Michigan Cancer Research Consortium

BackgroundMedications such as proton pump inhibitors (PPIs), antihistamines, and nonsteroidal anti‐inflammatory drugs have been linked to immune checkpoint inhibitor (ICI) efficacy in patients with non–small cell lung cancer (NSCLC), but these associations may reflect unmeasured confounding rather than true pharmacologic effects. This study evaluated whether commonly prescribed medications influence ICI outcomes, using a national patient sample and a negative control cohort.MethodsThe authors identified Veterans Health Administration (VHA) patients with stage IV NSCLC treated with first‐ or second‐line ICI therapy (n = 3739) or chemotherapy (n = 6585) from 2005 to 2023. Baseline use of 20 common medication classes and an immunomodulatory drug score were assessed. Propensity‐weighted Cox regression evaluated associations between each medication class and overall survival (OS) or time‐to‐next treatment (TTNT) in the ICI group. For any medication with a nominally significant association (p < .05), the same analysis was repeated in the chemotherapy group to test for nonspecific effects.ResultsAfter propensity weighting, 14 of 20 medication classes showed no association with OS or TTNT in the ICI cohort. Loop diuretics, anticoagulants, opioids, penicillin antibiotics, and fluoroquinolone antibiotics were associated with worse outcomes, but similar effects were seen in the chemotherapy group. A higher immunomodulatory drug score was also associated with inferior outcomes among ICI patients, but this association was likewise present in the chemotherapy cohort.ConclusionIn this study, commonly prescribed medications did not appear to alter ICI efficacy in stage IV NSCLC. Prior associations reported in the literature may be attributable to unmeasured confounding rather than true drug–immunotherapy interactions.

265 Background: Cancer rates in Michigan often exceed national averages, highlighting the need for improved patient-centered care. The Michigan Oncology Quality Consortium (MOQC), its Patient and Caregiver Oncology Quality Council (POQC), and the Patient Advocate Foundation (PAF) collaborated to develop a blueprint for patient-driven and practice-informed social drivers of health (SDOH) screening in cancer care settings. While SDOH significantly impact outcomes, current screening processes lack patient and caregiver input and standardization. This project engaged patients and stakeholders to understand how SDOH screenings affect oncology workflows and experiences, identify reporting and care delivery challenges, and explore improvements that support patient needs while reducing burdens on practices. Methods: Three small oncology practices in rural Michigan serving low-income and under-resourced populations in outpatient settings were chosen to examine their SDOH screening processes. A thorough literature review was conducted and clinical documents were reviewed to inform tailored interview guides, with POQC and PAF contributing patient-centered insights. A team from MOQC/POQC conducted 42 interviews with a range of staff, including clinicians, navigators, and administrators, focusing on SDOH screening use, workflow impacts, patient support resources, follow-up practices, and opportunities for improvement. Results: All three practices conducted a SDOH or social needs screening, but with inconsistent implementation. Thematic analysis identified three key social needs- transportation, housing, and financial hardship. Common barriers included patient stigma, staff discomfort with sensitive topics, limited resources (especially in rural areas), and lack of staff training. Practices reported no formal follow-up process to track whether patients accessed referred resources. While challenges persist, some practices are beginning to adapt in anticipation of the upcoming Centers for Medicare and Medicaid Services’ requirements to collect health-related social needs data in outpatient settings. Conclusions: This collaborative effort to understand how SDOH screenings function in Michigan oncology practices reveals critical gaps in consistency, follow-up, and support for patient needs. These findings provide the foundation for co-designing an equitable, patient-centered screening and response framework that can better address social needs while being practical for lower-resourced settings. Grounded in the experiences of both clinicians and patients, this work will inform a scalable model to improve outcomes and reduce disparities in oncology care.

SummaryKRAS is the archetypal oncogenic driver of pancreatic cancer. To identify new modulators of KRAS activity in human pancreatic ductal adenocarcinoma (PDAC), we performed regulatory network analysis on a large collection of expression profiles from laser capture microdissected samples of PDAC and benign controls. We discovered that BMAL2, a member of the PAS family of transcription factors, promotes tumor initiation, progression, and post-resection survival, and is highly correlated with KRAS activity. Functional analysis of BMAL2 target genes suggested a role in regulating the hypoxia response, a hallmark of PDAC. Knockout of BMAL2 in multiple human PDAC cell lines reduced cancer cell viability, invasion, and glycolysis, leading to broad dysregulation of cellular metabolism, particularly under hypoxic conditions. We find that BMAL2 directly regulates hypoxia-responsive target genes and is necessary for the stabilization of HIF1A under low oxygen conditions, while simultaneously destabilizing HIF2A. Notably, in vivo xenograft studies demonstrated that BMAL2 loss significantly impairs tumor growth and reduces tumor volume, underscoring its functional importance in tumor progression. We conclude that BMAL2 is a master transcriptional regulator of hypoxia responses in PDAC that works downstream of KRAS signaling, possibly serving as a long-sought molecular switch that distinguishes HIF1A- and HIF2A-dependent modes of hypoxic metabolism.

