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Importance The Surgery as Needed for Oesophageal Cancer (SANO) trial introduced active surveillance as a noninferior alternative to esophagectomy for patients with esophageal cancer who achieve a clinical complete response (cCR) after neoadjuvant chemoradiation (nCRT). However, concerns remain about recurrence risk, long-term survival, and quality-of-life trade-offs with organ-preserving strategies. Objective To evaluate the long-term comparative effectiveness of active surveillance vs standard esophagectomy in patients with cCR following nCRT for locally advanced esophageal cancer, using updated data from the SANO trial. Design, Setting, and Participants This decision analytical model used Markov modeling and probabilities and utility inputs derived from the SANO trial and existing literature. The base case was a 60-year-old male with good functional status and cT3N1M0 esophageal cancer achieving cCR after nCRT. Exposures Standard routine esophagectomy vs active surveillance after neoadjuvant chemoradiation. Main Outcomes and Measures The primary outcome was quality-adjusted life-years (QALYs); the secondary outcome was life-years. Additional model scenarios explored (1) quality-of-life impacts of esophagectomy modeled as a time-varying covariate and (2) 2-year outcomes to align with the SANO trial time horizon. Sensitivity analyses evaluated recurrence probabilities and surgery-related quality-of-life trade-offs. Results At 5 years, standard surgery yielded greater QALYs (1.74 vs 1.34; incremental gain of 0.40 QALYs or ~4.8 months in perfect health) and life-years (3.11 vs 2.41; incremental gain of 0.70 life-years or ~8.4 months) compared with active surveillance. However, at a 2-year horizon, active surveillance was preferred for QALYs (incremental gain of ~15 days), consistent with the SANO trial. Sensitivity analyses revealed the model favored active surveillance when the recurrence probability was less than 43%, the likelihood of local/resectable recurrence was greater than 94%, or the negative quality-of-life impact of esophagectomy was substantial. Modeling esophagectomy’s quality-of-life impact as time limited further strengthened surgery’s long-term QALY benefit. Conclusions and Relevance This study found that while active surveillance offers short-term quality-of-life benefits and may be appropriate in select patients, particularly those at low recurrence risk or with high surgical risk, esophagectomy remains the preferred strategy for maximizing long-term survival and QALYs. These findings support a nuanced, individualized approach to post-nCRT management, balancing organ preservation with long-term oncologic outcomes.

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

Context.— The US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for SARS-CoV-2 assays encompassed both in vitro diagnostic and laboratory-developed tests. Related testing data and documents from EUAs were published on the FDA website as PDF files, constituting a rich data resource. Objective.— To highlight the value of structured descriptive and validation data and provide recommendations on improving the quality, accessibility, and shareability of the FDA’s digital resources. Design.— SARS-CoV-2 diagnostics EUAs and related files were acquired from the FDA, and data were extracted through an iterative manual or automated process with quality assurance in accordance with a set of data entry definitions to generate a data product (ie, data analysis and presentation of data into tables, graphs, and reports, optionally including different data sets) that could be disseminated. Results.— Four challenges limited the usability of FDA EUA data, including (1) distinguishing EUA tests owing to similar names or inconsistent naming conventions; (2) document location and tracking owing to inconsistent EUA document identifiers, resource locators, and versioning; (3) data location and retrieval owing to heterogeneous structure and data formatting within EUA documentation; and (4) maintenance of existing data owing to lack of clear and traceable communication around EUA amendments. Conclusions.— Converging efforts from disparate groups to extract and synthesize FDA test data reveal an unaddressed need for better organization and communication. Existing FDA data reporting systems must be improved and adapted for the demands of the connected data science era.

