JCO Precision Oncology

PurposeThe addition of PARP inhibitors to chemotherapy has been assessed in [~]80 clinical trials across multiple malignancies, on the premise that PARP inhibitors will increase chemotherapy effectiveness regardless of whether cancers have underlying disruption of DNA repair pathways. Consequently, the majority of combination therapy trials have been performed on patients without biomarker selection, despite the use of homologous recombination deficiency to dictate use of PARP inhibitors in the maintenance setting. An unresolved question is whether biomarkers are needed to identify patients who respond to combination PARP inhibitors and chemotherapy. MethodsA systematic literature review identified studies using PARP inhibitors in combination with chemotherapy versus chemotherapy alone, where the study included a biomarker of DNA repair function (BRCA1, BRCA2, BRCAPRO, ATM, ERCC1, SFLN11). Hazard ratios (HR) were pooled in a meta-analysis using generic inverse-variance and fixed or random effects modelling. Subgroup analyses were conducted on biomarker selection and type of malignancy. ResultsNine studies comprising 2,084 patients met the inclusion criteria. Progression-free survival (PFS) was significantly better in patients with a DNA repair biomarker (HR 0.52, 95% confidence interval (CI) 0.43-0.63; p < 0.00001), but there was no benefit in patients who lacked a biomarker (HR 0.94, 95% CI 0.82-1.08; p = 0.38). Subgroup analysis showed that BRCA mutation and SFLN11 biomarkers could predict benefit, and biomarker-driven benefit occurred in ovarian, breast and small cell lung cancers. The addition of PARP inhibitors was associated with increased grade 3/4 side effects, and particularly neutropenia. ConclusionsCombination therapy only increases PFS in patients with identifiable DNA repair biomarkers. This indicates that PARP inhibitors do not sensitise patients to chemotherapy treatment, except where their cancer has a homologous recombination defect, or an alternative biomarker of altered DNA repair. While effective in patients with DNA repair biomarkers, there is a risk of high-grade haematological side-effects with the use of combination therapy. Thus, the benefit in PFS from combination therapy must be weighed against potential adverse effects, as individual arms of treatment can also confer benefit. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/23290442v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1c2dddcorg.highwire.dtl.DTLVardef@73d1e3org.highwire.dtl.DTLVardef@1d8cef0org.highwire.dtl.DTLVardef@fa22cc_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundPractice guidelines recommend using panitumumab in combination with chemotherapy to treat KRAS wild-type (WT) metastatic colorectal cancer (mCRC) patients where it was shown to significantly extend progression-free survival (PFS) and overall survival (OS). Still, a proportion of patients will not achieve this goal. We propose a simplified predictive score to identify patients who are likely to benefit from panitumumab treatment. MethodsNCT00364013 (TRDS) (n=460) was used as training dataset and NCT00339183 (VALDS) (n=479) as validation set. Datasets were obtained from www.projectdatasphere.org and included KRAS WT mCRC patients treated with panitumumab in combination (P/FOL) or not with FOLFOX (FOL) (TRDS) or FOLFIRI (VALDS) as 1st and 2nd line therapy. TRDS was used to generate synthetic representations (SRs) for each patient through the integration of 36 clinical and analytical features collected, respectively, during the screening phase and the first month of inclusion. These SRs were then input into a machine learning (ML) framework to identify subgroups of patients based on their similarities. The resultant subpopulations were correlated with PFS and OS. Differential variables between subgroups were identified through feature contribution analysis and included in a multivariable logistic regression model. Independent predictive factors found to be statistically significant were used to generate a predictive score of panitumumab response at baseline that was validated in VALDS. ResultsML identified two different subpopulations on the TRDS: SPA (n=162) and SPB (n=298). Only SPA patients had a lower risk of death when treated with P/FOL compared to FOL (HR 0.68 95%CI 0.48-0.99; p=.04). Patients in SPB showed no significant differences on OS between P/FOL and FOL (p=.27). Feature contribution analysis identified 15 differential features between both subpopulations. From these, CEA, ALP, LDH, and platelets were selected to create a simplified predictive score for panitumumab response ranging 0-18. When applied to TRDS, this score yielded an area under the curve of 0.81 (95% CI: 0.77 to 0.85). A score [&ge;]8.5 was correlated to a lower risk of progression (HR 0.67 95% CI 0.47-0.97; p=.03) and death (HR 0.65 95%CI 0.43-0.98; p=.04) after P/FOL compared to FOL. No significant differences were observed for PFS and OS between P/FOL and FOL in patients with a score <8.5. The predictive score was then validated in the VALDS set with similar results (score [&ge;]8.5: PFS: HR 0.48 95%CI 0.33-0.70; p=.002; OS: HR 0.60 95%CI 0.42-0.87; p=.007; score <8.5, PFS: p=.2; OS: p=.9). ConclusionsBased on CEA, ALP, LDH and platelet baseline levels, this easily applicable predictive score might be helpful to accurately select KRAS WT mCRC patients who would benefit from addition of panitumumab to chemotherapy treatment in first- or second-line therapy. Further work is required to validate this approach in prospective cohorts of patients.

