian disorder. Whether PCOS-associated ovarian dysregulation and ovarian cancer share convergent transcriptomic candidates remains unclear. This study aimed to identify shared transcriptomic candidates and define their cellular localization without implying a causal or clinical comorbidity relationship. Public bulk transcriptomic datasets from PCOS and ovarian cancer underwent platform-specific preprocessing, within-disease-arm harmonization, differential-expression analysis, robust rank aggregation, and machine-learning-based feature prioritization with SHapley Additive exPlanations. Single-cell RNA sequencing datasets were used to localize prioritized genes in PCOS-related ovarian cell populations and high-grade serous ovarian cancer (HGSOC)-derived compartments. Preliminary validation used DHEA-treated KGN cells and siRNA-mediated SIX4 knockdown in SKOV3 cells. Exploratory docking and molecular dynamics simulation assessed the structural tractability of a SIX4-centered axis. Integrated analysis identified shared molecular dysregulation enriched in cell-cycle regulation, chromosome segregation, epithelial remodeling, and Wnt-related pathways. Five candidate genes were prioritized: SIX4, CCNE1, MMP7, KIF2C, and GPX3. SIX4 was the highest-ranked contributor within the computational model. Single-cell analysis showed compartment-specific localization, with SIX4 enriched in HGSOC-derived epithelial populations. DHEA increased SIX4 expression in KGN cells, whereas SIX4 knockdown suppressed SKOV3 proliferation, migration, and colony formation. Molecular dynamics suggested stable predicted engagement between SIX4 and a Benzbromarone-related scaffold. This study identifies SIX4 as a candidate epithelial target in ovarian cancer within a shared, noncausal transcriptomic program associated with PCOS-related ovarian dysregulation.
Despite the growing burden of prostate cancer in China and the widespread use of androgen deprivation therapy (ADT), no validated disease-specific instrument has been used to systematically characterize symptom clusters and their impact on quality of life (QoL) in this population. This exploratory application of the newly developed Prostate Cancer Endocrine Therapy Symptom Cluster Assessment Scale (PCET-SCAS) addresses this gap. To characterize symptom cluster profiles and QoL in Chinese patients with prostate cancer undergoing ADT, examine their correlations, and identify independent predictors of QoL using a disease-specific assessment instrument. This cross-sectional study consecutively enrolled 188 patients receiving ADT at one tertiary hospital in Guangzhou, China. Symptom clusters were assessed using the PCET-SCAS, and QoL was evaluated with the EORTC QLQ-C30 and QLQ-PR25. Spearman correlation and multiple linear regression were performed for statistical analysis. This exploratory application of the PCET-SCAS aimed to characterize symptom cluster profiles and their impact on QoL in this cohort. Five distinct symptom clusters were identified, including the urological-sleep, pain-digestive-nutritional, emotional-energy, endocrine therapy-related, and sexual function clusters. The sexual function cluster had the highest severity (median 2.50, IQR 2.25-3.00). Cognitive function was the lowest-scoring functional domain (median 50.00). All five clusters were significantly negatively correlated with functional domains and overall health status (r = -0.167 to -0.630, all P < 0.01), and positively correlated with symptom domains (r = 0.156 to 0.636, all P < 0.05). Univariate analysis identified age, cohabitation status, physical activity level, Karnofsky Performance Status (KPS) score, disease progression, bone metastasis, and all five symptom cluster scores as significant correlates of QoL (all P < 0.05). Multivariate regression (16 separate models, adjusted R² range: 0.139-0.541) identified symptom cluster severity as the most consistent independent predictor of QoL across domains. KPS score predicted physical, role, and social functioning but not emotional or cognitive outcomes (sexual outcomes were not analyzed in regression due to insufficient data). The emotional-energy cluster was the dominant predictor of emotional function, and the urological-sleep cluster was the strongest predictor of urinary symptoms. Chinese patients with prostate cancer undergoing ADT experience a multidimensional, co-occurring symptom burden across five distinct clusters, all significantly associated with impaired QoL. KPS predicted physical, role, and social functioning but not emotional or cognitive outcomes (sexual outcomes were not analyzed in regression due to insufficient data), underscoring its role as a physical performance measure rather than a global QoL indicator. These findings support the development of cluster-targeted supportive care interventions to optimize QoL in this population.
