Clinical Cancer Research最新文献

{"title":"Abstract PR013: Distinct Oral Bacterial Signatures in Rectal Cancer Tumors Associated with Age of Onset and Treatment Response","authors":"Nadim J. Ajami, Ashish V. Damania, Abderrahman Day, Matthew C. Wong, Pranoti V. Sahasrabhojane, Yasmine M. Hoballah, Vivian R. Orellana, Jillian S. Losh, Brenda D. Melendez, Mona M. Ahmed, Lon W. Fong, Bharat B. Singh, Melissa W. Taggart, Khalida Wani, Davis R. Ingram, Diana D. Shamsutdinova, Alexander Lazar, Jumanah Y. Alshenafi, Zuzana Lutter-Berka, Ryan B. Morgan, Taylor M. Neilson, Laurence Diggs, Ramy S. Behman, Paula M. Smith, George J. Chang, David Menter, Christopher D. Johnston, Susan Bullman, Yi-Qian Nancy. You, Scott Kopetz, Michael G. White, Jennifer A. Wargo","doi":"10.1158/1557-3265.earlyonsetca25-pr013","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-pr013","url":null,"abstract":"Young-onset rectal cancer (YORC, <50 years) incidence is rising, representing 20% of colorectal cancers, yet underlying mechanisms driving this epidemic remain unclear. The tumoral microbiome has emerged as a critical modulator of colorectal cancer pathogenesis, affecting tumor growth, inflammation, metastasis, and chemoresistance through complex host-microbe interactions. Emerging evidence demonstrates that specific bacterial species, including Fusobacterium nucleatum, promote tumorigenesis and therapeutic resistance in colorectal cancer models. We previously reported distinct microbial signatures between YORC and later-onset rectal cancer (LORC, ≥50 years), with tumor-associated oral bacteria correlating with treatment failure. Building on these findings, we expanded our analysis to quantify oral bacterial burden across multiple sample types and determine its clinical impact on therapeutic response. We conducted metagenomic analysis on oral (61), fecal (82), tumor (110), and 111 tumor-adjacent normal (TAN) samples from 227 treatment-naïve patients with locally advanced rectal cancer receiving standardized neoadjuvant chemoradiotherapy. Oral bacterial burden was quantified using reference bacterial taxonomies from the Human Oral Microbiome Database. Major pathological response (MPR) was defined as ≤10% residual viable tumor cells following neoadjuvant therapy. Metagenomes are being evaluated to detect and quantify known microbial genomic markers associated with colorectal cancer, including Bacteroides fragilis toxin and polyketide synthase genes found in colibactin producing E. coli. In this expanded cohort, both YORC and LORC tumors demonstrated significantly higher burden of oral bacteria compared to paired TAN tissues (p<0.001), confirming tumor-specific bacterial enrichment. Predominant oral species colonizing tumors included Parvimonas micra, Gemella morbillorum, Streptococcus sanguinis, Streptococcus salivarius, Prevotella intermedia, and multiple Fusobacterium species. Remarkably, tumoral oral bacterial burden negatively correlated with achieving MPR (p=0.014), with the strongest association observed in LORC patients. TAN tissues showed no correlation with pathological response (p>0.05), while fecal samples demonstrated significantly lower oral bacterial burden than tumors (p<0.05) with no correlation to treatment response, emphasizing the unique and clinically relevant tumoral microenvironment. Tumoral oral bacterial burden represents a potential biomarker for predicting neoadjuvant therapy response in rectal cancer patients. This discovery suggests that precision medicine approaches through targeted antimicrobial interventions to deplete tumor-associated oral bacteria may improve therapeutic outcomes. Our findings support the scientific rationale for ongoing clinical trials testing anaerobe-targeting antibiotics as adjuvant therapy (NCT06569368). Further validation in expanded cohorts and additional clinical ","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"181 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract C020: Novel insights from the investigation of experimental mutational signatures in early-onset colorectal cancer and colonic polyps","authors":"Peter Georgeson, Alysha Prisc, Jihoon Joo, Khalid Mahmood, Romy Walker, Mark Clendenning, Julia Como, Natalie Diepenhorst, Julie McDonald, Steven Gallinger, Robert Grant, Dylan E. O’Sullivan, Darren R. Brenner, Finlay Macrae, Christophe Rosty, Ingrid M. Winship, Mark A. Jenkins, Daniel D. Buchanan","doi":"10.1158/1557-3265.earlyonsetca25-c020","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-c020","url":null,"abstract":"Introduction: Profiling colorectal cancers (CRCs) for tumor mutational signatures (TMS) offers new