PURPOSE:To evaluate exemestane, an aromatase inhibitor, as a preventive intervention for endometrial cancer. EXPERIMENTAL DESIGN:This is a multicenter, single-arm, "window of opportunity" pilot study of exemestane (25 mg daily for 21-42 days) in postmenopausal individuals undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine the change in proliferation, measured by Ki-67 expression, in pre- and posttreatment endometrial tissue specimens. Secondary outcomes include measurement of circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety, and adverse effects. RESULTS:Forty participants were accrued to the study. The mean body mass index was 40.3 (range, 22.8-60.5, SD = 9.8). Preoperative diagnoses included EIN (n = 11, 27.5%), grade 1 endometrial cancer (n = 26, 65%), and grade 2 endometrial cancer (n = 3, 7.5%). Median Ki-67 score decreased from 40.7% [IQR (33.9, 50.3)] at baseline to 18.1% [IQR (8.8, 31.8)] at surgery, representing a median absolute change from baseline of 20.4% [IQR (-29.9, -6.7), P < 0.001]. In a matched historic control cohort, participants also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7, -1.3), P< 0.001]. However, the decrease in Ki-67 was greater in the study participants than the historic controls, with a median difference between the groups of -13.4% [IQR (-23.3, 6.9), P ≤ 0.01]. Both tissue estrogen receptor and progesterone receptor expression declined significantly with exemestane treatment (P < 0.001). However, serum estradiol levels did not change between baseline and after treatment (P = 0.16). CONCLUSIONS:In this pilot study, exemestane demonstrated antiproliferative effects in EIN and low-grade endometrial cancer. This agent warrants further evaluation for the prevention of endometrial cancer.

We performed a clinical trial in patients with non-muscle-invasive (NMI) urothelial cancer randomized (2:1) to the EGFR tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly × 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor-adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib therapy. Thirty-seven volunteers (6 female/31 male; mean age 70; 35 White/2 non-White) with confirmed or suspected NMI urothelial cancer were enrolled into either erlotinib (n = 24; 900 mg-13, 600 mg-11) or placebo (n = 13). IHC assessment of phosphorylated and total EGFR in tumor-adjacent normal urothelium (20 erlotinib and 9 placebo subjects) or tumor (21 erlotinib and 11 placebo subjects) at study end showed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, E-cadherin, p53, and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g., 38% experienced grade 1 with rare grade 2 diarrhea and skin toxicity versus 8% in placebo. Clinically insignificant but statistically significant (P = 0.001) elevations in serum total bilirubin and creatinine were observed in participants receiving erlotinib. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all subjects receiving erlotinib and did not significantly differ between the 600 and 900 mg doses. Despite compelling preclinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib therapy to prevent progression of NMI bladder cancer. Prevention Relevance: We evaluated the potential of erlotinib in preventing cancer by performing a randomized, double-blind, placebo-controlled trial of weekly erlotinib therapy in participants undergoing surgical removal of suspected noninvasive bladder neoplasia. Weekly erlotinib therapy was tolerated with common grade 1 to 2 toxicities but without evidence of beneficial effect upon urothelial tissue. See related Spotlight, p. 7.

