PURPOSE Circulating tumor DNA (ctDNA) may serve as a biomarker to facilitate early identification of asymptomatic distant tumor spread in patients with breast cancer. The primary objective of this study was to assess clinical validity and prognostic value of post-treatment tissue-free ctDNA detection by evaluating its sensitivity for distant metastatic recurrence and its association with long-term outcomes. PATIENTS AND METHODS Plasma samples were prospectively collected from patients with stage I-III early breast cancer who participated in the adjuvant SUCCESS-A phase III clinical trial (ClinicalTrials.gov identifier: NCT02181101 ). In this study, plasma samples collected approximately 2 years after completion of adjuvant chemotherapy from 313 SUCCESS A patients without evidence of prior disease recurrence were retrospectively analyzed using a tissue-free epigenomic ctDNA assay (Guardant Reveal). Survival analyses were performed using a landmark approach based on the time of sample collection. RESULTS Overall, ctDNA was detected in 18 of 313 samples (5.8%). Of all ctDNA detected samples, 94% (17/18) were from patients who subsequently developed a distant recurrence, with ctDNA detected at a median interval of 7.9 months before recurrence. ctDNA positivity was strongly associated with a significantly shorter distant recurrence-free interval (hazard ratio [HR], 33.3 [95% CI, 4.12 to 268]; P < .0001) and poorer overall survival (HR, 27.3 [95% CI, 1.15 to 647]; P < .0001). The sensitivity for distant recurrence in patients who had a sample collected within 1 year before recurrence was 73% (11/15). The specificity in nonrecurred patients was 99.6% (267/268). CONCLUSION Tissue-free detection of ctDNA 2 years after adjuvant chemotherapy was highly prognostic in an early-stage breast cancer cohort, and can be used to stratify patients with early-stage breast cancer at high risk for recurrence during follow-up who may benefit from early interventions.
PURPOSE Oral potentially malignant disorders (OPMDs) pose a significant clinical challenge due to their potential to develop into oral squamous cell carcinoma, a prevalence of 4%-5% of the US population, and malignant transformation rates that approach 10%. Current methods to assess risk of OPMD progression to oral cancer are fraught with limitations and incompletely predict risk. METHODS We review existing diagnostic and prognostic tools for OPMDs, examining their validation evidence, performance characteristics, and clinical utility. RESULTS Although some tools provide rule-in or rule-out capabilities, each tool interrogates a single biological layer, and none provides comparable positive predictive value and negative predictive value in a single tool. CONCLUSION A framework integrating multiomic data across multiple different biologic processes and time points inclusive of benign mimics is needed to better identify which lesions are true OPMDs, and which warrant escalation and intervention versus surveillance or de-escalation.
Cholangiocarcinomas (CCAs) are aggressive biliary tumors that can develop within the intrahepatic (iCCA) or perihilar and distal bile ducts. The prognosis of patients with iCCA is poor due to its relative resistance to chemotherapy. Comprehensive genomic profiling of CCA biopsies by next-generation sequencing has revealed a rich landscape of genomic alterations, including fibroblast growth factor receptor (FGFR) gene fusions and rearrangements that are constitutively active and oncogenic. Several FGFR inhibitors (FGFRis) targeting these FGFR genomic alterations have been developed as potential treatments for iCCA, each of which are highly potent but differ in structure, mechanism of inhibition (ie, adenosine triphosphate-competitive reversible v covalent/irreversible v allosteric), pharmacologic/pharmacodynamic profiles, and selectivity for the four FGFR isoforms. Because of these differences, and due to resistance mutations acquired during FGFRi treatment, determining the optimal sequencing of FGFRis for the treatment of CCA remains contentious and is the subject of ongoing debate. To address this question, this review conducted an analysis of the literature on the FGFRi currently approved or in development, focusing on their distinct mechanisms of action and FGFR selectivity. Publicly available data from case reports on FGFRi sequencing in second and later lines of treatment were compiled from a PubMed search of published congress abstracts and articles. The results support a hypothesis that strategic sequencing of reversible followed by irreversible FGFRi may potentially prolong the duration of treatment benefit from FGFR inhibition compared with nonsequenced treatments. A hypothetical treatment-sequencing algorithm for reversible and irreversible FGFRi is discussed.
