Supplemental Methods. Supplemental Table 1: Dose levels for irinotecan, 5-FU, leucovorin and nab-paclitaxel

TP53 wild-type and mutant patients received similar definitive treatment.

Patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC) treated with single-agent cetuximab (C) or panitumumab (P), have improved progression-free survival (PFS) and overall survival (OS) compared to best supportive care but an objective response rate (ORR) of only 13–17

1506 Background: Typical workflows for clinical trial start-up and screening are time- and resource-intensive. The Tempus AI TIME program offers a novel clinical trial solution, collaborating with clinical sites to increase trial access and alleviate site burden by streamlining study activation and screening methods. Methods: The TIME program consists of an algorithmic trial screening platform (TApp), team of oncology nurses, diverse trial portfolio, and rapid study activation processes. Patient-level clinical information is centralized within the TIME database and includes structured and unstructured data generated from Electronic Medical Record integration, next generation sequencing results, and natural language processing models. The TApp used this data combined with trial eligibility criteria to algorithmically match patients to TIME trials. TApp searches were triggered by changes to study criteria and/or updates to clinical data. Algorithmic matches were filtered based on site capabilities, site interest in the trial, and trial lookback criteria, which defined the required recency of a patient's latest clinical document or encounter. Qualifying matches were then reviewed by a Tempus nurse and sent to sites if confirmed eligible. Trial activations followed TIME’s streamlined operational methods using a pre-negotiated rate card for site reimbursement of all clinical trial activities, standardized clinical trial agreement, and central IRB. Trials could be activated prospectively before the first eligible patient was identified, or in a “just-in-time” (JIT) manner if a patient was ready to consent. Data collected included TIME network information, TApp and nurse screening results, activation timelines, and enrollments across all active TIME sites and trials from 01/01/2024 - 12/31/2024. Results: During 2024, the TIME network consisted of 87 sites (79 Community, 8 Academic) and 98 trials. The TApp completed 1,323,259,353 searches across 1,281,676 patients resulting in 2,251,505 potential TApp trial matches. After applying site capability and trial lookback filters, TIME nurses screened 35,912 of these matches with 5,034 confirmed. These matches led to 186 activations (82 JIT, 104 prospective) and 573 consents. Conclusions: The Tempus AI TIME program facilitated the screening of 1.28M+ patients for over 95 clinical trials, averaging 1.57 consents per day over 1 year. Future trial matching strategies should utilize algorithmic screening and rapid activation processes to improve patient access and trial success. 2024 patient screening and consents. Patient Population 1,281,676 TIME Trials 98 TApp Searches 1,323,259,353 Algorithmic Matches 2,251,505 Matches Screened 35,912 Matches Confirmed 5,034 Interventional Consents 225 Observational Consents 348 Total Activations JIT: 82, Prospective: 104 Avg Activation Time (business days) JIT: 16.1, Prospective: 39.6

List of all observed somatic mutations in TP53.

Adverse events at least possibly related to study drug by NIH-NCI Common Terminology Criteria for Adverse Events (CTCAE), version. 4.0.

PURPOSE To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-na & iuml;ve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined fi ned by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined fi ned by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-na & iuml;ve tumors from long-term survivors (overall survival > 3 years) compared with short-term survivors (overall survival < 1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs-na & iuml;ve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.

