Background and purpose - Soft tissue sarcomas are a heterogeneous group of malignant tumors with a high risk of metastasis, primarily to the lungs, making accurate survival prediction an essential part of long-term planning. No machine learning (ML) survival prediction models have been developed using a modern, population-based dataset from Scandinavia. We aimed to develop and compare ML models with logistic regression in predicting 5-year survival in soft tissue sarcoma patients and identify key predictive variables. Methods - This retrospective cohort study included patients diagnosed with deep-seated, high-grade soft tissue sarcomas of the extremities and trunk wall in Denmark from 2000 to 2016. Logistic regression was compared with 4 developed ML models, including random forest. Performance was assessed using the area under the curve (AUC), sensitivity, specificity, and calibration metrics, with a 70:30 training-test split and 5-fold cross-validation to evaluate the models. Results - 516 patients were included, of whom 226 (44%) died within 5 years following surgery. Random forest demonstrated the best ML performance on the training set and was compared with logistic regression on the test set. Logistic regression achieved an AUC of 0.74 (95% confidence interval [CI] 0.66-0.82), outperforming random forest's AUC of 0.65 (CI 0.56-0.74). Logistic regression also had higher sensitivity (0.65 vs 0.59) and specificity (0.72 vs 0.69), while random forest had a lower Brier score (0.38 vs 0.41). Conclusion - Although the developed random forest ML model performed well during training, logistic regression outperformed it after internal validation. Soft tissue sarcomas located in the trunk, grade 3 tumors, and chemotherapy within 3 months of surgery demonstrated the highest negative effect on survival, consistent with current treatment protocols in which patients with high-risk disease are managed with more aggressive multimodal therapy. Further external validation and assessment of clinical utility are required before potential clinical implementation.

Complete gene list for 6 cell types (Related to Figure 5F)

Although the role of neutrophils in modulating antitumor T-cell responses has been extensively studied, their direct effects on tumor cells remain less well understood. In this study, we investigated whether neutrophils have the capacity to directly kill tumor cells independently of T cells. We found that anti-CD40-based therapy, when combined with IL10 receptor blockade, initiates a Batf3-dependent pathway in which IL12 and IFNγ secretion results in oncolytic neutrophil activity. Using a combination of microscopy, single-cell, and functional assays, we observed that killing of tumor cells by neutrophils is dependent on physical contact and degranulation. This degranulation-mediated killing is associated with an atypical dynamic invasive neutrophil phenotype. In line with our preclinical findings, our phase I trial of anti-CD40 shows that circulating IL12, IFNγ, and IL10 increase in response to anti-CD40, whereas our phase Ib/2 PRINCE study shows that lower circulating IL10 is associated with favorable overall survival (OS) specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony-stimulating factor is associated with improved OS, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.

Real-world data suggest that SARS-CoV-2 mRNA vaccines, administered within 100 days of immune checkpoint inhibitor (ICI) treatment ("peri-ICI vaccination"), may improve ICI effectiveness, potentially through synergistic immune priming. Although peri-ICI vaccination was associated with longer survival when we applied a previous framework to our independent dataset, additional patterns emerged. Peri-ICI vaccination benefit diminished after 2021, a pattern confirmed in re-analysis of a published cohort. Benefit extended to patients treated with non-ICI antineoplastics. Benefit also dissipated in landmarked analyses restricted to periods of vaccine eligibility. Finally, progression-free survival in time periods with high vaccine uptake was not longer than in periods without vaccination. These analyses suggest peri-ICI vaccination's observed association with survival largely reflects selection bias in which patients with better prognosis were more likely to receive SARS-CoV-2 vaccines.

This cross-sectional study examines the risk for an immune-related cutaneous adverse event following antibiotic use.