Most oncology trials define superiority of an experimental therapy compared to a control therapy according to frequentist significance thresholds, which are widely misinterpreted. Posterior probability distributions computed by Bayesian inference may be more intuitive measures of uncertainty, particularly for measures of clinical benefit such as the minimum clinically important difference (MCID). Here, we manually reconstructed 194,129 individual patient-level outcomes across 230 phase III, superiority-design, oncology trials. Posteriors were calculated by Markov Chain Monte Carlo sampling using standard priors. All trials interpreted as positive had probabilities > 90% for marginal benefits (HR < 1). However, 38% of positive trials had [&le;] 90% probabilities of achieving the MCID (HR < 0.8), even under an enthusiastic prior. A subgroup analysis of 82 trials that led to regulatory approval showed 30% had [&le;] 90% probability for meeting the MCID under an enthusiastic prior. Conversely, 24% of negative trials had > 90% probability of achieving marginal benefits, even under a skeptical prior, including 12 trials with a primary endpoint of overall survival. Lastly, a phase III oncology-specific prior from a previous work, which uses published summary statistics rather than reconstructed data to compute posteriors, validated the individual patient-level data findings. Taken together, these results suggest that Bayesian models add considerable unique interpretative value to phase III oncology trials and provide a robust solution for overcoming the discrepancies between refuting the null hypothesis and obtaining a MCID. SIGNIFICANCE STATEMENTThe statistical analyses of oncology trials are usually performed by calculating P values, although these are poorly understood. Using P value cutoffs, such as P < 0.05, may lead to some treatments being accepted which have little benefit, and other therapies being rejected which have considerable benefit. A more intuitive and direct probability-- that an experimental treatment is better than a standard treatment--can be calculated by Bayesian statistics. Here we used software to obtain the outcomes of 194,129 patients enrolled across 230 trials and then calculated probabilities of benefit. Interpretations based on P values disagreed with the probabilities of benefit in one-third of trials. This study suggests that probabilities of benefit would considerably enhance the interpretation of oncology trials.

Patient-derived xenografts (PDX) and organoids (PDO) are widely used to model cancer and predict treatment response in matched patients. However, their predictive accuracy has not been systematically studied nor compared. We conducted a systematic review and meta-analysis of studies using PDX or PDO from solid tumors treated with identical anti-cancer agents as the matched patient, identifying 411 patient-model pairs (267 PDX, 144 PDO). Overall concordance in treatment response between patients and matched models was 70%, with no significant differences between PDX and PDO. Sensitivity, specificity, positive and negative predictive value were also comparable. Patients whose matched PDO responded to therapy had prolonged progression-free survival. For PDX, this association held only when analyses were restricted to patient-model pairs with low risk of bias after applying a bias assessment metric. Together, these findings suggest that PDO perform similarly to PDX in predicting matched-patient response, while potentially offering lower financial and ethical burdens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/25333051v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@b635d7org.highwire.dtl.DTLVardef@88ee03org.highwire.dtl.DTLVardef@1c21ed3org.highwire.dtl.DTLVardef@175beef_HPS_FORMAT_FIGEXP M_FIG C_FIG

PURPOSEPediatric supportive care trials frequently rely on analyses of multiple clinically relevant outcomes, posing challenges for overall trial interpretation. Hierarchical composite endpoints (HCEs) rank relevant outcomes by prespecified clinical importance and offer potential advantages such as harmonizing trial conclusions. METHODSWe reanalyzed two randomized supportive care trials utilizing post-hoc HCE, each conducted through the Childrens Oncology Group. ACCL0934 evaluated levofloxacin for prevention of bloodstream infection (BSI) in patients with acute leukemia (AL) or undergoing hematopoietic cell transplant (HCT) and was chosen because of observed multidimensional benefits of levofloxacin. ACCL0431 evaluated sodium thiosulfate (STS) for prevention of cisplatin-induced hearing loss. ACCL0431 analyses were performed for overall and localized disease subgroups, chosen due to conflicting effect directionality on hearing vs survival by cohort. We estimated treatment effects on HCEs using win-odds ratios (WO). For ACCL0934, the primary HCE included death, severe infection, BSI, and neutropenic fever. For ACCL0431, the HCE included death, relapse/progression, and hearing loss. RESULTSIn ACCL0934, levofloxacin reduced BSI incidence, but only with corresponding p-value <0.05 in the AL cohort (22% vs 43% on control; P=0.003; HCT: 11% versus 17% on control; P=0.06). Using HCE reanalysis, the estimated win-odds achieved statistical significance in both cohorts (AL: WO=1.74, P=0.002; HCT: WO=1.28, P=0.031). In ACCL0431, HCE analyses resulted in an estimated null effect (WO=1) in the overall cohort but resulted in beneficial effects (WO>1) for analyses of the localized cohort. CONCLUSIONHCEs can provide a harmonized framework for interpreting complex supportive care trials by integrating outcomes of varying clinical importance. These post-hoc analyses should not be used to reinterpret either trial but motivate consideration of prospective use of HCE going forward.

BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPi) are effective in patients with germline BRCA 1/2 and PALB2 mutations but have been largely ineffective as monotherapy in others. PARP interacts with, and is recruited to, DNA damage sites along with epigenetic factors, such as DNA methyltransferase 1 (DNMT1). In addition to increasing PARP-trapping, inhibitors of DNMT modulate ROS-cAMP/PKA signaling and induce a pathogen mimicry, inflammasome signaling response and a BRCAness phenotype that further sensitizes cells to PARPi. In preclinical in vitro and in vivo studies, combined DNMTi + PARPi therapy was effective in both triple negative (TNBC) and hormone resistant (HRBC) models with intact BRCA. MethodsWe conducted a phase I study combining the oral DNMTi ASTX727 with the PARPi talazoparib in patients (pts) with previously treated TNBC or HRBC; pts with deleterious mutations of BRCA were excluded. Pts with TNBC had received at least one prior chemotherapy and pts with HRBC had received prior endocrine therapy with a cyclin-dependent kinase inhibitor for metastatic disease. An ECOG PS 0-1 and adequate organ function was required. A classical 3+3 design guided dose escalation/de-escalation with dose-limiting toxicity (DLT) defined as Grade 4 neutropenia or thrombocytopenia lasting [&ge;]7 days, or clinically significant grade [&ge;]3 non-hematologic toxicity in cycle 1; 28 days constituted each cycle. Serial peripheral blood mononuclear cells (PBMCs) were analyzed for changes in methylation using the Infinium Methylation EPIC BeadChip and LINE1 sequencing. Results34 evaluable pts were enrolled and treated in 8 dose cohorts. Median age was 59 years, 12% identified as Black. Myelosuppression was common with grade [&ge;]3 neutropenia in 42% and grade 3 anemia and thrombocytopenia in 13%. DLT was limited to neutropenia. Efficacy was assessed in 29 pts. There were no objective responses, 6 pts had stable disease persisting for > 4 months in 3 pts. LINE1 demethylation ranged from [~]2-10% and immune-specific CpGs (methylation in immune cells) changed 1-5% by differential methylation locus analysis at Day 15. Methylation changes were not dose dependent. ConclusionsASTX727 plus talazoparib produces significant myelosuppression but is otherwise well tolerated. Low dose ASTX727 (10 mg decitabine: 100 mg cedazuridine) on Days 1,3,5 with talazoparib 0.5 mg daily on Days 1-21 of each 28-day cycle is recommended for phase II trials. Methylation changes in PBMCs were detected and some heavily pre-treated pts had prolonged stable disease despite the attenuated doses. Statement of Translational RelevanceInhibitors of poly (ADP-ribose) polymerase (PARPi) have significant clinical benefit in patients with advanced breast cancer who harbor deleterious mutations of BRCA1, BRCA2, or PALB2 but have had limited benefit in those without mutations. Similarly, epigenetic therapies such as the DNA methyltransferase inhibitors (DNMTi) slow disease progression in some hematologic malignancies and myelodysplastic syndromes but have not found a role in solid tumors. Despite limited clinical activity as monotherapy, the combination of PARP and DNMTi significantly inhibited tumor growth in several preclinical models with intact BRCA. In the first clinical trial combining talazoparib and ASTX727, myelosuppression limited drug exposure but the combination was otherwise well tolerated. Strategies to reduce myelosuppression with this combination should be explored. Despite the attenuated doses, methylation changes in peripheral blood mononuclear cells (PMBCs) and clinical benefit were observed; neither were clearly dose dependent.

BackgroundSoft tissue sarcomas (STS) comprise over 150 histological subtypes, with advanced cases showing poor prognosis (5-year survival <10%). Trabectedin, a synthetic alkaloid, is frequently used after anthracycline-based chemotherapy failure. Despite the withdrawal of reimbursement in France in 2018 due to debated efficacy and safety, it remains in clinical use, imposing financial strain on hospitals. MethodsThis retrospective single-center study evaluated trabectedins efficacy, safety, and cost in 68 patients treated between 2019 and 2023. ResultsL-sarcomas accounted for 78% of cases, including uterine leiomyosarcomas (n=16), soft-tissue leiomyosarcomas (n=17), and myxoid liposarcomas (n=8). Non-L-sarcomas (22%) included mostly synovial sarcomas. The overall disease control rate was 71%, with a median progression-free survival (PFS) of 4.1 months. Subtype-specific median PFS was 6.8 months for liposarcomas (11.3 for myxoid vs. 4.5 for other subtypes), 3.1 months for leiomyosarcomas (3.4 months for uterine vs 3.1 for soft-tissue), and 2.4 months for non-L-sarcomas. Patients received a median of 5 cycles (range: 1-38), with an average total dose of 16 mg [2 - 81], and an average hospital cost of {euro}9,900. Adverse events occurred in 91%, mainly hematological; cardiac toxicity was seen in 9%. ConclusionDespite limited reimbursement, trabectedin remains a relevant treatment, particularly in L-sarcoma management.