Abstract Measurable residual disease (MRD) assessment has become central to risk-adapted treatment strategies in multiple myeloma, yet the prognostic value of MRD negativity following autologous stem cell transplantation (ASCT) across individual high-risk cytogenetic abnormalities (HRCAs) remains unclear. We analyzed 351 newly diagnosed patients who achieved MRD negativity (sensitivity 2.4×10 − 6 ) at Day 100 following ASCT and had baseline cytogenetic data available. Median follow-up was 50.4 months. Standard-risk cytogenetics were present in 46% (n = 162), while 34% (n = 118) had one HRCA and 20% (n = 71) had ≥ 2 HRCAs. Despite uniform MRD negativity, several HRCAs continued to confer inferior progression-free survival (PFS). Compared with the standard-risk group (4-year PFS 84%), patients with del(17p), 1q21+, t(4;14), or MAF translocations [t(14;16)/t(14;20)] had significantly lower 4-year PFS rates: 56% (HR 2.89; p = 0.0001), 60% (HR 2.46; p = 0.0001), 43% (HR 3.50; p = 0.0001), and 58% (HR 2.51; p = 0.01), respectively. Isolated del(17p) and 1q21 + also conferred inferior PFS. The 4-year PFS was 65% for patients with one HRCA (HR 2.31; p = 0.0004) and 55% for those with ≥ 2 HRCAs (HR 2.75; p = 0.0001). In this large MRD-negative post-ASCT cohort, several HRCAs, including isolated HRCAs, remained clinically meaningful drivers of inferior PFS, highlighting that early MRD negativity does not uniformly mitigate the impact of high-risk biology.

Background: Knee injuries are among the most common injuries in female basketball players. Despite the growing popularity of professional women's basketball, particularly the Women's National Basketball Association (WNBA), there are limited recent data evaluating the incidence of and risk factors for knee injuries in WNBA athletes. Hypothesis: Older age, minutes played per game, number of games played, and player usage rate would be significantly associated with having a knee injury in WNBA players from the 2017 to 2022 seasons. Study Design: Descriptive epidemiology study. Methods: Publicly available data on the injury history and player records of active WNBA players between the 2017 and 2022 seasons were reviewed to identify players with a knee injury resulting in ≥1 games missed. The primary outcome was the incidence of knee injuries reported per 1000 minutes-exposures (MEs). Player demographics, statistics, and injury characteristics were recorded. Secondary analysis was conducted using bivariate and multivariable logistic regression to investigate risk factors associated with having a knee injury. Results: A total of 87 players (10.8% of all players) sustained a combined 104 knee injuries between the 2017 and 2022 seasons, indicating a rate of 6.03 knee injuries per 1000 MEs. Accounting for potential confounders, having a knee injury was significantly associated with older age (OR, 1.11; 95% CI, 1.05-1.18; P = .0002) and higher usage rate (OR, 1.06; 95% CI, 1.02-1.11; P = .02). Conclusion: This study showed that knee injuries occurred in 10.8% of players, with an overall rate of 6.03 injuries per 1000 MEs. The most significant risk factors associated with having a knee injury in WNBA athletes were older age and higher player usage rate. Implementing targeted load management strategies for players with higher usage rates or advanced age may help reduce the incidence of knee injuries among female basketball athletes.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

Abstract Despite the reported benefits of testosterone replacement therapy (TRT), prior studies have shown that TRT is correlated with increased incidence of adverse outcomes after orthopedic procedures. There is a paucity of literature assessing the outcomes of patients on preoperative TRT undergoing distal radius open reduction and internal fixation (DR-ORIF). Our purpose was to evaluate rates of surgical and medical complications in patients on TRT undergoing DR-ORIF with a matched control cohort. The PearlDiver database was queried for patients who used TRT within 3 months prior to the index procedure. Patients were matched 1:4 with nonuser controls using propensity score matching. Matching was conducted based on age, Elixhauser Comorbidity Index, hypogonadism, osteoporosis, and other comorbidities. Complications were assessed at 90 days and 2 years. Statistical analyses were conducted using chi-square tests. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for each complication. Statistical significance was determined at a p-value of < 0.05. The matched group included 657 TRT users and 2,236 controls. There were significant differences in depression (control: 40.6% vs. TRT: 45.7%, p = 0.02) and rates of hypogonadism (control: 74.1% vs. TRT: 77.9%, p = 0.05) between the groups. No other statistically significant demographic or characteristic differences were noted. TRT use was not associated with increased surgical or medical complication rates at 90 days postoperatively. At 2 years, TRT use was associated with a greater incidence of revision (OR: 2.80, 95% CI: 1.34–5.85) and nonunion (OR: 2.76, 95% CI: 1.59–4.81). There were no other associations noted at 2 years. Preoperative TRT was associated with an increased risk of revision surgery and nonunion at 2 years postoperatively. No other significant associations in the risk of major or minor complications were observed. Level III