BACKGROUND:Sarcopenic obesity and muscle attenuation have been associated with survival in patients with borderline resectable and advanced pancreatic ductal adenocarcinoma (PDA); however, these relationships are unknown for patients with resectable PDA. This study examined the associations between skeletal muscle and adipose tissue as measured on baseline computed tomography (CT) and the overall survival (OS) of participants with resectable PDA in a secondary analysis of the Southwest Oncology Group S1505 clinical trial (identifier: NCT02562716). METHODS:The S1505 phase II clinical trial enrolled patients with resectable PDA who were randomized to receive modified FOLFIRINOX or gemcitabine and nab-paclitaxel as perioperative chemotherapy, followed by surgical resection. Baseline axial CT images at the L3 level were analyzed with externally validated software, and measurements were recorded for skeletal muscle area and skeletal muscle density, visceral adipose tissue area (VATA) and density, and subcutaneous adipose tissue area and density. The relationships between CT metrics and OS were analyzed using Cox regression models, with adjustment for baseline participant characteristics. RESULTS:Of 98 eligible participants with available baseline abdominal CT, 8 were excluded because of imaging quality (eg, orthopedic hardware), resulting in 90 evaluable cases: 51 men (57.0%; mean age, 63.2 years [SD, 8.5]; mean body mass index [BMI], 29.3 kg/m2 [SD, 6.4]), 80 White (89.0%), 6 Black (7.0%), and 4 unknown race (4.0%). Sarcopenia was present in 32 participants (35.9%), and sarcopenic obesity was present in 10 participants (11.2%). Univariable analyses for the 6 variables of interest indicated that the standardized mean difference (hazard ratio [HR], 0.75; 95% CI, 0.57-0.98; P = .04) was statistically significantly associated with OS. In models adjusted for sex, race, age, BMI, performance score, contrast use, sarcopenia, and sarcopenic obesity, VATA was statistically significantly associated with OS (HR, 1.58; 95% CI, 1.00-2.51; P = .05). No difference was observed in OS between participants according to sarcopenic obesity or sarcopenia categories. The median OS estimates were 25.1 months for participants without sarcopenic obesity, 18.6 months for participants with sarcopenic obesity, 23.6 months for participants without sarcopenia, and 27.9 months for participants with sarcopenia. CONCLUSION:This was the first study to systematically evaluate body composition parameters in a prospective multicenter trial of patients with resectable PDA who received perioperative chemotherapy. Visceral adipose tissue was associated with survival; however, there was no association between OS and sarcopenia or sarcopenic obesity. Further studies should evaluate these findings in more detail.

1527 Background: Understanding of information needs and information-seeking styles of patients with cancer is critical for shared decision-making and high quality care. Most patients with cancer want to be involved in the decision-making process but have unmet information needs regarding their disease and its treatment. The goal of this study is to 1) identify information needs and 2) investigate factors associated with information-seeking styles pre-and-post treatment among patients with cancer. Methods: This is a secondary data analysis of a longitudinal study of 1003 patients from nine community oncology practices across the United States that assessed information needs of patients with cancer. We recruited patients aged ≥18 years with a newly diagnosed cancer. Patients supplied demographic and clinical information at enrollment; information needs assessment including concerns (score ranging, 0-100) and anticipated side effects (0-60), questions on information-seeking styles (1-item), decision-making preferences (1-item), and resource usage (5-items) were obtained within two weeks pre-and-post treatment. We performed multinomial logistic regression to evaluate the association of information needs including concerns, anticipated side effects, and decision-making preferences with information-seeking styles (active vs. passive) at pre-and-post treatment. The analysis was adjusted for age, gender, race, marital status, education, overall health, and cancer and treatment types. Results: Mean age was 60.5 (SD=13.0) years. Most were White (93.0%), female (64.0%), had some college (54.3%), and were diagnosed with breast cancer (47.0%). The sources of health information included friends (52.7%), pamphlets (60.2%), and experts (75.6%). Of the total, 43.8% reported that they preferred shared decision making but had concerns about understanding the diagnosis (70.2%) and treatment plan (70.7%). On logistic regression, preference for shared decision making (vs. doctor making all decisions; Odds Ratio (OR) pre-treatment=1.87, p=.01; OR post-treatment =2.3, p<.001), taking notes while meeting with doctor (vs. not taking notes; OR pre-treatment =2.2, p<0.001; OR post-treatment =1.8, p=0.01), and information sought that could be useful later (vs. not useful; OR pre-treatment = 1.9, p=.03; OR post-treatment =1.3, p=0.38) were associated with greater odds of active information seeking. Education and cancer type (pre-treatment) and age, cancer, and treatment types (post-treatment) were significantly associated with active information seeking. Conclusions: Shared decision making and taking notes during doctor visits are crucial factors associated with active information seeking. Interventions tailored to meet information needs of these patients may help increase patient participation in healthcare decision making.