BACKGROUND:Anal squamous intraepithelial lesions are identifiable and treatable precancerous lesions that lack defined risk factors determining screening necessity. OBJECTIVE:Assess the prevalence and risk factors associated with low- and high-grade anal squamous intraepithelial lesions and anal squamous-cell carcinoma. DESIGN:Retrospective cohort analysis of veterans with HIV between 1999 and 2023. SETTINGS:National multicenter study of the Department of Veterans Affairs. PATIENTS:Veterans with HIV who had >1 year of follow-up and no anal squamous intraepithelial lesions or anal cancer diagnosis before the study period. MAIN OUTCOME MEASURES:Primary outcomes include the prevalence, disease-free survival rates, and HRs associated with risk factors for developing anal squamous intraepithelial lesions and/or anal cancer. RESULTS:A total of 48,368 patients were analyzed. The mean age of patients at study initiation was 47.8 years, with a mean follow-up of 12.3 years. Seven thousand five hundred seventy-two patients (16%) had at least 1 anal cytopathology or histopathology result. The prevalence of anal disease was recorded for low-grade disease (n = 1513; 3.1%), high-grade disease (n = 1484; 3.1%), and cancer (n = 664; 1.4%). Mean (SD) times to first incident low-grade disease, high-grade disease, and cancer were 8.5 (6.0), 9.1 (6.0), and 9.7 (6.2) years, respectively. Five-year, 10-year, and 20-year disease-free survival rates for the development of low-grade disease, high-grade disease, or cancer were 97.5%, 94.5%, and 88.4%, respectively. Cox regression modeling demonstrated that CD4/CD8 ratios of <0.5 were associated with an increased risk of anal cancer (HR, 3.93; 95% CI, 3.33-4.63; p < 0.001). LIMITATIONS:Retrospective study that focused almost exclusively on male US veterans. Results might not apply to non-male, non-US populations. CONCLUSIONS:National analysis of more than 48,000 veterans with HIV demonstrates that 16% had anal cytopathology or histopathology results with an anal cancer prevalence of 1.4%. CD4/CD8 ratios of <0.5 correlate strongly with the severity of anal disease and can help identify patients at the highest risk for anal cancer to prioritize screening efforts. See Video Abstract. ANLISIS NACIONAL DE MS DE VETERANOS CON VIH DEMUESTRA QUE LA RELACIN CD/CD ES UN MARCADOR DE RIESGO DE LESIONES INTRAEPITELIALES ANALES Y CNCER ANAL:ANTECEDENTES:Las lesiones intraepiteliales escamosas anales son lesiones precancerosas identificables y tratables que carecen de factores de riesgo definidos que determinen la necesidad de detección.OBJETIVO:Evaluar la prevalencia y los factores de riesgo asociados con las lesiones intraepiteliales escamosas anales de grado bajo y alto y el carcinoma de células escamosas anal.DISEÑO:Análisis de cohorte retrospectivo de veteranos con VIH entre 1999 y 2023.ESTABLECIMIENTO:Estudio multicéntrico nacional del Departamento de Asuntos de Veteranos.PACIENTES:Veteranos con VIH que tuvieron >1 año de seguimiento y sin lesiones intraepiteliales escamosas anales ni diagnóstico de cáncer anal antes del período de estudio.PRINCIPALES RESULTADOS Y MEDIDAS:Los resultados primarios incluyen la prevalencia, las tasas de supervivencia libre de enfermedad y los cocientes de riesgo asociados con los factores de riesgo para desarrollar lesiones intraepiteliales escamosas anales y/o cáncer anal.RESULTADOS:Se analizaron 48.368 pacientes. La edad promedio de los pacientes al inicio del estudio fue de 47,8 años con un seguimiento medio de 12,3 años. 7.572 (16%) pacientes tuvieron al menos un resultado de citopatología o histopatología anal. Se registró la prevalencia de enfermedad anal para enfermedad de bajo grado (n = 1.513, 3,1%), enfermedad de alto grado (n = 1.484, 3,1%) y cáncer (n = 664, 1,4%). Los tiempos medios hasta el primer incidente de enfermedad de bajo grado, enfermedad de alto grado y cáncer fueron 8,5 (DE = 6,0), 9,1 (DE = 6,0) y 9,7 (DE = 6,2) años, respectivamente. Las tasas de supervivencia libre de enfermedad a 5 años, 10 años y 20 años para el desarrollo de enfermedad de bajo grado, enfermedad de alto grado o cáncer fueron 97,5%, 94,5% y 88,4%, respectivamente. El modelo de regresión de Cox demostró que los índices CD4/CD8 <0,5 se asociaban con un mayor riesgo de cáncer anal (HR: 3,93, IC del 95 %: 3,33-4,63, p < 0,001).LIMITACIONES:Estudio retrospectivo que se centra casi exclusivamente en veteranos estadounidenses de sexo masculino. Los resultados podrían no aplicarse a poblaciones no masculinas ni estadounidenses.CONCLUSIONES:El análisis nacional de más de 48 000 veteranos con VIH demuestra que el 16 % tenía resultados de citopatología o histopatología anal con una prevalencia de cáncer anal del 1,4 %. Los índices CD4/CD8 <0,5 se correlacionan fuertemente con la gravedad de la enfermedad anal y pueden ayudar a identificar a los pacientes con mayor riesgo de cáncer anal para priorizar los esfuerzos de detección. (Traducción-Dr Yolanda Colorado ).