556 Background: Cancer-related fatigue (CRF) is reported by ~75% of patients receiving chemotherapy for breast cancer. CRF has been linked to inflammation. Chronic, low grade systemic inflammation is a polygenic trait, and a polygenic risk score for inflammation (iPRS) might be associated with risk of CRF. Methods: Using data from the UK Biobank,we developed an iPRS using the INFLA-score, a composite measure of serum C-reactive protein, white-cell count, platelet count, and neutrophil-lymphocyte ratio. The iPRS was evaluated for association with CRF among women with non-metastatic breast cancer enrolled in one of two completed multi-site clinical trials of the University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP) Research Base. CRF was measured before and after standard-of-care chemotherapy using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Linear regression evaluated the change in MFSI-SF score from pre- to post-chemotherapy; logistic regression evaluated a binary outcome of any vs no worsening of scores. Analyses were adjusted for patient and treatment factors. Results: The NCORP cohort included 802 women who received chemotherapy (anthracycline-based = 51.8%; previous surgery = 85.0%) at a median age of 55 years (range = 22 to 81). There was an increase in MFSI in 55% of the women, with a mean increase of 8 (range=-64 to 71) from prechemotherapy (mean=8, range = -24 to 83) to post-chemotherapy (mean=15.3, range = -24 - 88), indicating an overall increase in CRF. The iPRS was associated with a significant decrease in MFSI-SF (β=-3.29; 95%CI=-6.25 to -0.34; P =0.029; covariate-adjusted β=-2.71; 95%CI=-5.50 to 0.08; P =0.057) and lower odds of worsening CRF (OR=0.66; 95%CI=0.47-0.93; P =0.016; covariate-adjusted OR=0.67; 95%CI=0.47 to 0.96; P =0.029). The negative relationship between the iPRS and change in CRF was partially explained by the finding that women with an iPRS in the highest quartile have worse pre-chemotherapy MFSI-SF scores (β=4.33; 95%CI=0.23 to 8.43; P =0.038). Conclusions: Women with genetic predisposition to low-grade systemic inflammation, indicated by a higher iPRS, have worse CRF pre-chemotherapy that does not worsen, and may improve, over the course of treatment while women with a lower iPRS have less CRF pre-chemotherapy and are at greatest risk of developing new or worsening CRF during treatment. If validated, the iPRS could identify patients in need of supportive care interventions to reduce CRF. This work was supported by the National Institutes of Health National Cancer Institute Contract No. HHSN261201500003I, Task Order No. HHSN261000039 and by UG1CA189961, URCC NCORP Research Base.

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with ATM mutation (mut) or deletion (del) treated with Tala are reported. Methods: Eligible pts had metastatic solid tumors, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Low accruing histology-specific cohorts with ATM alterations were collapsed into 1 histology-pooled cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR) and SD, and safety. Results: 29 pts with nine different solid tumors with ATM mut (n=28) or del (n=1) were enrolled. 1 pt was not evaluable for efficacy. Table shows demographics, outcomes, and toxicity. 2 PR (lung and thyroid) and 10 SD16+ (pancreas [3], prostate [2], colon, breast, kidney, rectum, stomach, thyroid) were observed in pts with ATM mut for a DC rate of 41% (1-sided 90% CI, 29 to 100) and an OR rate of 7% (95% CI, 1 to 23). The null DC rate was rejected (p=0.0005). The pt with PR and lung cancer is still on tx and has exceeded 73 wks on study as of October 2024. 8 pts had ≥1 grade 3-4 tx-related adverse event (AE). No tx-related serious AE were reported. Conclusions: Tala met prespecified criteria to declare a signal of activity in pts with solid tumors with ATM mut. Citation Format: Elie G. Dib, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Dustin Bivins, Mark Gitau, Apar K. Ganti, Arthur Winer, Vijay Suhag, Darryl Outlaw, Michael J. Hall, Olatunji B. Alese, Reza Nazemzadeh, Evan Pisick, Fengting Yan, Navid Hafez, Carmen J. Calfa, Lex Leonhardt, David DeRemer, Abigail Gregory, Dominique C. Hinshaw, Gina N. Grantham, Susan Halabi, Richard L. Schilsky. Talazoparib (Tala) in patients (pts) with solid tumors with ATM alterations: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT228.