Abraha, Feven

Abstract The Mayo Clinic Breast Disease Registry (MCBDR) was developed to serve as a cohort of newly diagnosed breast cancer patients to address questions of etiology, prognosis, and survivorship. Eligibility is limited to patients 18 years or older with a confirmed first stage 0-4 breast cancer diagnosis within the last year. Consent is completed via phone, patient portal, or in-person. Upon enrollment, a baseline questionnaire and blood collection are completed. Annual follow-up surveys that capture BC outcomes are sent to all living participants. The MCBDR cohort (N=9,215, enrolled between 2001 and 2023) is 99% female, with an average age at diagnosis of 58 years (SD=12.7). Currently, MCBDR has an average time since diagnosis of 9.8 years (SD=6.4). The participants are 94% white, and 55% live in Minnesota. At the time of baseline questionnaire completion, 77% were married, 84% had a bachelor’s degree or higher, and 8% reported financial hardship. Further, 35% reported a history of smoking, 11% consumed more than two drinks per day, and 9% reported fair or poor social relationships. Within MCBDR, 53% of the participants had stage 0 or 1 cancer at diagnosis, while 28% had stage 2, 9% stage 3, and 3% stage 4 BC. Tumors were triple negative in 9%, HER 2 positive in 9%, hormone receptor-positive and HER2 low or negative in 55%, and 27% had missing HER2 status. Pathological TNM staging was available on 98%, among which 33% were staged at T2 or higher and 27% were node-positive. Definitive BC surgery was completed at Mayo Clinic for 73%, with 35% undergoing mastectomies and 44% having lumpectomies. 74% were treated with radiation, 56% underwent chemotherapy, and 79% were treated with endocrine therapy. Clinical genetic testing results have been nurse-abstracted for 94% of the cohort. Of those known to be tested, 521 (6%) had a pathogenic or likely pathogenic mutation identified in a BC causing gene. In addition, whole exome sequencing was completed on 71% of MCBDR participants in 2020, in which 167 previously unknown pathogenic or likely pathogenic mutations were identified. After the initial diagnosis and active treatment phase, nurse abstraction identified 151 (2%) participants known to have been diagnosed with a contralateral BC diagnosis, and 4% known to have been diagnosed with a second primary other than breast. Recurrence in the same breast has been reported for 242 (3%), with 72% of those recurrences occurring within 5 years of initial diagnosis and another 19% occurring 5-10 years post diagnosis. Among the 1,262 (14%) who are deceased, 24% died from BC and 19% had distant metastases at diagnosis or a distant recurrence. Amongst all deceased, 6% died within 1 year of their diagnosis and 43% died within 5 years of diagnosis. For participants who died from BC, 10% died within 1 year of their diagnosis and 64% died within 5 years of diagnosis. MCBDR data has been used in numerous publications and is an essential resource for efficient observational research analyses. Citation Format: Nicole L. Larson, Janet Olson, Kathryn Ruddy, Fergus Couch, Denise Herman, Feven Abraha. Mayo Clinic breast cancer cohort: A valuable resource for breast cancer research [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 7339.

Abstract Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignancies. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysis-independent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion. Supported by grants from Mayo Clinic Foundation and NIH (R01CA 256927-2)

Abstract Introduction: The utilization of self reported chemotherapy treatment data is common in epidemiologic research but there is little understanding of its accuracy and limitations. Methods: The Mayo Clinic Breast Disease Registry (MCBDR) has over 9,600 participants enrolled within one year of a first breast cancer diagnosis. Participants receive annual follow up surveys through the mail to capture data on breast cancer treatments and outcomes. We compared nurse abstracted medical record chemotherapy data to self reported chemotherapy data from women diagnosed with stage 0 to 3 breast cancer that completed five consecutive annual follow up surveys. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) statistics were assessed for the report of broad chemotherapy receipt (yes, no, DK) within each yearly survey compared to the gold standard medical record data. To assess the accuracy of the self reported use of specific chemotherapy regimens, a sub cohort known as the “congruent sub cohort” was created for each survey year that included subjects that agreed with the nurse abstractors report of their broad chemotherapy usage. Sensitivity, specificity, PPV, NPV, and concordance statistics were calculated for the congruent sub cohorts followed by an assessment of the proportion of subjects providing correct responses for all chemotherapy regimens queried compared to those that had at least one discrepancy with the nurse abstracted data and the proportion of subjects with 0, 1, 2 and 3 or more discrepancies within each survey year. Results: For the 430 survey respondents, the average age was 59.5 years (SD 11.7) with a range of 29 to 94. The mean time between diagnosis and the year 1 follow up survey was 13.5 months, with an average of 61.2 months between diagnosis and the year 5 survey. The respondents were 97% white, 100% female, and 53.5% had a bachelor’s degree or higher. The self-reported receipt of chemotherapy had substantial agreement across all 5 follow up surveys with the nurse abstracted treatment data from the medical record with kappa values ranging from 0.70 (0.63 to 0.76) to 0.64 (0.57 to 0.71). For subjects in the congruent sub cohort (N=125, 120, 122, 121, and 121 subjects across the 5 survey years, respectively), self reported use of specific chemotherapy regimens were reported with an average concordance of 90% across the 5 annual surveys, however only 23% had perfect agreement with nurse abstracted data. The average number of discrepant responses provided by subjects was 1.2, with at least 12% of subjects reporting 3 or more erroneous responses for the specific chemotherapy regimens each survey year. Discussion: This study supports previous findings that self-reported chemotherapy usage may be utilized when resources are unavailable for medical record abstraction, but may have less utility when analyzing specific chemotherapy regimens. Citation Format: Nicole L. Larson, Kathryn J. Ruddy, Feven Abraha, Denise M. Herman, Fergus J. Couch, Janet E. Olson. Accuracy of self reported chemotherapy usage in annual follow up surveys for a breast cancer registry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 748.

Background. Early-onset gastric cancer (EOGC,age≤60years at diagnosis) now comprises >30% of new gastric cancers in the United States. It is hypothesized that chronic acid suppression with proton-pump inhibitors (PPIs) may promote tumorigenesis, while other medications including statins, nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, and cyclooxygenase-2 (COX-2) inhibitors have been proposed as protective. We aimed to assess for an association between use of the aforementioned commonly prescribed medications and EOGC development. Methods. We used a population-based medical record linkage system, to identify cases of EOGC in Olmsted County, Minnesota, between January 1, 1995, and December 31, 2020. Patients were matched 1 : 1 with controls based on age at diagnosis, sex, smoking status, and body mass index (BMI). Conditional logistic regression was used to examine associations with the odds of EOGC development. Results. Ninety-six cases of EOGC were identified during the study period. On both univariate and multivariate regression analysis, there was no significant association between use of PPIs, statins, NSAIDs, or metformin and EOGC development. In a final multivariable model, there was a significant reduction in odds of EOGC with COX-2 inhibitor use for six months or more prior to cancer diagnosis (OR=0.39, 95% CI 0.16-0.94). Conclusion. In this retrospective, population-based study of individuals in Olmsted County, MN, we found significantly reduced odds of EOGC development associated with COX-2 inhibitor use for six months or more prior to diagnosis, but no association between EOGC development and use of PPIs and other commonly prescribed medications.

Abstract Purpose: Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking. Patients and Methods: Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR. Results: 128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7−CD45RA−) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS. Conclusions: This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.