776 Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT. Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS -mutated ( KRAS mut) and KRAS wild-type ( KRAS wt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p<0.05) for survival. Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C <1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRAS mut pts showed a clinically meaningful worse mOS compared to KRAS wt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 - 2.63); p=0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 - 1); p=0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRAS wt, KRAS mut pts were enriched for TP53 (76% vs 22%; p<0.001), SMAD4 (28% vs 5.8%; p<0.001), CDKN2A (33% vs 8.5%; p<0.001), MTAP deletions (7.7% vs 1.2%; p<0.001), and chromatin-regulator alterations ( ARID1A 7.8% vs 1.2%; p<0.001; KMT2C 2.5% vs 0.6%; p=0.034). KRAS wt pts were enriched for BRAF V600E (1.5% vs 0%; p<0.001). PD-L1 TPS ≥1% was more frequent in KRAS mut compared to KRAS wt (11.0% vs 8.1%; p=0.033). Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRAS wt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

629 Background: NENs are a heterogeneous group of tumors with variable clinical behavior. While most NENs occur sporadically, a subset arises in the context of germline cancer predisposition syndromes. The prevalence of GPVs in NENs is increasingly recognized, but the reported frequency and spectrum of genes involved remain inconsistent across studies. Therefore, systematic review and meta-analysis is helpful to clarify the prevalence and clinical significance of PGVs in pts with NENs. Methods: A systematic review with meta-analysis of prospective and retrospective studies reporting germline testing in pts with NENs was conducted according to the PRISMA guidelines. The primary outcome was the prevalence of GPVs. Random-effects models (GLMM) with logit transformation were applied to estimate pooled prevalence with 95% confidence intervals (CIs). Results: Nine studies comprising 1304 patients with NENs were included. The median age was 53.8 (10-88.5) years, 52% were female (n=678/1304), and 56% (n=736/1304) were unselected cohorts (all-comers) and 44% (568/1304) were selected cohorts (testing based on clinical suspicion and high-risk features defined by each study). Across all cohorts, the pooled prevalence of PGVs was 19.6% (95% CI: 10.68–33.15%), with high heterogeneity (I² ≈ 96%). Subgroup analyses demonstrated comparable GPV prevalence between selected (13.2%, 95% CI 6.3–25.8) and unselected cohorts (23.0%, 95% CI 12.0–39.6) (p=0.25). GPV prevalence stratified by pancreatic NENs (17.8%, 95% CI 12.6–24.5) and other NENs (10.6%, 95% CI 6.5–17.0) was also not statistically different (p=0.08). The most altered genes involved DNA repair and cellular signaling pathways, including APC, ATM, BRCA1/2, BAP1, CHEK2, MEN1, MUTYH, VHL, RET, and TSC1/2. Germline variants in mismatch repair (MMR) genes were reported in approximately 2.5% of cases. Conclusions: This study represents the first systematic review and meta-analysis evaluating the prevalence of germline mutations in NENs. Approximately 20% of pts with NENs harbor a germline pathogenic variant, underscoring the importance of genetic counseling and germline testing. The wide variability across studies highlights the need for standardized genetic testing approaches. These findings support routine referral for genetic counseling and panel testing in patients with NENs to guide management and familial risk assessment.