BACKGROUND:Recurrence is a key oncologic endpoint but is difficult to automatically capture from electronic health records (EHR). METHODS:We evaluated rule-based algorithms to detect recurrence and its timing using a publicly available clinico-genomic database of patients with breast, colorectal, non-small cell lung, or pancreatic cancer. Algorithms evaluated varying anchor dates, defined as the time at which patients were assumed eligible to recur for the purposes of the algorithm, including diagnosis and four-, six-, and twelve-months post-diagnosis, as well as varying criteria for subsequent evidence of cancer from radiology, pathology, medical oncology assessments, or cancer-directed regimen initiation. Algorithm-derived recurrence results were compared with manually curated institutional data. Performance was measured by sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and concordance of recurrence timing. RESULTS:The best algorithms, anchored at six months post-diagnosis and requiring two reports demonstrated high sensitivity (≥0.95), PPV (≥0.81), and NPV (≥0.84), reasonable specificity (≥0.75), and estimated recurrence within a median of one month of institutional reference data. CONCLUSIONS:This scalable method enables derivation of real-world endpoints from EHR-based data. IMPACT:The algorithm may be used to characterize outcomes for patients treated outside of prospective clinical trials and may inform the creation of synthetic control cohorts to support regulatory approvals for new drugs in rare tumor or biomarker defined populations.

BACKGROUND:We leveraged observational data to conduct a target trial emulation (TTE) framework evaluating the association of exercise on distant disease-free survival (DDFS) in a pan-cancer cohort. METHODS:To emulate a randomized controlled trial (RCT), a "historical" exercise assessment (Th) identified non-exercising (<10 metabolic equivalent of task-hours per week [MET-h/week]) patients. Repeat assessment 9-15 months later (T0) was used to classify patients into an exercise group (≥10 MET-h/week: increased exercise from Th) and a control group (up to 10 MET-h/week: minimal increase in exercise from Th). Kaplan-Meier methods and Cox proportional hazards models from the T0 assessment were used to estimate hazard ratios (HRs) for the exercise versus control group on DDFS and overall survival (OS). RESULTS:A total of 3,022 patients were classified into the exercise group and 1,183 into the control group. With 5.2 years (IQR 2.7, 7.0 years) median follow-up from T0, the 5-year DDFS was 95% (95% CI, 93-96) in the exercise group and 92% (95% CI, 91-94) in the control group. Compared with the control group, the adjusted HR for the exercise group was 0.80 (95% CI, 0.59-1.09, p=0.20) for DDFS and 0.78 (95% CI, 0.55-1.11, p=0.20) for OS. CONCLUSIONS:In this pan-cancer TTE, we estimated a potential 20-30% improvement in DDFS in the exercise group compared to control. IMPACT:These data add to a growing body of evidence supporting further development of exercise as a therapeutic-intent strategy in primary solid tumors.

BACKGROUND CONTEXT:Sacral and sacrococcygeal chordomas present surgical and clinical challenges distinct from those of chordomas in the mobile spine. Over the last 30 years, 3 primary treatment modalities have emerged: wide surgical resection alone, surgical resection with radiotherapy (RT), and increasingly definitive RT. However, no studies have directly compared outcomes among the 3 treatment methods. PURPOSE:To compare local recurrence (LR), overall survival (OS), perioperative outcomes, and complications among patients with primary solitary sacral or sacrococcygeal chordomas treated with wide surgical resection alone, surgical resection with RT, or definitive RT. STUDY DESIGN:Retrospective cohort study. PATIENT SAMPLE:One hundred thirteen patients with sacral or sacrococcygeal chordoma who were treated at a single institution between January 1994 and February 2024. OUTCOME MEASURES:Primary outcome measures were LR and OS. Secondary outcome measures were 30-day and long-term complications. METHODS:Differences in LR and OS among treatment groups were analyzed using multivariable Cox proportional hazard models weighted by inverse probability of treatment weights. Rates of 30-day complications were compared using chi-squared tests; incidence of complications at any time following treatment was modeled using a negative-binomial regression model. RESULTS:Median follow-up was 7.6 years (interquartile range, 2.7-11). Fifty-five patients (49%) underwent wide surgical resection alone, 40 (35%) underwent wide surgical resection with neoadjuvant or postoperative adjuvant RT, and 18 (16%) received definitive RT. Negative margins were achieved in 83 patients (87%) undergoing surgery. OS varied significantly across treatment modalities and was shorter among patients who underwent surgical resection alone (hazard ratio [HR], 2.01; 95% confidence interval [CI], 0.96-4.20) or definitive RT (HR, 3.73; 95% CI, 1.15-12.1) compared to patients who underwent surgery with RT. LR was seen in 31 patients and did not differ across treatments in multivariable analysis (p=.3); the HRs for surgery with RT and definitive RT were 0.48 (95% CI, 0.17-1.31) and 1.01 (95% CI, 0.25-4.12), respectively, relative to surgery alone. Among patients who received RT, a higher biologically effective dose was associated with a lower risk of LR (HR, 0.92; 95% CI, 0.86-0.98; p=.01). Complication rates at 30 days differed among the surgery plus RT (85%), surgery alone (55%), and definitive RT (5.6%) groups (p<.001), but total complication rates at final follow-up did not vary significantly across groups. CONCLUSIONS:Wide surgical resection has been the recommended treatment for solitary primary sacral and sacrococcygeal chordoma. The addition of an RT regimen may improve LR and survival. Although definitive RT demonstrated short-term outcomes comparable to those of surgery alone, longer follow-up is required to determine the durability of response and the late-toxicity profile. Therefore, definitive RT should be considered selectively rather than as a replacement for surgery.

