Citations

Abstract Chronic inflammation is a well-established carcinogenic pathway for colorectal cancer (CRC), but the role of inflammation in CRC prognosis is not well understood. Since cytokines are central in extensive biological networks to regulate inflammation, it is of great importance to investigate inflammatory cytokines and CRC survival. Among an NCI-sponsored adjuvant chemotherapy trial for patients with stage III colon cancer conducted between 2010 and 2015 (CALGB/SWOG 80702), we collected serum samples from 1,498 participants at a median of 1.6 months (interquartile [IQR]: 1.3-1.9 months) after surgery. IL-6, TNFR2, and hsCRP were assayed as biomarkers of chronic inflammation and were categorized into quintiles. The primary outcome was disease-free survival, defined as time from randomization to recurrence or death from any cause. Secondary outcomes included overall survival and time to recurrence. We estimated the associations of inflammatory biomarkers with survival using multivariable Cox proportional hazards regression. Of 1,498 participants (median follow-up: 5.9 years), mean age was 61.3 years, 82.2% were White, 55.5% were male, and 387 experienced recurrence or death. Medians (IQRs) of biomarkers were 2.6mg/L (1.2-5.6mg/L) for IL-6, 2.9×103pg/mL (2.3-3.6×103pg/mL) for TNFR2, and 2.6mg/L (1.2-5.6mg/L) for hsCRP. Compared to the lowest quintile (Q1), the highest quintile (Q5) in inflammatory biomarkers was significantly associated with worse disease-free survival (hazard ratios were 1.52 [95% CI, 1.08-2.15] for IL-6, 1.76 [95% CI, 1.22-2.54] for TNFR2, and 1.66 [95% CI, 1.17-2.35] for hsCRP). Similar patterns were observed for overall survival and time to recurrence. Our findings suggest that higher levels of inflammation after diagnosis were significantly associated with worse survival among those with stage III colon cancer, and reducing inflammation may be considered as a potential intervention to improve CRC survival. ‬‬ Associations of Inflammatory Biomarkers with Survival after Adjustment for Clinicopathologic Factors Q1 Q2 Q3 Q4 Q5 P for Trend Disease-free survival IL-6 1.00 1.14 (0.80-1.62) 1.37 (0.97-1.94) 1.44 (1.02-2.03) 1.52 (1.08-2.15) 0.02 TNFR2 1.00 1.21 (0.84-1.74) 1.43 (0.99-2.05) 1.56 (1.09-2.25) 1.76 (1.22-2.54) 0.002 hsCRP 1.00 1.34 (0.95-1.90) 1.62 (1.15-2.29) 1.26 (0.88-1.80) 1.66 (1.17-2.35) 0.04 Overall survival IL-6 1.00 1.44 (0.91-2.29) 1.56 (0.98-2.48) 1.48 (0.93-2.34) 1.68 (1.07-2.65) 0.09 TNFR2 1.00 1.57 (0.94-2.63) 1.88 (1.13-3.13) 1.92 (1.15-3.20) 2.31 (1.39-3.84) 0.003 hsCRP 1.00 1.27 (0.81-2.00) 1.72 (1.11-2.65) 1.22 (0.77-1.92) 1.73 (1.12-2.69) 0.06 Time to recurrence IL-6 1.00 1.34 (0.92-1.95) 1.48 (1.01-2.16) 1.55 (1.06-2.27) 1.54 (1.05-2.26) 0.07 TNFR2 1.00 1.14 (0.78-1.67) 1.28 (0.87-1.87) 1.48 (1.01-2.16) 1.54 (1.04-2.27) 0.02 hsCRP 1.00 1.27 (0.87-1.83) 1.64 (1.14-2.36) 1.21 (0.82-1.77) 1.55 (1.07-2.26) 0.12 Citation Format: En Cheng, Shi Qian, Anthony F. Shields, Elizabeth M. Cespedes Feliciano, Andrew B. Nixon, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Dequincy Lewis, Benjamin Tan, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Bette J. Caan, Jeffrey A. Meyerhardt. Associations of inflammatory biomarkers with survival among patients with stage III colon cancer (CALGB/SWOG 80702 [Alliance]) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 682.