opportunities to characterize molecular subtypes. Recently, COSMIC published a comprehensive set of experimental mutational signatures that directly link specific environmental exposures to mutational patterns observed in human cancers. Environmental exposures are recognized as major contributors to CRC development and have been hypothesized to drive the recent rise in early-onset CRC (EOCRC), but the molecular fingerprints of these exposures in EOCRCs have not been systematically characterized. Methods: We performed whole exome sequencing (WES) on tumor and matched blood-derived DNA from 324 non-hereditary, mismatch repair proficient early-onset samples (diagnosed <55 years of age) comprising 277 CRCs and 47 pre-malignant polyps. Mutational signatures were calculated using a novel approach that combined COSMIC v3.4 signatures previously observed in CRC (n=26) and a curated set of experimental mutational signatures (n=50). Environmental signatures were filtered to human iPSC-derived signatures, excluding those with a negative AMES test, those marked as controls, and signatures not seen previously in CRC. Signature definitions with >95% cosine similarity were merged. Results: On average, 24.7% ± 10.1% (mean ± s.d, range 0.1%-60.1%) of somatic mutations were assigned to environmental signatures. Across the cohort, 14% (46/324) exhibited a dominant environmental signature, with N-nitrosopyrrolidine being the most prevalent (6.2%, 20/324). Premalignant lesions showed higher rates of dominant environmental signatures (21%, 10/47) compared to invasive cancers, suggesting environmental exposures may be a key component in early carcinogenesis. Conclusions: This study provides a comprehensive view of the landscape of mutational processes in non-hereditary mismatch repair proficient EOCRC and early-onset polyps through assessment of both tumor mutational signatures and experimental mutational signatures. Environmental exposures represent a significant component of the mutational landscape in early-onset colorectal neoplasia, with enhanced prevalence in premalignant lesions. These findings support the likely role of environmental drivers in the rising incidence of EOCRC. Citation Format: Peter Georgeson, Alysha Prisc, Jihoon Joo, Khalid Mahmood, Romy Walker, Mark Clendenning, Julia Como, Natalie Diepenhorst, Julie McDonald, Steven Gallinger, Robert Grant, Dylan E. O’Sullivan, Darren R. Brenner, Finlay Macrae, Christophe Rosty, Ingrid M. Winship, Mark A. Jenkins, Daniel D. Buchanan. Novel insights from the investigation of experimental mutational signatures in early-onset colorectal cancer and colonic polyps [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A015: Retinoblastoma points to solutions for Early-Onset Cancers","authors":"Brenda Gallie, Kaitlyn Flegg, Kelvin Chau","doi":"10.1158/1557-3265.earlyonsetca25-a015","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-a015","url":null,"abstract":"Retinoblastoma exists in two starkly different worlds. In our high-income world, >95% of children survive useful vision. In the darker low- and middle-income countries (LMICs), 30% survive with often poor or no vision. Retinoblastoma is the same nasty cancer of infant retina where ever the child lives. The World Health Organization Global Initiative for Childhood Cancer prioritized retinoblastoma as a key indicator because of profound inequity in survival, depending on where the child lives. The 2017 cancer stage includes “H1” for persons with a damaged tumor suppressor RB1 gene, which carries a high risk of retinoblastoma and subsequent malignant neoplasms (SMN). Canadian familial H1 infants are delivered early term, when 30% already have retinal tumors that can be cured with simple therapy, saving vision, eyes, and life. Early identification of H1 persons with other cancer predisposition syndromes will contribute to appropriate monitoring and early low morbidity treatment, but also increase the incidence of early onset cancers. The eCancerCareRB database (only inside SickKids) includes a timeline displaying all treatment events, a key tool in patient care. A potentially “game-changing” clinical trial of Chemoplaque (sustained release 6 weeks of topotecan to the eye only) used our novel SwimmerMatch analysis tool to compare Chemoplaque participants to propensity-matched eCancerCareRB patients, showing improved recurrence-free eye survival (p-value 0.0002, log rank test). Since eCancerCareRB is ONLY inside SickKids, we built cloud-based DEPICT HEALTH (DEPICT) to connect global retinoblastoma care centers worldwide. Families view their DEPICT data. Real-time DEPICT access to