Pediatric cancer care in Spain lacked a national personalized medicine program. The SEHOP-PENCIL initiative, established by the SEHOP, was designed to address this gap. A national survey identified the genomic sequencing needs of hospitals treating pediatric patients with cancer. Results showed improved access to targeted next-generation sequencing panels but revealed persistent variability in implementation, limited availability of advanced sequencing (whole-exome sequencing, whole-genome sequencing, RNA sequencing, and DNA methylation profiling), and gaps in cancer predisposition clinics and molecular tumor boards (MTBs). SEHOP-PENCIL is organized as a network of 10 specialized genomic centers serving 45 hospitals through a centralized inclusion system. The program standardizes patient eligibility, genomic workflows, and result interpretation, supported by a national MTB. This framework enables informed clinical decision making, ensures access to molecular diagnosis and innovative therapies, and supports systematic data collection to advance pediatric cancer research and personalized care. SEHOP-PENCIL represents a pioneering national model for integrating precision oncology into pediatric cancer care in Spain. By fostering collaboration, standardizing genomic practices, and promoting equitable access, it aims to reduce disparities and improve outcomes, offering a scalable example for other decentralized health care systems.
PURPOSE:As biomarker-directed therapy increasingly shapes GI oncology, it remains unclear whether early-onset (EO) and later-onset (LO) GI cancers harbor comparable opportunities for clinically actionable targeting. We compared the landscape of potentially actionable genomic alterations in EO versus LO GI cancers using American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange v19.0. METHODS:GI tumor samples were assigned to 10 prespecified tumor groups using OncoTree codes. Samples were annotated with OncoKB therapeutic levels and classified as potentially actionable if they harbored at least one level 1-3B alteration. EO and LO disease were defined as age at sequencing <50 years and ≥50 years, respectively. Group-wise comparisons used Wilcoxon rank-sum, chi-square, or Fisher exact testing as appropriate and with false discovery rate correction. Multivariable logistic regression evaluated age group associations overall and within tumor groups. RESULTS:Among 53,945 GI tumor samples, 10,573 (19.6%) were EO and 43,372 (80.4%) were LO. EO tumors had lower prevalence of potentially actionable alterations in colorectal (71% v 78.1%, q < 0.001), esophagogastric (53.3% v 57.9%, q = 0.0097), GI stromal tumor (GIST) (75.1% v 90.9%, q < 0.001), liver (25.4% v 35.4%, q = 0.0021), and pancreatic tumors (82.9% v 90.7%, q < 0.001). In the overall model, LO status was associated with higher odds of potential actionability (odds ratio, 1.39 [95% CI, 1.33 to 1.47]; P < .001). Tumor group-specific associations persisted in colorectal, GIST, liver, and pancreatic tumors after multivariable adjustment. CONCLUSION:Potential clinical actionability differs between EO and LO GI cancers in a tumor lineage-specific manner. Several major EO GI tumor groups appear relatively depleted of potentially actionable alterations, suggesting that the expanding therapeutic reach of precision oncology may not be distributed evenly across age-defined GI cancer populations and underscoring the need for EO-focused biomarker discovery and therapeutic development.
In oncology, interpreting clinical trials solely through statistical significance (P < .05) often conflates true biological futility with methodological false negatives. This binary oversimplification risks prematurely abandoning active therapies while wasting resources on futile programs. We aimed to develop a structured framework to evaluate late-phase trials beyond simple P value assessments. Through a critical review of literature and landmark late-phase oncology trials, we analyzed common failure mechanisms and methodological pitfalls to construct a comprehensive, three-step methodology for the post hoc evaluation of negative studies. The review yielded a synthesized framework that approaches trial interpretation through three sequential steps. First, classification stratifies trials into five distinct categories: true negatives, false negatives, inconclusive trials, positive but irrelevant results, and nonsuperior but clinically valuable. Second, diagnosis uses root-cause analysis to identify underlying trial design flaws, execution biases, or statistical pitfalls. Third, recommendations outline targeted actionable strategies, including trial redesign, supplementary biomarker validation, precision medicine approaches, or scientific confirmation of therapeutic futility. This framework shifts trial interpretation from a simple win/loss assessment to a nuanced, value-based strategy. By systematically dissecting the root causes of trial failures, it empowers researchers to rescue therapies with latent clinical benefit or confidently confirm futility, thereby optimizing the evidence landscape for precision oncology.
