Cancer Medicine最新文献

{"title":"Survival Outcomes in Chronic Lymphocytic Leukemia During the Novel Agent Era: A Population-Based Analysis.","authors":"Mengyang Di, Scott F Huntington, Jenna M Voutsinas, Vicky Q Wu, Chaitra S Ujjani, Scott D Ramsey, Jennifer J Huang, Ajay K Gopal, Mazyar Shadman","doi":"10.1002/cam4.72408","DOIUrl":"https://doi.org/10.1002/cam4.72408","url":null,"abstract":"<p><p>Chemoimmunotherapy (CIT) had long been used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) until 2014 when the first novel agent, ibrutinib, was approved in the United States. Numerous novel therapies have since become available. Nevertheless, as novel therapies have largely replaced CIT in CLL/SLL, its impact on survival has yet to be examined on the population level. In this study, we used the SEER (Surveillance, Epidemiology, and End Results) database to compare survival in patients with CLL/SLL before and after the approval of the first novel therapy. We included 9913 patients who started treatment within 2 years of CLL/SLL diagnosis. In the multivariable analyses, the overall survival improved significantly (hazard ratio [HR]: 0.86, 95% confidence interval: 0.81, 0.92), and death from CLL/SLL and other cancer (subdistribution-HR: 0.69 and 0.77) also decreased significantly. Nevertheless, CLL/SLL remains the main cause of death during the novel agent era.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72408"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated mRNA-Based Detection of ER, PR, HER2, and Ki-67 in Breast Cancer Tissue and Cytology Samples in Resource-Limited Settings.","authors":"Partha Basu, Anuradha Talukdar, Poulome Mukherjee, Richard Muwonge, Eric Lucas, Monoj Kumar Deka, Amanjit Bal, Upasana Gautam, Manish Rohilla, Baneet Bansal, Veenu Singla, Siddhant Khare, Andre Lopes Carvalho, Anita Gadgil, Ravi Kannan, Radhika Srinivasan","doi":"10.1002/cam4.72359","DOIUrl":"10.1002/cam4.72359","url":null,"abstract":"<p><strong>Background: </strong>Accurate detection of estrogen and progesterone receptors (ER/PR), HER2, and Ki-67 is essential for molecular classification of breast cancer and in deciding upon tailored treatment. In many low- and middle-income countries (LMICs), access to histopathology and immunohistochemistry (IHC) is limited. STRAT4, an automated RT-qPCR assay performed on the widely available GeneXpert platform, offers a potential alternative. We evaluated the performance of STRAT4 on core biopsy, unstained smear of fine-needle aspiration biopsy (FNAB-US), and cellblock samples compared with conventional IHC in 178 histopathology-confirmed breast cancer patients.</p><p><strong>Methods: </strong>Matched core biopsy, cellblock, and FNAB-US samples were analyzed using STRAT4. Concordance with IHC for ER, PR, HER2, and Ki-67 was assessed using percentage agreement and kappa statistics. The effect of alternative dC_t cut-offs used in an earlier study was also examined. Molecular subtype classification derived from STRAT4 was compared with IHC-based classification.</p><p><strong>Results: </strong>Concordance between STRAT4 and IHC was high for ER across all sample types (κ: 0.78-0.86). PR detection showed substantial agreement for core biopsies (κ = 0.78) and cellblocks (κ = 0.63), but only fair for FNAB-US samples (κ = 0.53). HER2 detection showed moderate agreement (κ = 0.41-0.58), improving with modified cut-offs (κ = 0.57-0.66), especially for FNAB-US. Ki-67 concordance was low (agreement 58.9%-71.0%). Kappa values indicating agreement between molecular subtype classifications using STRAT4 on various samples and routine IHC were as follows: core biopsies = 0.60; cellblocks = 0.61; FNAB-US samples = 0.45.</p><p><strong>Conclusion: </strong>Detection of ER from FNAB-US, cellblocks, and core biopsies using STRAT4 showed high concordance with IHC. However, the concordance was low to moderate for other markers.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72359"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors Associated With Perceived Cognitive Dysfunction in Patients With Primary Brain Tumors: The Utility of the Neuro-QoL Cognition Function Scale.","authors":"Morgan Johnson, Kimberly Reinhart, Vivian A Guedes, Michelle L Wright, Elizabeth Vera, Alvina Acquaye-Mallory, Hope Miller, Anna Choi, Tricia Kunst, Jennifer Reyes, Jing Wu, Marta Penas-Prado, Byram Ozer, Eric Burton, Mark R Gilbert, Terri S Armstrong, Tito Mendoza","doi":"10.1002/cam4.72203","DOIUrl":"https://doi.org/10.1002/cam4.72203","url":null,"abstract":"<p><strong>Background: </strong>Primary brain tumor (PBT) patients commonly experience cognitive dysfunction. This study aims to describe the prevalence and factors associated with perceived cognitive function (PCF) in PBT patients enrolled in a natural history study (NCT02851706: Principal Investigator T. S. Armstrong).