clinical data and treatments empowers active family participation in care, a full view for life. Regions/countries will have point-of-care DEPICT data in support of transformative National Guidelines relevant to their financial and technical realities, for them to be ready for the demonstrated increase in incidence of early onset cancers. The World Health Organization's prioritization of retinoblastoma as a key indicator is achieving global cooperation that will be assisted by DEPICT HEALTH. Just as rare retinoblastoma first pointed out that cancer is a genomic disease, these novel clinical trial global data of DEPICT and its analysis tools can be a prototype for any cancer worldwide. Citation Format: Brenda Gallie, Kaitlyn Flegg, Kelvin Chau. Retinoblastoma points to solutions for Early-Onset Cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl): nr A015.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA001: Integrative cancer population sciences to decipher the etiology of early-onset colorectal cancer","authors":"Tomotaka Ugai","doi":"10.1158/1557-3265.earlyonsetca25-ia001","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-ia001","url":null,"abstract":"The rise in early-onset cancer has been a growing global concern. Our recent global analysis using the Cancer Incidence in Five Continents and World Health Organization (WHO) mortality databases showed that steeper increases in early-onset cancers compared with later-onset cancers were observed in colorectal cancer, cervical cancer, pancreatic cancer, and multiple myeloma among females and in prostate cancer, colorectal cancer, and kidney cancer among males after 2000 in more than 5 countries. Our analysis also showed significant increases in both the incidence and mortality of uterine cancer (5 countries) and colorectal cancer (3 countries in females and 5 countries in males). We also observed strong positive correlations between the increasing obesity prevalence among young populations (aged 20-49 years) and the rising incidence of early-onset obesity-related cancers in many countries; however, even after adjusting for obesity prevalence, we still observed increasing trends of early-onset cancers. Such data might indicate that the increase in early-onset cancers is (at least partly) driven by shifts in risk factor exposure among younger generations. Tumor tissue analyses can provide valuable insights into the pathogenesis of early-onset cancer. We have shown that, compared to later-onset colorectal cancer (CRC), early-onset CRC tends to exhibit CIMP-negative/low phenotype, BRAF-wildtype, tumoral LINE-1 hypomethylation (an indicator of genomic DNA hypomethylation), immunosuppressed microenvironmental features, and pks + Escherichia coli enrichment / colibactin-induced mutational signatures. We further integrated these tumor profiles into large-scale prospective cohort studies. Our integrative research demonstrated that dietary scores related to insulin resistance were strongly associated with increased incidence of pks + E. coli-high colorectal cancer (CRC) but not with that of pks + E. coli-low or pks + E. coli-negative CRC in prospective cohort studies (P for heterogeneity <0.001). Similarly, our study showed that long-term excessive alcohol intake was associated with increased incidence of CRC with tumor LINE-1 hypomethylation (but not cancer with LINE-1 high-level methylation) (P for heterogeneity <0.001). Combined findings on exposures and early-onset CRC-associated tumor profiles suggest that these exposures may promote the development of early-onset CRC through related molecular changes. Therefore, the integrative approach that can link long-term exposures with early-onset tumor characteristics improves our understanding of the etiology of early-onset CRC. In conclusion, our integrative descriptive and molecular epidemiologic studies demonstrated significant heterogeneity in early-onset cancers by cancer types, countries, and molecular subtypes, highlighting a need for further studies to investigate potential biological, environmental, and lifestyle factors contributing to the rising burden of specific early-onset cancer typ","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract C026: Disparate response to chemoradiation in early onset vs late onset rectal cancer","authors":"Joshua E. Meyer, Jordan Fredette, Christopher G. Cann","doi":"10.1158/1557-3265.earlyonsetca25-c026","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-c026","url":null,"abstract":"Purpose: The study aimed to evaluate the response to neoadjuvant chemoradiation (CRT) in early onset (EO) rectal cancer (RC) patients in a large