PURPOSE:Comprehensive genomic profiling (CGP) is increasingly adopted in the management of patients affected by GI cancers. However, the applicability, performance, and clinical utility of CGP in the real-world setting are still undefined. METHODS:We retrospectively evaluated CGP performance and clinical benefit in consecutive patients with GI tumor at the Veneto Institute of Oncology-IRCCS, Padua. We assessed CGP success and its advantage over routine diagnostics in detecting actionable molecular targets. A custom list of gain alterations was defined, including targets not classified as ESMO Scale for Clinical Actionability of molecular Targets tier IA at the time of analysis. RESULTS:Of the 1,450 samples, 140 (9.7%) were inadequate for CGP. Failure was mainly due to low quantity of extracted tumor DNA (P = .002). Of the 1,265 metastatic patients, GAs were detected in 355 (28.1%) cases, of whom 55 (15.5%) were treated with targeted therapy. Survival did not differ between patients with no GAs and those with GAs who were not treated accordingly (median overall survival 12.0 v 10.9 months), whereas it was significantly longer for those receiving treatment for actionable GAs (26.4 months). This advantage was confirmed in an exploratory, inverse probability of treatment-weighted analysis (adjusted hazard ratio, 0.72 [95% CI, 0.58 to 0.89]; P = .002). Among 283 (83.7%) untreated patients with complete follow-up, 41.6% did not receive targeted therapy due to lack of clinical trial or failure to meet inclusion criteria. CONCLUSION:Appropriate specimen selection and early molecular assessment at the time of advanced disease diagnosis are essential to detect clinically actionable molecular alterations and therapeutic opportunities in patients with GI cancers. Our results support CGP in comprehensive cancer centers.
PURPOSE:The molecular analysis of urine cell-free DNA offers a noninvasive tool to advanced bladder cancer (BC) management. Assessment of somatic copy number aberration (SCNA) and DNA methylation analysis have emerged as promising approaches for BC detection. Here, we developed an integrated analysis to assess both SCNA and targeted methylation changes from the same template molecules, which we named the integrated sequencing-based copy number and methylation analysis in urine (iSECURE) method. MATERIALS AND METHODS:Urine samples of 30 patients with primary BC, 28 patients with recurrent BC, and 31 hematuria controls were collected at home. Copy number profiling and tumor fraction (TF) estimation were performed by shallow whole-genome enzymatic methyl sequencing. Methylation sequencing libraries were also used for the measurement of a previously validated three-gene methylation marker panel (GALR1/HAND2/NRN1) by the quantitative methylation-specific polymerase chain reaction. Diagnostic accuracy was evaluated by logistic regression analysis using Youden's index for sensitivity and specificity and validated using leave-one-out cross-validation (LOOCV). RESULTS:TF and methylation levels were significantly higher in patients with BC compared with controls (P < .0001). The individual assays yielded an AUC of 0.91 at 79% sensitivity and 97% specificity for the methylation marker panel and 0.81 at 74% sensitivity and 87% specificity for copy number profiling. The iSECURE workflow yielded a higher diagnostic accuracy with an AUC of 0.94 at 88% sensitivity (90% for primary tumors and 86% for recurrent tumors) and 94% specificity. LOOCV demonstrated an AUC of 0.91 at 84% sensitivity and 90% specificity. CONCLUSION:We developed a single workflow for copy number profiling and targeted methylation analysis, requiring less input DNA and hands-on time. The high accuracy of iSECURE in home-collected urine samples for detecting both primary and recurrent BC underscores its clinical potential.
PURPOSE:Despite increasing evidence supporting the validity and utility of pharmacogenomic (PGx)-guided prescribing, clinical PGx testing in oncology remains limited. However, expanding professional guidelines and recommendations have accelerated PGx implementation efforts in the United States. Given the availability of actionable PGx guidelines for several medications commonly prescribed to patients with cancer, this study evaluated US oncologists' knowledge, attitudes, and perceived barriers regarding PGx-guided medication management. METHODS:A survey focused on oncology-relevant medications with actionable PGx guidelines, including fluoropyrimidines, thiopurines, irinotecan, and opiates/antidepressants, was distributed to clinical oncologists in the United States from December 2023 to August 2024 through ASCO Research Survey Pool, the Association of Northern California Oncologists, and regional ASCO-affiliated groups. RESULTS:A total of 146 providers completed the survey, most through ASCO (n = 125). Opiates and antidepressants were the most frequently prescribed medications in the previous 6 months (92%), followed by fluoropyrimidines (75%). Nearly all respondents (93%) had heard of PGx, although most were only moderately familiar (57%), and PGx awareness for chemotherapies (92%) was much greater than opiates/antidepressants (47%). Reported barriers to PGx testing for chemotherapy management included uncertain utility, concerns for treatment delay, and unclear National Comprehensive Cancer Network recommendations, and barriers for opiate/antidepressant management included uncertain utility, lack of awareness, and uncertainty regarding test ordering and result interpretation. CONCLUSION:These findings provide valuable insights into the perspectives of oncologists on implementing PGx testing; however, awareness and utilization were higher than previously reported. Importantly, the identified implementation barriers for oncology are both actionable and timely, particularly given the evolving updates to drug labels and professional guidelines supporting PGx testing for medications relevant to patients with cancer.
