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Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Introduction In the South African Breast Cancer and HIV Outcomes (SABCHO) study, early-stage breast cancer patients living with HIV, compared to their HIV-negative counterparts, demonstrated higher overall mortality and lower rates of pathologic complete response if treated with neoadjuvant chemotherapy. We aimed to determine if comorbid HIV also impacted receipt of timely and complete neoadjuvant and adjuvant chemotherapy. Methods We retrospectively identified Black, stage I-III SABCHO participants diagnosed with breast cancer from June 2015 to July 2019 and who received at least 2 doses of neoadjuvant or adjuvant chemotherapy at either Charlotte Maxeke Johannesburg Academic Hospital (Gauteng) or Grey’s Hospital (KwaZulu-Natal). Data on the originally prescribed chemotherapy regimen and the dose and timing of all received chemotherapy was extracted from patients’ medical records, as well as values from all complete blood counts and metabolic panels performed during treatment. Relative dose intensity (RDI) was calculated for each agent in the prescribed regimen with the mean RDI of all agents representing the RDI of the full regimen. We assessed for associations between full regimen RDI and HIV status using a multivariable linear regression model that included demographic and clinical covariates also shown to impact RDI. We also compared rates of myelosuppression, alkaline phosphatase elevation, and creatinine elevation using linear regression. Using previously collected survival data, we compared overall mortality based on overall RDI above or below 0.85. Results We analyzed data from 325 eligible subjects, 166 of whom were living with HIV. No differences based on HIV status were appreciated in the prescribed chemotherapy regimens. For women without HIV median RDI was 0.87 (interquartile range (IQR) 0.77-0.94) and, in those living with HIV, it was 0.89 (IQR 0.77-0.95). HIV status showed no significant association with RDI on multivariable analysis, and the only patient characteristics associated with RDI were estrogen/progesterone receptor (ER/PR) and HER2 status. Patients living with HIV experienced more CTCAE v5.0 grade 3+ anemia and leukopenia than those without HIV (anemia: 10.8% vs 1.9%, p=0.001; leukopenia: 8.4% vs 1.9%, p=0.008) and were more likely to receive at least one dose of filgrastim (24.7% vs 10.7%, p=0.001). Receipt of RDI greater or less than 0.85 did not predict overall mortality in the full cohort or HIV status subgroups. A trend towards improved survival with RDI greater than 0.85 was seen among the 69 participants with ER/PR negative disease (hazard ratio: 0.60, 95% confidence interval: 0.30-1.21, p = 0.15). Conclusions Neoadjuvant and adjuvant chemotherapy RDI did not differ by HIV status among women in the SABCHO study, although women living with HIV experienced more myelotoxicity during treatment. Efforts to reduce chemotherapy dose reduction and delays should target all South African breast cancer patients. Citation Format: Daniel S. O’Neil, Oluwatosin A Ayeni, Hayley A. Farrow Woolridge, Wenlong Carl Chen, Georgia Demetriou, Ines Buccimazza, Sharon Cacala, Maureen Joffe, Michael Antoni, Gilberto Lopes, Yoanna Pumpalova, Witness Mapanga, Judith S. Jacobson, Katherine D. Crew, Alfred I. Neugut, Paul Ruff, Herbert Cubasch. The Impact of Comorbid HIV infection on Neoadjuvant and Adjuvant Chemotherapy Relative Dose Intensity in South African Breast Cancer Patients [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 P1-01-03.

Introduction Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. Materials and Methods The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Results Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03–0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Conclusion Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Implications for Practice Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

The 2020 National Comprehensive Cancer Network guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for borderline resectable/locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC).The purpose of our study was to compare treatment outcomes, toxicity profiles, costs, and quality-of-life measures between these two treatments to further inform clinical decision-making.We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over 12 years. The model inputs were estimated using clinical trial data and published literature. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100 000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care, QALYs, PDAC resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). FOLFIRINOX was the cost-effective strategy, with an ICER of $60856.47 per QALY when compared to G-nP. G-nP had an ICER of $44639.71 per QALY when compared to natural history. For clinical outcomes, more patients underwent an "R0" resection with FOLFIRINOX compared to G-nP (84.9 vs. 81.0%), but FOLFIRINOX had higher TRAE costs than G-nP ($10905.19 vs. $4894.11). A one-way sensitivity analysis found that the ICER of FOLFIRINOX exceeded the threshold when TRAE costs were higher or PDAC recurrence rates were lower.Our modeling analysis suggests that FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings.