national dataset. Methods: The National Cancer Database (NCDB) is a large hospital-based oncology registry that captures case-level data on approximately 70% of newly diagnosed cancers in the United States. A cohort of locally advanced RC patients, stage II-III, who were treated with CRT prior to surgical resection was identified using the 2022 participant user file, covering 2004-2022. The cohort was divided into EO (<40 years of age) RC and later onset (LO) RC. Downstaging was defined as decreased stage from initial clinical to final pathologic staging. Continuous variables were compared using Wilcoxon rank sum tests and categorical variables were compared using Chi-square and Fisher’s Exact Tests. Logistic regression models were used to assess the associations of pathologic complete response (pCR) and downstaging with reference to age as a 6-level categorical variable (18-39, 40-49, 50-59, 60-69, 70-79, 80+) while adjusting for possible confounders including stage, Charlson-Deyo Comorbidity Classification (CDCC), sex, race, ethnicity, year of diagnosis, insurance status and income. All analysis was conducted in SAS 9.4 and R 4.4.2. Results: 37,508 patients were identified, including 1,722 EORC patients. EO patients were more commonly female, Black, Asian or Hispanic (p<0.001). EO patients also had lower CDCC scores (e.g. 93% vs 77% CDCC 0; p<0.001) and higher-grade tumors (e.g. 12% vs 9.2% poorly differentiated; p<0.001). Examining clinical staging, EO patients exhibited slightly increased frequency of T2 staging [6.6% vs 4.9%] and decreased T3 staging [81.5% vs 83.7%] (p=0.007) with more advanced lymph node (LN) staging [N1:49.4% vs 44.4%; N2:23.3% vs 13.2%] (p<0.001). On univariate analysis, EO patients had higher numbers of examined LNs (median 17 vs 14; p<0.001) and positive LNs (mean 1.60 vs 0.93, p<0.001). While the rate of pathologic complete response did not differ by age, EO patients had less downstaging of the primary tumor (47.6% vs 50.9%, p=0.007). EO also had more N downstaging and N upstaging (Downstaging: 46.3% vs 39.8%; Upstaging: 15.4% vs 12.6%, p<0.001). On adjusted analysis, probability of pCR was greatest at age 70-79 (OR 1.24, p=0.03). All age groups 50 and above were associated with increased LN downstaging (ORs 1.20-1.42; p values <0.01). Also, higher T stage correlated with greater odds of LN downstaging (e.g. cT4 OR 2.24, p<0.001). Odds of primary T downstaging increased for ages 60-69 (OR 1.13, p=0.014) and 70-79 (OR 1.20, p=0.001). Also, these odds decreased with greater N stage (N1: OR 0.73, p<0.001; N2: OR 0.68, p<0.001). Conclusions: EORC patients presented with higher grade tumors and more aggressive LN staging than LORC. Generally, pathological response after CRT was stronger with increa","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A026: Use of recommended diagnostic breast imaging among women under 40 in a community-based registry","authors":"Sarah J. Nyante, Thad Benefield, Anisha P. Ganguly, Caroline A. Thompson, Sasha Anderson, Erin J. Aiello Bowles, Genevieve A. Woodard","doi":"10.1158/1557-3265.earlyonsetca25-a026","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-a026","url":null,"abstract":"Diagnostic imaging is a critical step in obtaining a timely breast cancer diagnosis. The American College of Radiology (ACR) recommends initial diagnostic evaluation with breast ultrasound for women 18-29 with focal breast symptoms and initial diagnostic evaluation with mammography and/or ultrasound for women 30-39 with symptoms. These guidelines are evidence-based and deviation from them has the potential to lead to performance of unnecessary exams and/or delayed diagnosis. We evaluated the prevalence of appropriate diagnostic imaging among breast cancer patients <40 years. Data were from the Carolina Mammography Registry (CMR), a community-based registry of breast imaging in North Carolina that links to cancer diagnoses from the North Carolina Central Cancer Registry. The analysis included CMR women aged 18-39 years who were diagnosed with breast cancer between 2005-2021 and had at least one breast imaging exam (any type or indication) in the year before diagnosis (n=311). Women with a self-reported first-degree family history of breast cancer or imaging facility-reported increased risk were excluded due to differing guidelines for high-risk women. Presence of self-reported symptoms (lump, nipple discharge, pain or other) were obtained from pre-diagnosis exams. Use of appropriate imaging was based on the ACR Appropriateness Criteria for women with symptoms (described above). Between-group differences were assessed using the Fisher exact text. The majority of patients were 35-39 years old (63%), with fewer in 30-34 year (27%) and 18-29 year (10%) age groups. Symptom data was available for 98% of women, with symptoms present for 59% (18-29: 60%; 30-34: 70%; 35-39: 54%). The most common diagnostic approach in the year prior to diagnosis was ultrasound alone (50%) followed by mammography alone (28%). Use of multiple diagnostic modalities was uncommon (ultrasound plus mammogram: 10%; ultrasound plus MRI: 1%). 