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease. MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses. FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=<0.001) correlated with improved EFS and OS in multi-variable analyses. EFS and OS for patients treated with only conventional dose chemotherapy (CC) was 0% and respectively 37%{+/-}14% and 32%{+/-} 13% for patients treated with HDC. Patients with GTR or sub-total resection (STR) treated with HDC and RT had superior EFS (GTR 73%{+/-}14%, p=0.018; STR 67%{+/-}19% p=0.009) and OS (GTR 66%{+/-}17%, p=0.05; STR 67%{+/-}16%, p=0.005). Amongst 21 long-term survivors (OS 24-202 months); 38%, 24% and 24% respectively received craniospinal, focal or no RT. InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival. FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Talis Funds, Garron Cancer Centre, Graces Walk, Meagans Walk, Nelinas Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Childrens Cancer Foundation and the Spanish Society of Pediatrics, Consejeria de Salud y Familias de la Junta de Andalucia Project EF-0451-2017.

BackgroundGastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor, driven by tyrosine-protein kinase KIT and platelet-derived growth factor receptor A (PDGFRA) mutations. Specific variants, such as KIT exon 11 deletions, carry prognostic and therapeutic implications, whereas wild-type (WT) variants derive limited benefit from tyrosine kinase inhibitors (TKIs). Given the limited reproducibility of established clinicopathological risk models, deep learning (DL) applied to whole-slide images (WSIs) emerged as a promising tool for molecular classification and prognostic assessment. Patients and methodsWe analyzed 8398 GIST cases from 21 centers in 7 countries, including 7238 with molecular data and 2638 with clinical follow-up. DL models were trained on WSIs to predict mutations, treatment sensitivity, and recurrence-free survival (RFS). ResultsDL predicted mutational status in GIST from WSIs, with area under the curve (AUC) of 0.87 for KIT, 0.96 for PDGFRA. High performance was observed for subtypes, including KIT exon 11 delinss 557-558 (0.67) and PDGFRA exon 18 D842V (0.93). For therapeutic categories, performance reached 0.84 for avapritinib sensitivity, 0.81 for imatinib sensitivity. DL models predicted RFS, with hazard-ratios (HR) of 8.44 (95%CI 6.14-11.61) in the overall cohort and 4.74 (95%CI 3.34-6.74) in patients receiving adjuvant therapy. Prognostic performance was comparable to pathology-based scores, with highest discrimination in the overall cohort and in patients without adjuvant therapy (9.44, 95%CI (5.87-15.20)). ConclusionDL applied to WSIs enables prediction of molecular alterations, treatment sensitivity, and RFS in GIST, performing comparably to established risk scores across international cohorts, providing a baseline for future multimodal predictors. HighlightsO_LIDeep learning on histology predicts KIT and PDGFRA mutations in a large international cohort of GISTs from multiple centers C_LIO_LIWhole-slide image models stratify recurrence-free survival comparable to pathology-based risk scores C_LIO_LIPrognostic value of deep learning is preserved in adjuvant therapy subgroups, supporting treatment duration decisions C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/26345350v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@652548org.highwire.dtl.DTLVardef@729a2borg.highwire.dtl.DTLVardef@1e7b6b9org.highwire.dtl.DTLVardef@18d6721_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Overview of study design and dataset characteristics. (A) Multinational collection of WSIs from seven countries (Spain, France, Italy, Germany, the Netherlands, Poland, and Japan), followed by standard image preprocessing with the STAMP pipeline and clinical data preprocessing/standardization via the Grammar Data Curation framework. The workflow was divided into two main branches: (i) molecular mutation and treatment sensitivity prediction, and (ii) RFS prediction. Model performance was evaluated using AUROC and F1 score for classification tasks, and Kaplan-Meier survival curves with hazard ratios for RFS. Model explainability was assessed through heatmaps of WSIs and identification of top predictive tiles. (B) Summary of clinical dataset composition: proportion of cases receiving adjuvant therapy, tumor location distribution, mutation distribution at the exon level, and mutation distribution at the codon level. C_FIG

Epithelial ovarian cancer (EOC) can be highly lethal, with limited therapeutic options for patients with non-homologous recombination deficient (HRD) disease. Folate receptor alpha (FOLR1/FR)-targeting agents have shown promise both alone and in combination with available therapies, but the relationship of FR to other treatment-driving biomarkers is unknown. The Cancer Genome Atlas (TCGA) was queried to assess protein and mRNA expression and mutational burden in patients with differential FR protein-expressing ovarian tumors, and the results referenced against the standard 324 mutations currently tested through FoundationOne Companion Diagnostics to identify targets of interest. Of 585 samples within TCGA, 121 patients with serous ovarian tumors for whom FR protein expression was quantified were identified. FR protein expression significantly correlated with FOLR1 mRNA expression (p=7.19x10- 14). Progression free survival (PFS) for the FR-high group (Q1) was 20.7 months, compared to 16.6 months for the FR-low group (Q4, Logrank, p=0.886). Overall survival (OS) was 54.1 months versus 36.3 months, respectively; however, this result was not significant (Q1 vs. Q4, Logrank, p=0.200). Mutations more commonly encountered in patients with high FR-expressing tumors included PIK3CA and FGF family proteins. Combinations of FR-targeting agents with PI3K, mTOR, FGF(R) and VEGF inhibitors warrant investigation to evaluate their therapeutic potential. Simple SummaryEpithelial ovarian cancer can be highly lethal, with limited therapeutic options for patients without BRCA mutations or non-homologous recombination deficient disease. Folate receptor alpha (FR)-targeting agents have shown promise in the setting of platinum-sensitive and platinum-resistant ovarian cancer, both alone and in combination with available therapies, but the relationship of FR to other treatment-driving biomarkers is unknown. This study identifies potential targetable mutations in FR-expressing tumors, including PIK3CA and FGF/R family proteins, and provides a basis for future investigations of novel combinations of FR-targeting agents with PIK3CA, mTOR, FGF/R, and VEGF inhibitors.

