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.

Background. Early-onset gastric cancer (EOGC, age ≤ 60 years 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.

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High stage cutaneous squamous cell carcinoma (CSCC) has an elevated risk of recurrence (5-25%). Current staging systems stratify patients rely on tumor factors only. We sought to develop an RPA incorporating patient-, tumor-, disease-, and treatment-related factors to identify prognostic subgroups for high-stage CSCC patients receiving definitive therapy. Materials/Methods: All high-stage CSCCs, defined as Brigham & Women's Hospital (BWH) tumor (T) staging system T2B and T3, treated with curative intent were included. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log rank test. Recursive partitioning analysis (RPA) was performed to identify prognostic factors for RFS and OS. Results: A total of 444 patients (76% male, 95% Caucasian, median age 74 years) with 523 primary tumors were included. Median follow up was 31 months (range 1-194). 31% of patients were immunosuppressed (organ transplant 13%, chronic lymphocytic leukemia (CLL) 14%, and other reasons 3%). 432 tumors were BWH T2b and 91 were BWH T3, of whom 12% were node-positive, 32% node-negative, and 56% unknown nodal status. 33% of patients experienced recurrence. Immunosuppression, recurrent tumor, perineural invasion (PNI), and lymphovascular space invasion (LVSI) were associated with significantly worse RFS (median RFS 23 months, 95% CI, 19-28), while immunosuppression, lymph node positivity, and extranodal extension (ENE) were associated with significantly worse OS (median OS 40 months, 95% CI, 33-46). RPA identified 4 prognostic subgroups with distinct RFS patterns (P < 0.0001): class I included age < 77 years without LVSI (N = 212, 2-year RFS: 63%; 95% CI, 56-70%), class II included age ≥ 77 years without PNI (N = 132, 2-year RFS: 44%, 95% CI, 36-55%), class III included age < 77 years with LVSI (N = 36, 2-year RFS: 29%; 95% CI, 17-50%), and class IV included age ≥ 77 years with PNI (N = 60, 2-year RFS: 25%; 95% CI, 15-41%). RPA identified 4 prognostic subgroups with distinct OS patterns (P < 0.0001): class I included age < 78 years and ≤ 1 lymph node positive (N = 221, 2-year OS: 84%; 95% CI, 79-90%), class II included age ≥ 78 years and no or immunosuppression other than CLL (N = 141, 2-year OS: 64%; 95% CI, 55-73%), class III included age < 78 years and > 1 lymph node positive (N = 48, 2-year OS: 54%; 95% CI, 41-71%), and class IV included age ≥ 78 years and immunosuppression from CLL (N = 34, 2-year OS: 37%; 95% CI, 23-57%). Conclusion: An RPA classification system was created for patients with high-stage primary CSCC treated with definitive intent that identifies 4 prognostic subgroups associated with recurrence-free survival and overall survival based on age, LVSI, PNI, burden of nodal metastasis, and immunosuppression status. This has implications for patient counselling, clinical trial design and post-treatment surveillance.

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