97% of patients with diagnostic imaging received an exam consistent with ACR guidelines, though appropriate imaging was lower among women 18-29 (76%) compared with women 30-34 (100%) or 35-39 (99%) (P<0.0001). This pattern was consistent for women with symptoms (18-29: 65%; 30-34: 100%; 35-39: 100%; P<0.0001), but there was no difference by age among women without symptoms (18-29: 100%; 30-34: 100%; 35-39: 97%; P>0.99). Limitations of our analysis include that some women may have obtained exams at facilities outside the CMR, which may lead to under-ascertainment of appropriate imaging or of symptoms if ongoing symptoms were not documented on subsequent exams. In sum, 35% of women 18-29 with self-reported symptoms received diagnostic imaging that was not consistent with ACR recommendations. Departures from ACR guidelines may be due to unique clinical situations, non-receipt of a recommended exam, or other factors. Future research will investigate provider, patient, and health system factors that influence breast imagi","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B003: Risk Factors, Clinical and Molecular Characteristics of de novo Metastatic Early Onset Colorectal Cancer","authors":"Emma Schatoff, Ramzi Homsi, Joanne F. Chou, Marinela Capanu, Henry Walch, Lerie Palmaira, Jill Weiss, Jordana Kaller, Callahan Wilde, Walid Chatila, Robin Mendelsohn, Andrea Cercek","doi":"10.1158/1557-3265.earlyonsetca25-b003","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-b003","url":null,"abstract":"Background: Early onset colorectal cancer (EO CRC) is rising worldwide. Epidemiologic studies have shown diets high in sugar are associated with EO CRC when compared to healthy controls. Preclinical work reported that high fructose diets increase colorectal tumor size; however, an association with clinical outcomes has not yet been established. Investigating risk factors, clinical and molecular characteristics of de novo metastatic EO CRC is an unmet need. Methods: All eligible EO CRC patients were enrolled in MSK’s Center for Young Onset Colorectal and Gastrointestinal Cancer and completed a risk factor questionnaire (MSK-approved IRB #20-315). We analyzed questionnaire responses and compared risk factors between patients with de novo metastatic disease vs localized disease using Wilcoxon rank sum test or Fisher’s exact test. Overall survival was estimated using Kaplan-Meier methods. Tumors (n=206) were sequenced using MSK-IMPACT (MSK-approved IRB #12-245) and underwent genomic analyses. A subset of samples (n=37) were recaptured using Whole Exome Sequencing (WES) and processed using the Tempo pipeline at MSKCC. Somatic mutations from WES samples were fitted to 11 predefined CRC-relevant COSMIC SBS mutational signatures using tempoSig. Stool samples (n=87) were also collected for 16S sequencing and aggregated to genus level for analysis. Alpha diversity (Shannon index) was compared using Wilcoxon rank-sum test. Beta diversity was assessed using Aitchison distance and tested using PERMANOVA. Results: 303 patients completed the questionnaire (median age at diagnosis 42; 51% Female; 88% left-sided tumors). 112 had de novo stage IV disease and 191 had stage I-III disease. Patients with de novo metastatic disease were younger, 40.9 [95%CI: 36.8 - 44.8] vs. 43.0 [95%CI: 38.4 - 46.4] (P-value0.037). High sugar diets were significantly associated with de novo metastatic disease, with 30 (45%) vs. 37 (29%) (P-value, 0.004) patients reporting daily consumption of high sugar foods. 