PURPOSE:Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations are common in intrahepatic cholangiocarcinoma (ICC), but their prognostic value is unclear. Using a large data set, we assessed their impact in resected and nonresected ICC. METHODS:Adults from two medical centers (MSKCC and Erasmus) with ICC treated with curative-intent resection (resected) or managed nonoperatively (unresectable) who underwent next-generation sequencing were analyzed retrospectively. Kaplan-Meier and Cox regressions assessed the impact of IDH status on outcomes. RESULTS:Of the 795 patients analyzed, 25% had IDH1/2 mutations (IDHmut) and 43% underwent resection. Median overall survival (OS) of the cohort was 32 months in IDHmut and 28 months for IDHwt (P = .2). High-risk genetic alterations (TP53mut, KRASmut, and CDKN2Adel) were more frequent in IDH wild-type (IDHwt; odds ratio, 2.26; q < 0.001). OS was 19 months in patients with high-risk alterations versus 40 months in patients without (P < .001). In resected patients, recurrence-free survival (RFS) in IDHmut was 20 months versus 14 months for IDHwt (P = .018), and OS was 69 months versus 50 months, respectively (P = .2). However, after controlling for high-risk alterations, the potential benefit of IDHmut was no longer apparent (RFS: hazard ratio [HR], 0.78; P = .095; OS: HR, 0.88; P = .4). In unresectable IDHmut patients, progression-free survival was 9.4 months versus 9.1 months for IDHwt (P = .7), and OS was 22 months versus 18 months, respectively (P = .13). There remained no differences after controlling for high-risk alterations. IDH status was not a significant survival predictor in multivariable models. CONCLUSION:In this cohort of patients with ICC, IDHmut was not an independent predictor of survival, after controlling for high-risk alterations and clinical variables. IDH mutational status alone should, therefore, not be used to guide prognosis.
PURPOSE:TRK inhibitors (TRKis) have transformed the therapeutic landscape for patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors. However, approval of TRKis is based on evidence derived mainly from small, pooled, single-arm clinical trial cohorts. The REALTRK registry aims to describe real-world molecular diagnostic practices, treatment patterns, and clinical outcomes for adult patients with NTRK fusion-positive cancers. PATIENTS AND METHODS:The REALTRK registry was a multicenter cohort study that included adults with advanced solid tumors harboring NTRK1/2/3 fusions, from Germany and Switzerland. Both retrospective and prospective data were collected from diverse clinical settings. NTRK fusions had to be diagnosed via validated assays. RESULTS:Of 88 patients screened, 47 adults with advanced NTRK fusion-positive solid tumors were included in the full analysis set. Across all treatment lines after NTRK fusion diagnosis, 29 patients received TRKi therapy, eight received non-TRKi therapy, and 10 received no therapy. Lung cancer, colorectal cancer, and soft tissue sarcoma were the most common tumor types. Next-generation sequencing was the primary diagnostic method, with a median turnaround time of 2 weeks. After NTRK fusion diagnosis, TRKi therapy was immediately initiated in 26 patients, of whom 13 received TRKi as first-line treatment in the advanced/metastatic setting. About half of the patients responded to TRKi treatment as the first treatment line after NTRK fusion diagnosis (46.2%), with an overall response rate of 46.2% and a disease control rate of 73.1%. The median progression-free survival was 15.7 months, and the overall survival was 27.6 months in TRKi-treated patients. CONCLUSION:The REALTRK registry provides important real-world insights into the patient path of adult patients with locally advanced or metastatic solid tumors harboring NTRK1/2/3 gene fusions.
PURPOSE:Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (DPYD) polymorphisms on dose reduction and safety remain limited. METHODS:In this retrospective study, 200 patients with human epidermal growth factor receptor 2 (HER2)-negative MBC were treated at the ASST Cremona Hospital (2015-2023) with metronomic Cape (1000 mg twice daily, in normal metabolizers; 500 mg twice daily, in DPYD variant carriers) + VNL (20 mg/day, once daily, 5-days-on/2-days-off). All patients underwent pretreatment DPYD genotyping and dose adjustment. Treatment was administered in the second-to-fourth setting. The primary end point was time-to-next treatment or death (TNTD); secondary end points included overall survival (OS), disease control rate (DCR) ≥24 weeks, overall response rate (ORR), safety, and genotype-toxicity correlations. RESULTS:The median age was 61 years, and DPYD variants were present in 14.5% of patients; 34%, 41%, and 25% received therapy as second-, third-, and fourth-line treatment. The median TNTD was 22.0 weeks, and the OS was 64.0 weeks. The DCR was 38.5%, and the ORR was 22.0%. Efficacy was comparable between DPYD variant carriers and normal metabolizers (all P values > .05). In later lines, Eastern Cooperative Oncology Group performance status 2 and >2 metastatic sites were independent negative prognostic factors (all values P < .05). Overall, 7.5% grade 3 toxicities occurred, especially in variant carriers without dose reduction and grade 4-5 events. CONCLUSION:These RW data suggest that metronomic Cape + VNL may represent a clinically active and manageable option in heavily pretreated HER2-negative MBC. Our findings support prospective evaluation of DPYD-guided dose individualization as a strategy to optimize the benefit-risk balance of fluoropyrimidine-based metronomic regimens.
