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BackgroundOf the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy.MethodsThis was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19–9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1–21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)—time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting.ResultsForty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36–81), 53% male, 73% node positive, 49% elevated CA 19–9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9–36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46–1.87,p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46–2.05,p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms.ConclusionsTreatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.

BackgroundThe prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). MethodsWe identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status. Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. ResultsOf the 784 eligible patients, 506 were KRAS negative (KRAS-) and 278 were KRAS positive (KRAS+). Median survival was 63.6 months and 76.3 months for KRAS+ and KRAS- patients respectively, with propensity adjusted 3 and 5-year survival of 79.9% vs. 83.6% and 56.7% vs 61.9% respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS+ disease was associated with poorer survival on unadjusted and propensity adjusted multivariable analyses. ConclusionsOur analysis of KRAS+ LARC suggest that KRAS+ disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted.

e16229 Background: Obesity has been associated with decreased survival in patients with pancreatic ductal adenocarcinoma (PDAC). However, exact reasons remain unclear. Reduced response to chemotherapy because of obesity-induced desmoplasia has been proposed as a mechanism for the suboptimal response to treatment and therefore worse outcome. To this end, we attempted to determine the effect of obesity on the efficacy of neoadjuvant chemotherapy in patients with resectable and potentially resectable PDAC who underwent surgical resection. We assessed rates of microscopic tumor-free margins as a surrogate for treatment response. Methods: We performed a retrospective review of all patients diagnosed with PDAC from 2017-2019 at Allegheny Health Network. Obesity was defined as BMI > 30 kg/m2. Patients with resectable and potentially resectable disease who eventually received surgical treatment were included.Demographics, treatment details, and surgical pathology results were reviewed. Two-sided Mann-Whitney U test and Fischer’s exact test were used to evaluate differences between groups with continuous and categorical variables, respectively. A p value of < 0.05 was considered as level of significance. Results: Out of 121 patients who received and completed treatment at our institution, 29 patients underwent neoadjuvant chemotherapy followed by surgical resection. Most patients were female (61%), Caucasians (90%), had stage I (76%) and potentially resectable disease (72%). Eleven (38%) patients were categorized as obese and remaining non-obese. Among patients who underwent surgery after neoadjuvant chemotherapy, 10 out of 11 patients (90.9%) had microscopic tumor-free margins in the obese group when compared to 17 out of 18 patients (94.4%) in the non-obese group. (Table). Conclusions: Our study revealed no significant difference in obese patients compared to non-obese patients in terms of tumor-free margins assessed microscopically after surgical resection. Our study is limited by its small sample size, retrospective nature, and unidentifiable confounding factors that could potentially affect outcomes. Larger scale studies are needed to investigate the effect of obesity on treatment outcomes in resectable and potentially resectable pancreatic cancer patients treated with neoadjuvant chemotherapy.[Table: see text]

e14591 Background: Combined immune checkpoint inhibitors (ICPI) have revolutionized treatment of solid tumors. Their use can lead to treatment-related adverse events (TRAEs) resulting in hospital admissions, treatment discontinuation and increased morbidity. We aim to evaluate gastrointestinal (GI) TRAEs of different combination ICPI. Methods: A comprehensive search of multiple databases from inception to October 2021 was performed. Phase 2 and 3 trials assessing safety and efficacy of combined ICPI in solid tumors were included. Trials reporting concurrent use of chemotherapy, immunosuppressants, targeted therapy, or sequential ICPI therapy were excluded. Primary outcome was pooled luminal, hepatic and pancreatic TRAEs. A meta-analysis of proportions was done for outcomes using a random-effects model. I2 % was used to assess heterogeneity. Results: Out of 3696 citations screened, 53 trials reporting TRAEs in 6186 patients were included. Data from 41 study arms of 35 trials in nivolumab plus ipilimumab (N+I), 15 study arms of 15 trials in durvalumab plus tremelimumab (D+T), 4 study arms of 3 trials in pembrolizumab plus ipilimumab (P+I). The most common indications for combined ICPI were melanoma (26.4%) and lung cancer (24.5%). Pooled GI TRAE rates from the D+T, P+I and two different dosing combinations of N+I are shown in the table. Conclusions: Our study provides pooled data of TRAEs from different combination ICPI use in solid tumors and demonstrates high incidence of all grades and ≥ 3 GI TRAEs. Combined ICPI related TRAEs should be recognized early, as it may require treatment discontinuation. Further studies are required to assess overall impact of TRAEs on treatment course and outcomes.[Table: see text]