ObjectivesBone sarcomas are aggressive malignancies with limited treatment options in advanced stages. Regorafenib, an oral multi-kinase inhibitor, has showed potential efficacy in early-phase trials. However, its overall effectiveness and safety profile in bone sarcoma remain unclear. This systematic review and meta-analysis aim to assess the clinical impact of regorafenib on survival outcomes and adverse events in patients with bone sarcomas. MethodsA systematic search was conducted across PubMed, Web of Science, and Scopus for randomized controlled trials (RCTs) published between September 27, 2012, and April 2024. Eligible studies included full-text RCTs comparing regorafenib to placebo in the treatment of bone sarcomas. Meta-analyses, reviews, case reports, conference abstracts, ongoing trials, and animal studies were excluded from the analysis. The primary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Data synthesis was performed using a random-effects model, and heterogeneity was assessed via the I{superscript 2} statistic. The Cochrane Risk of Bias tool (RoB 2) was applied to evaluate study quality. Statistical analysis was conducted using R version 4.3.1. ResultsA total of five RCTs met the inclusion criteria. Regorafenib significantly improved PFS compared to placebo (MD = 9.69 weeks; 95% CI: 4.54, 14.84; I{superscript 2} = 0%), while no statistically significant improvement was observed in OS (MD = 0.85 weeks; 95% CI:-36.33, 38.02; I{superscript 2} = 0%). Predominantly observed treatment-emergent effects linked to regorafenib included hand-foot skin reaction, hypertension, asthenia or fatigue, and diarrhea. ConclusionRegorafenib significantly improves progression-free survival in bone sarcoma but does not show a clear benefit in overall survival. While adverse events are common, they are generally manageable. Further research is needed to optimize dosing, patient selection, and to determine the long-term survival benefits.

PurposePrognosis in metastatic non-seminomatous germ cell tumors (mNSGCT) is currently guided by the IGCCCG classification, which incorporates tumor markers, organs involved with metastatic disease, and primary site but not histologic subtype. We aimed to evaluate whether specific histological components provide additional prognostic information in a large international mNSGCT cohort. Patient and MethodsWe analyzed clinical, pathologic, and outcome data from 662 patients with mNSGCT across multiple international centers. Cox regression and multivariable stepwise models were used to evaluate the impact of age, tumor histology, serum markers, primary site of disease, chemotherapy, IGCCCG, and post-chemotherapy surgery on overall survival. Analyses were performed using both complete-case and imputed datasets to account for missing values. ResultsThe presence of any percentage of embryonal carcinoma (EC) was independently associated with improved overall survival HR 0.603 (95% CI: 0.37-0.98, p=0.040), whereas yolk sac tumor (YST) predicted worse prognosis in complete-case analysis HR 2.27 (95% CI: 1.43 - 3.61 p = 0.001). Choriocarcinoma was also associated with a HR 1.58 (95% CI: 1.08 - 2.32 p= 0.019) adverse outcomes. IGCCCG risk classification remained a strong predictor of mortality HR up to 8.9 for Poor vs Good risk, (95% CI: 4.63 - 17.09 p < 0.001), but histologic components added significant independent prognostic value. Post-chemotherapy retroperitoneal lymph node dissection (RPLND) conferred a substantial survival benefit HR 0.44 (95% CI: 0.258 - 0.754 p=0.003). Interestingly, teratoma was not associated with mortality but was linked to younger age, testicular primaries, and higher likelihood of residual disease requiring surgery. ConclusionsHistological composition, particularly the presence of EC or YST, has a significant and independent impact on survival in mNSGCT, beyond established risk classifications. Integration of histological subtypes may enhance prognostic accuracy and guide individualized treatment strategies in advanced germ cell tumors.