Background: Capecitabine (Cap) is an established treatment alternative to 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. We compared outcomes and toxicities using Cap versus 5-FU in non-metastatic anal cancer patients at Stanford. Methods: All non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997–2016 were included. Fisher’s exact and Mann-Whitney U tests were used to compare nominal and continuous variables. Gray’s test was used to compare incidence of recurrence and colostomy, and Log-rank test was used to compare survival. Results: Sixty-eight patients were included. Thirty-six patients received Cap and 32 received 5-FU (12 received standard 5-FU and 20 received low-dose continuous 5-FU). Patient characteristics were similar between the two groups. There was no difference in the 3-year overall and disease-specific survival between Cap and 5-FU (94% vs . 80%, P=0.197; 100% vs . 86%, P=0.051). Overall incidence of recurrence was equivalent between Cap and 5-FU (11% vs . 13%, P=0.703), but incidence of locoregional recurrence was higher in the 5-FU group (0% vs . 13%, P=0.042); patients treated with Cap had longer recurrence-free intervals (18 vs . 6 months, P=0.400), and all recurrences were distant. More colostomies were needed with 5-FU (3% vs . 13%, P=0.133). Toxicities were similar between the two groups. The most common grade ≥2 toxicities were dermatitis (77%), anal pain (78%), and diarrhea (56%). Conclusions: Overall survival (OS), cancer-specific survival and incidence of recurrence were equivalent between Cap and 5-FU in anal cancer. Patients treated with Cap had statistically significant lower incidence of loco-regional relapses.

This study sought to assess access to utilities, basic needs, financial burden, and perceived safety among households in the Rockaway Peninsula of New York City, United States, four months after Hurricane Sandy struck in 2012. A modified cluster survey design was used to select households for inclusion in the study. Survey content was created using the Community Assessment for Public Health Emergency Response (CASPER) toolkit, gathering relevant data on access to food and water, basic utilities, financial burden, household demographics, and safety. Four months after Sandy, electricity and heat had been restored to all households. However, around one-third of them still had difficulty in obtaining food, and about one-half believed that their neighborhood was unsafe. One-quarter had problems in acquiring prescription medications, and approximately one-half reported anxiety. While basic utilities were almost entirely restored, there were ongoing challenges in Rockaway four months after Sandy, relating to financial hardship, food insecurity, healthcare, and psychologic distress.

We provide the first comprehensive analysis of any transcription factor family in Cryptosporidium, a basal-branching apicomplexan that is the second leading cause of infant diarrhea globally. AP2 domain-containing proteins have evolved to be the major regulatory family in the phylum to the exclusion of canonical regulators. We show that apicomplexan and perkinsid AP2 domains cluster distinctly from other chromalveolate AP2s. Proteinbinding specificity assays of C. parvum AP2 domains combined with motif conservation upstream of co-regulated gene clusters allowed the construction of putative AP2 regulons across the in vitro life cycle. Orthologous Apicomplexan AP2 (ApiAP2) expression has been rearranged relative to the malaria parasite P. falciparum, suggesting ApiAP2 network rewiring during evolution. C. hominis orthologs of putative C. parvum ApiAP2 proteins and target genes show greater than average variation. C. parvum AP2 domains display reduced binding diversity relative to P. falciparum, with multiple domains binding the 5 � -TGCAT-3 � ,5 � -CACACA-3 � and G-box motifs (5 � G[T/C]GGGG-3 � ). Many overrepresented motifs in C. parvum upstream regions are not AP2 binding motifs. We propose that C. parvum is less reliant on ApiAP2 regulators in part because it utilizes E2F/DP1 transcription factors. C. parvum may provide clues to the ancestral state of apicomplexan transcriptional regulation, pre-AP2 domination.