180 Background: Rural populations and racial minorities are often underrepresented in cancer clinical trials. The low representation is determined by multilevel factors, including lack of geographic access to facilities in rural locations and mistrust in the medical and scientific community. Presented here are partial results of an educational intervention to improve clinical trials-related knowledge among rural residents and racial minorities. Methods: The Center to Reduce Cancer Health Disparities (CRCHD) from the National Cancer Institute (NCI) developed the study materials, that were available in English or Spanish, to be utilized according to participants' preferences. The University of Wisconsin Carbone Cancer Center implemented this intervention in northern Wisconsin, which consisted of a baseline questionnaire, a recorded educational intervention, and a post-educational questionnaire. The chosen community is largely rural and Native American. The questionnaires consisted of 11-knowledge- and 6-intention-related questions. After being screened by the rural Community Health Educator (CHE), subjects self-administered the intervention online or received the intervention from the CHE during tribal or other educational group events in rural communities. Results: Between January and May 2024, 62 participants started the intervention. Participants’ mean age was 45.1 (±15.36) years, 64.5% (40/62) were female, and 53.2% (33/62) self-identified as American Indian/ Alaska Native. All resided in rural community, defined as Rural-Urban Continuum Codes 7 or 8. Three participants did not respond to the post-educational questionnaire, and one skipped its intentions section. Although the two questions about informed consent presented the highest percent of correct answers post-intervention, the median total knowledge score pre and post-intervention remained the same (p>0.05). Post-intervention, participants more often agreed it is important for minority groups to participate in clinical trials, reported being likely to search for a clinical trial they might be eligible for, join a clinical trial, and talk to family/friends about joining a clinical trial (p<0.05). Conclusions: The CHE successfully engaged rural community members to participate in the intervention. In addition, the intervention facilitated building trust and partnerships for future cancer-related community driven work.

Abstract Introduction: The purpose of this study is to evaluate exemestane, an aromatase inhibitor, as a potential agent for the chemoprevention of endometrial cancer. Experimental procedures: This is a multi-center, phase IIA, single arm ‘window of opportunity’ pilot study of 25 mg per day of exemestane for 21-42 days in postmenopausal patients undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer. The primary objective is to determine if there is a decrease in proliferation index, measured by percent Ki-67 expression in endometrial tissue, from pre-treatment to post-exposure. Results of Ki-67 are compared with a historic control cohort of tumors from patients matched by preoperative histologic diagnosis, age, BMI category. Specimens from the historic control cohort included a preoperative endometrial biopsy as well as a surgical specimen, separated in time by less than 42 days. Secondary outcomes include comparison of Ki67 to historic controls, circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety and adverse effects. Summary of Data: Forty patients accrued to the study between January of 2018 and March of 2021. The mean age was 63 (range 52-75). Thirty-nine patients (97.5%) self identifiedself-identified as white; 1 patient (2.5%) identified as Asian. The mean BMI was 40.3 (SD 9.75, range 22.8-60.5). Preoperative diagnoses included EIN, grade 1 endometrial adenocarcinoma, and grade 2 endometrial adenocarcinoma in 11 (27.5%), 26 (65%), and 3 (7.5%) patients respectively. Thirty-nine patients (97.5%) were compliant with exemestane dosing. All patients completed the study and no patients discontinued or interrupted therapy due to treatment related adverse events. Thirty-eight patients had evaluable specimens for both pre and post-treatment Ki-67 analysis. Median Ki-67 score decreased from 40.7% [IQR (33.9%, 50.3] at baseline to 18.1% [IQR (8.8%, 31.8%)]. This represents a median absolute change from baseline of -20.4% [IQR (-29.9, -6.7), p<0.001]. In total, percentage of Ki-67 in tumor cells declined in 31 patients and increased in 7 patients. In the historic control cohort, patients also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7%, -1.3%), p<0.001]. However, the decrease in Ki-67 was greater in the study patients than the matched historic controls, with a median difference between the groups of -13.4% [IQR= (-23.3%, 6.9%), p=0.0095]. Serum estradiol levels did not change significantly between baseline and post-treatment (p=0.16). There was a small but significant increase from baseline to post-treatment in serum progesterone (0.14 ng/mL vs 0.37 ng/mL, p<0.001). Conclusion: In this pilot window of opportunity study, exemestane demonstrates anti-proliferative effects in endometrial intraepithelial neoplasia and low-grade endometrial cancer. This agent warrants further evaluation for the chemoprevention of endometrial cancer. Citation Format: Britt K. Erickson, Lisa Barrioullet, Rebecca C. Arend, Dina El-Rayes, Mahmoud Khalifa, Amy Skubitz, Kristin Boylan, Andrew Nelson, Bharat Thyagarajan, Thomas Havighurst, Richard Chappell, Eileen Dimond, Katina Deshong, Goli Samimi, Eva Szabo, Howard Bailey. Pilot study of daily exemestane in patients with Endometrial Intraepithelial Neoplasia (EIN) or grade 1 endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A021.

