Vanderbilt-Ingram Cancer Center Research Articles

Oncogenic GNAS drives a pyloric-type transcriptomic program in pancreatic intraepithelial papillary mucinous neoplasms

BACKGROUND & AIMS: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions of the pancreas which can serve as precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia (ADM), an injury repair program associated with pancreatic tumorigenesis, is characterized by a pyloric-type transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for SPEM markers and to identify molecular drivers of this program. METHODS: Published RNA-seq studies of IPMN were assessed for SPEM markers, which were validated by immunostaining in patient samples. Murine cell lines expressing KrasG12D +/- GNASR201C were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify drivers of SPEM in the pancreas. Expression of candidate drivers was evaluated in patient samples by RNA-seq and immunostaining and a role for SPDEF was investigated. RESULTS: SPEM markers were identified in human IPMN. GNASR201C drove expression of these markers in murine cell lines and siRNA targeting of GNASR201C or KrasG12D demonstrates that GNASR201C amplifies a mucinous phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. CONCLUSIONS: De novo expression of a pyloric-type/SPEM phenotype has been identified in pancreatitis, oncogenic KrasG12D-driven pancreatic neoplasia, and in KrasG12D;GNASR201C-driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. IPMN-specific GNASR201C drives a SPEM phenotype characterized by the formation of mucus producing cells at the expense of other lineages. AMR was supported by NIH T32GM139400. AM is supported by the MD Anderson Pancreatic Cancer Moon Shot Program, the Sheikh Khalifa Bin Zayed Al-Nahyan Foundation and NIH (U01CA200468, U54CA274371, U24CA274274, R01CA220236). M.C.B.T is supported by a Vanderbilt Digestive Disease Research Center Pilot and Feasibility Grant (P30 DK058404) and a Nikki Mitchell Foundation Pancreas Club Seed Grant. M.C.B.T and N.J. are supported by The Department of Defense (DOD W81XWH2211121-1). The DelGiorno laboratory is supported by the Vanderbilt Ingram Cancer Center Support Grant (NIH/NCI P30 CA068485), the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer (NIH/NCI 5P50 CA236733), the Vanderbilt Digestive Disease Research Center (NIH/NIDDK P30 DK058404), an American Gastroenterological Association Research Scholar Award (AGA2021-13-02), NIH/NIGMS R35 GM142709, The Department of Defense (DOD W81XWH2211121), The Sky Foundation, Inc (AWD00000079), and Linda’s Hope (Nashville, TN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 6476: Solving the real-world data challenge: A hybrid resourcing model to curate RWD at scale

Abstract Introduction: As cancer treatments become more complex, the need for structured real-world data (RWD) to support clinical research is critical. However, researchers often lack resources to curate data in-house. Organizations are challenged with timely data curation at the quality and scale needed for real world applications. Methods: As members of the AACR Project GENIE (Genomics Evidence Neoplasia Information Exchange) Biopharma Collaborative (BPC), Memorial Sloan Kettering Cancer Center (MSK) and Dana-Farber Cancer Institute (DFCI) partnered with Vasta Global, an Omega Healthcare company, to build a model for curating RWD at scale, allowing for cost-effective RWD curation while leveraging expert resources and best practices. The approach includes managing a hybrid onshore and offshore team with clear communication and recurring check-ins, cross-training curators on different EHRs to reallocate Vasta Global resources and maintain project pace, building program-specific clinical data curation training, establishing QA and delivery methods, standardizing data curation, assigning productivity standards, aligning data quality practices and benchmarks, and developing data visualizations and analytics to show progress and insights. Results: In Phase 1 of the AACR GENIE BPC, data was curated from four sites: MSK, DFCI, Vanderbilt Ingram Cancer Center (VICC) in Nashville, and Princess Margaret Cancer Centre, University Health Network (UHN) in Toronto. During Phase 1, MSK and DFCI, with Vasta Global’s assistance, delivered high-quality RWD for 6,475 patients (NSCLC = 1,591; CRC = 1,264; Bladder = 639; Breast = 957; Pancreas 989; and Prostate = 1,035). All data for these cohorts will be publicly available by Spring 2024 in the AACR Project GENIE cBioPortal. MSK and DFCI generated usable and fit-for-purpose RWD to help advance oncology clinical decision-making and data sharing. Conclusion: Accelerating RWD curation will empower the oncology community to leverage data-driven insights and advance treatment opportunities for cancer patients. Working alongside lead sites, a partner like Vasta Global enables researchers to leverage extensive expertise in the BPC data model, allowing for consistency and scalability of the BPC program. In this hybrid model, research partners can curate RWD in a cost-effective way, while remaining focused on core research responsibilities. Citation Format: Julia Rudolph, Kenneth L. Kehl, Melanie Bernstein. Solving the real-world data challenge: A hybrid resourcing model to curate RWD at scale [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6476.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study.

Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease. A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis. Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00-1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88-1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70-1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21-2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00-1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74-1.81; p=0.52]). APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease. This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Association between APOL1 risk variants and the occurrence of sepsis in Black patients hospitalized with infections: a retrospective cohort study

Background:Two risk variants in the apolipoprotein L1 gene (APOL1) have been associated with increased susceptibility to sepsis in Black patients. However, it remains unclear whether APOL1 high-risk genotypes are associated with occurrence of either sepsis or sepsis-related phenotypes in patients hospitalized with infections, independent of their association with pre-existing severe renal disease.Methods:A retrospective cohort study of 2242 Black patients hospitalized with infections. We assessed whether carriage of APOL1 high-risk genotypes was associated with the risk of sepsis and sepsis-related phenotypes in patients hospitalized with infections. The primary outcome was sepsis; secondary outcomes were short-term mortality, and organ failure related to sepsis.Results:Of 2242 Black patients hospitalized with infections, 565 developed sepsis. Patients with high-risk APOL1 genotypes had a significantly increased risk of sepsis (odds ratio [OR]=1.29 [95% CI, 1.00–1.67; p=0.047]); however, this association was not significant after adjustment for pre-existing severe renal disease (OR = 1.14 [95% CI, 0.88–1.48; p=0.33]), nor after exclusion of those patients with pre-existing severe renal disease (OR = 0.99 [95% CI, 0.70–1.39; p=0.95]). APOL1 high-risk genotypes were significantly associated with the renal dysfunction component of the Sepsis-3 criteria (OR = 1.64 [95% CI, 1.21–2.22; p=0.001]), but not with other sepsis-related organ dysfunction or short-term mortality. The association between high-risk APOL1 genotypes and sepsis-related renal dysfunction was markedly attenuated by adjusting for pre-existing severe renal disease (OR = 1.36 [95% CI, 1.00–1.86; p=0.05]) and was nullified after exclusion of patients with pre-existing severe renal disease (OR = 1.16 [95% CI, 0.74–1.81; p=0.52]).Conclusions:APOL1 high-risk genotypes were associated with an increased risk of sepsis; however, this increased risk was attributable predominantly to pre-existing severe renal disease.Funding:This study was supported by R01GM120523 (QF), R01HL163854 (QF), R35GM131770 (CMS), HL133786 (WQW), and Vanderbilt Faculty Research Scholar Fund (QF). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the CTSA grant UL1TR0004from NCATS/NIH. Additional funding provided by the NIH through grants P50GM115305 and U19HL065962. The authors wish to acknowledge the expert technical support of the VANTAGE and VANGARD core facilities, supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA068485) and Vanderbilt Vision Center (P30 EY08126). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C–mutated metastatic colorectal cancer in AACR Project GENIE.

41 Background: KRAS mutation accounts for ~37% of colorectal cancer (CRC), with KRAS G12C occurring in ~3% of CRC tumors. KRAS G12C mutation is associated with poorer prognosis in terms of real-world progression-free survival (rwPFS) and overall survival (OS) compared to other KRAS mutations and KRAS wild-type. As KRAS G12C mutated metastatic CRC (mCRC) is recognized as a discrete potentially druggable target, there is a need to further describe this patient population. This retrospective cohort study provides real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes (OS, rwPFS) in patients with KRAS G12C mutated mCRC. Methods: Adult (≥18 years old) patients diagnosed between 01 January 2009 and 01 February 2019 with KRAS G12C mutated mCRC were assessed from three US academic centers in AACR Project GENIE: Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Vanderbilt-Ingram Cancer Center. Patient characteristics and treatment patterns were reported, and median OS and rwPFS by line of therapy (LOT) were estimated with the Kaplan-Meier method, including exploratory analyses by co-mutation profile. Results: Among 71 mCRC patients, median age at initial diagnosis was 52.1 years, 59% were women, 83% were White, and 68% had initial stage 4 disease. Co-mutations with an oncogenic, likely oncogenic, or predicted oncogenic OncoKB annotation were assessed, and the most commonly observed were APC in 79% of patients, TP53 in 63%, and PIK3CA in 20%. Only 8% of patients had high tumor mutational burden (>10 mut/Mb), and no patients had microsatellite instability-high among those measured (n=48). Most patients (71%) had evidence of surgical resection in the metastatic setting. Nearly all (93%) patients had received systemic therapy: 15 (23%) had only one LOT, 20 (30%) had only two LOTs, and 31 (47%) had three or more. Most patients received oxaliplatin- or irinotecan-based regimens in the first two LOTs. Median OS from the start of first LOT was 33.5 months (95% CI: 26.9, 37.1), 20.7 months (95% CI: 6.4, 23.2) from start of second LOT, and 15.8 months (95% CI: 3.1, 23.4) from start of third LOT. Median rwPFS from start of first LOT was 20.9 months (95% CI: 8.4, 32.0), 4.0 months (95% CI: 2.2, 9.7) from start of second LOT, and 3.1 months (95% CI: 1.1, 7.2) from start of third LOT. Patients with FBXW7 co-mutation had shorter OS and patients with PIK3CA co-mutation had longer rwPFS, compared to those with KRAS G12C alone. Conclusions: In this select patient cohort with KRAS G12C mutated mCRC from US academic centers, outcomes, particularly rwPFS, were poor in later lines of therapy. Frontline OS and rwPFS were longer than in other similar studies, which may be attributable to the young median age and high proportion of surgical resection in the metastatic setting observed in this cohort.