BackgroundDespite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors.MethodsHere, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high.ResultsThe OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control.ConclusionsHere, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors.Trial registration numberNCT04510129.

6008 Background: Anti-PD1 therapy has become an essential treatment in recurrent and metastatic head/neck squamous cell carcinoma (HNSCC). The optimal use of anti-PD1 therapy in the curative setting is not established. Understanding the benefits of adjuvant anti-PD1 treatment in high risk HNSCC patients treated with curative intent is necessary. Methods: The PATHWay trial (NCT02841748) is a multi-site, randomized, placebo (PL) controlled trial of pembrolizumab (IO) in patients following curative treatment of high recurrence risk HNSCC. Patients with AJCC 7 th edition stage IVa, IVb, and select III HNSCC or multiple primaries were eligible if their cancers had an estimated > 40% chance of recurrence and were not eligible for additional therapy. Patients enrolled into six group criteria: A) high risk nodal disease or interrupted radiation treatment; B) salvage surgery including positive margin; C) Indeterminate distant lesions concerning for metastasis; D) Oligometastatic disease treated definitively; E) Microscopic residual disease after surgery; or F) Multiple prior recurrences or multiple treated primaries who have undergone surgery ≥ 2 times. Patients were randomized with stratification for HPV and EBV status, and received pembrolizumab 200mg IV or placebo for up to 18 cycles. The primary study endpoint was progression-free survival (PFS). The targeted sample size was N=100 patients (50 per arm), which provided >90% power to detect a hazard ratio (HR) of 0.45, based on a stratified logrank test at a one-sided alpha level of 0.10. Results: A total of n=49 IO and n=51 PL patients were enrolled between 2016 and 2023 across 10 US sites. Mean age was 62; 33% female; 45% nonsmoker; 20% HPV+, 2% EBV+. Cancers were stage III (24%), IVa (39%), IVb (8%), with prior surgery in 95% and prior RT in 78%. Median follow-up was 33 months. Compared to PL, IO treated patients had superior PFS with HR 0.61 (80% CI: 0.43-0.86, one-sided p=0.021). PFS rates for IO were 65% and 54% at 1 and 2 years, respectively compared to 48% and 33%, respectively for PL. Overall survival (OS) was not significantly different in IO vs. PL treatment (HR = 1.00, 80% CI: 0.6-1.68, p=0.45). IO improved PFS in 2 sub-groups: In post-salvage surgery patients (group B, n=37), IO had superior PFS vs. PL (HR 0.34, 80% CI: 0.18-0.67, p=0.016); In patients with multiple recurrences/primaries (group F, n=37) IO had superior PFS vs. PL (HR 0.48, 80% CI: 0.27-0.88, p=0.057). Adverse events between treatments were comparable, with 3 (6%) grade 4 adverse events in PL and 1 (2%) grade 5 (2%, unrelated) and 1 grade 4 (2%) in IO. Conclusions: Pembrolizumab treatment for 1 year in patients with high risk of recurrent HNSCC following curative therapy resulted in a statistically significant improvement in PFS compared to placebo, and the benefit was maintained in key subgroups. Clinical trial information: NCT02841748 .

Myelofibrosis (MF) in the chronic phase is a challenging disease entity to treat, and conventional treatment options are geared towards symptom palliation. In this prospective, multicenter, phase II trial, 21 patients with myelofibrosis (18 chronic-phase, 2 accelerated-phase, 1 blast-phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg/day. The overall response rate was 33% (95% CI, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44). A high IPSS risk score, high baseline fetal hemoglobin level, and sustained decreases in circulating CD34+ cell counts were associated with response to decitabine. All patients experienced at least one grade 3 or 4 cytopenia. Non-hematologic toxicities were less frequent, with fatigue, anorexia, and hypocalcemia being the most common. Given the lack of effective therapies in myelofibrosis with severe cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. NCT00095784.