e16246 Background: Obesity has been identified as a risk factor for pancreatic cancer. The prevalence of obesity has been on a rise in the last two decades. Obesity is defined by the world health organization (WHO) as body mass index (BMI) > 30.0 kg/m2. Studies have shown obese patients to have worse survival than non-obese patients with pancreatic cancer. However, there is limited data on effect of obesity on disease progression. We sought to identify the relationship between obesity and time to progression in patients with resectable and potentially resectable pancreatic ductal adenocarcinoma (PDAC). Methods: We performed a retrospective review of charts of all patients diagnosed with PDAC from 2017-2019 at Allegheny Health Network. Demographics (including age, sex, and race), treatment details, and time to progression date of diagnosis (rounded off in months) were obtained. Two-sided Mann-Whitney U test and Fischer’s exact test were used to evaluate differences between groups with continuous and categorical variables respectively. Furthermore, paired t test was used to compare mean time to progression between the patients in the obese and non-obese groups. A p-value of < 0.05 was considered as level of significance. Results: Out of the 121 patients who received treatment at our institution, 40 patients who had resectable or potentially resectable disease and had progression of disease were included in the analysis. The median age of patients was 68. The majority were females (60%), Caucasians (90%), had Stage I (65%) and potentially resectable disease (55%). Around 70% of patients were treated surgically, 80% received chemotherapy and 26% received radiation therapy. Twelve out of 42 patients were obese (27.5%). No difference in patient characteristics including demographics, staging, and treatment characteristics (proportion of patients who received surgery, chemotherapy, and radiotherapy) was identified between obese and non-obese group patients. The mean time to progression was 11.9 months in obese group as compared to 13.7 months in non-obese group (p = 0.63). Conclusions: Our study showed no significant difference in time to progression of disease between obese and non-obese patients with resectable/potentially resectable pancreatic cancer. Our study is limited by its small sample size, retrospective nature, and unidentifiable confounding factors that could potentially affect outcomes. Larger scale studies are needed to investigate the effect of obesity as a prognostic factor for disease progression in patients with pancreatic cancer.

e16271 Background: Obesity is an established risk factor for cancer and cancer-related mortality. Adipocytes may act as a “damage” signal resulting in the accumulation of innate immune cells, fueling an inflammatory micro-environment. Among the innate immune cells, tumor-associated neutrophils (TANs) are confirmed to accumulate inside the tumor. As obesity is a significant risk factor for a poorer prognosis in pancreatic ductal adenocarcinoma (PDAC), we hypothesize that obesity-driven adipose fuels the progression of PDAC in a TAN and inflammasome-facilitated manner. This may happen through several mechanisms, including genomic instability of aggressive PDAC clonal populations. Methods: Tissue from resected tumors of PDAC patients (n = 44) with a body-mass index (BMI) > 27 (obese [n = 21]) and BMI < 22 (normal [n = 23]) were incubated with anti-human CD66b antibodies and detected using standard immunofluorescent microscopy techniques. Images were acquired in a Zeiss Axioplan microscope workstation and analyzed by ZEN and Metamorph software. Results: We identified the presence of adipocytes in all tissue sections and CD66b+ neutrophils in all tissue sections of normal BMI patients and in 81% of high BMI patients. There is a significantly greater density of adipocytes in the tumor environment when compared to adjacent normal areas, suggesting that these cells are acting as a damage signal. We have also shown that there are fewer total cells per area in the tumor region, suggesting a disorganization that may allow more adipose tissue to form in these areas of high BMI patients. Our novel data also shows that high BMI results in a significantly higher neutrophil count in tumor specific tissue when compared to patients with a low BMI. These data suggest an association between BMI and inflammasome accumulation in the tumor environment. Conclusions: Our data uniquely shows that CD66b+ neutrophils tend to accumulate inside PDAC in high BMI patients and this is associated with intra-tumoral active inflammasomes. The higher concentrations of these inflammasomes in higher BMI patients may be of mechanistic relevance in understanding how inflammation induces progression of PDAC. A larger cohort of tissues from PDAC obtained from low and high BMI individuals will be needed to test our hypothesis and to begin to decipher the role of obesity on inflammation and PDAC progression.

e21036 Background: The oligometastatic state is one of limited metastases, amenable to local therapies of curative potential. Stereotactic body radiation therapy (SBRT) is a non-surgical treatment with a primary goal of rapid local tumor control and low toxicity allowing prompt return to systemic therapy. Breast (BRC), colorectal (CRC) and non-small cell lung cancers (NSCLC) have oligometastases as first presentation. In these patients, consolidative SBRT offers effective local control and low toxicity, with the potential for improved survival benefit without affecting quality of life. We report our experience on such patients. Methods: 31 patients with BRC (9), CRC (16) and NSCLC (6) with ≤ 5 unresectable metastases to one to three organ sites were identified. Data were obtained from chart review. Primary end point was infield local control. Lesions with at least 6 months of radiographic follow-up were assessable. Secondary end points were toxicity and survival. Results: All patients completed SBRT to 38 lesions (≤2/patient). 29 received prior chemotherapy for metastatic disease. 14 were treated with at least 1 prior regimen and 15 at least 2 (0-8). At a median follow-up of 16 months (4-32), 22 patients (8 BRC, 10 CRC and 4 NSCLC) were assessable. At 6 months, 20 patients had infield local control and 3 demonstrated distant metastases. At 1 year, this was seen in 19 and 7 patients respectively. The most common toxicity was grade ≤2 fatigue. All BRC had infield local control at 6 months and 1 year. Among CRC, 9 had infield local control at 6 months and 7 at 1 year. 3 NSCLC patients had infield local control at 6 months and 1 year. No BRC demonstrated distant progression at 6 months; at 1 year, it was seen in 2 patients. 3 CRC had evidence of distant progression at 6 months and 1 year. 1 NSCLC patient had distant progression at 6 months and 2 at 1 year. 6 patients died from their underlying malignancy; the median survival for 5 of these patients was 20 months (5-34). Conclusions: The combination of systemic chemotherapy and consolidative SBRT is safe and effective for patients with oligometastatic disease