Updated analysis: Effect of biweekly dosing schedule of trifluridine-tipiracil (TAS-102) on rates of myelosuppression and maintenance of therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).

95 Background: For surgically unresectable metastatic colorectal cancer pts, a continuum of treatment is required to improve the OS of our pts. Oral trifluridine-tipiracil (TAS-102) is FDA approved in refractory mCRC per the RECOURSE trial. As per the FDA insert, the recommended dose is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles commonly resulting in Grade 3-4 neutropenia (38%), dose delays (53%), dose reductions (14%) and requiring G-CSF support (9%). To maintain efficacy and to potentially reduce toxicity, we analyzed an alternative biweekly dosing (Days 1-5 and Days 15-19 q28 days). Methods: A retrospective analysis was completed (2019-2022) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed ≥ 12 days of TAS-102 therapy and underwent surveillance imaging every 8-12 weeks. Patient data was assessed for ECOG performance status (PS), prior lines of therapy, the use of bevacizumab and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was completed in mCRC pts. Results: Forty-three patients met the inclusion criteria, with a mCRC:appendiceal CA ratio of 39:4. The median age = 50 y/o (range 30-80); male:female 23:20; median ECOG PS = 1; median number of prior therapies = 3; and median duration of therapy = 97 days (range: 12-396). Associated grade 3/4 hematologic toxicities included: Neutropenia 39% [Grade 3 (12.2%), Grade 4 (2.4%)]; anemia 36.5% [Grade 3 (12.2%)]. No pts required G-CSF. No incidences of neutropenic fever were reported. Five pts (11.6%) required a dose delay and 3 pts (7%) required a dose reduction due to myelosuppression. In mCRC pts, the median PFS was 2.53 months. To date, 6 pts remain on treatment (range: 97-331). Conclusions: In our updated analysis, biweekly dosing of TAS-102 (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA demonstrated tolerable myelosuppression, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may potentially broaden utilization of TAS-102 in patients with borderline PS and may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this remains the first analysis of biweekly TAS-102 in a US patient population.

Concordance of genomic alterations in anal cancer by next-generation sequencing in tissue and circulating tumor DNA.

2 Background: The feasibility of identifying genomic alterations via next-generation sequencing (NGS) of peripheral blood (PB) to spare patients an invasive biopsy is an active area of investigation. High concordance of mutations between tissue and PB has been observed in several cancer types. However, the concordance between tissue and PB in patients with SCCA is unknown. Methods: We identified 11 patients with SCCA who had NGS (TEMPUS) performed on tissue and PB between 2017 - 2022. The IRB at Vanderbilt-Ingram Cancer Center approved this study. Results: See Table. Conclusions: In 6 of the 11 patients, concordant genomic alterations found in tissue were also identified in PB. More patients with anal cancer should be studied to better understand this phenomenon and the impact of therapy on ctDNA kinetics.[Table: see text]

Association between decline of neutrophil-to-eosinophil ratio (NER) at week 6 after ipilimumab plus nivolumab initiation and improved clinical outcomes in metastatic renal cell carcinoma (mRCC).

4527 Background: Low baseline NER has been associated with improved response to immunotherapy in mRCC (PMID:34732251). The current study aimed to investigate the early decline of NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. Methods: Retrospective chart review of ipi/nivo-treated mRCC patients at Vanderbilt-Ingram Cancer Center and Duke Cancer Institute was conducted. Landmark analysis at week 6 after ipi/nivo initiation was performed to assess the association between change in NER and clinical responses [progression-free survival (PFS)/overall survival (OS)]. Results: There were 150 mRCC patients included in the analysis: 78% had clear cell histology, 78% were IMDC intermediate/poor risk, and 74% were male. The median follow-up time was 11.9 months. After ipi/nivo initiation, the median NER decreased from 23.8 (interquartile range: 15.0-57.1) at baseline to 19.8 (10.6-40.8) at week 6; 102 (68%) patients had decreased NER. The NER at week 6 was grouped by percent change (≥ 50% decrease vs <50% decrease vs increase). In multivariable regression analysis after adjustment for age, sex, race, IMDC risk group, baseline NER, histology, prior systemic therapy, and prior nephrectomy (Table), decreased NER ≥ 50% was associated with improved PFS [adjusted hazard ratio (AHR): 0.55, p-value: 0.03] and OS (AHR: 0.38, p-value: 0.02) (Table). Stratified analysis was conducted by baseline NER [≥vs < baseline median NER (23.8)]: decreased NER ≥ 50% was associated with improved PFS (AHR: 0.46, p-value: 0.048) and OS (AHR: 0.29, p-value: 0.01) in the subgroup with high baseline NER. These associations were not observed in the subgroup with low baseline NER (p-value for PFS: 0.25; p-value for OS: 0.61). Conclusions: The decline of NER ≥50% at week 6 after ipi/nivo initiation was associated with improved PFS/OS in mRCC patients with high baseline NER. Prospective studies are warranted to validate NER change as a biomarker to predict response to ICIs in mRCC. [Table: see text]