12004 Background: Cancer-related cognitive impairment (CRCI) is common among breast cancer survivors (BCS). Prior studies of late CRCI suggest repurposing cognitive enhancing medication may benefit survivors. The REMEMBER prospective, randomized, double-blind, placebo-controlled trial compared the efficacy of donepezil, an acetylcholine esterase inhibitor, versus placebo to reduce late CRCI among BCS previously exposed to chemotherapy. (Clinical Trials #NCT02822573). Methods: Women ≥ 18 years of age, with a history of breast cancer who completed ≥ 4 cycles of chemotherapy 1 to 5 years prior to enrollment, self-reported CRCI, with evidence of a memory deficit on the Hopkins Verbal Learning Test-Revised (HVLT-R) were eligible. Women were randomized to a 24-week course of donepezil (5mg/daily x 6 wk. titrated to 10mg/daily x 18 wk.) or placebo. A cognitive battery assessing memory, attention, executive function, verbal fluency, and processing speed was administered at baseline, week 12, 24 (end of intervention), and 36 (wash-out) along with patient-reported outcome measures and adverse events. There was 90% power to detect a treatment difference of 2 words for HVLT-IR (effect size=0.47) Mixed effects repeated measures analysis of covariance (RMANCOVA) models were utilized to assess treatment differences in memory (primary outcome) and other cognitive domains (secondary outcomes) with model covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification and an unstructured covariance matrix to account for within participant correlation over time. Results: A total of276 patients from 87 NCORP sites (mean age=57.1yr, SD=10.5) an average of 29.6 months post-chemotherapy completion were randomized to donepezil (n=140) or placebo (n=136). The primary outcome of memory (HVLT-R total) at 24 weeks was not different between treatments (donepezil mean=25.98, placebo = 26.50, p=0.32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks on attention, executive function, verbal fluency, or processing speed. Exploratory analyses additionally adjusting for education, baseline fatigue and depression as well as independent analyses considering treatment interaction with endocrine therapy and menopausal status also did not result in any differences by group for any outcomes. Twenty-five grade 3 or 4 adverse events were reported with no differences by treatment. Conclusions: BCS 1-5 years after completing chemotherapy, randomized to 24 weeks of a daily dose of 5-10mg of donepezil, did not perform differently at the end of treatment on tests of memory or other cognitive functions than survivors randomized to placebo. Funding: NIH/NCI 2UG1CA189824. Clinical trial information: NCT02822573 .

Purpose Anti-PD-1 therapy provides clinical benefit in 40–50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. Methods Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. Results The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). Conclusion This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Background The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)-based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. Methods In this double-blind, phase III trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease free after 5 years of an AI or tamoxifen followed by an AI, were randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. Results Between September 2006 and January 2010, 3966 patients were randomly assigned (letrozole: 1983; placebo: 1983). Median follow-up time for 3923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared with placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.74 to 0.96; P = .01; 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference = 3.3%). There was no difference in the effect of letrozole on overall survival (HR = 0.97, 95% CI = 0.82 to 1.15; P = .74). Letrozole statistically significantly reduced breast cancer-free interval events (HR = 0.75, 95% CI = 0.62 to 0.91; P = .003; absolute difference in cumulative incidence = 2.7%) and distant recurrences (HR = 0.72, 95% CI = 0.55 to 0.92; P = .01; absolute difference = 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. Conclusions The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also improved breast cancer-free interval and distant recurrences without improving overall survival. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT.

Figure SF3 Comparisons of the expression of the NRG family of ERBB ligands, at the RNA level, between post-anti-EGFR metastatic biopsies collected upon enrollment into FC-7, and post-neratinib residual tumor tissue samples.

Figure SF2: cfDNA mutational analysis cfDNA from plasma collected upon enrollment was analyzed for mutations with a 74-gene Guardant panel (1). Alterations were identified in 30 genes as shown in the figure. Patient IDs: Green=Stable Disease, Red=Progressive Disease, and Black=non-evaluable. Specific patients are discussed below and in the main text.

Perspectives on this Article from Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer

Supplementary Figure from Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer