HIF-2α signaling is a central driver of clear cell renal cell carcinoma biology. With regulatory approval of the HIF-2α inhibitor, belzutifan, in the third- and fourth-line refractory setting, therapeutic targeting of th...HIF-2α signaling is a central driver of clear cell renal cell carcinoma biology. With regulatory approval of the HIF-2α inhibitor, belzutifan, in the third- and fourth-line refractory setting, therapeutic targeting of this pathway has entered clinical practice. At the 2026 ASCO GU Cancer Symposium, two randomized phase III trials evaluated earlier integration of belzutifan: LITESPARK-022 (belzutifan plus pembrolizumab vs pembrolizumab alone in the adjuvant setting) and LITESPARK-011 (belzutifan plus lenvatinib vs cabozantinib in the post-PD-(L)1 setting). LITESPARK-022 demonstrated a disease-free survival benefit (HR 0.72; 95% CI, 0.59-0.87; P = .0003), with early and sustained curve separation, though grade ≥3 adverse events doubled and overall survival data remain immature. LITESPARK-011 enrolled patients after progression on prior PD-(L)1 therapy in the metastatic setting. The combination improved median progression-free survival (PFS; 14.8 vs 10.7 months; HR 0.70), objective response rate (ORR; 52.6% vs 40%), and duration of response (23 vs 12 months), with a manageable toxicity profile. Together, these studies suggest that earlier targeting of HIF-2α biology may improve disease control and durability. However, patient selection, toxicity considerations, and the absence of mature OS data remain critical factors in determining the optimal role of belzutifan-based strategies across disease states.
Ki-67 is widely used in breast cancer; however, the fraction of patients in whom it meaningfully alters treatment decisions is not well established. Using a guideline-based approach anchored in National Comprehensive Can...Ki-67 is widely used in breast cancer; however, the fraction of patients in whom it meaningfully alters treatment decisions is not well established. Using a guideline-based approach anchored in National Comprehensive Cancer Network (NCCN) recommendations (v2.2026), we identified clinical scenarios in which Ki-67 directly modifies adjuvant therapy decisions and estimated their prevalence using population-level data and complementary datasets, recognizing that fully annotated datasets capturing all relevant clinicopathological variables remain limited. A back-of-the-envelope calculation suggests that only a small fraction of patients meet the combined criteria of HR+/HER2- subtype, T2 stage, grade 2 histology, and Ki-67 ≥ 20%. This estimate, compared to population-scale (n = 117 990 patients) and curated datasets (n = 1356 patients), indicates that the clinically relevant subset remains in the low single digits (3-5%). Ki-67 impacts care only in specific decision settings, particularly near clinically relevant thresholds where small analytic variation may translate into treatment changes; outside these contexts, its routine use has limited evidence for clinical utility. Its application should therefore be selective, context-dependent, and focused on scenarios in which threshold-adjacent precision is clinically consequential.
Hanevelt J, de Groot JWB, Rademaker E
… +9 more, Zamaray B, Brohet RM, Moons LMG, Vleggaar FP, Consten ECJ, Tanis PJ, de Vos tot Nederveen Cappel WH, van Westreenen HL, Dutch Snapshot Research Group (DSRG), Dutch Complex Colon Cancer Initiative (DCCCI) and Collaborators Snapshot Registry
BACKGROUND: Patients with node-positive colon carcinoma commonly receive adjuvant chemotherapy, regardless the tumor's T-stage. However, early-stage tumors (pT1-2 CC) are largely underrepresented in landmark studies supp...BACKGROUND: Patients with node-positive colon carcinoma commonly receive adjuvant chemotherapy, regardless the tumor's T-stage. However, early-stage tumors (pT1-2 CC) are largely underrepresented in landmark studies supporting this treatment. This study evaluates the application of adjuvant chemotherapy in those patients based on daily practice. PATIENTS AND METHODS: Patients who underwent surgery for either pT1- or pT2-CC were identified from the nationwide SNAPSHOT database and stratified by age (<75 or ≥75 years). Competing risk regression and (cause-specific) Cox proportional hazard models identified factors associated with 5-year cumulative incidence of recurrence and overall survival (OS), respectively. RESULTS: Lymph node metastases were found in 381 out of 2,312 (16.5%) patients, of whom 275 (72.2%) received adjuvant chemotherapy. The cumulative incidence of recurrence was 0.09 (95% CI 0.06-0.12) and 0.18 (95% CI 0.11-0.27) in patients who did or did not receive adjuvant chemotherapy, respectively (P = .007). In patients under 75, adjuvant chemotherapy was associated with significantly higher OS (91.3% vs 68.1%, P < .001). Corresponding OS probabilities in elderly patients (≥75 years) were 84.5% vs 55.1%, P = .003. After adjusting for confounding, this difference remained only significant in patients under 75: HRadj 0.5, 95% CI 0.1-0.7 and HRadj 0.5, 95% CI 0.2-1.3, respectively. The recurrence rate was not significantly different between patients receiving capecitabine/oxaliplatin (CapOx) and those on Capecitabine monotherapy (CIF 0.09, 95% CI 0.06-0.14 vs 0.05, 95% CI 0.01-0.16, P = .49). CONCLUSION: Adjuvant chemotherapy is associated with reduced risk of recurrence in patients with node-positive pT1-2 CC. Advantages on OS could not be demonstrated in elderly pT1-2N1-2 patients.