3-year OS in the metastatic population was 72% [95%CI: 62% - 84%] vs. 99% [95%CI: 98% - 100%]. Within the metastatic group, no association was observed between daily high sugar consumption and non-daily consumption in terms of PFS or OS. 3-year OS in the daily high sugar group was 79 % [95%CI: 62%-100%] vs 74% [95%CI: 57%-95%]. Genomic analyses revealed no significant differences in tumor mutational burden, fraction genome altered, frequency of oncogenic or signaling pathway alterations in de novo metastatic vs. non-metastatic patients. Similarly, in metastatic patients who reported daily consumption of high sugar foods, there was no distinct genomic profiles. Microbiome analyses also showed no differences in alpha or beta diversity. Conclusions: In a single center study, in EO CRC patients, high sugar diets may be associated with de novo metastatic disease. There were no significant differences at the genome or microbiome level. Future studies are warranted to interrogate the c","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B012: Sociodemographic and clinical determinants associated with early-onset breast cancer","authors":"Tara M. Friebel-Klingner, Tlotlo Ralefala, Lebogang Laletsang-Mokokwe, Babe Gaoleabale, Nkhabe Chinyepi, Peter Vuylsteke, Dipho I. Setlhako, Scott Dryden-Peterson, Mosepele Mosepele, Robert Gross, Yehoda M. Martei","doi":"10.1158/1557-3265.earlyonsetca25-b012","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-b012","url":null,"abstract":"Purpose Early-onset breast cancer (EOBC) diagnosed before age 50 is increasing globally and comprises approximately 15% of all breast cancer (BC) cases in the United States. In Botswana, almost 50% of patients present with EOBC, but risk factors are poorly understood. We aimed to identify sociodemographic and clinical factors associated with EOBC in Botswana. Methods We analyzed a prospective cohort of newly diagnosed BC patients at Princess Marina Hospital between 2015 and 2023. Logistic regression examined the association of sociodemographic and clinical factors, including BC molecular subtypes (i.e, ER+/Her2-, ER+/Her2+, ER-/Her2+, triple negative BC), with EOBC. Factors that had a crude association of p<0.20 were retained in the multivariable model. EOBC was compared to BC patients diagnosed at ≥50 years. A secondary exploratory analysis of BC diagnosed before age 40 was also conducted. Analysis done using STATA 19.5. Results There were 641 BC patients included in the analyses (median age 51.0 (IQR 42.0, 62.9)) with 299 ( 46.7%) EOBC, and 117 (18.3%) diagnosed before 40 years. Of the whole cohort, 31.8% had HIV, 55.9% were from socioeconomically disadvantaged districts (SDD), 44.5% were ever married, 72.9% diagnosed at stage III-IV, and 22.8% were triple negative BC. In the univariate analysis, people with HIV had higher odds of EOBC (OR: 2.32; 95% CI: 1.65-3.26), while living in a SDD (OR: 0.59; 95% CI: 0.43-0.80) and ever being married (OR: 0.33; 95% CI: 0.23-0.46) were associated with lower odds of EOBC. There were no significant associations between EOBC and smoking history, alcohol use, family history of breast cancer, stage at diagnosis, or BC subtypes. In the multivariable model, adjusting for HIV, SDD, marital status, and alcohol, HIV remained significantly associated with higher odds of EOBC (aOR:1.86; 95% CI:1.30-2.66), while living in an SDD (aOR: 0.64; 95% CI: 0.46-0.89) and ever being married (aOR: 0.38; 95% CI: 0.27-0.54) showed reduced odds of EOBC. In the exploratory analysis of BC diagnosed before 40, alcohol use was associated with a greater odds of EOBC (aOR: 2.52, 95%CI: 1.26-5.05), and ever being married was associated with lower odds (aOR: 0.16; 95% CI: 0.09-0.28). HIV status was not associated with diagnosis before age 40 (aOR: 0.78; 95%CI: 0.48-1.26). Conclusion Our analysis found that women with HIV had a higher odds of EOBC, aligning with reports of younger age at diagnosis in this group. Lower odds were observed among married patients, possibly reflecting social support, and among those in SDDs, which may relate to lifestyle or environmental exposures. Alcohol use showed increased odds with a diagnosis before age 40, but not before age 50. This finding should be explored further. Future studies incorporating detailed behavioral, lifestyle, environmental, and clinical data in high-burden populations may identify targetable risk factors and guide precision BC control strategies relevant to efforts to reduce ear","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA002: Early-Onset Colorectal Cancer as a Model for Precision Cancer Prevention","authors":"Andrew T. Chan","doi":"10.1158/1557-3265.earlyonsetca25-ia002","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-ia002","url":null,"abstract":"The rising incidence of early-onset colorectal cancer (EOCRC)—diagnosed before age 50—represents a sentinel trend for other early-onset cancers. While EOCRC is the most well-characterized early-onset malignancy, it also serves as a model for understanding shared mechanisms and prevention strategies across tumor types. Current prevention efforts emphasize earlier screening, yet early detection and interception alone cannot address the growing burden of early-onset cancers, particularly as carcinogenic