PURPOSE:Chemoradiotherapy (CRT) is a standard treatment for rectal cancer, yet patients show marked variability in response. Identifying reliable biomarkers that predict CRT response remains an unmet clinical need. METHODS:Pretreatment biopsy samples from patients who received neoadjuvant CRT were analyzed using RNA sequencing. Differentially expressed genes (DEGs) were identified between responders and nonresponders, followed by functional enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. To complement DEG-based results, gene-set enrichment analysis (GSEA) was performed to assess pathway activity across the ranked transcriptome and to prioritize biologically relevant pathways. Pathway-derived gene signatures were evaluated using receiver operating characteristic curves and validated in three independent data sets. RESULTS:A total of 1,477 DEGs were detected, including 729 upregulated and 748 downregulated genes in responders. Functional enrichment analysis indicated immune activation and epithelial polarity in responders, whereas nonresponders showed enrichment of extracellular matrix organization, focal adhesion, and phosphoinositide 3-kinase-protein kinase B signaling. GSEA further identified four pathways associated with CRT response: antigen presentation, extracellular matrix-receptor interaction, focal adhesion, and drug metabolism. Among these, the antigen presentation pathway consistently predicted treatment response across data sets. Elastic net regression defined a six-gene signature (KLRC1, CTSS, HLA-DMA, HLA-DQB1, HLA-DQB2, and CIITA) with strong predictive performance, with area under the curve values ranging from 0.76 to 0.81. CONCLUSION:These genes participate in major histocompatibility complex class II antigen-processing and immune-regulatory pathways that enhance CD4 T-cell activation. Overall, the findings indicate that an immune-active, antigen presentation phenotype underlies radiosensitivity in rectal cancer and that the six-gene signature may serve as a biomarker to guide personalized treatment strategies.
PURPOSE:Motivated by the rising incidence of cancers at younger ages, this study compares tumor genomic alterations between adolescents and young adults (AYAs; 18-39 years) and non-AYAs (40 years and older) and explores the relationship with continuous age in patients with relapsed/refractory ovarian, breast, and colorectal cancers accrued to the NCI-MATCH trial. METHODS:Tumor genomic profiles generated by a next-generation sequencing 143-gene panel (NCI-MATCH assay, v2) were analyzed for association with age (AYA/total: 21/455 ovarian, 27/576 breast, 43/759 colorectal cancers). For each gene, AYA and non-AYA DNA alteration proportions were compared (Fisher exact test) and alteration association with continuous age (logistic regression) was evaluated (false discovery rate‑adjusted P value <.1 statistically significant). For colorectal cancer, sex-stratified analysis was also performed. RESULTS:No significant AYA versus non-AYA differences were observed in the prevalence of gene mutations (single nucleotide variant [SNV]/indel). A significant association of gene amplification with AYAs (odds ratio [OR], 95% CI) was CCND1 (0.2, 0.1-0.4), favoring AYAs in breast cancer. Examining age as a continuous variable, significant associations of gene mutations (SNV/indel) with older age, expressed as 5-year OR (OR [95% CI]), were observed: TP53 (1.3 [1.1 to 1.4]), ovarian cancer; CDH1 (1.4 [1.2 to 1.6]) and PIK3CA (1.1 [1.1 to 1.2]), breast cancer; and BRAF (1.4 [1.2 to 1.7]), female colorectal cancer. Associations with younger age included SMAD4 (0.8 [0.7 to 0.9]), male colorectal cancer. Significant associations of gene amplification with age (continuous) were as follows: CCNE1 (1.3 [1.1 to 1.6]), older ovarian cancer, and CCND1 (0.8 [0.8 to 0.9]), younger breast cancer. CONCLUSION:Comparing AYAs with non-AYAs among patients having relapsed/refractory disease, no significant differences in SNV/indel prevalence were observed, but CCND1 amplifications were more prevalent in AYA breast cancer. For several genes, DNA alterations were associated with continuous age and may depend on sex in colorectal cancer.