BACKGROUND: Fibroblast growth factor receptors inhibitors (FGFRi) are approved treatments for various malignancies. FGFRi-associated retinopathy is a class effect of FGFRi, including erdafitinib, pemigatinib, infigratini...BACKGROUND: Fibroblast growth factor receptors inhibitors (FGFRi) are approved treatments for various malignancies. FGFRi-associated retinopathy is a class effect of FGFRi, including erdafitinib, pemigatinib, infigratinib, and rogaratinib. PATIENTS AND METHODS: We summarized FGFRi-associated retinopathy with erdafitinib across 5 clinical studies in patients with metastatic urothelial cancer (mUC pooled studies) and one study in patients with advanced solid tumors (RAGNAR). We also present changes in visual acuity, retinal pigment epithelial elevation, and subretinal fluid in RAGNAR. RESULTS: One hundred and three (21.5%) of 479 patients in the mUC pooled studies and 43/314 (13.7%) patients in RAGNAR experienced FGFRi-associated retinopathy. Most FGFRi-associated retinopathy were Grade 1/2 events. Grade 3 FGFRi-associated retinopathy were infrequent (mUC pooled studies, 11/479 [2.3%]; RAGNAR, 3/314 [1.0%]). No Grade 4 events occurred. Most FGFRi-associated retinopathy events (mUC pooled studies, 81/103 [78.6%]; RAGNAR, 30/43 [70.0%]) occurred within 90 days of treatment initiation and were managed with erdafitinib dose interruption (mUC pooled studies, 41/479 [8.6%]; RAGNAR, 23/314 [7.3%]) or reduction (mUC pooled studies, 58/479 [12.1%]; RAGNAR, 21/314 [6.7%]); few required treatment discontinuation (mUC pooled studies, 14/479 [2.9%]; RAGNAR, 3/314 [1.0%]). By the data cutoff, 63.1% (65/103) patients in the mUC pooled studies and 65.1% (28/43) patients in RAGNAR had their FGFRi-associated retinopathy events resolve. Most unresolved FGFRi-associated retinopathy events were persistent Grade 1 events. In RAGNAR, 92.0% of patients had their visual acuity return to baseline and 78.5% of patients had their retinal pigment epithelial elevation resolve. CONCLUSIONS: FGFRi-associated retinopathy with erdafitinib can be managed with dose reductions, interruptions, or discontinuations. Proactive collaboration between oncologists and ophthalmologists is required to ensure that erdafitinib delivers clinical benefit to patients while managing their potential adverse symptoms of FGFRi-associated retinopathy.
BACKGROUND: The ATA risk stratification system has evolved from the 2015 framework toward a more composite nodal risk assessment in the 2025 update. Whether low-volume lateral neck disease remains clinically meaningful i...BACKGROUND: The ATA risk stratification system has evolved from the 2015 framework toward a more composite nodal risk assessment in the 2025 update. Whether low-volume lateral neck disease remains clinically meaningful is uncertain. We evaluated the prognostic significance of N1b vs N1a disease in papillary thyroid carcinoma (PTC) with ≤5 metastatic lymph nodes. MATERIALS AND METHODS: We identified 11 878 patients with PTC and N1a or N1b disease with ≤5 metastatic lymph nodes from the SEER database (2000-2022). One-to-one propensity score matching was performed. OS and CSS were assessed using Kaplan-Meier analysis, and CSD and OCD using cumulative incidence functions and Fine-Gray models. RESULTS: Among eligible patients, 9392 had N1a disease and 2486 had N1b disease. After matching, 2467 patients remained in each group. N1b was associated with significantly worse OS, CSS, and CSD in both unmatched and matched cohorts. In the matched cohort, 5-year CSD increased from 1.5% to 2.8%. On multivariable Fine-Gray analysis, N1b remained independently associated with higher CSD risk (SHR, 2.52; 95% CI, 1.85-3.43; P < .001). The adverse effect was more evident in patients with positive ETE, tumor diameter >2 cm, and older age. CONCLUSION: Among patients with PTC and ≤5 metastatic lymph nodes, N1b retains independent adverse prognostic significance despite low nodal burden. Low-volume nodal disease should not be considered uniformly low risk when lateral neck involvement is present, particularly in patients with positive ETE, tumor diameter >2 cm, or older age.
The treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved in recent years towards combination therapy, enhancing survival outcomes when compared with androgen deprivation therapy (ADT) alone. Howe...The treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved in recent years towards combination therapy, enhancing survival outcomes when compared with androgen deprivation therapy (ADT) alone. However, many patients who are eligible for combination therapy are still receiving ADT monotherapy, and a significant proportion of those treated with doublet combinations still experience suboptimal outcomes. Furthermore, the value of adding docetaxel to an androgen receptor pathway inhibitor (ARPI)/ADT doublet in mHSPC has not been delineated, particularly in patients with low-volume disease, and chemotherapy toxicity and tolerability remain a major concern for patients. This review addresses the significant unmet need for additional or novel treatment strategies for mHSPC, utilizing prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in a combination regimen that uses a non-chemotherapeutic approach for the treatment of mHSPC. PSMA-targeted RLT has been shown to improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ARPIs +/- taxanes and is now under evaluation for the treatment of mHSPC, given its demonstrated success in the mCRPC space. Thus, continued education on RLT and its use for patients with mHSPC is important to optimize patient care. This review provides a brief outline of the mHSPC treatment landscape, focusing on the challenges and unique considerations faced by healthcare professionals when treating these patients. We also evaluate the potential role of RLT in surmounting these challenges, discussing potential barriers and solutions to its integration as a treatment for mHSPC.
BACKGROUND AND OBJECTIVE: Despite treatment advances, treatment resistance for metastatic castration-resistant prostate cancer (mCRPC) is nearly universal. We studied the efficacy, safety, and pharmacokinetic properties...BACKGROUND AND OBJECTIVE: Despite treatment advances, treatment resistance for metastatic castration-resistant prostate cancer (mCRPC) is nearly universal. We studied the efficacy, safety, and pharmacokinetic properties of the combination of enzalutamide and cabazitaxel in patients with mCRPC. For phase 1, we examined the safety of combination therapy and determined the recommended phase 2 dose. Phase 2 primary endpoint included the percentage of patients achieving a ≥ 90% PSA decline (PSA90) as a measure of response to therapy. METHODS: A phase 1/2 single-arm, multi-institutional clinical trial enrolled adults with histologically confirmed progressive mCRPC without prior docetaxel or cabazitaxel chemotherapy for mCRPC. Co-administration of enzalutamide 160 mg orally once daily, cabazitaxel 25 mg/m2 IV once every 21 days, and prednisone 5 mg orally twice daily in mCRPC. Descriptive statistical analysis was used for all primary and secondary endpoints. Estimated proportions are with 95% confidence interval using the exact method. KEY FINDINGS: The study met its primary endpoint with 61.1% (95% CI, 43.5% to 76.9%) of patients achieving PSA90. Observed toxicities were similar to those seen with either agent alone. CONCLUSIONS: The combination of enzalutamide and cabazitaxel exhibited robust activity with tolerable side effects. Chemo-hormonal therapies warrant further study in mCRPC. WHAT DOES THE STUDY ADD: This study of enzalutamide and cabazitaxel combination therapy in patients with advanced, pre-treated mCRPC showed promising efficacy, indicating strong rationale for further investigation. PATIENT SUMMARY: In this report we looked at outcomes for patients with metastatic prostate cancer treated at multiple institutions with enzalutamide and cabazitaxel at the same time after castration therapy alone had stopped working. We found the combination was safe and had anti-cancer effect, warranting further investigation.