processes may begin decades before diagnosis. Because early-onset cancers remain relatively rare, advancing risk stratification is critical to identify individuals most likely to benefit from early intervention. Accumulating evidence implicates early-life and mid-life exposures—including diet, obesity, sedentary behavior, and gut microbial dysbiosis—in shaping cancer susceptibility. These insights call for a life course prevention framework that integrates molecular and microbial biomarkers into precision risk models. Promising strategies include aspirin to block inflammation, GLP-1 receptor agonists to reverse obesity-related metabolic dysfunction, and dietary interventions—such as high-fiber and plant-forward diets—to favorably modulate the microbiome and reduce systemic inflammation. By viewing EOCRC as both a sentinel and prototype, we can move beyond early detection toward proactive, risk-targeted prevention—disrupting carcinogenic pathways before disease emerges and reimagining cancer control across the lifespan. Citation Format: Andrew T. Chan. Early-Onset Colorectal Cancer as a Model for Precision Cancer Prevention [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl): nr IA002.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract C013: Spatial immune profiling of early- and late-onset colorectal cancer","authors":"Baohua Sun, Saxon Rodriguez, Shanyu Zhang, Zuzana Lutter-Berka, Yi-Qian Nancy You, Scott Kopetz, Cara Haymaker, Luisa Maren Solis Soto","doi":"10.1158/1557-3265.earlyonsetca25-c013","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-c013","url":null,"abstract":"Introduction Early-onset colorectal cancer (EOCRC) frequency has increased in the last years; elucidating the immune landscape in tumor and normal appearing colon mucosa of these patients can aid to better understand the tumor immune response and develop strategies for therapy. The purpose of this study is to evaluate if EOCRC has a distinct immune landscape compared to middle-, and late-onset CRC (MOCRC and LOCRC) and normal colonic tissues. Methods We retrospectively collected FFPE biopsies tissues from patients with CRC. Fourteen TMAs were constructed with 35 normal-appearing colon mucosa (N), 66 adenocarcinomas (AC), and 45 paired N and AC. The samples were stained with PhenoCycler Fusion (PCF) panel which contains 24 biomarkers to identify T cells (CD3, CD4, CD8, FOXP3); B cells (CD20, CD21); macrophages (CD68, CD206); NK cells (CD56); epithelial cells (CK); vascular endothelial cells (CD31); and leukocytes (CD45). The panel also contains markers for checkpoint inhibitors (PD1, PDL1, CTLA4); arginase signaling (Arg-1); adenosine pathway (CD73); activation (OX40, HLA-DR); memory (CD45RO); and cytotoxicity and proliferation (GrB, Ki67). The qptiff images from PCF platform were visualized with QuPath software. Cell segmentation was performed with the StarDist deep learning algorithm. Biomarker colocalization, cell classification and density calculation were achieved with R package Phenoptr. We defined 9 major cell lineage phenotypes: epithelial cells (CK+); Treg cells(CD45+CD3+CD4+CD8-FOXP3+); T helper cells(CD45+CD3+CD4+CD8-FOXP3-); cytotoxic T cells(CD45+CD3+CD4-CD8+); NK cells(CD45+CD3-CD56+); M2 macrophages (CD45+CD68+CD206+); other macrophages/dendritic cells (CD45+CD68+CD206-); B cells(CD45+CD20+); and endothelial cells(CD45-CD31+). The T-test was used to compare differences between AC and N samples. The two-way ANOVA was applied for multiple group comparisons, and Spearman’s rank correlation test was used for correlation analysis. Results Within paired samples, cell densities of GrB expressing cytotoxic T cells (CD45+CD3+CD8+GrB+) and memory helper T cells (CD45+CD3+CD4+CD45RO+) showed positive correlation with age increase in N. Immunosuppressive and proliferating macrophages (CD68+CD73+ and CD68+Ki67+), also had an age-related increase in AC tissue. AC tissues contained significantly higher Tregs and lower NK cells (p<0.001) than their N tissue counterparts. For un-paired samples, AC tissues contained significantly higher Tregs, T helper, cytotoxic T cells (p<0.001) and marginally lower NK cells (p=0.058) than that in N tissues. Overall, AC tissues contained significantly higher PD1+ cytotoxic and helper T cells (p<0.05) than that in N tissues. In all AC tissues, LOCRC samples contained significantly higher PDL1+ helper T cells (p=0.013) and M2 macrophages (p=0.045) than that in EOCRC or MOCRC samples. Conclusion CRC tumors display age- and onset-dependent distinct immune profile in tumor and normal colon mucosa, w","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}