</p><p><strong>Methods: </strong>The Neuro-QoL Cognition Function was used to measure PCF with T-scores < 40 categorized as cognitively impaired. Clinical and demographic characteristics, patient-reported outcomes (PROs: symptom burden, depression, anxiety), and KPS were collected and characterized using descriptive statistics. Univariate tests on PCF with p-value < 0.10 were performed and included in a subsequent multivariate logistic regression with backward selection. Clinical variables and PROs were evaluated separately, then combined for a final multivariate model with p-value < 0.05.</p><p><strong>Results: </strong>The cohort included 327 patients (median age: 47 years [range: 18-85], primarily white [78%] males [55%] with high-grade tumors [73%]). Perceived cognitive impairment occurred in 29% of patients. Patients presenting with cognitive dysfunction at diagnosis, or who had undergone multiple surgeries, were more likely to have poor PCF, as were those currently on corticosteroids and reporting cognitive symptoms and symptom interference. Evaluated together, a multivariate model found that only higher scores on symptom interference and the cognitive symptom factor increased the likelihood of cognitive impairment (symptom interference odds ratio [OR] = 1.25, 95% confidence interval [CI] [1.09, 1.44], p < 0.001; cognitive symptom factor OR = 1.81, 95% CI [1.50, 2.19], p < 0.001) with an 84% classification rate.</p><p><strong>Conclusions: </strong>Self-reported cognitive symptoms and interference were the strongest patient-reported correlates of PCF and should be interpreted as concurrent associations among related constructs. Further psychometric and longitudinal work is needed to clarify the incremental clinical value of the Neuro-QoL Cognition Function Short Form in PBT care and research.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72203"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Under One Roof: Household Composition and Health-Related Quality of Life Among Cancer Survivors.","authors":"Qaidar Alizai, Lorenza Arena, Charalampos M Charalampous, Abdulaziz Elemosho, Rida Ejaz, Areesh Mevawalla, Meher Angez, Timothy M Pawlik","doi":"10.1002/cam4.72385","DOIUrl":"10.1002/cam4.72385","url":null,"abstract":"<p><strong>Background: </strong>Household size and composition may be associated with health-related quality of life (HRQoL), yet these associations remain poorly characterized among cancer survivors. We examined how household adult composition and presence of children were associated with HRQoL among U.S. cancer survivors.</p><p><strong>Methods: </strong>Adult (aged ≥ 18 years) cancer survivors were included from the Behavioral Risk Factor Surveillance System (BRFSS) 2017-2024. Household composition was defined by number of adults (1, 2, or ≥ 3) and presence of children (none vs. ≥ 1). Outcomes included poor physical health (PPH), poor mental health (PMH; each defined as ≥ 14 days/month), and fair/poor general health. Multivariable Poisson regression was used to estimate adjusted prevalence ratios (aPRs) with 95% confidence intervals.</p><p><strong>Results: </strong>Among 138,360 cancer survivors, 45.2% (n = 62,605) resided in single-adult households, 47.1% (n = 65,132) in two-adult households, and 7.7% (n = 10,623) in households with ≥ 3 adults; children were present in 5.1% (n = 7063) of households. After adjustment, two-adult household residence was associated with lower prevalence of poor physical health (adjusted prevalence ratio [aPR] 0.93, 95% CI 0.87-0.99), poor mental health (aPR 0.90, 95% CI 0.82-0.98), and fair/poor general health (aPR 0.92, 95% CI 0.88-0.97; all p ≤ 0.019) compared with single-adult households. Residence with ≥ 3 adults and child presence was not associated with any examined HRQoL outcome after adjustment. Exploratory stratified analyses identified associations within several sociodemographic subgroups.</p><p><strong>Conclusion: </strong>Two-adult household residence was consistently associated with better HRQoL. Single-adult household status may represent a simple social risk marker to inform survivorship assessment.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72385"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Prophylactic Protection of Inferior Parathyroid Gland Vein Blood Supply on Reducing Postoperative Hypoparathyroidism.","authors":"Liping Liu, Dehao Yu, Shichao Li, Lei Liu, Xinhua Yang, Haoxi Liu","doi":"10.1002/cam4.72360","DOIUrl":"10.1002/cam4.72360","url":null,"abstract":"<p><strong>Background: </strong>The objective of this study was to verify that a strategy involving prophylactic exposure of the inferior parathyroid glands and preservation of their venous blood flow-achieved through early identification and protection of their venous drainage-can enhance the success rate of maintaining glandular perfusion and effectively reduce the incidence of postoperative hypoparathyroidism.</p><p><strong>Methods: </strong>This study included 600 patients who underwent total thyroidectomy with concomitant bilateral central neck dissection between November 2019 and December 2025. Patients were divided into two groups based on the surgical technique: Group A (n = 244), in which a prophylactic approach was used to protect the venous drainage of the inferior parathyroid glands, and Group B (n = 356), which underwent conventional in situ preservation of the inferior parathyroid glands. A comparison was made between the two groups regarding both the percentage of inferior parathyroid glands successfully preserved in situ and the incidence of postoperative hypoparathyroidism.</p><p><strong>Results: </strong>The rate of visualization of inferior parathyroid glands with optimal blood supply was significantly higher in Group A than in Group B (p < 0.001). Postoperation parathyroid hormone level in Group A was significantly higher than that in Group B (25.15 [19.39, 33.58] pg/mL vs. 19.12 [9.82, 28.85] pg/mL, p < 0.001). In Group A, the rates of postoperative hypoparathyroidism-encompassing both transient and permanent forms-were significantly lower than those in Group B (p < 0.001).</p><p><strong>Conclusions: </strong>The method of prophylactically exposing the inferior parathyroid glands and preserving their venous system-termed prophylactic preservation of inferior parathyroid venous blood flow-is achieved through early identification and protection of their venous drainage. This approach enhances the success rate of maintaining glandular blood supply and effectively reduces the incidence of postoperative hypoparathyroidism.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72360"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay Between Epigenetics and Reactive Oxygen Species in Tumor Radioresistance: Mechanisms and Therapeutic Strategies for Radiotherapy.","authors":"Zhengmao Yang, Jiaxin Wang, Guofang Wang, Jiamin Zhu, Shengnan Zhang, Wenjian Guo","doi":"10.1002/cam4.72388","DOIUrl":"10.1002/cam4.72388","url":null,"abstract":"<p><p>Radiotherapy efficacy is constrained by tumor radioresistance, which arises in part from the interplay between reactive oxygen species (ROS) and epigenetic regulation. This review systematically synthesizes the bidirectional \"epigenetics-ROS interactive network\" that governs tumor radiosensitivity. We propose that this network operates through three core principles: stress adaptation (acute ROS triggers transient epigenetic adjustments for redox recovery), malignant reinforcement (chronic ROS drives stable epigenetic reprogramming toward therapy resistance), and contextual determinacy (cellular outcomes depend on integrated ROS-epigenetic patterns rather than individual signals). Mechanistically, we delineate four regulatory layers including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, through which the epigenetic machinery controls ROS homeostasis, and conversely, how radiation-induced ROS reshape the epigenetic landscape via oxidative modification of epigenetic enzymes and signaling pathways. These bidirectional interactions form feedback circuits that ultimately dictate whether cells undergo repair, senescence, apoptosis, or ferroptosis. Based on this mechanism, we propose a context-dependent decision framework that matches four distinct combination strategies (ROS amplification, epigenetic priming, hypoxia relief, and multi-pathway cell death induction) with four tumor subtypes defined by their oxidative and epigenetic profiles. We also identify five translational roadblocks including toxicity, delivery inefficiency, manufacturing scalability, regulatory uncertainty, and preclinical-clinical discordance. Resolving these barriers is essential for unlocking the therapeutic potential of this regulatory axis. Strategically targeting the epigenetics-ROS network offers a transformative paradigm for overcoming radioresistance and personalizing cancer radiotherapy.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72388"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival Outcomes of Post-Induction Treatment Strategies in Patients With Partial Response Hypopharyngeal Squamous Cell Carcinoma: A Propensity Score-Weighted Analysis.","authors":"Hui-Ching Lau, Huiying Huang, Ji Li, Tian Wang, Xinhui Mao, Zhenwei Wang, Chi-Yao Hsueh, Ming Zhang, Chengzhi Xu","doi":"10.1002/cam4.72400","DOIUrl":"10.1002/cam4.72400","url":null,"abstract":"<p><strong>Background: </strong>Most patients with hypopharyngeal squamous cell carcinoma (HPSCC) achieve partial response (PR) after induction chemotherapy. However, optimal post-induction management remains controversial. We compared survival outcomes of post-induction strategies for PR-HPSCC, with emphasis on advanced post-induction tumor stage (ycT) using inverse probability of treatment weighting (IPTW-ATO) to mitigate confounding by indication.