Immune checkpoint inhibitors have transformed outcomes in melanoma and other aggressive malignancies. However, subsequent lines of therapy remain limited: modest efficacy, lack of publicly funded options, and declining p...Immune checkpoint inhibitors have transformed outcomes in melanoma and other aggressive malignancies. However, subsequent lines of therapy remain limited: modest efficacy, lack of publicly funded options, and declining performance status frequently restrict clinicians' choices. In this context, temozolomide has re-emerged as a feasible bridge therapy, with emerging evidence suggesting synergistic activity when used alongside anti-PD-1 agents. Here, we describe two cases of single-agent temozolomide administered after progression on prior systemic therapies, including anti-PD-1 and, in one case, targeted therapy, both demonstrating meaningful clinical responses and great patient tolerability. We also briefly discuss how these observations may support further exploration of temozolomide within modern treatment sequencing strategies.
PURPOSE: Despite emerging genomic discoveries, few have been translated into practical management strategies for people with gastroenteropancreatic neuroendocrine carcinoma (GEPNEC). This study aims to identify key genes...PURPOSE: Despite emerging genomic discoveries, few have been translated into practical management strategies for people with gastroenteropancreatic neuroendocrine carcinoma (GEPNEC). This study aims to identify key genes and their potential clinical relevance to improve care for this patient group. METHODS: In the analytical cohort, we reported high-frequency alteration genes, significantly mutated genes, and driver genes and defined their overlap as key genes. Genotypes were identified as Type I/II/III. For further validation, we prospectively recruited eligible patients to build a main cohort, through which we performed univariate/multivariate Cox regression analysis and sketched Kaplan-Meier survival plot. Targetable genes were defined by the OncoKB database. RESULTS: The analytical cohort consisted of 124 patients. The genes most frequently altered were TP53 (78%), RB1 (35%), APC (27%), and KRAS (17%). Key genes were identified as TP53, RB1, APC, and KRAS. The main cohort included 171 patients. We defined the genotype "Type I" (defined as TP53/RB1 co-alterations) as a reference. In midgut/hindgut NEC, we identified a "Type II" subtype characterized by mutations in either APC or KRAS alterations without TP53/RB1 co-alterations. Type II of midgut/hindgut NEC patients had elevated carcinoembryonic antigen (CEA) levels and longer median overall survival (mOS) than others (not reached vs 11.4 months, HR = 0.19[0.08, 0.44], P = .0028). In foregut NEC, we identified "Type III" (either APC/KRAS alterations or TP53/RB1 co-alterations). Type III of foregut NEC patients showed shorter mOS than others (11.6 vs 19.0 months, HR = 1.93[1.13, 3.25], P = .01). Type II patients who received non-platinum/etoposide (EP) chemotherapy had longer first-line progression-free survival (PFS) compared to EP regimen. They also benefited from second-line immunotherapy. Targeted therapy as second-line was also suitable for targetable patients (longer PFS than others: 12.5 vs 3.0 months, HR = 0.40[0.21-0.75], P = .0017). CONCLUSIONS: Our study identified key gene-based genotypes (Type II/III) of distinct GEPNEC patients and yielded their prognosis and therapeutic utility.
The expert review by Alexander and colleagues addresses a long-standing yet insufficiently interrogated paradox in contemporary oncofertility item: While sperm cryopreservation prior to gonadotoxic cancer therapy is wide...The expert review by Alexander and colleagues addresses a long-standing yet insufficiently interrogated paradox in contemporary oncofertility item: While sperm cryopreservation prior to gonadotoxic cancer therapy is widely endorsed, technically straightforward, and increasingly accessible, its subsequent utilization by male cancer survivors remains consistently low. This discrepancy, persisting across institutions, health-care systems, and decades, suggests that the challenge is no longer primarily technical or educational, but structural, temporal, and psychosocial in nature. The central merit of this review lies in its deliberate shift away from a narrow, procedure-centered conception of fertility preservation toward a longitudinal, survivorship-oriented framework. In doing so, the authors implicitly challenge the field to reconsider what constitutes "success" in oncofertility. If success is defined merely as successful banking prior to treatment, then current practice may appear satisfactory. If, however, success is defined as enabling informed, autonomous, and timely reproductive decision-making across the survivorship trajectory, then the low utilization rates described in this review represent a clear failure of care continuity.