BackgroundWhile the incidence of newly diagnosed early-onset colorectal cancer has been increasing, age-related disparity of survival outcome and treatment-related adverse events in patients with metastatic CRC (mCRC) has been inadequately studied with inconclusive findings. In this study, we aimed to evaluate such age-related disparity in this patient population. MethodsWe used individual patient data from three clinical trials (Study 1: NCT00272051, NCT 00305188 and Study 2: NCT00364013) in Project Data Sphere. All patients were diagnosed with mCRC and received first-line 5-fluorouracil and oxaliplatin. Clinical and genomic data of 763 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external and real-world validation cohort to evaluate overall survival (OS) disparity. Survival outcomes and treatment-related adverse events were estimated and compared in patients among three age groups: <50, 50-65, and >65 years. ResultsAmong 1223 patients from previous clinical trials, 179 (14.6%) were younger than 50 years. These patients had significantly shorter progression-free survival (PFS) (HR=1.46; 95%CI=1.22-1.76; p<0.001) and OS (HR=1.48; 95%CI=1.19-1.84; p<0.001) compared to patients in the 50-65 group of both Study 1 and Study 2 after adjustment for gender, race, and performance status. Significantly shorter OS was also observed in patients from the <50 group in the Moffitt cohort. When compared to other age groups, the <50 group had significantly higher incidence of nausea/vomiting (69.3% vs 57.6% vs 60.4%, p=0.019), severe abdominal pain (8.4% vs 3.4% vs 3.5%, p=0.018), severe anemia (6.1% vs 1.0% vs 1.5%, p<0.001), and severe rash (2.8% vs 1.2% vs 0.4%, p=0.047), but significantly lower incidence of fatigue, severe diarrhea, severe fatigue, and severe neutropenia. The <50 group had earlier onset of nausea/vomiting (1.0 vs 2.1 vs 2.6 weeks, p=0.012), mucositis (3.6 vs 5.1 vs 5.7 weeks, p=0.051), and neutropenia (8.0 vs 9.4 vs 8.4 weeks, p=0.043), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks, p=0.006). In the <50 group, severe abdominal pain and severe liver toxicity were associated with both shorter OS and PFS. In contrast, moderate peripheral neuropathy was associated with longer PFS. Our genomic data showed that the <50 group had higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%, p=0.047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%, p=0.005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%, p=0.050), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%, p=0.002). ConclusionsPatients with early-onset mCRC had worse survival outcome and unique adverse-event patterns, which could be partially attributed to distinct genomic profiles. Our findings might improve an individualized approach to chemotherapy, counseling, and management of treatment-related adverse events in this patient population.

PurposeDifferential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that are easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer (mCRC). Patients and MethodsIndividual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab + FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. ResultsPatients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter (P<0.001) median progression-free survival (PFS) of 7.27 months (95%CI 6.12-7.96 months) and overall survival (OS) of 16.0 months (95%CI 13.8-18.2 months) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95%CI 8.75- 10.89 months) and OS of 22.4 months (95%CI 20.1-26.7 months), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (HR 4.17, 95%CI 2.49-6.99, P<0.001) and shorter OS (HR 2.57, 95%CI 1.64-4.01, P<0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts. ConclusionTumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with mCRC. Implications for PracticeRoutine clinical decision making heavily relies on radiographic assessment of disease response to therapy. For patients with heterogeneous tumors, the degree and kinetics of individual tumor response to the same therapy can sometimes be vastly different. We explored a novel quantitative parameter to describe response-speed heterogeneity by utilizing individual patient data from previous clinical trials. This parameter was an independent prognostic factor associated with early disease progression and shorter survival. Complementary to existing molecular and radiographic tumor heterogeneity parameters, it may help practicing oncologists describe tumor response disparity and serve as a new prognostic factor for patients with mCRC.

BackgroundWe previously established an ovarian carcinoma (OC) BRCA-like genomic copy number aberration profile classifier ("BRCA-like classifier"), which identifies tumors with deleterious mutations and epigenetic alterations in the homologous recombination pathway (1). We explored whether the classifier may also be predictive for therapies targeting tumors with homologous recombination deficiency (HRD) such as olaparib, a PARP inhibitor with synthetic lethal interaction with HRD, in combination with bevacizumab. MethodsAs part of the ENGOT (European Network of Gynaecological Oncological Trial groups) HRD initiative, the OC BRCA-like classifier was evaluated using tumor-derived DNA samples from 469 out of 806 patients enrolled in the PAOLA-1/ENGOT-ov25 trial. PAOLA-1 is a randomized, double-blind, international phase 3 trial (NCT02477644) including advanced high grade OC patients. Prolonged progression-free survival (PFS) and overall survival (OS) was observed for patients treated with maintenance olaparib and bevacizumab versus placebo and bevacizumab, and particularly for those patients tested HRD positive according to Myriad MyChoice(R) CDx HRD test. ResultsResults were obtained for 442 patients (failure rate of 6%, 27 of 469 samples). A survival benefit from adding maintenance olaparib was observed in the 298 (67%) patients with a BRCA-like tumor (hazard ratio (HR) for PFS: 0.49, 95% confidence interval (CI) 0.37-0.65, p = 0.01; OS: 0.64, 95% CI 0.45-0.90, p < 0.01). No benefit was detected in patients with a non-BRCA-like tumor when treated with olaparib (HR for PFS: 1.02, 95% CI 0.68-1.51, p = 0.93; OS 1.48, 95% CI 0.94-2.33, p = 0.09). P values for interaction between BRCA-like status and olaparib for PFS and OS were both 0.004. Multivariate analysis revealed comparable results. The concordance rate with the Myriad test was 77% in samples that were successfully analysed with both assays. In the survival analyses, the CIs of the BRCA-like classifier and the Myriad test overlap. ConclusionThe BRCA-like classifier is a high-sensitive predictive biomarker for survival benefit of olaparib/bevacizumab as maintenance therapy in advanced ovarian carcinoma with a low drop-out rate.