INTRODUCTION:Although increased cartilage cap thickness (CCT) is associated with secondary chondrosarcoma in patients with osteochondroma, no studies have assessed its relationship with histologic grade or outcomes after primary resection. Thus, the objectives of this study were to determine whether CCT is associated with (1) histologic grade in secondary chondrosarcoma and (2) oncologic outcomes after primary resection of secondary chondrosarcoma. METHODS:Patients who had a history of osteochondroma and were diagnosed with a biopsy-proven secondary chondrosarcoma at a single institution between January 2000 and December 2023 were included. CCT was measured on T2-weighted imaging or through direct measurement of the resected gross specimen. The primary outcome measure was of histologic grade. Secondary outcome measures were overall survival, local recurrence, distant recurrence, and margin positivity. Grade and margin positivity were evaluated using logistic regression models; time-to-event outcomes were assessed using Kaplan-Meier and cumulative incidence methods and Cox models. RESULTS:Forty-five patients (30 male; median age, 39 years) were included. Thirty (67%) had grade 1 secondary chondrosarcoma, 12 (27%) had grade 2, and 3 (6.7%) had grade 3. Mean CCT was smaller in grade 1 chondrosarcoma (35 mm; SD, 18 mm) than in grade 2 or 3 disease (76 mm; SD, 30 mm; P < 0.001). Thicker cartilage cap was associated with increased odds of high (grade 2 or 3) versus low histologic grade (odds ratio, 1.11; 95% confidence interval, 1.05 to 1.21; P < 0.001). No statistically significant associations were observed between CCT and overall survival, local recurrence, distant recurrence, or margin positivity. CONCLUSIONS:Although CCT may be a useful diagnostic marker for secondary chondrosarcoma, thickness itself is not a reliable prognostic marker for predicting long-term patient outcomes. However, its positive association with tumor grade may have implications for surgical planning. TYPE OF STUDY:Diagnostic Study. LEVEL OF EVIDENCE:III.