HR-positive HER2-low-expressing breast cancer is a unique subtype that has been refined from the traditional HER2 binary classification system in recent years, accounting for nearly 60% of the overall incidence of breast cancer. It has significant value for precise diagnosis and treatment research. This review systematically elaborates on the epidemiological characteristics, biological basis, diagnostic technology progress, and treatment strategy evolution of this subtype. HR-positive HER2-low-expressing breast cancer is characterized by the dominance of the estrogen receptor pathway and the core molecular feature of the intersection of HER2 low-expression signals. Its diagnosis requires a balance between the fundamental role of endocrine therapy and the precise screening of anti-HER2 targeted therapy. In terms of diagnosis, the initial screening by immunohistochemistry combined with fluorescence in situ hybridization has formed a standardized process. The integration of digital pathology, next-generation sequencing, and circulating tumor DNA in liquid biopsy technologies has effectively improved diagnostic accuracy and dynamic monitoring capabilities. In terms of treatment, endocrine therapy is the cornerstone, and the CDK4/6 inhibitor combination regimen is the standard for advanced first-line treatment. Antibody-drug conjugates, especially deruxtecan, have significantly improved patient prognosis and reshaped the treatment landscape. In summary, HR-positive HER2-low-expressing breast cancer has entered the era of individualized precise treatment guided by molecular typing. In the future, further exploration of new biomarkers, optimization of combination therapy strategies, and high-quality clinical research are needed to continuously improve patient survival outcomes.
Endocrine resistance remains a critical challenge in hormone receptor-positive (HR+) breast cancer. The impact of the immune microenvironment on endocrine therapy efficacy is increasingly recognised, but its mechanisms are not fully understood. Here, we investigated that nuclear HMGB1 expression in tumour cells was closely associated with endocrine therapy resistance in HR+ breast cancer using tumour genomic databases. Specially, tumours with high HMGB1 expression induced M2-like macrophage polarisation, which was related to HMGB1 paracrine signalling. Mechanistically, HMGB1 bound to the RAGE receptor on macrophages, activating the downstream MAPK signalling pathway and was closely linked to the activation of fatty acid metabolism pathways. Macrophages co-cultured with high-HMGB1 tumour cells exhibited metabolic characteristics associated with carcinogenesis, a loss of glycolytic intermediates and a shift toward a pro-tumourigenic metabolic state compared to those co-cultured with low-HMGB1 cells. Co-culture with M2-like macrophages significantly activated growth signalling pathways like NF-κB in the high-HMGB1 tumour cells. Taken together, high expression of HMGB1 in tumour cells promotes fatty acid metabolic remodelling and functional polarisation in macrophages, contributing to endocrine therapy resistance in HR+ breast cancer. HMGB1 acts as a candidate for immune mediator and paved a way to develop potential target drug.
Neuroendocrine prostate cancer (NEPC) is a rare and aggressive variant of prostate cancer (PC) that can be de-novo (d-NEPC) or transform from prior prostate adenocarcinoma (PCa) as treatment-emergent NEPC (t-NEPC). This study aimed to study the clinical characteristics and overall survival (OS) of NEPC using data from the SEER and NCRAS registries, and to compare their OS. A total of 1,465 patients with NEPC were extracted from SEER (N=990, 2010-2022) and NCRAS (N=475, 2010-2021). Patients were classified as t-NEPC if preceded by a documented PCa. The primary outcome is OS measured from the date of NEPC diagnosis. Kaplan-Meier analysis, log-rank test, and Cox regression were performed for SEER, NCRAS, and pooled cohorts. t-NEPC represented 9.9% in NCRAS and 15.2% in SEER. Small cell carcinoma was the most common subtype (80.2% NCRAS, 74.7% SEER). Median time to transformation was 4.63 years in NCRAS and 5.0 years in SEER. In the pooled cohort, median OS was 9 months for d-NEPC and 7 months for t-NEPC (log-rank p<0.001). The 60-month OS was 7.9% for d-NEPC and 4.0% for t-NEPC. In the pooled multivariable Cox regression, t-NEPC was independently associated with worse OS (aHR 1.30, 95% CI 1.11-1.53, p=0.001). Data source was not associated with OS (aHR 1.08, p=0.206), indicating comparable OS between the USA and England. In this bi-national, population-based study, t-NEPC was associated with worse OS than d-NEPC. OS for NEPC was comparable between the USA and England. These findings support distinguishing d-NEPC from t-NEPC.