PURPOSEIdentification of discrete sub-groups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Childrens Oncology Group biology study AEWS18B1-Q was to perform molecular characterization of a large cohort of patients with localized Ewing sarcoma treated on prospective trials with modern standard of care therapy. METHODSWe analyzed clinical and molecular features from patients with localized EWS enrolled on AEWS0031, AEWS1031, or INT-0154 frontline trials. All patients had available FFPE tissue, frozen tissue, or whole-genome amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations in TP53 and STAG2. Where available, tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses. RESULTSThree hundred and fifty-one cases had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 cases (80.3%). Pathogenic mutations in TP53 and STAG2 were identified in 5.1% and 7.6% of cases, respectively and 63.1% of cases were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients with TP53 mutation (5-year cumulative incidence of relapse 43%, CI [17%, 67%] vs. 22%, CI [17%, 27%]; Grays test P = 0.039), STAG2 mutation (53%, CI [29%, 73%] vs. 21%, CI [16%, 26%]; P < 0.001), and recurrent CNAs (30%, CI [22%, 37%] vs. 16%, CI [9%, 24%]; P = 0.005). In a multivariable analysis, STAG2 mutation was the only molecular biomarker that remained prognostic. CONCLUSIONThis is a prospective validation of the molecular prognostic features of localized EWS receiving standard of care therapy on therapeutic clinical trials. Building on prior work, patients with STAG2 mutations were at high risk of relapse. CONTEXTO_ST_ABSKey ObjectiveC_ST_ABSTo determine if molecular features can identify clinically relevant disease sub-groups applicable to frontline clinical trial design among patients with localized Ewing sarcoma. Knowledge GeneratedAmong 351 patients with localized Ewing sarcoma treated on prospective trials, canonical fusions were identified in 80% of cases. In a multivariable analysis of patients with genomically defined Ewing sarcoma, the presence of STAG2 mutations identified a high-risk population. Relevance (added by Associate Editor)

BackgroundThe province of Quebec has progressively implemented paired tumour-germline sequencing in paediatric oncology through two coordinated precision research programs, preceding a province-wide mainstream clinical genomics initiative. We report the prevalence, spectrum, and clinical relevance of germline findings (GFs) in children with primary extracranial cancers, integrating molecular, phenotypic, and pathological data. MethodsPatients enrolled between 2014 and 2022 underwent germline whole-exome sequencing (WES) using a virtual 352-cancer gene panel. Sequencing, bioinformatics and variant interpretation followed best practices standards based on GATK, ACMG/AMP and ClinGen recommendations. Somatic WES and transcriptomic data were integrated when available. GFs were categorised as diagnostic findings (DFs; established or suspicious association with the cancer phenotype) or as other findings further subcategorised according to actionability and age of disease onset. FindingsAmong 484 children, 130 (26.9%) carried 149 GFs, including 49 (10.1%) with a DF (42 with well-established associations with cancer phenotypes). DFs involved 21 genes related to childhood cancer predisposition, trisomy 21 and one clinical Beckwith-Wiedemann syndrome. Six DFs were initially missed by standard exome pipelines, and mosaic constitutional cancer predisposition syndrome (CPS) was confirmed in 4/49 children, underscoring the value of integrative analyses. A CPS was known at the time of primary cancer in 10/49 children. Among those diagnosed with a CPS after cancer onset, suggestive phenotypic features were present in 36/39. Other non-diagnostic findings were identified in 92 children; 21 (4.3% of the cohort) with actionable implications in childhood (n=7) or adulthood (n=14). Somatic sequencing was informative for refining causality, as somatic second hit alterations were identified in 29/33 (87.9%) DFs involving monoallelic tumour suppressor genes, whereas no such alterations were observed in non-DFs counterparts (0/57; p<0.0001). Interpretation: This provincial research experience highlights the analytical and practical challenges of germline evaluation in paediatric oncology and supports a shift toward integrative interpretation frameworks combining complementary germline, somatic, pathology, and phenotypic data. Flexibility in investigative strategies and nuanced categorisation of findings are warranted, guided by a child-centred interpretative framework. This approach underpins Quebecs paediatric oncology genomics mainstreaming initiative.