Introduction The AUA/SUO guidelines for upper tract urothelial carcinoma (UTUC) recommend endoscopic evaluation as part of the diagnostic workup with grade of tissue as the driving factor for risk stratification. In addition to being a risk factor for intravesical recurrence, ureteroscopic biopsy has a poor concordance with final pathologic stage. Because of this, patients and clinicians must make uninformed decisions regarding various aspect of treatment such as the use of neoadjuvant chemotherapy and intraoperative lymph node dissection. As such, we sought to create a genomic model that was predictive of stage in patients with UTUC. Methods A retrospective cohort of patients that underwent nephroureterectomy and next generation sequencing with MSK-IMPACT, a targeted sequencing panel covering up to 505 genes were included. Diagnoses were dichotomized into low (<T2) or high (≥T2) stage based on final pathology. Genes mutated with ≥5% prevalence and oncogenic or likely oncogenic based on OncoKB annotation were considered for inclusion. Five-fold cross validation was used to compare the following logistic regression models: (1) including only known predictors of stage, TP53 and FGFR3; (2) including only genes significant in univariable analyses after adjustment for TP53 and FGFR3; and (3) logistic regression with stepwise selection. The median and interquartile range (IQR) for sensitivity, specificity, and the area under the curve (AUC) are reported, where sensitivity refers to the proportion of high stage tumors that were predicted to be high stage, and specificity refers to the proportion of low stage tumors that were predicted to be low stage. Results 242 chemotherapy naïve patients were included in the discovery cohort, of which 152 (63%) were stage ≥T2. Stage based on biopsy was only 32% concordant with pathologic stage, with 7% sensitivity and 100% specificity for distinguishing high versus low stage disease (Figure 1). HRAS mutations were significantly associated with increased likelihood of low stage disease after adjustment for TP53 and FGFR3. The multivariable logistic regression model with TP53, FGFR3, and HRAS was selected as the optimal model. Using these three genes in a logistic model resulted in a median AUC of 0.79 (IQR 0.76-0.85). The sensitivity and specificity of the model were 0.60 (IQR 0.50-0.70) and 0.78 (IQR 0.74-0.83), respectively. Conclusions We developed a three-gene model that was predictive of high stage disease. Our model significantly outperforms the accuracy of uretereoscopic biopsy in a development set but is yet to be validated in this population. Ultimately, the clinical utility of this model may be seen not only in improving ureteroscopic biopsy accuracy, but also as applied to sequenced urinary tumor DNA as a non-invasive biomarker. The candidate model is supported by previously published feasibility and concordance studies; validation of this prediction model is planned.

PURPOSE:We conducted a mouse-human co-clinical trial to evaluate the biological efficacy of exercise therapy in breast cancer prevention. PATIENTS AND METHODS:In a phase I randomized trial, 75 nonexercising women at high risk of breast cancer were allocated to receive (1:1 ratio) usual care or one of three exercise therapy dose regimens: 75, 150, or 300 minutes/week for 24 consecutive weeks. Biological efficacy was evaluated by changes in breast epithelial cell proliferation (Ki67). Correlative proteomic analysis of paired tissue and plasma samples was also performed. A corresponding preclinical study tested the dose-response effect of exercise therapy on breast tumor latency. RESULTS:Change in Ki67 was not different between groups (global P value = 0.2). Among participants with paired Ki67 measures, the mean (SD) change in Ki67 was: -1.26 (4.32) for 75 minutes/week, -1.74 (5.04) for 150 minutes/week, -0.45 (5.16) for 300 minutes/week, and 3.40 (5.53) for usual care (global P value = 0.04). Only 150 minutes/week is associated with significant reductions in Ki67 compared with usual care (Bonferroni-adjusted P value = 0.03). The "response rate" (reduction in Ki67) was 29% for usual care compared with 52% for 150 minutes/week. Proteomics revealed a marked reduction in genes involved in epithelial-mesenchymal transition in the tissues of responding patients. In the preclinical study, only 150 minutes/week significantly delayed tumor latency compared with control (Benjamini-Hochberg-adjusted P value = 0.02). CONCLUSIONS:Exercise therapy is a promising strategy for the early interception of breast cancer in high-risk women. See related commentary by McTiernan, p. 3353.