BACKGROUND: Metastatic uveal melanoma (UM) primarily affects the liver, and due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for hepatic tumor control. Direct head-to-head...BACKGROUND: Metastatic uveal melanoma (UM) primarily affects the liver, and due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for hepatic tumor control. Direct head-to-head trials comparing these LDTs are still lacking. METHODS: A retrospective multicenter explorative analysis was conducted to evaluate the clinical outcomes of transarterial chemoembolization (TACE), selective internal radiotherapy (SIRT), and percutaneous hepatic perfusion (PHP, chemosaturation). RESULTS: The present analysis was conducted on a cohort of 121 patients who had been treated for metastatic UM with LDT at five different skin cancer centers. A total of n = 15 patients received TACE (12.4%), n = 51 SIRT (42.1%), and n = 55 PHP (45.5%). The estimated median overall survival (OS) for SIRT was 25.1 months (95% confidence interval [CI], 15.3-34.8), for TACE, 11.4 months (95% CI, 7.8-14.9), and for PHP, 24.9 months (95% CI, 13.7-36.0). In the multivariate analysis that included LDH and additional systemic therapies, there was no significant difference in OS between SIRT and PHP (HR 1.14, 95% CI 0.67-1.93, P = .63), whereas TACE was found to be associated with a substantially reduced in OS compared to PHP (HR 3.25, 95% CI 1.31-8.04, P = .01). Adverse events occurred in 41.6% of patients undergoing SIRT, 64.3% of patients receiving TACE, and 84.6% of patients receiving PHP. CONCLUSION: The findings of this study indicate that SIRT and PHP demonstrate equivalent survival rates in a real-world setting.
BACKGROUND: Y101D is a novel bispecific antibody targeting PD-L1 and TGF-β. This multicenter phase I study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of Y101D in patients with metastatic o...BACKGROUND: Y101D is a novel bispecific antibody targeting PD-L1 and TGF-β. This multicenter phase I study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of Y101D in patients with metastatic or locally advanced solid tumors. METHODS: Patients who failed standard therapies were enrolled. In the dose-escalation and -expansion phases, Y101D was administered intravenously every 2 weeks (Q2W) at 1, 3, 10, 20, and 30 mg/kg. Primary objectives were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in escalation, safety, and objective response rate (ORR) in expansion. Secondary objectives included pharmacokinetics/pharmacodynamics parameters, and immunogenicity. RESULTS: Among 50 enrolled patients, the most common treatment-related adverse events (TRAEs) were aspartate aminotransferase elevation (20.0%), gingival bleeding (18.0%), alanine aminotransferase elevation (14.0%), rash (14.0%), and proteinuria (14.0%). Grade ≥ 3 TRAEs occurred in 10.0% of patients, with no grade 4/5 TRAEs. Immune-related adverse events (irAEs) occurred in 22.0%, predominantly grades 1-2. No DLTs were observed, and MTD was not reached. One extensive-stage small cell lung cancer (ES-SCLC) patient (20 mg/kg Q2W) achieved a confirmed partial response (ORR: 2.1%, 95% CI, 0.1%-11.3%). Median progression-free survival and overall survival were 1.3 months (95% CI, 0.9-1.3) and 10.5 months (95% CI, 6.6-12.7), respectively. The pharmacokinetic characteristics of single and multiple doses of 20 mg/kg Q3W and 1200 mg Q3W supported the administration schedule of once every 3 weeks. PD-L1 target occupancy exceeded 95% at 2 h post-dose across all cohorts and remained sustained pre-dose. CONCLUSIONS: Y101D monotherapy exhibited a manageable safety profile and on-target pharmacodynamic activity, with limited antitumor activity as a single agent. Further evaluation in disease-focused cohorts and rational combination regimens is warranted, including in ES-SCLC. CLINICAL TRIAL NUMBER REGISTRATION: NCT05028556.
BACKGROUND: Guideline-recommended nontargeted systemic therapies for previously treated metastatic colorectal cancer (mCRC) include regorafenib, trifluridine/tipiracil, and fruquintinib, but no consensus exists on the de...BACKGROUND: Guideline-recommended nontargeted systemic therapies for previously treated metastatic colorectal cancer (mCRC) include regorafenib, trifluridine/tipiracil, and fruquintinib, but no consensus exists on the definition of clinically meaningful improvements for later-line mCRC treatments. MATERIALS AND METHODS: Trials were identified from systematic searches in MEDLINE, Embase, and the Cochrane Library. Meta-analyses were performed to characterize overall survival (OS) and progression-free survival (PFS) improvements with systemic therapy vs placebo in previously treated mCRC. Meta-analyses were conducted using fixed-effect and random-effects (RE) frequentist models of difference in medians, hazard ratios (HRs), and 12-month restricted mean survival time (RMST). RESULTS: Six randomized, placebo-controlled, phase III trials of 3277 patients comparing oral systemic monotherapies with placebo were analyzed. Using the RE model, the meta-analyzed OS estimate for oral systemic monotherapy vs placebo was 1.86 months (95% confidence interval [CI], 1.30-2.42) for the difference in medians, 0.69 (95% CI, 0.64-0.76) for HRs, and 1.25 months (95% CI, 0.69-1.82) for the difference in 12-month RMST. For PFS, meta-analyzed median improvement was 0.97 months (95% CI, 0.28-1.66), HR was 0.38 (95% CI, 0.30-0.47), and 12-month RMST difference was 1.90 months (95% CI, 1.41-2.39). Sensitivity analyses, excluding the FRESCO-2 trial due to prior treatment differences, confirmed the primary meta-analysis results. CONCLUSION: When assessing the clinical benefit of later-line mCRC treatments, the broad clinical picture, including individualized treatment goals, should be evaluated. Considering multiple survival measures in the later-line mCRC context, an incremental survival improvement with oral systemic monotherapy vs no active therapy is clinically meaningful.