Tumor-associated nerves have recently emerged as an understudied key regulator of cancer biology. However, its quantification using histological or transcriptomic approaches is challenging because their small diameters hinder reliable detection and their cell bodies that hold most mRNA reside outside the tumor. This study evaluated a Schwann cell (SC)-related transcriptomic score as a surrogate for tumor-associated nerves in tumors from triple-negative breast cancer (TNBC) patients. Transcriptomic and clinical data from three independent TNBC cohorts, TCGA (n = 170), METABRIC (n = 335), and SCAN-B (n = 174) were analyzed. An SC score was calculated from SC-related gene signatures, and spatial transcriptomics was used to validate SC localization. In addition, seven independent neoadjuvant chemotherapy (NAC) cohorts were analyzed to evaluate the association between SC score and treatment response. Associations between the SC score and clinical features, genomic features, proliferation, treatment response, and the tumor microenvironment (TME) were evaluated. SC signature genes spatially localized to intratumoral nerve regions, confirming that the SC score reflects their presence within tumors. SC-high tumors were associated with lower mutation burden and with less cell proliferation in the TCGA, METABRIC, and SCAN-B cohorts. SC-high tumors were also associated with low immune activity and fewer infiltrating immune cells, along with enrichment of epithelial-mesenchymal transition (EMT), TGF-beta signaling and stromal remodeling pathways. The SC score-high TNBC is associated with lower cell proliferation, enhanced stromal remodeling and EMT and suppressed immune activity, suggesting a role of neural-associated TME features in shaping TNBC biology.
Despite clinical advances, breast cancer screening adherence remains stagnant in Japan (<50%) compared with the United States (>70%). Understanding distinct cross-cultural barriers is essential; however, traditional methodologies often fail to capture visceral, real-world individual experiences and hidden deterrents to screening. This study aims to characterize and compare cross-cultural informatics profiles of barriers to breast cancer screening across Japanese-language and English-language social media discourse. We developed an automated natural language processing pipeline on a cloud-based informatics platform to analyze 46,823 screening-related posts (30,027 in Japanese and 16,796 in English) from X (formerly Twitter) collected in 2025, derived from an initial 76,955 posts after noise exclusion. The methodology integrated large language model-assisted sentiment polarity scoring with strict negation-handling, co-occurrence network topology analysis, and advanced distributional visualizations, including raincloud and ridgeline plots. Subgroup comparisons (prescreening vs postscreening and ultrasound with vs without mammography) were evaluated. Among the 46,823 screening-related posts, overall sentiment distributions showed no practically meaningful cross-cultural divergence (Cohen d=0.049); however, domain-specific analyses revealed sharp disparities in barrier prevalence. Within the English-language cohort containing 16,796 posts, discourse exhibited a concentrated, moderate negative sentiment regarding systemic barriers, featuring "Cost" as the primary barrier (n=1239, 7.4%), while "Pain" ranked considerably lower (n=842, 5.0%). In contrast, the Japanese-language cohort containing 30,027 posts was heavily bottlenecked by psychosomatic barriers, governed by a tightly interconnected network of "Pain," "Fear," and "Appointment." "Pain" emerged as the overwhelmingly dominant barrier (n=5788, 19.3%). In the English-language cohort, "Dense" breasts emerged as a prominent clinical topic due to elevated public awareness, distinct from the financial narrative. The Japanese subgroup analyses identified a temporal transition from anticipatory psychological anxiety ("Fear," 739/3805, 19.4%) and logistical concerns ("Appointment," 1556/3805, 40.9%) before screening to a strong persistence of the discomfort memory of "Pain" (1160/7419, 15.6%). Furthermore, sentiment scores for mammography were significantly more negative than those for ultrasound alone (P<.001, Cohen d=0.264), and pain-related descriptors for ultrasound spiked from 5.0% (106/2110, ultrasound alone) to 18.2% (733/4017) when performed concurrently with mammography. Despite comparable overall emotional equilibrium, a fundamental dichotomy emerged. The English-language discourse predominantly reflects US-specific systemic financial burdens, whereas the Japanese experience is characterized by emotional volatility transitioning from anticipatory anxiety to a tightly interconnected "Pain-Fear-Appointment" network. Physical discomfort of mammography dominates the screening narrative, overshadowing concurrent painless modalities like ultrasound. Improving adherence in Japan requires individualized pain-mitigating compression protocols and optimized clinical workflows to decouple mammographic discomfort from supplemental screening, thereby preventing pain-associated defensive avoidance and reducing logistical hurdles to improve equitable access.