Using a standard implementation science framework to improve clinical trial enrollment for a community Tennessee oncology center.

e18586 Background: Recommendations for clinical trial consideration are ubiquitous across all cancers. However, it is challenging to identify patients from underrepresented communities and offer them opportunities to enroll in clinical trials due to a multitude of reasons including social determinants of care, distance from clinical resources, lack of resources, etc. As part of the Leukemia & Lymphoma Society (LLS) Influential Medicine Providing Access to Clinical Trials (IMPACT) study, Vanderbilt-Ingram Cancer Center (Nashville, TN) partnered with Baptist Cancer Center (BCC, Memphis, TN) to improve accrual of trials for patients with Hodgkin’s lymphoma. BCC has an active NCI Community Oncology Research Program (NCORP) grant with 12 affiliated sites spread across Arkansas, Tennessee, and Mississippi and provides care for underrepresented minority, and underserved communities. Methods: We chose the Consolidated Framework for Implementation Research (CFIR), as a conceptual model to guide assessment of the existing process and inherent opportunities. We created a secure REDCap survey to identify timepoints in the existing clinician workflow and research sites that provide the best opportunities to discuss clinical trials with the patient. Retrospective data was collected for 67 patients diagnosed with Hodgkin’s lymphoma, who received care at six sites affiliated with BCC. A manual chart review was performed to extract data from the electronic medical record. Results: We observed that 73% of the patients from 2 sites already had an established diagnosis of Hodgkin’s lymphoma at the time of referral to the medical oncologist. By contrast, only 33% of patients from the remaining 4 sites had an established diagnosis at the time of referral. In these cases, the diagnosis was established after pathological testing ordered by the oncologist was performed. Conclusions: Using our analysis, we identified 2 sites from a large healthcare network that would benefit greatest from implementing pre-screening for clinical trials before the first visit with a medical oncologist. Further, we determined that efforts/resources for trial screening at the remaining 4 sites would be best served after pathological evidence of disease was established. Clinical trial enrolment is a multi-step process and needs substantial human and financial resources. Implementation science interventions can help to guide judicious use of resources while improving patient care in rural and underserved communities.[Table: see text]

Alternative biweekly dosing schedule of trifluridine-tipiracil (TAS-102) reduces rates of myelosuppression while maintaining therapeutic efficacy in patients (pts) with previously treated metastatic colorectal cancer (mCRC).

3559 Background: Colorectal cancer remains a significant source of morbidity and mortality within the United States, causing nearly 53,000 deaths in 2021. For unresectable pts, the estimated 5-year survival rate is 14%. Given recent advances in treatment, 50% of pts with mCRC will receive third-line therapy or greater, making optimization of therapy in these settings pivotal. Trifluridine-tipiracil (TAS-102) is FDA approved for third-line or greater in mCRC per the RECOURSE Trial. Standard dosing is 35 mg/m2 twice daily (maximum = 80 mg/day) on Days 1-5 and Days 8-12 of 28-day cycles. This dosing schedule is associated with Grade 3-4 neutropenia (38%), requiring treatment delays (53%), dose reductions (14%) and G-CSF support (9%). To reduce this toxicity while maintaining efficacy, we studied an alternative biweekly dosing (Days 1-5 and Days 15-19 of 28-day cycles). Methods: A retrospective analysis was completed (2019-2021) at Vanderbilt-Ingram Cancer Center in pts with refractory mCRC and appendiceal cancer (CA) who completed > 12 days of TAS-102 therapy. Diagnostic imaging was completed every 8-12 weeks. Patient data was evaluated for lines of prior therapy, ECOG performance status (PS), the addition of bevacizumab, and CTCAE grade of treatment-related myelotoxicity. Evaluation of progression-free survival (PFS) was performed only in mCRC pts. Results: 24 pts met the criteria, with a mCRC:appendiceal CA ratio of 20:4 and Male:Female 13:11. Median age 61.5 yrs (range 31-80); median number of prior therapies 3; median ECOG PS of 1; and median duration of therapy 73.5 days. Hematologic toxicities: Neutropenia 30% [Grade 3 (13%), Grade 4 (0%)]; anemia 17.4% [Grade 3 (8.7%), Grade 4 (0%)]; thrombocytopenia 4.3% [Grade 3/4 (0%)]. No pts required G-CSF. One patient required a treatment-related dose delay (neutropenia), and 2 pts required dose reductions (fatigue). In mCRC pts, the median PFS was 2.3 months. To date, 7 mCRC pts remain on treatment (range: 38-385). Conclusions: In our retrospective cohort analysis, TAS-102 biweekly dosing schedule (35 mg/m2 twice daily; Days 1-5 and Days 15-19 of 28-day cycles) for pts with refractory mCRC and appendiceal CA reduced Grade 3 myelotoxicity without Grade 4 toxicities, while preserving PFS in pts with mCRC. With an improved toxicity profile, this alternative TAS -102 dosing schedule may be a more favorable option for future combination studies. Additional prospective data are needed to validate these findings. To our knowledge, this is the first analysis of biweekly TAS-102 in a US patient population.