BackgroundLarge scale genomics projects have identified driver alterations for most childhood cancers that provide reliable biomarkers for clinical diagnosis and disease monitoring using targeted sequencing. However, there is lack of a comprehensive panel that matches the list of known driver genes. Here we fill this gap by developing SJPedPanel for childhood cancers. ResultsSJPedPanel covers 5,275 coding exons of 357 driver genes, 297 introns frequently involved in rearrangements that generate fusion oncoproteins, commonly amplified/deleted regions (e.g., MYCN for neuroblastoma, CDKN2A and PAX5 for B-/T-ALL, and SMARCB1 for AT/RT), and 7,590 polymorphism sites for interrogating tumors with aneuploidy, such as hyperdiploid and hypodiploid B-ALL or 17q gain neuroblastoma. We used driver alterations reported from an established real-time clinical genomics cohort (n=253) to validate this gene panel. Among the 485 pathogenic variants reported, our panel covered 417 variants (86%). For 90 rearrangements responsible for oncogenic fusions, our panel covered 74 events (82%). We re-sequenced 113 previously characterized clinical specimens at an average depth of 2,500X using SJPedPanel and recovered 354 (91%) of the 389 reported pathogenic variants. We then investigated the power of this panel in detecting mutations from specimens with low tumor purity (as low as 0.1%) using cell line-based dilution experiments and discovered that this gene panel enabled us to detect [~]80% variants with allele fraction of 0.2%, while the detection rate decreases to [~]50% when the allele fraction is 0.1%. We finally demonstrate its utility in disease monitoring on clinical specimens collected from AML patients in morphologic remission. ConclusionsSJPedPanel enables the detection of clinically relevant genetic alterations including rearrangements responsible for subtype-defining fusions for childhood cancers by targeted sequencing of [~]0.15% of human genome. It will enhance the analysis of specimens with low tumor burdens for cancer monitoring and early detection.

BackgroundPreclinical studies support targeting PI3K/AKT/mTOR signalling in platinum-resistant ovarian cancer (PROC). A phase I study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel (wP) showed activity. We report the results of Arm 1 of OCTOPUS, the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer. MethodsPatients with platinum-resistant or refractory high grade serous carcinoma were randomised (1:1) to wP (80mg/m2 D1,8,15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (P). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results140 patients (median age 63, range: 36-86; 18% platinum-refractory; 54% [&ge;]3 prior therapies) were randomised. There was no difference in PFS (median 4.5 vs 4.1m (HR 0.84; 80% CI (0.67, 1.07); 1-sided p=0.18), OS (median 9.7 vs 11.1m (HR 1.21; 80% CI (0.91, 1.60); 1-sided p=0.80) or RR (odds ratio 0.86; 80% CI (0.55, 1.36); 1-sided p=0.66). Grade 3/4 adverse events were 41.2% (wP+V) vs 36.7% (wP+P). Low tumour PTEN expression was associated with longer PFS in the wP+V arm (9.4 vs 4.1m p=0.003) but not in the wP arm (4.8 vs 4.2m p=0.60). Tumour genome-wide copy number (CN) analysis suggested that high CN signature 4 was associated with worse outcome in the wP+P arm (2.3 vs 4.6m p=0.018) but not the wP+V arm (5.4 vs 3.3m). ConclusionsVistusertib did not improve clinical activity of wP in PROC. However, low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. Translational RelevancePreclinical studies suggest that activation of the PI3K/AKT/mTOR signalling pathway contributes to platinum-resistance in ovarian high grade serous carcinoma (HGSC). Based on activity in a phase I study, we evaluated the clinical efficacy of the dual mTORC1/mTORC2 inhibitor vistusertib in combination with weekly paclitaxel in the OCTOPUS study - a multi-centre, randomised, placebo-controlled, phase II trial in platinum-resistant ovarian (HGSC). In the first randomised trial of weekly paclitaxel and dual mTORC1/2 inhibition in ovarian cancer, vistusertib did not improve clinical activity of weekly paclitaxel. However, translational analyses indicated that low tumour cell PTEN expression may be a predictive biomarker for vistusertib activity. We also showed genome-wide copy number (CN) analysis, in particular high exposure to CN signature 4, may also allow identification of patients with greater chance of benefit from dual mTORC inhibition. Potential predictive biomarkers identified in our study should be evaluated in ongoing/future studies.

BackgroundIn immune checkpoint inhibitor (ICI) trials, overall survival (OS) benefits are well established, yet improvements in quality of life (QoL) are often inconsistent or absent in conventional analyses. This apparent discordance raises important questions: are QoL outcomes truly unrelated to survival, and how can QoL results be better utilized and interpreted? MethodsA model-based meta-analysis (MBMA) of longitudinal EORTC QLQ-C30 global health status/quality of life data from randomized ICI trials was conducted. Longitudinal QoL trajectories were analyzed using a nonlinear mixed-effects model to estimate treatment-related toxicity and long-term QoL improvement. Associations between QoL trajectory parameters and OS were assessed using spearman rank correlation tests and Cox proportional hazards models. ResultsTwenty-seven studies (8,149 ICI and 5,593 control patients) contributed longitudinal QoL data, and 18 studies provided matched OS data. Raw QoL trajectories showed overlap between treatment arms, while OS consistently favored ICIs. MBMA revealed that ICIs had similar toxicity but significantly faster QoL improvement than control therapies (p < 0.0001). Baseline QoL, toxicity, and QoL improvement rate were all significantly associated with OS (p < 0.001). MBMA-based QoL comparisons were more sensitive in detecting associations with survival than raw QoL data, with the strongest association observed at Week 24 (R = -0.37, p = 0.067). ConclusionsConventional analyses comparing QoL at a single time point may obscure meaningful patient-reported benefits. By capturing longitudinal QoL trajectories across trials, MBMA reveals how patient experience evolves alongside survival outcomes and supports improved interpretation and utilization of QoL data in treatment evaluation.