This study investigated the associations between tumor-infiltrating lymphocytes (TILs), genomic features, and prognosis in HER2+ early breast cancer (EBC) patients receiving adjuvant trastuzumab. We retrospectively analyzed 864 HER2+ EBC patients from Shanghai Ruijin Hospital (2009-2017). The optimal threshold of TILs for predicting disease free survival (DFS) and overall survival (OS) was explored. Whole-exome sequencing (WES) on 261 tumors assessed the mutational profiles, tumor mutational burden (TMB), and copy number alteration (CNA). Associations of these genomic features, TILs levels and prognosis were further evaluated. TILs showed a right-skewed distribution (median 15%, IQR 1-30%), and higher TILs were significantly associated with hormone receptor negativity and high histologic grade (p < 0.001). A 15% TILs threshold optimally predicted prognosis, with low TILs (≤15%, 63.0%) patients showing inferior DFS (HR 1.63, p = 0.009) and OS (HR 2.12, p = 0.037). WES identified frequent mutations in TP53 (62.8%), PIK3CA (34.5%), and BRCA2 (9.6%). Higher TILs density was observed in TP53-wild-type, low-TMB or low-CNA tumors (p < 0.05). PIK3CA mutations conferred a significant DFS advantage. Integrating TILs level with PIK3CA or BRCA2 mutational status yielded distinct DFS trajectories (log-rank p = 0.023 and 0.040, respectively); patients with both high TILs and either PIK3CA or BRCA2 mutations had the most favorable outcomes. Stromal TILs at a 15% cut-off provide robust prognostic information in trastuzumab-treated HER2+ EBC. Integrating TILs levels with PIK3CA or BRCA2 mutational status enables refined risk stratification, offering a practical framework for personalized treatment decisions.
Thyroid cancer (TC) is a common endocrine malignancy with a rising global incidence. This study examined trends in TC incidence and mortality in the United States over the past two decades. TC mortality data from 1999-2023 and incidence data from 1999-2022 were obtained from Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research. Age-adjusted incidence rates (AAIRs) and age-adjusted mortality rates (AAMRs) per 100,000 person-years were standardized to the 2000 United States standard population. Temporal trends were analyzed using the Joinpoint Regression Program to calculate annual percent changes (APCs) and average annual percent changes (AAPCs) with 95% confidence intervals. Analyses were stratified by sex, age, race, and census region. A sensitivity analysis restricted to 1999-2019 was also conducted. Overall, 933,521 TC cases and 43,071 TC-related deaths were identified, with an AAIR of 12.12 and an AAMR of 0.49. Incidence rose markedly from 1999 to 2009 (APC=7.25%), stabilized during 2009-2014, and declined from 2014 to 2022 (APC=-2.42%), especially among females. In males, incidence increased until 2011 and then declined slightly. Mortality increased modestly overall (AAPC=0.30%), mainly among males and adults aged ≥75 years. The Northeast had the highest AAIR (15.73), whereas the West had the highest AAMR (0.55). Non-Hispanic Whites had increasing mortality, while non-Hispanic Blacks had the lowest incidence. In the United States, TC incidence shifted from increase to decline, coinciding with growing awareness of potential overdiagnosis. In contrast, mortality continued to show a modest upward trend, underscoring the importance of ongoing surveillance and focused attention to high-risk populations.
Management of second ipsilateral breast cancer events (iBCEs) remains controversial, and there is a need to collate existing evidence and international guidance on patient selection and local treatment strategies. This project, endorsed by US and European surgical and radiation oncology societies, aimed to gather expert consensus on these issues. A questionnaire on second iBCE local treatment was developed and reviewed by a core group of eight experts, and Delphi methodology was applied over two rounds to 36 panellists, including radiation oncologists, breast surgeons, a plastic surgeon, and medical physicists. Consensus was predefined as agreement of 75% or higher. After two rounds, consensus was reached for 78 (80%) of 97 items. Panellists agreed that patient preferences are central to decision making (100%) and that a second breast-conserving therapy represents a reasonable option for selected patients (100%). Criteria associated with greater suitability for second breast-conserving therapy included an interval between surgeries of at least 60 months, low-risk accelerated partial breast irradiation classification, luminal molecular profile, and no grade 3 late toxicity related to the first breast-conserving therapy. HER2 (also known as ERBB2)-positive or triple negative subtypes were not viewed as absolute contraindications. Strong consensus was also observed regarding the importance of tumour-to-breast volume ratio, clear surgical margins, and tumour bed reirradiation. For patients undergoing mastectomy, immediate autologous reconstruction was preferred (94%) over implant-based approaches (75%). This international Delphi consensus offers structured guidance for the local management of second iBCE and supports shared decision making and individualised treatment planning.