Oncologist participation in pilot testing a crowdsourcing platform to build a survivorship care risk model.

e13568 Background: Crowdsourcing as a means of codifying the knowledge of many individuals can be an effective way to build models where data do not exist to inform these models. Risk for health complications during cancer survivorship is one area where there are limited large datasets that track detailed outcomes. While many survivorship care expert groups such as the National Comprehensive Cancer Network (NCCN) and Children’s Oncology Group (COG) Survivorship Guidelines Panels recognize the need for a stratified system of assigning survivorship care, criteria for assigning risk to individuals at the end of active cancer treatment are not well agreed upon. To build a model for risk of health complications during survivorship care, we created an online crowdsourcing platform called Follow-up Interactive Long-Term Expert Ranking (FILTER). With FILTER we invite oncologists from a range of backgrounds to determine which case, among two cases, is higher risk. This process is repeated many times by many oncologists to achieve a consensus rating for risk for each case. The purpose of this preliminary study was to understand the characteristics of oncologists who were willing to participate in pilot testing FILTER and the number of cases they were able to adjudicate. Methods: We released the FILTER application in November 2021 to members of the NCCN Survivorship Guidelines Panel, COG Survivorship Guidelines Panel, and Vanderbilt-Ingram Cancer Center oncologists. Through the registration process, we collected institution and specialty information about each expert to determine whether a diverse range of experts were contributing their experience to the risk model. Results: Out of over 100 oncologists who were invited to participate in pilot testing of FILTER, 29 users have signed up for an account and adjudicated at least one matchup. These experts came from 13 institutions and have adjudicated a total of 1665 matchups generating risk scores for 78 synthetic cases. The median number of matchups adjudicated per expert was 45. There were 15 medical oncologists, 3 radiation oncologists, a surgical oncologist, and 10 pediatric oncologists who participated in pilot testing. Conclusions: We succeeded in recruiting a limited number of experts to date from a diverse range of oncology specialties, institutions, and backgrounds to pilot test FILTER. However, recruitment has been inadequate to meet the needs of the project. We therefore will seek to recruit more oncologists to refine these scores and will use meetings of oncology groups such as ASCO to achieve this goal. With enough adjudications by oncologists, a reliable ranking of cases by risk score will allow us to create a model to inform a survivorship risk calculator. This calculator, which will be made publicly available once finalized and validated, will provide another resource to help triage cancer survivors to appropriate survivorship care needs.

Impact of PSMA-targeted PET/CT in the clinical management of men with advanced prostate cancer.

e17053 Background: 18F-DCFPyL (piflufolastat F 18) is a PSMA-targeted agent FDA-approved for PET imaging in men with prostate cancer. Given the recent availability for clinical use, we sought to evaluate the impact and potential changes in management after the incorporation of 18F-DCFPyL (PyL) PET/CT at an academic medical center. Methods: We reviewed the first 100 PyL PET/CT scans performed at the Vanderbilt-Ingram Cancer Center for men with prostate adenocarcinoma. Patient demographics, treatment history, and prior imaging results were recorded, along with PyL PET results, most recent PSA, and clinical management plans. Management changes were designated as change in systemic therapy, radiation, or surgery and were determined by two independent reviewers with a third reviewer for any discordant cases. Results: There were 100 men included with PyL PET scans dating from 9/1/21 to 12/31/21. The median age was 69 years, 76% of patients were white and 13% were black. The median Gleason sum at diagnosis was 7 (4+3), 55% of men had prior prostatectomy, and 38% had prior radiation to the prostate/pelvis. The median PSA prior to PyL PET scan was 1.86 (IQR 0.53-9.95 ng/mL), 32% of men had previous ADT exposure, and 15% were on ADT at the time of PyL PET scan. The clinical setting prior to PyL PET scan was initial staging 22%, biochemical recurrence 59%, m1HSPC 14%, m0CRPC 2%, and m1CRPC 3%. There were 16 patients who had a prior 18F-fluciclovine within six months of PyL PET; of these 69% (11/16) had additional disease on PyL PET not previously identified. Activity in lymph nodes was observed in 48%, bone 37%, visceral sites 3%, prostate/prostate bed 46%, and 15% had no PSMA-avid disease. Clinical staging was altered after the PyL PET scan in 55% of patients, with the most common change being from BCR to m1HSPC (40/55). Clinical management was altered in 59% of cases: systemic therapy 38%, radiation planning 46%, and surgical planning 6% (Table). Conclusions: Clinical management was affected in 59% of cases after implementation of PyL PET in this retrospective, single center review. Given the rapid adoption of PSMA-targeted PET imaging agents, further studies are needed to evaluate the clinical impact of subsequent changes to management planning, as well as to develop multidisciplinary consensus statements and protocols to guide management.[Table: see text]

Association between on-treatment eosinophil dynamics and outcomes in metastatic renal cell carcinoma patients treated with ipilimumab/nivolumab.