4116 Background: Despite the therapeutic promise of ICIs for patients (pts) with some advanced malignancies, they are FDA-approved for only a few GI cancer pts. In NSCLC, melanoma and urothelial carcinoma, there is emerging data that pts who experience IRAEs while on ICIs have improved outcomes compared with pts who do not. This association in GI cancer pts has not been reported. Methods: We retrospectively analyzed outcomes for metastatic GI cancer pts receiving ICIs for FDA-approved indications (later-line MSI-H tumors, 2nd line hepatocellular carcinoma (HCC), 3rd line PD-L1+ gastric (GA)/gastroesophageal junction (GEJ) adenocarcinoma), at Vanderbilt Ingram Cancer Center, Winship Cancer Institute and Stanford Cancer Institute. Our primary aim was to compare progression-free survival (PFS) and overall survival (OS) between pts who did and did not experience IRAEs. Secondary aims were comparison of these outcomes within pts who experienced IRAEs, by initial IRAE severity (Grade (G)3/G4 vs G1/G2) (CTCAE v5.0), time-to-onset (TTO) (≤ 6 weeks (w) vs > 6 w) and management (steroids vs drug cessation vs observation). PFS and OS were determined by Kaplan-Meier (KM) analysis; KM comparisons were done by the logrank test. Results: Between 1/2015-12/2018 61 GI cancer pts with HCC (28), colorectal cancer (27) and GA/GEJ cancer (6) were treated with ICIs; median age was 63 years. The majority (59) received single-agent nivolumab or pembrolizumab while minority (2) received nivolumab and ipilimumab; median time on ICIs was 5.9 months (mos). Twenty-four pts experienced initial IRAEs (6 G3/G4, 18 G1/G2); median TTO was 3.8 mos. Pts who experienced any IRAE had improvements in PFS and OS compared to those who did not (PFS: 32.4 mos (95% confidence interval (CI), 32.4-not reached (NR)) vs 4.8 mos (95% CI, 2.9-8.7), p = 0.0001; OS: 32.4 mos (95% CI, 32.4-NR) vs 8.5 mos (95% CI, 6-NR), p = 0.0036). Among pts who experienced IRAEs, PFS and OS differences between above-specified subgroups did not meet statistical significance. Conclusions: GI cancer pts who experienced IRAEs while on ICIs had marked improvements in PFS and OS compared to those who did not, suggesting the predictive potential for IRAEs as a clinical biomarker in this population.

e15573Background: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal can...

710 Background: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. The objective of this retrospective study was to compare outcomes and toxicities in non-metastatic anal cancer patients undergoing definitive radiotherapy (RT) at Stanford combined with capecitabine/mitomycin (CM) versus 5-FU/mitomycin (FM). Methods: We included all non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997 – 2016. Patients who received cisplatin or induction chemotherapy were excluded. Patient charts were reviewed and cause of death determined from the cancer registry. Fisher’s exact test was used to compare nominal parameters, Mann-Whitney U test for continuous variables. Gray’s test for equality was used to compare recurrence and colostomy incidence, and Log-rank test to compare disease-specific and overall survival. Results: Sixty-eight patients were treated at Stanford. Twenty-nine received FM and RT, 12 received standard 5-FU and 17 received low-dose continuous 5-FU; 39 patients received CM and RT. Median age was 59.5 years, and 56% were female. There was no difference in the 3-year overall and disease-specific survival between the FM and CM groups (81.5% v 90.5% p = 0.262; 88.1% v 96.0% p = 0.229). Incidence of recurrence was equivalent between the two groups (13.8% v 10.6%, p = 0.927) but patients in the combined FM group recurred earlier (6.9 v 20 months, p = 0.004) and distant recurrences were only seen in the CM group. Colostomy rates were higher in the FM group (14.6% v 2.8%, p = 0.082); all colostomies in the FM group were in patients receiving continuous 5-FU. Toxicities were similar between the two groups. The most common grade 2 or higher toxicities were dermatitis (77%), anal pain (77%), diarrhea (54%), stomatitis (19%), and nausea (22%). Conclusions: Overall and disease-specific survival and recurrence rates were equivalent between FM and CM groups. Recurrence patterns differed with loco-regional recurrences and higher colostomy rates in the FM group, while most recurrences in the CM group were distant.