Background/Objective: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for HR+/HER2- advanced/metastatic breast cancer (a/mBC), yet no head-to-head randomized trials have compared palbociclib, ribociclib, and abemaciclib. This systematic literature review (SLR) aimed to synthesize available real-world evidence (RWE) on the comparative effectiveness of these three CDK4/6i in the first-line setting. Methods: An SLR was conducted following PRISMA guidelines. Searches of MEDLINE, Embase, Cochrane, and gray literature (January 2015-September 2025) identified RWE studies reporting real-world progression-free survival (rwPFS) and/or overall survival (OS) for first-line CDK4/6i regimens. Eligible studies included adults with HR+/HER2- a/mBC receiving palbociclib, ribociclib, or abemaciclib, combined with endocrine-based therapy. Comparative outcomes were summarized qualitatively; study quality was assessed using the Newcastle-Ottawa Scale, ISPOR-AMCP-NPC questionnaire, and ESMO-GROW checklist. Results: From 13,345 records, 39 publications (32 unique studies) were identified, of which 21 were full-text studies meeting inclusion criteria. Most included studies used retrospective cohort designs, and approximately 50% evaluated all three CDK4/6is. Given the comparative nature of the included studies, quality issues were found to be related to study design and analytical approaches. Several analyses were unadjusted, and reporting of follow-up duration varied across studies, with some analyses providing incomplete follow-up information. Study sample sizes differed substantially across agents, with smaller populations generally reported for ribociclib and abemaciclib. Among the studies reporting rwPFS hazard ratios (HRs), 8/11 studies showed comparable rwPFS and 5/6 studies reported comparable OS outcomes between CDK4/6i regimens. Three full-text studies reported HRs favoring ribociclib or abemaciclib relative to palbociclib; these analyses primarily included populations receiving palbociclib, with smaller comparator cohorts for ribociclib and abemaciclib, as well as varied follow-up times. Conclusions: Most real-world studies included in the SLR suggested similar effectiveness of the three CDK4/6is in first-line HR+/HER2- a/mBC. Heterogeneity in patient characteristics, definitions of outcomes, follow-up time, sample size, and statistical approach may have important implications on study interpretability.
Clinically inapparent node metastases, requiring neck dissection in addition to thyroidectomy, pose a diagnostic challenge in patients with medullary thyroid cancer (MTC). Although desmoplasia negativity has emerged as a powerful marker of node negative disease, its clinical utility in hereditary MTC remains ill-defined. This cross-sectional investigation employed multivariable logistic regression on, and stratification of clinical variables by, nodal status of 124 RET carriers with MTC who underwent initial total thyroidectomy with at least central neck dissection between 2000 and 2025 at a tertiary center. Unlike tumor size, grade, laterality, index status, and sex, only desmoplasia (>10% vs. ≤5%), basal serum calcitonin (>500 pg/ml >> 101-500 pg/ml vs. ≤100 pg/ml), and RET category (highest [p.Met918Thr] vs. any other) were independently associated with node metastases. In unilateral MTC, desmoplasia ≤5% was always associated with freedom from node metastases (0 of 15 patients), whereas tumor size ≤5 mm and basal serum calcitonin ≤100 pg/ml were associated with node metastases in 4 (18%) of 22 patients and 4 (15%) of 26 patients, respectively. In bilateral MTC, none of the above thresholds were sufficiently discriminatory, suggesting cross-contamination by the contralateral MTC. In unilateral MTC with desmoplasia ≤5%, node metastases were always absent, regardless of whether basal calcitonin levels were ≤100 (based on 13 patients) or >100 pg/ml (based on 2 patients). This comprehensive proof-of-concept study demonstrates that RET carriers with desmoplasia negative unilateral MTC may forgo node dissection at specialist centers, similarly to what has been proposed for patients with desmoplasia negative sporadic MTC.
Trastuzumab deruxtecan (T-DXd) is a key treatment for HER2-positive metastatic breast cancer (mBC); however, data on T-DXd rechallenge remain limited. This post-hoc subgroup analysis evaluated T-DXd rechallenge in patients with HER2-positive mBC using data from EN-SEMBLE, a nationwide cohort study in Japan (N = 664). Twenty-six patients were included. Median real-world progression-free survival, real-world time to treatment failure, and overall survival were 6.5, 4.9, and 14.2 months, respectively. The objective response rate was 27%. Patients who discontinued initial T-DXd without progressive disease had numerically longer real-world progression-free survival. No interstitial lung disease occurred during rechallenge. T-DXd rechallenge may have clinical activity in selected patients with HER2-positive mBC. jRCT1030220506.