1088 Background: Observational studies show post-diagnosis exercise is associated with reduced risk of cancer death in patients with HR-positive breast cancer. We conducted a phase 1a dose-finding trial of exercise therapy as first-line treatment for HR-positive advanced breast cancer (TBCRC 054). Methods: This multicenter trial was conducted using a patient-centric, decentralized platform (NCT03988595). Non-exercising patients receiving first line endocrine plus CDK4/6 inhibitor therapy were allocated using an adaptive continual reassessment design to one of four escalated exercise therapy dose levels (range: 90 to 300 min/week) of individualized, moderate-intensity treadmill walking for 6 consecutive months. The trial was later amended to add a fifth dose level of 375 min/week and to allow dose cohort backfilling. Exercise therapy sessions were conducted remotely in patient’s homes with real-time monitoring. The primary objective was to identify the recommended phase 2 dose (RP2D) as determined by feasibility and preliminary clinical efficacy. Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if ≥70% of patients achieved a REDI ≥75%. One-year progression free survival (PFS) rates were assessed by the Kaplan-Meier method. Results: Fifty-four women (median age 53 [46 to 63] years) were enrolled between August 2019 and April 2024; 23 (43%) had visceral metastases, 43 (80%) received an aromatase inhibitor, 11 (20%) received fulvestrant, and 53 (98%) received a CDK4/6 inhibitor. The proportion of patients with REDI ≥75% in each dose level was: 90 min/week (n = 10): 80%, 150 min/week (n = 10): 60%, 225 min/week (n = 11): 82%, 300 min/week (n = 13): 62%, and 375 min/week (n = 10): 40%. Among the two feasible dose levels (90, 225 min/week), 1-year PFS rate was 70% (95% CI, 47% to 100%) in the 90 min/week dose level and 91% (95% CI 75% to 100%) in the 225 min/week dose level. No serious adverse events were observed. Overall, 225 min/week (~ 45 minutes per treatment at 5 times weekly) was selected as the RP2D. Conclusions: This multicenter phase 1 trial showed that exercise therapy doses of 90 and 225 min/week are feasible and safe in patients receiving first line endocrine-based therapy. These data also support the rationale for a phase 2 trial testing the preliminary clinical efficacy of exercise at the RP2D of 225 min/week in HR-positive advanced breast cancer. Clinical trial information: NCT03988595 .

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced cancers, but overall response rates remain modest and adjunct therapies to enhance efficacy of ICI are of great interest. This retrospective study examines the association between exercise and clinical outcomes in 258 patients with advanced solid tumors receiving ICI. The results suggest an association between exercise and better clinical outcomes, particularly in patients with high tumor mutation burden, though improvements in clinical benefit rate (58% vs. 51% for exercisers and non-exercisers, respectively) and one-year overall survival (67% vs. 58% for exercisers and non-exercisers, respectively) are not statistically significant. Our discovery-based findings in conjunction with preclinical evidence create a strong rationale for translational studies to formally investigate the effects of structured exercise therapy in combination with ICI in patients with solid tumors.

Background For patients with advanced non-small cell lung cancer lacking targetable genomic alterations, the impact of clinicogenomic characteristics on the effectiveness of combining chemotherapy with immunotherapy is unclear.Methods We evaluated 4 statistical methods for detecting heterogeneous treatment effects related to clinical factors, including programmed death-ligand 1 expression, tumor mutation burden, and stage at diagnosis, using the American Association for Cancer Research Project Genomics Evidence Neoplasia Exchange BioPharma Collaborative dataset supplemented with institutional data collected under the same data curation model. A 2-sided P value of no more than .05 was used to denote statistical significance for all analyses.Results The mixture model revealed 2 latent subgroups: in one subgroup, there was no meaningful treatment effect, with average progression-free survival (PFS) only 5% longer with immunotherapy alone (95% confidence interval [CI] = -19% to 35%); in the second subgroup, immunotherapy alone was associated with a 35% decrease in average PFS (95% CI = -59% to 2%), corresponding to a ratio in treatment effects of 1.62 (95% CI = 1.02 to 2.57). There was a marginal association between lower tumor mutation burden levels and membership in the subgroup with improved PFS following receipt of chemoimmunotherapy. The causal survival forest highlighted the importance of tumor mutation burden (variable importance ranking: 1) and programmed death-ligand 1 (variable importance ranking: 3) when assessing heterogeneity. In contrast, the accelerated failure time and Cox proportional hazards models did not detect any statistically significant heterogeneous treatment effects. In simulations, the mixture model identified heterogeneous treatment effects more frequently than other methods, especially with weak covariate relationships, demonstrating its utility for informing personalized treatment approaches.Conclusions The application of novel statistical methods to large scale clinico-genomic databases offers an opportunity to more accurately identify heterogeneous treatment effects in some settings as compared to traditional statistical methods. Applying such methods to the AACR Project GENIE BPC non-small cell lung cancer data indicated a potential association between decreasing tumor mutation burden and improved outcomes with chemoimmunotherapy as compared to immunotherapy alone.

Supplemental Figure 1: OS and PFS for KRAS-mutated NSCLC treated with first-line platinum-based chemotherapy.