BACKGROUND: BladderGATE evaluated the safety, tolerability, and efficacy of intravenous (IV) atezolizumab combined with intravesical Bacillus Calmette-Guérin (BCG) in patients with BCG-naïve high-risk non-muscle invasive...BACKGROUND: BladderGATE evaluated the safety, tolerability, and efficacy of intravenous (IV) atezolizumab combined with intravesical Bacillus Calmette-Guérin (BCG) in patients with BCG-naïve high-risk non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: This was a phase Ib/II open-label, nonrandomized, dose de-escalation clinical trial of atezolizumab (1200 mg IV infusion on day 1 of each 21-day cycle) plus BCG (1 instillation/week) with an induction treatment period of 6 weeks, followed by a maintenance treatment period of 52 weeks maximum. During induction, dose-limiting toxicity (DLT) and maximum tolerated dose of atezolizumab were determined. The primary study outcome was recurrence-free survival (RFS). RESULTS: A total of 36 patients with high-risk NMIBC with a median age of 70 years were enrolled in this study. Twenty participants completed the whole treatment schedule. No DLTs were recorded during the study period. The median RFS was not reached; RFS rates were 83% (95% CI 70.6%-95.4%) and 73% (95% CI 57.4%-88.2%) at the end of the first and second year, respectively. The incidence of serious drug-related adverse events was low. Additionally, no impairment in Health-related quality of life status throughout the study was observed. CONCLUSIONS: IV atezolizumab plus intravesical BCG in high-risk BCG-naïve NMIBC patients resulted in a high RFS rate and a manageable safety profile. These results appear consistent with those of the ALBAN study, which did not demonstrate a significant benefit of this combination over BCG alone.
BACKGROUND: Immunotherapy has improved outcomes in metastatic colorectal cancer (mCRC), but benefits remain largely restricted to the minority with specific biomarkers like microsatellite instability-high (MSI-H). This s...BACKGROUND: Immunotherapy has improved outcomes in metastatic colorectal cancer (mCRC), but benefits remain largely restricted to the minority with specific biomarkers like microsatellite instability-high (MSI-H). This study aims to develop and validate a revised tumor burden score (rTBS) as a prognostic model to stratify survival outcomes in mCRC patients receiving immunotherapy. METHODS: We analyzed a retrospective cohort of 339 immunotherapy-treated mCRC patients (2019-2024). Univariable and multivariable Cox regression analysis were employed to identify independent prognostic factors and construct a model for progression-free survival (PFS). rTBS was developed by integrating CEA, metastatic organ count, and target lesion count. rTBS prognostic performance was validated via bootstrapping, internal and external dataset, ROC curves, and Kaplan-Meier analysis across MSI/TMB subgroups. RESULTS: Independent risk factors included TMB level, CEA, metastatic organ count, and target lesion count. The integrated rTBS outperformed TMB (AUC = 0.768 vs 0.656) and traditional metrics. Low rTBS patients showed superior PFS and overall survival (Both P < 0.0001), higher objective response rate (ORR: 37% vs 21.4%, P = 0.002) and disease control rate (DCR: 73.6% vs 51.1%, P < 0.0001). rTBS also stratified outcomes in both MSI-H/TMB-High and MSI-L/MSS/TMB-Low subgroups (both P < 0.0001). Moreover, split-sample testing, external validation, and bootstrap analysis collectively demonstrated the model's robust validity. CONCLUSIONS: The rTBS is a robust, cost-effective prognostic model that stratifies survival in immunotherapy-treated mCRC across subtypes, particularly in the MSI-L/MSS/TMB-Low subgroup lacking reliable biomarkers. It bridges molecular heterogeneity and clinical practice, and warranting further multicenter validation.