AIM:To assess the risk and natural history of developing advanced anal disease after diagnosis of anal condyloma in people living with HIV (PLWH). METHODS:This was a single-centre retrospective cohort study of PLWH and anal condyloma from 2001 to 2021. Patients who developed advanced anal disease (AAD; anal high-grade squamous intraepithelial lesions and/or anal cancer) were compared to those who did not progress (non-AAD). We assessed the potential association between AAD and condyloma location, recurrence, and treatment modality. AAD-free survival was calculated utilizing Kaplan-Meier methods. RESULTS:A total of 118 PLWH and anal condyloma were included. Mean overall follow-up time was 9.3 years. A total of 31% of patients developed AAD (n = 37). Average time to AAD from condyloma diagnosis was 5.6 years. On multivariate analysis, risk for AAD development was associated with perianal location of condyloma (OR 4.39, p = 0.038) and increased time from initial condyloma diagnosis (OR 1.12, p = 0.008). Higher CD4/CD8 ratios were associated with lower risk of AAD (OR 0.15, p = 0.029). Condyloma recurrence and treatment type were not associated with development of AAD. AAD-free survival was longer in those with intra-anal only condyloma versus those with either perianal disease alone or combined intra-anal/perianal disease (mean survival times: 22.8 vs. 8.7 vs. 10.7 years, p = 0.017). CONCLUSION:Our study demonstrates the need for careful, long-term follow-up of PLWH and condyloma, particularly in the setting of perianal disease and low CD4/CD8 ratio. Risk of anal disease progression is present even in the setting of condyloma regression following treatment.

Background: HER2, IGFBP-2, and IGF-IR are proteins that are overexpressed in breast cancer. These three proteins, when used as immunogens, provide broad antigenic coverage to all molecular breast cancer subtypes. The proteins are also up-regulated in pre-invasive and high-risk breast lesions which are associated with progression to invasive cancer. Therefore, generating protective immunity against these antigens could have the result of preventing cancer development in high risk patients. We identified epitopes derived from these proteins, termed Th1 selective epitopes, that specifically stimulated T-helper 1 immune responses in humans and mice. The tri-antigen vaccine was effective in preventing the development of breast cancer in a transgenic mouse model of neu-expressing mammary cancer. We conducted a dose finding study of a plasmid-based vaccine encoding three extended Th1 selective epitopes derived from these antigens in breast cancer patients. Methods: Patients with non-metastatic, node positive, HER2 negative breast cancer that are in remission and defined as no evidence of disease were enrolled sequentially to one of 3 dose arms: 150, 300, and 600 mcg of the tri-antigen vaccine plasmid with 10 evaluable patients per arm (NCT02780401). Vaccines were given monthly intradermally for three total doses with rhu-GM-CSF (100mcg) as an adjuvant. The primary endpoint was safety through the 6-month follow-up visit and the secondary endpoints were immunogenicity, persistence of the immune response after vaccination, and assessment of potential stimulation of T-regulatory (T-reg) cells or myeloid derived suppressor cells to the overexpressed non-mutated antigens as well as determining the recommended Phase II dose. Results: Thirty-two patients were enrolled and 97% received all three vaccinations. The mean age at enrollment was 51.9 years with 61% of patients being pre-menopausal and 39% post-menopausal. The majority of patients were Stage II/III. Eighty-eight percent of patients had hormone receptor positive tumors and twelve percent were triple negative disease. The majority of adverse events (AE) (>95%) were grade 1 or 2. The most common AE were injection site reactions, flu like symptoms, fatigue, chills, myalgia, and nausea. All doses were immunogenic with the greatest magnitude antigen specific Type I immune responses seen in the low and intermediate doses. Eighty percent of patients at the 300mcg dose retained high levels of antigen specific immunity at 1 and 6 months after immunization as compared to 57% and 50% at the 100 and 600mcg doses respectively. No antigen specific Th2 cells, MDSC or T-reg were generated with vaccination. Immunizations did not upregulate PD-1 on CD4 or CD8 T-cells. Conclusions: A plasmid-based vaccine encoding extended Th1 selective epitopes derived from HER2, IGFBP-2, and IGF-IR could be administered safely and generate high levels of antigen specific interferon gamma secreting T-cells (Th1). The 300mcg dose elicited significant immune responses in the majority of patients which persisted at least 6 months after the end of immunization. A Phase II study of the vaccine given in the neoadjuvant setting to patients with HER2 positive breast cancer is ongoing (NCT04329065). Citation Format: Sasha E. Stanton, Kari B. Wisinski, William R. Gwin, Andrew Coveler, John B. Liao, Mark Burkard, Howard Bailey, KyungMann Kim, Thomas Havinghurst, Katina DeShong, Jennifer S. Childs, Eileen Dimond, Margaret Wojtowicz, Brandy M. Heckman-Stoddard, Denise Cecil, Mary Disis. Phase I trial of the safety and immunogenicity of a tri-antigen vaccine targeting HER2, IGFBP-2, and IGF-IR in patients with non-metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-02.

BACKGROUND Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Summary of Assessment of Ki-67 Staining Problems. Supplementary Table 1: Summary of Values, Changes, and Statistical Results for Ki-67 Assessments. Supplementary Table 2: Summary of Analyses of Different Subsets of Subjects.

Perspective on this Article from A Randomized, Double-Blind, Placebo-Controlled Phase 3 Skin Cancer Prevention Study of α-Difluoromethylornithine in Subjects with Previous History of Skin Cancer

BACKGROUND Here we report clinical risk factors and event rates for the development of new non-melanoma skin cancer (NMSC) in a randomized, double-blind, placebo-controlled trial of the irreversible ornithine decarboxylase (ODC) inhibitor, difluromethylornithine (DFMO), over a 3-5-year follow-up. METHODS 147 placebo patients (white; mean age 60.2 years; 60% male) were evaluated for event rates and association of initial skin biomarkers and baseline patient characteristics with the development of squamous cell (SCC) and basal cell (BCC) carcinomas. RESULTS Post-study evaluation (median follow-up 4.4 years) indicates the measures of prior NMSCs (P ≤ 0.001), prior BCCs (P ≤ 0.001), prior SCCs (P = 0.011), prior tumor rate (P = 0.002), hemoglobin (P = 0.022), and gender (P = 0.045) as significant predictors for new NMSC development. Similarly, all measures of prior BCCs and NMSCs (P < 0.001), prior tumor rate (P = 0.014), and SCCs in the prior 2 years (P = 0.047) were statistically significant predictors for new BCC development. Total prior NMSCs and those in the prior 5 years (P < 0.001), total prior SCCs and those in the prior 5 years (P < 0.001), total prior BCCs and those in the prior 5 years (P ≤ 0.001), prior tumor rate (P = 0.011) as well as age (P = 0.008), hemoglobin (P = 0.002), and gender (P = 0.003) were statistically significant predictors of new SCC development. TPA-induced ODC activity at baseline showed no statistically significant association with the development of new NMSC (P = 0.35), new BCCs (P = 0.62), or new SCCs (P = 0.25). CONCLUSION In the studied population, the history of and rate at which prior NMSCs occur are predictive and should be controlled for in future NMSC prevention trials.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

3117 Background: Low response rates in immune checkpoint blockade (ICB) treated head and neck squamous cell carcinoma (HNSCC)drive a critical need for robust clinically validated biomarkers that can predict response to ICB. Stress keratin 17 (K17) is a known prognostic marker in various types of cancer, including HNSCC; however, its predictive value for ICB response has not been investigated. Preclinical studies suggest K17 suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors. Furthermore, knocking out K17 results in restored response to ICB in a HNSCC mouse model. Here, we evaluated if K17 protein expression predicts response to ICB in human HNSCC patients. Methods: We conducted a retrospective analysis of 26 HNSCC patients that received at least one cycle of pembrolizumab at the University of Wisconsin-Madison Carbone Cancer Center. Pretreatment, archival, formalin-fixed, paraffin-embeded samples were stained by immunohistochemistry using a K17 monoclonal antibody. Clinical outcomes were investigator-assessed for all patients with at least one post-treatment scan or evidence of clinical progression after treatment initiation. Based on independent pathology review, cases were categorized into K17 high vs K17 low based on a cut-off of > 5% strong cytoplasmic staining intensity of tumor cells in the invasive carcinoma component. Correlation between K17 expression and clinical outcomes was assesed using Fischer's exact test and log rank test. Results: The 26 patients included in this study were 85% male, median age 60.5 years, 74% ECOG performance status < 2, with 80% having received prior chemotherapy. Primary site included oral cavity (54%), oropharynx (23%), larynx (4%), or other (19%). Seventeen tumors (65%) showed high K17 expression, and 9 tumors (35%) showed low K17 expression. Eleven patients (42%) had programmed death ligand 1 (PD-L1)+ tumors as determined by combined positive score. Six patients (23%, all K17 low) achieved clinical benefit, while 20 patients (77%, 17 K17 high and 2 K17 low) had progressive disease. High K17 expression was associated with lack of clinical benefit (p < 0.001), shorter time to treatment failure (p < 0.001), progression-free (p = 0.004) and overall survival (p = 0.02). PD-L1 expression by immunohistochemistry (clone 22C3) did not correlate with K17 expression or clinical outcome. Conclusions: Our findings suggest that K17 expression may predict clinical benefit from ICB in HNSCC patients, thus supporting further validation studies. [Table: see text]

Objective Evaluate the effects of α‐difluoromethylornithine (DFMO) on hearing thresholds as part of a randomized, double‐blind, placebo‐controlled trial. Methods Subjects were randomized and assigned to the control (placebo) or experimental (DFMO) group. DFMO or placebo were administered orally (500 mg/m 2 /day) for up to 5 years. Results Subjects taking DFMO had, on average, increased hearing thresholds from baseline across the frequency range compared to subjects in the control group. Statistical analysis revealed this was significant in the lower frequency range. Conclusions This randomized controlled trial revealed the presence of increased hearing thresholds associated with long‐term DFMO use. As a whole, DFMO may help prevent and treat certain types of cancers; however, it can result in some degree of hearing loss even when administered at low doses. This study further highlights the importance of closely monitoring hearing thresholds in subjects taking DFMO. Laryngoscope , 133:676–682, 2023

Resveratrol (3,4,5-trihydroxystilbene) is a naturally occurring phytoalexin with purported health-promoting effects, but with limited oral bioavailability. Our prior murine modeling research observed enhanced resveratrol bioavailability with piperine co-administration. In this study, single-dose pharmacokinetics of resveratrol with or without piperine and the associated toxicities were studied on a cohort of healthy volunteers. We performed a double-blind, randomized, three-arm pilot study. Participants were randomized to receive a single dose of resveratrol 2.5 g, with piperine in 0 mg, 5 mg, or 25 mg dose. An improved liquid chromatography/mass spectrometry assay was used to determine serum levels of resveratrol and resveratrol-glucuronide. Baseline through 24 h post-study drug serum analyses were performed and adverse events were followed for 30 days. Twenty-four participants were enroled. No significant relationship between dose and pharmacokinetic values were found. In the sex stratified analysis, Cmax for resveratrol in women showed a trend (P = 0.057) toward an increase with piperine. Pharmacokinetic values for resveratrol were: Cmax - 18.5 ± 16 ng/mL resveratrol alone, 29 ± 29 resveratrol + 5 mg piperine, 16 ± 13 resveratrol + 25 mg piperine; area under the concentration × time curve - 1270 ± 852 ng/h/mL resveratrol alone, 2083 ± 2284 resveratrol + 5 mg piperine, 1132 ± 222 resveratrol + 25 mg piperine. All subjects tolerated their protocol therapy with minimal to no toxicity and no evidence of differences between the three groups. The co-administration of resveratrol with piperine at 5 and 25 mg doses did not sufficiently alter the pharmacokinetics of resveratrol or resveratrol-glucuronide to demonstrate the significant enhancement observed in murine modeling.

INTRODUCTION OR OBJECTIVE:Men with favorable-risk prostate cancer (PCa) on active surveillance may benefit from intervention strategies to slow or prevent disease progression and the need for definitive treatment. Pomegranate and its extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, but its effect on human prostate cancer as a target tissue remain unclear. Objectives of this trial include pomegranate's ability to alter serum and prostate tissue biomarkers and the ability of an active surveillance cohort to adhere to a chemoprevention trial for 1 year. METHODS:Men with organ-confined, favorable-risk PCa on AS were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the 1-year intervention. Plasma and urinary biomarkers were analyzed utilizing immunoassays and HPLC. Tissue proteins were assessed by immunohistochemistry (IHC) and measured by automated quantitation. RESULTS:PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the 1-year intervention. No differences in plasma insulin-like growth factor-1 (IGF-1) levels, prostate-specific antigen doubling time, or biopsy kinetics were observed. Metabolites including urolithin A and urolithin A-gluc were detected more frequently in the PFE arm in both urine and plasma (p < .001 and p = .006, respectively). IHC analyses revealed reductions from baseline in 8-OHdG (a DNA damage marker) (p = .01) and androgen receptor expression (p = .04) in prostate tumor associated with PFE treatment. CONCLUSION:PFE administration for 12-month was well-tolerated and the protocol followed in an active surveillance population. Analyses suggest that PFE contains bioactive compounds capable of altering biomarkers involving oxidative stress and androgen signaling in prostate tumor and normal-appearing adjacent tissue. No alterations in the IGF axis were noted. This finding of study adherence and target activity provides a rationale for the further investigation of PFE in the active surveillance population.

285 Background: Due to its high prevalence and often indolent natural history, prostate cancer(PC) active surveillance(AS) is an ideal setting for chemoprevention. Studies assessing pomegranate and its extracts have shown promising anti-proliferative and pro-apoptotic effects in cell lines and animal models and a single-arm clinical trial of pomegranate fruit extract(PFE) reported an increase in PSA doubling time(PSADT) during AS. The primary objective of this trial was to assess the effect of PFE supplementation on plasma levels of Insulin-like Growth Factor-1(IGF-1). Secondary objectives addressed PSA doubling time(PSADT), tumor volume on end-of-study(EOS) biopsy and plasma and prostate tissue biomarkers. Methods: Men with organ-confined favorable-risk PC on AS were randomly assigned to receive PFE 1,000 mg(n=15) or placebo(n=15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the one-year intervention. Tissue biomarkers were assessed by immunohistochemistry(IHC) with automated quantitation. Results: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the one-year intervention. No differences in plasma IGF-1 levels(p=0.5), PSADT, or tissue biomarkers of apoptosis or proliferation were observed. A significant increase in urolithin A(a urinary metabolite of pomegranate) was observed in the PFE arm. IHC analyses of both tumor (Table) and normal-appearing tissue adjacent to tumor showed reductions from baseline in IGF-1, 8-OHdG(DNA damage marker), and androgen receptor expression associated with PFE treatment. A trend towards a reduction in the maximum percent of biopsy core tumor involvement was observed(p=0.06) in PFE. Conclusions: PFE administration for 12-months was not associated with a decrease in plasma IGF-1 levels nor an increase in PSADT. However, exploratory analyses suggest that PFE may contain bioactive compounds capable of altering biomarkers in PC and normal-appearing adjacent tissue providing a rationale for further investigation of PFE in the active surveillance population.