364 Background: Baseline neutrophil to eosinophil ratio (NER) has been associated with response to immunotherapy in metastatic renal cell carcinoma (mRCC). The association of on-treatment changes in NER and absolute eosinophil count (AEC) during induction with ipilimumab/nivolumab and relation to clinical outcomes are reported. Methods: Patients with mRCC treated with ipilimumab/nivolumab at Vanderbilt-Ingram Cancer Center were identified. Contal and O’Quigley’s method was used to determine the optimal cutpoint associated with improved progression free survival (PFS) and overall survival (OS). Multivariable Cox proportional hazard function was used to assess the association between clinical outcomes and on treatment (week 3/6/9/12) maximum AEC and lowest NER, separately. Results: 63 patients were identified: 81% clear cell histology and 79% male; 24% IMDC favorable risk, 52% intermediate risk, and 24% poor risk. When maximum AEC was coded as a continuous variable, every increase of 100 AEC was associated with improved PFS (HR: 0.89, p-value: 0.017) and OS (HR: 0.87, p-value: 0.053). When the on treatment maximum AEC was dichotomized at the optimal cutpoint of 380 cells/µL, patients with maximum AEC ≥ 380 cells/µL had longer PFS (mPFS: 11.5 months vs 2.7 months, p-value: 0.001) and OS (mOS: 29.6 months vs 16.8 months, p-value: 0.08). When on treatment lowest NER was dichotomized at the optimal cutpoint of 13.2, patients with lowest NER <13.2 had improved PFS (mPFS: 12.5 months vs 2.7 months, p-value:<0.001) and OS (mOS: non-reached vs 16.5 months, p-value: 0.003). After baseline characteristic adjustment (Table), higher on treatment AEC was associated with improved PFS (HR: 0.38, p-value: 0.004), and lower on treatment NER was associated with improved PFS (HR:0.34, p-value:0.002) and OS (HR: 0.38, p-value: 0.036). Conclusions: Higher AEC and low NER while on treatment are associated with improved clinical outcomes in ipilimumab/nivolumab-treated patients with mRCC. Prospective study is warranted to validate these biomarkers.[Table: see text]

External Validation of a Clinical Score for Patients With Neuroendocrine Tumors Under Consideration for Peptide Receptor Radionuclide Therapy

Despite the benefit of peptide receptor radionuclide therapy (PRRT) for patients with well-differentiated neuroendocrine tumors (WD NETs), no clinical metric to anticipate benefit from the therapy for individual patients has been previously defined. To assess whether the prognostic ability of the clinical score (CS) could be validated in an external cohort of patients with WD NETs. This multicenter cohort study's analysis included patients with WD NETs who were under consideration for peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-dotatate between March 1, 2016, and March 17, 2020. The original cohort included patients from Vanderbilt-Ingram Cancer Center. The validation cohort included patients from Ochsner Medical Center, Markey Cancer Center, and Rush Medical Center. Patients with paragangliomas, pheochromocytomas and neuroblastomas were excluded. Statistical analysis was performed from June to November 2021. PRRT with 177Lu-dotatate or alternate therapies such as everolimus, sunitinib, or capecitabine plus temozolomide. The primary outcome was progression-free survival (PFS) and was estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusting for primary tumor site, tumor grade, and number of PRRT doses administered was used to analyze association between CS and outcomes. A total of 126 patients (median age [IQR] age: 63.6 [52.9-70.7] years; 64 male individuals) were included in the validation cohort, and the combined cohort (validation and original cohorts combined) had a total of 248 patients (median [IQR] patient age: 63.3 [53.3-70.3] years; 126 male individuals). In the validation cohort, on multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.61; 95% CI, 1.64-4.16). After finding an association of the CS with PFS in the validation cohort, the original and validation cohorts were combined into the cohort for this analysis. On multivariable analysis, for each 2-point increase in CS, PFS decreased significantly (hazard ratio, 2.52; 95% CI, 1.89-3.36). Increases in CS were associated with worsening PFS in the validation cohort, validating findings from the original cohort. These findings suggest that the CS, to our knowledge, represents the first clinical metric to estimate anticipated benefit from PRRT for patients with WD NETs and may be a clinical tool for patients being considered for PRRT.

The Meharry-Vanderbilt-Tennessee State University Cancer Partnership (MVTCP): History and Highlights of 20 Years of Accomplishments.

Cancer health disparities among populations are the result of a combination of socioeconomic, environmental, behavioral, and biological factors, which affect cancer incidence, prevalence, mortality, survivorship, financial burden, and screening rates. The long-standing Meharry Medical College (MMC), Vanderbilt-Ingram Cancer Center (VICC), Tennessee State University (TSU) Cancer Partnership has built an exceptional cancer research and training environment to support the efforts of diverse investigators in addressing disparities. Over the past 20 years, collaborative partnership efforts across multiple disciplines have supported research into the determinants of cancer health disparities at a National Cancer Institute-designated comprehensive cancer center (VICC) along with enhancing research infrastructure and training at MMC and TSU, two institutions that serve predominantly underserved populations and underrepresented students. Moreover, the geographical placement of this partnership in Tennessee, a region with some of the highest cancer incidence and mortality in the United States, has provided an especially important opportunity to positively affect outcomes for cancer patients.

Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma

BackgroundThe identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC.MethodsWe performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients.ResultsA total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with <mNER compared to 21.8% among patients with >mNER (OR 2.39, p = 0.04). The median PFS for patients with <mNER was significantly longer at 8.6 months (mo) compared to 3.2 mo for patients with >mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with <mNER compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with <mNLR showed improvement in OS (HR 0.42, p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group.ConclusionsA lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

731 Concurrent immunotherapy and dipeptidyl peptidase-4 inhibition among patients with solid tumors

BackgroundDurable remissions are possible for patients with solid tumors treated with immune checkpoint inhibitors (IO); however, response rates remain relatively low. Recent preclinical data with dipeptidyl peptidase-4 inhibitors (DPP4i), widely used for diabetes management, have shown synergistic anti-tumor activity with IO in mouse models.1 2 However, there are no currently available data on concurrent use of DPP4i among patients treated with IO.MethodsWe performed a retrospective, IRB-approved, review of all patients with solid tumors treated with IO at Vanderbilt-Ingram Cancer Center and concurrent DDP4i treatment for diabetes mellitus through review of the electronic medical record. Inclusion criteria required patients were to be on DPP4i at the start of IO treatment. The cutoff date was June 22, 2021. Outcomes measured were objective response rate (ORR), time on treatment, time to next treatment (TTNT), immune-related adverse events (iRAE), and overall survival (OS). All patients were included in the toxicity analysis; however, patients treated in the adjuvant setting, those without measurable radiographic disease, and those without available post-treatment scan were excluded from the response analysis.ResultsIn total, 34 patients were identified on concurrent IO plus DPP4i. The most common tumor types were melanoma (29%), renal cell carcinoma (21%), and non-small cell lung cancer (21%). Pembrolizumab was the most common IO agent (47%), followed by nivolumab (41%), ipilimumab (15%), atezolizumab (6%), and durvalumab (3%). Sitaglipitin (74%) was the most common DPP4i, followed by linagliptin (18%), saxagliptin (6%), and alogliptin (3%). 14/34 patients (41%) developed any grade IRAE while on treatment with 6/34 (18%) requiring discontinuation of IO. Of the 26 patients who met inclusion criteria for the response analysis, 18 (69%) had PR or CR, 4 (15%) had stable disease, and 4 (15%) had PD as best response (figure 1). The median follow-up time was 19.0 months (IQR: 11–25.2) and the median time on treatment was 10.1 months (95 CI: 4.9–14.5). The median TTNT was 23.9 months (95% CI:10.7–34.5) and median OS was 31.4 months (95% CI: 21.0-NE).ConclusionsThis analysis represents the first data on concurrent DPP4i with IO in the treatment of solid tumors. While the cohort for response analysis was small, the ORR was high. Prospective evaluation of IO plus DPP4-i is needed to determine potential clinical efficacy of this combination.ReferencesBarreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol 2015;16(8):850–858. doi:10.1038/ni.3201.Hollande C, Boussier J, Ziai J, et al. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nat Immunol. 2019;20(3):257–264. doi:10.1038/s41590-019-0321-5Ethics ApprovalVanderbilt University Institutional Review Board approved this study under “exempt” status (IRB# 202314). All patient information was de-identified and secured.Abstract 731 Figure 1Swimmers plot. An illustration of clinical events for 26 patients treated with concurrent checkpoint inhibitor (IO) and dipeptidyl peptidase-4 inhibitors (DPP4i). The timeline begins on the date of IO initiation. Each subject is represented along the y axis, with various symbols noting events such as Partial Response (PR), Complete Response (CR), start date of next line of therapy, continued response, or death. Duration of follow up ended with either patient death or study completion (6/22/21)

Framework for Implementing and Tracking a Molecular Tumor Board at a National Cancer Institute-Designated Comprehensive Cancer Center.

Over the past few years, tumor next-generation sequencing (NGS) panels have evolved in complexity and have changed from selected gene panels with a handful of genes to larger panels with hundreds of genes, sometimes in combination with paired germline filtering and/or testing. With this move toward increasingly large NGS panels, we have rapidly outgrown the available literature supporting the utility of treatments targeting many reported gene alterations, making it challenging for oncology providers to interpret NGS results and make a therapy recommendation for their patients. To support the oncologists at Vanderbilt-Ingram Cancer Center (VICC) in interpreting NGS reports for patient care, we initiated two molecular tumor boards (MTBs)-a VICC-specific institutional board for our patients and a global community MTB open to the larger oncology patient population. Core attendees include oncologists, hematologist, molecular pathologists, cancer geneticists, and cancer genetic counselors. Recommendations generated from MTB were documented in a formal report that was uploaded to our electronic health record system. As of December 2020, we have discussed over 170 patient cases from 77 unique oncology providers from VICC and its affiliate sites, and a total of 58 international patient cases by 25 unique providers from six different countries across the globe. Breast cancer and lung cancer were the most presented diagnoses. In this article, we share our learning from the MTB experience and document best practices at our institution. We aim to lay a framework that allows other institutions to recreate MTBs. With the rapid pace of molecularly driven therapies entering the oncology care spectrum, there is a need to create resources that support timely and accurate interpretation of next-generation sequencing reports to guide treatment decision for patients. Molecular tumor boards (MTB) have been created as a response to this knowledge gap. This report shares implementation strategies and best practices from the Vanderbilt experience of creating an institutional MTB and a virtual global MTB for the larger oncology community. This report describe a reproducible framework that can be adopted to initiate MTBs at other institutions.