</p><p><strong>Methods: </strong>This retrospective study included 149 patients with PR-HPSCC after induction chemotherapy who subsequently received surgery-based therapy (SBT; n = 71) or definitive chemoradiotherapy (CRT; n = 78). IPTW-ATO was used to address covariate imbalances between groups. Overall survival (OS) and progression-free survival (PFS) were evaluated using weighted Kaplan-Meier analyses and IPTW-ATO-adjusted Cox proportional hazards models. Sensitivity analyses compared findings across unadjusted, multivariable, and propensity score-weighted models.</p><p><strong>Results: </strong>In unadjusted analyses, OS and PFS did not differ significantly between groups. After IPTW-ATO adjustment, SBT was associated with improved OS and PFS versus CRT. Exploratory subgroup analyses suggested a potential differential treatment effect across ycT strata; however, interaction tests were not statistically significant, and no significant survival difference was observed in patients with early ycT disease. In multivariable analyses, thyroid invasion was independently associated with worse OS, whereas anti-PD-1 therapy was associated with improved OS.</p><p><strong>Conclusions: </strong>Outcomes among patients with PR-HPSCC are heterogeneous. After adjustment for covariate imbalances, SBT was associated with favorable survival. These findings suggest that PR should not be treated as a uniform entity and that post-induction ycT classification may help stratify patients for future prospective evaluation.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":"e72400"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intersectionality of Race, Rurality on Persistent Poverty Disparities in Cancer Mortality in Alabama","authors":"Mackenzie E. Fowler,&nbsp;Hayden D. Reeves,&nbsp;Suzanne Judd,&nbsp;Kelley Pettee Gabriel,&nbsp;Geetanjali Saini,&nbsp;Mahak Bhargava,&nbsp;Timiya S. Nolan,&nbsp;Ritu Aneja","doi":"10.1002/cam4.72333","DOIUrl":"10.1002/cam4.72333","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Counties in persistent poverty (PP) have higher cancer-related mortality rates. Intersectionality with race and rurality is present; individuals identifying as Black residing in rural PP counties have the highest cancer-related mortality rates. However, heterogeneity exists throughout counties (e.g., demographics). To date, few studies evaluated the effect of small-area PP residence on individual-level survival and intersectionality with race and rurality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective cohort utilized Alabama Statewide Cancer Registry data of adults with breast, prostate, colorectal, or lung cancer. The exposure was NCI-designated 2010 census tract-level PP (tracts with ≥ 20% population below poverty line for ≥ 30 years) at diagnosis and the outcome was overall survival from date of diagnosis to death or end of follow-up. Associations were estimated via sequential Cox proportional hazards models first with PP as the only predictor then adjusting for demographics (age, race, sex [colorectal, lung]), demographics plus clinical characteristics (stage, subtype [breast], and first course treatment), and finally demographics, clinical characteristics, and social determinants (rurality, insurance status). We also performed a decomposition analysis of the association between PP and survival through race and rurality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the fully adjusted model, living in a PP-tract was associated with higher risk of death among those with breast (hazard ratio [95% CI]: 1.18 [1.09–1.27]), prostate (1.21 [1.11–1.31]), and lung cancer (1.09 [1.05–1.14]) compared to living in a non-PP-tract. Race and rurality were independently associated with higher risk of death across cancers. Individuals identifying as Black residing in a rural PP-tract had the highest magnitude of risk for all cancers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Living in a PP-tract is associated with higher risk of death among patients with breast, prostate, and lung cancer in Alabama. This association is complicated by race and rurality. Multilevel interventions tailored to local context may help overcome adverse effects of social characteristics on cancer outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the Monolayer: Leveraging 3D Culture Systems to Decode Mechanisms of Drug Resistance and Therapeutic Vulnerabilities in Colorectal Cancer","authors":"Sarah J. Harmych,&nbsp;Bhuminder Singh","doi":"10.1002/cam4.72305","DOIUrl":"10.1002/cam4.72305","url":null,"abstract":"<p>Two-dimensional (2D) monolayer cultures remain the workhorse of colorectal cancer (CRC) research and high-throughput screening (HTS), yet they poorly recapitulate tissue architecture, extracellular matrix (ECM) cues, metabolic gradients, and multicellular heterogeneity that govern drug response in vivo. Over the past decade, three-dimensional (3D) culture systems—including spheroids, patient-derived organoids (PDOs), tissue-originated spheroids (CTOS), and collagen-embedded models—have revealed striking 2D vs. 3D discordance in proliferation, signaling, epithelial-mesenchymal transition (EMT), plasticity, and sensitivity to standard chemo- and targeted therapies. This review synthesizes how 3D CRC models are used to decode mechanisms of primary and acquired resistance to anti-CRC therapies, from metabolic phenotypes and ECM remodeling to EMT, polarity loss, and rare invasive trajectories identified by imaging and quantification of morphologic features of CRC cells grown in 3D. Parallel advances in PDO-based functional precision oncology demonstrate that organoid drug screens can prospectively predict patient response in advanced CRC, while 3D combination screens uncover format-specific synergies that are invisible in 2D. Building on this foundation, we highlight recent technical innovations and discuss how integrating morphometric, metabolic, and trajectory-level readouts can move CRC drug discovery “beyond live/dead.” Rather than propose a single best model, we outline practical guidelines for matching 3D platform choice (cell lines vs. PDO/CTOS, collagen vs. Matrigel, static vs. live-imaging HTS) to mechanistic questions and therapeutic goals in CRC. We propose an integrated roadmap—matrix-embedded 3D cultures, high-content morphological endpoints, trajectory analytics, and rigorous HTS validation—to decode resistance mechanisms and prioritize clinically actionable combinations in CRC.</p>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing the ER Cutoff in HER2-Positive Breast Cancer: ER ≥ 50% Predicts Low pCR Rates and Resistance to Antibody-Drug Conjugates in the Neoadjuvant Setting","authors":"Tian Du,&nbsp;Min Lin,&nbsp;Gehao Liang,&nbsp;Yan Wang,&nbsp;Hao Wu,&nbsp;Zixuan Zhao,&nbsp;Luhao Sun,&nbsp;Jun Tang","doi":"10.1002/cam4.72331","DOIUrl":"10.1002/cam4.72331","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Estrogen receptor (ER)-positive/HER2-positive breast cancer demonstrates significantly lower rates of pathological complete response (pCR) to neoadjuvant HER2-targeted therapies compared to ER-negative/HER2-positive disease. However, the optimal ER positivity cutoff for clinically meaningful patient stratification remains undefined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed a retrospective cohort of 741 HER2-positive breast cancer patients treated with neoadjuvant chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab) at Sun Yat-sen University Cancer Center. The optimal ER cutoff for predicting pCR was determined by ROC analysis with Youden index and validated by bootstrap resampling (1000 iterations). Transcriptomic data from TCGA and SCAN-B cohorts were analyzed to characterize biological differences between ER subgroups. Drug response was predicted using the oncoPredict algorithm, and cancer dependency was assessed using DepMap CRISPR screening data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ER ≥ 50% positivity was identified as the optimal predictive cutoff (bootstrap 95% CI: 25.0%–77.5%) and was an independent predictor of significantly lower pCR rates in multivariate analysis (OR = 0.27; 95% CI: 0.19–0.40; <i>p</i> &lt; 0.001). Transcriptomic analysis revealed that ER ≥ 50% tumors are characterized by activated estrogen response signaling, downregulated cell cycle and immune pathways. Predicted resistance to trastuzumab, T-DM1, and T-DXd was consistently enriched in this subgroup, consistent with lower HER2 and CD16A expression observed in ER ≥ 50% tumors. CCND1, a canonical transcriptional target of ESR1, was significantly upregulated in ER ≥ 50% tumors across both cohorts, and ER + /HER2 + cell lines exhibited significantly higher CCND1 and CDK4 dependency scores in DepMap CRISPR screening (<i>p</i> &lt; 0.05), supporting activation of the ESR1-CCND1-CDK4/6 axis in this subgroup.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>ER ≥ 50% positivity defines a clinically and biologically distinct HER2-positive subgroup with poor response to standard neoadjuvant therapy and predicted resistance to ADCs, consistent with lower HER2 and CD16A expression in this subgroup. The convergent transcriptomic and functional evidence for ESR1-CCND1 axis activation provides mechanistic support for combining CDK4/6 inhibitors with endocrine and anti-HER2 therapies to improve outcomes in this resistant subgroup.</p>\u0000 </section>\u0000 </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"15 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}