Abstract Background: Cemiplimab is the first treatment approved in the US (as cemiplimab-rwlc) for patients with metastatic basal cell carcinoma (mBCC) or locally advanced disease (laBCC) after hedgehog inhibitor (HHI) treatment or for whom an HHI is not appropriate. Cemiplimab provided substantial clinical benefit and an acceptable safety profile in patients with laBCC who discontinued HHI therapy due to progressive disease (PD), intolerance, or no better than stable disease (SD) after 9 months (NCT03132636). Here, we present the primary analysis of the mBCC cohort. Methods: Patients with mBCC (nodal or distant) post-HHI treatment received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until PD. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Key secondary endpoints included safety and tolerability, ORR per investigator (INV) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and complete response (CR) rate (data cutoff date: May 20, 2021). Results: Fifty-four patients were enrolled (70.4% male; median age 63.5 years [range, 38−90]; Eastern Cooperative Oncology Group performance status 0 [66.7%] and 1 [33.3%]). Median duration of follow-up was 8.4 months (range 1.5-36.2). ORR per ICR was 24.1% (95% confidence interval [CI], 13.5-37.6); with 1 CR and 12 partial responses (PRs). ORR per INV was 25.9% (95% CI, 15.0-39.7), with 2 CRs and 12 PRs. Among responders, median time to response per ICR was 4.0 months (range, 2.0−10.5). Estimated median DOR per ICR was 16.7 months (95% CI, 9.8-not evaluable). Disease control rate was 63.0% (95% CI, 48.7-75.7) per ICR and 70.4% (95% CI, 56.4-82.0) per INV. Median OS was not reached. Median PFS per ICR was 8.3 months (95% CI, 4.2-15.9). The most common treatment-related adverse events were fatigue (37.0%), diarrhea (14.8%), pruritus (13.0%), hyperthyroidism (9.3%), and arthralgia (9.3%) as well as hypothyroidism, asthenia, constipation, and maculo-papular rash (7.4% each). There were no treatment-related deaths. Conclusions: Cemiplimab provided clinically meaningful antitumor activity, including durable responses, and an acceptable safety profile in patients with mBCC who had progressed on or were intolerant to HHI therapy. Citation Format: Karl Lewis, Ketty Peris, Aleksander Sekulic, Alexander J. Stratigos, Lara Dunn, Zeynep Eroglu, Anne Lynn S. Chang, Michael R. Migden, Suk-Young Yoo, Kosalai Mohan, Ebony Coates, Emmanuel Okoye, Timothy Bowler, Jean-François Baurain, Oliver Bechter, Axel Hauschild, Marcus O. Butler, Leonel Hernandez-Aya, Lisa Licitra, Rogerio I. Neves, Emily S. Ruiz, Frank Seebach, David M. Weinreich, George D. Yancopoulos, Israel Lowy, Priscila Goncalves, Matthew G. Fury. Primary analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma who progressed on or were intolerant to hedgehog inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT165.

Abstract Gallbladder cancer (GBC) is one of the deadliest cancers, with a 5-year-survival-rate of less than 5 percent for late-stage disease. The response rate to chemotherapy among GBC patients is generally poor. Recent research has attempted to identify diagnostic, prognostic, and predictive biomarkers, however, currently, no biomarkers can accurately diagnose GBC and predict patients’ prognosis. Integrative analysis of molecular and clinical characterization has not been fully established, and minimal improvement has been made to the survival of these patients, in part due to the heterogeneity of GBC. Machine learning techniques have been proven to empower analysis of big data in oncology, allowing for improvement in the generation of biomarkers to predict patient outcomes. Using machine learning, we can utilize high-throughput RNA sequencing with clinicopathologic data to develop a predictive tool for GBC prognosis. Current predictive models for GBC outcomes often utilize clinical data only, with the highest C-statistic reported being 0.71. C-statistic values over 0.7 generally indicate good models, however 0.8 is the threshold for strong predictive models. We aim to build a superior algorithm to predict overall survival in GBC patients with advanced disease, using machine learning approaches to prioritize biomarkers for GBC prognosis. We have identified over 80 fresh frozen GBC tissue samples from Mayo Clinic Rochester, Dongsan Medical Center in Daegu, Korea, University of the Witwatersrand, in Johannesburg, South Africa, Lithuanian University of Health Science in Vilnius, Lithuania, and University of Calgary in Calgary, Canada, from patients enrolled between 2012 and 2021. We will perform next-generation RNA sequencing on these tissue samples. The patients’ clinical, pathologic and survival data will be abstracted from the medical record uniformly across sites. Feature engineering and dimensionality reduction will be performed. Then random forests, support vector machines, and gradient boosting machines will be applied to train the data. Variable importance will prioritize multi-omic markers. Standard 5-fold cross validation will be used to assess performance of each ML algorithm. If overall survival can be better predicted with the addition patients’ transcriptional sequencing data compared to using clinical profiles alone, we can gain a greater understanding of key biomarkers driving the tumor phenotype. Citation Format: Linsey Jackson, Loretta Allotey, Valles Kenneth, Gavin Oliver, Asha Nair, Daniel O'Brien, Rondell Graham, Mitesh Borad, Arjun Athreya, Lewis Roberts. Prognostic biomarkers for gallbladder cancer: A machine learning approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1944.

Abstract COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period.

10581 Background: MSI-H colorectal cancer is most often a result of deleterious mutations in mismatch repair genes, but can also occur through repressed gene transcription due to hypermethylation of the MLH1 promoter, often associated with BRAF V600E mutations. However, there is a subset of patients who have a “constitutional epimutation”, resulting in hypermethylation of MLH1 throughout normal tissue. We observed a young patient develop a second primary Lynch associated malignancy (see Table 1) who was found to have a constitutional epimutation in MLH1 that prompted us to review the frequency with which the test was ordered and the positivity rate, as well as outline the clinical history in the positive cases. Methods: We reviewed all of the testing ordered for MLH1 hypermethylation of peripheral blood (MLHPB) at the Mayo Clinic Laboratory between 09/01/2020 and 09/01/2021. To the best of our knowledge, this is the only clinically available testing lab in the United States. We reviewed positive casesfor characteristics including the number of malignancies, age of diagnosis, and family history. Results: 33 MLHPB total tests were ordered in the United States at the Mayo Clinic laboratories between 09/01/2020 and 09/01/2021. Three of the tests were positive, including the single test ordered by our institution, and one of the two additional positive tests was available for detailed review. Our institution’s positive test case was a 41 year old women who developed T4N2M0 colorectal cancer 5 years after being treated for endometrial cancer. She had endometrial cancer with absence of MLH1 and PMS2 staining and had a negative germline cancer risk panel at age 36. Five years later, she developed a T4N2 colorectal cancer after which repeat germline testing with RNA sequencing was negative and she was found to have constitutional MLH1 promoter hypermethylation. We were able to obtain clinical information about two of the three individuals with positive tests (See Table). Conclusions: Recognition of constitutional MLH1 hypermethylation may allow for earlier recognition of Lynch related malignancies in affected patients and families. Testing appears infrequent and this condition often goes unrecognized. Specific consensus guidelines may improve recognition and cancer screening in this population. [Table: see text]

e17036 Background: Elevated serum CGA is associated with an intrinsic or treatment-related neuroendocrine differentiation in men with mCRPC. We previously demonstrated that elevated serum CGA was negatively associated with OS in men with mCRPC. Fluctuations in serum CGA during mCRPC therapy is not well known. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with AA therapy. Methods: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial (“PROMOTE”; NCT#01953640) with uniform serum processing performed prior to initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients (pts) receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded). All patients underwent a composite response assessment at 12-weeks with imaging/PSA/QOL questionnaires. Kaplan Meier estimates, and Cox Regression models were used to calculate association with time-to-treatment failure (TTF) analyses, defined as time from treatment initiation to AA/P discontinuation based on disease progression (BlueSky Statistics, Chicago, IL, USA). Results: Of the 71 eligible pts, 67/71 had paired baseline and 12-week CGA and 70/71 pts had a baseline and a 12-week PSA available. The median baseline CGA was 83.0ng/ml (range: 53.0 - 127.0 ng/ml), median baseline PSA was 14.4 ng/ml (range: 6.4-40.2 ng/ml), and the median TTF was 10 months (range: 6-25 months). The median CGA after 12 weeks of AA/P was 98.0 ng/ml (58.0 -148.0 ng/ml) and we observed a CGA rise in 41/67 (61.2%) pts. An increase in chromogranin was associated with a lower risk of treatment failure (HR: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6 -16.0). An elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). Conclusions: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in pts with mCRPC were associated with a favorable response to AA/P. Further studies are needed to assess if rising CGA during therapy reflects neuroendocrine differentiation and may indicate a sign of treatment effect targeting the androgen susceptible cells. Clinical trial information: NCT#01953640.

TPS5107 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 3 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888. Clinical trial information: NCT04455750.