Validation of a clinical score (CS) for patients (pts) with well-differentiated neuroendocrine tumors (WD NETs) under consideration for peptide receptor radionuclide therapy (PRRT) with Lu 177 dotatate.

4109 Background: Questions remain regarding when to sequence PRRT and how to categorize pts being considered for the treatment (tx). We previously developed a CS (comprised of 5 categories: available non-PRRT tx for tumor type, prior systemic tx, pt symptoms, tumor burden in critical organs and peritoneal carcinomatosis presence) at Vanderbilt Ingram Cancer Center (VICC) for pts being considered for PRRT to help answer these questions and demonstrated the score to be associated with progression-free survival (PFS) in pts receiving PRRT. Herein, we present the performance of the CS in a validation cohort (VC) and combined cohort (CC). Methods: Our original cohort (OC) included pts with progressive WD NETs (N = 122) under consideration for PRRT between 3/1/2016-3/17/2020 at VICC while our VC included pts under consideration for PRRT (N = 126) between 1/25/2017-11/18/2019 at Ochsner Medical Center (OMC) (N = 51), Markey Cancer Center (MCC) (N = 51) and Rush Medical Center (RMC) (N = 24). All pts in the OC were prospectively scored while pts in the VC were scored retrospectively, with the CS-assigning investigator blinded to patient outcomes. The primary outcome PFS, was estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusting for primary tumor site, tumor grade and number of PRRT doses administered (0, 1-2 or 3-4) was used to analyze effect of CS. Overall survival (OS) was a key secondary outcome. Results: In our VC, on multivariable (MV) analysis, for each 2-point increase in CS, the hazard ratio (HR) for PFS was 2.58 (95% confidence interval (CI) 1.62-4.11). On MV analysis, for each 2-point increase in CS, the HR for OS was 3.89 (95% CI 1.8-4.83). We combined the OC and VC for this analysis in order to increase the predictive power of our originally developed Cox proportional-hazards models. In our CC, of the 248 total pts, median pt age, CS and number of prior tx were 63.3 years, 4 (range 0-8) and 1 (range 0-7), respectively. The most represented primary tumor sites were small intestinal (N = 136), pancreatic (N = 58), unknown primary (N = 26) and lung (N = 14). A total of 140, 82 and 26 pts received 3-4, 0 or 1-2 doses of PRRT, respectively. On MV analysis, for each 2-point increase in CS, the HR for PFS was 2.52 (95% CI 1.90-3.35). On MV analysis, for each 2-point increase in CS, the HR for OS was 3.48 (95% CI 2.33-5.18). No interaction between PRRT doses administered and CS was observed. Conclusions: Increases in CS were strongly associated with worsening PFS and OS in our VC and CC, validating findings from our OC. Although we cannot determine whether the CS specifically predicts PRRT response or is prognostic based upon these data, it is the first presented clinical metric which can categorize pts with WD NETs under consideration for PRRT and estimate anticipated benefit from PRRT for pts.

Association of baseline neutrophil-to-eosinophil ratio (NER) and neutrophil-to-lymphocyte ratio (NLR) with response to combination immunotherapy (IO) with ipilimumab plus nivolumab (ipi/nivo) in patients with metastatic renal cell carcinoma (mRCC).

4563 Background: Previous reports have shown that the baseline neutrophil-to-lymphocyte ratio (NLR) is associated with prognosis in patients with mRCC. However, NLR has not been shown to reliably predict for response to IO. Retrospective analyses in metastatic melanoma and mRCC have shown an association of eosinophilia with improved outcomes to single agent immunotherapy. We sought to evaluate and compare the baseline NLR and NER with response to ipi/nivo in patients with mRCC. Methods: A retrospective review of patients with mRCC treated at the Vanderbilt-Ingram Cancer Center or Duke Cancer Institute with ipi/nivo was performed. Patients with clear cell histology and a baseline complete blood count with differential were included. Patients previously treated with IO were excluded. Patients were separated into groups (above and below the median) based on baseline median NER and baseline median NLR. Analyses of progression free survival (PFS) and overall survival (OS) were conducted using the log rank test. The odds ratio (OR) for objective response rate (ORR) was analyzed using Fisher’s exact test. Results: 111 patients met inclusion criteria. The median age was 60, 77% of patients were male, 68% had prior nephrectomy, 74% were naïve to systemic therapy, and 84% were IMDC intermediate/poor risk. The median NER was 25.0 and median NLR was 3.4. Patients with &lt; median baseline NER had significant improvement in PFS, OS, and ORR (see table). Patients with &lt; median baseline NLR had significant improvement in OS but not in PFS or ORR. Conclusions: Baseline NER was associated with improved outcomes with ipi/nivo. While both NER and NLR were associated with improved OS, only NER was additionally associated with both improved PFS and ORR. With multiple first-line treatment options for mRCC, baseline NER may serve as an early non-invasive predictor for response to ipi/nivo.[Table: see text]