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e15601 Background: We evaluated demographic, treatment, and survival outcomes of adults age 18 to 49 years treated at our institution with long course chemoradiotherapy (CRT) followed by total mesorectal excision (TME) for locally advanced rectal cancer. Additionally, we compared outcomes between those age < 45 vs. > 45 years. Methods: The records of 219 patients diagnosed with non-metastatic, clinical T3, T4, or node positive rectal adenocarcinoma and treated between April 2000 and November 2017 were reviewed for age, sex, and presenting symptoms; clinical stage and microsatellite stable (MSS)/DNA mismatch repair (MMR) proficiency status; treatments delivered and sequence; pathologic response to pre-operative therapies; and the development of locoregional recurrence (LRR), distant metastasis (DM), and secondary pelvic malignancy. The Kaplan-Meier method and Log-Rank test were used to calculate and compare disease-free survival (DFS) and overall survival (OS) rates from the date of TME. Results: The median age at diagnosis was 44 years (range 19-49) and there was no sex predominance. Rectal bleeding was the most common presenting symptom (91%), with a median time to diagnosis of 5 months. Clinical tumor/nodal categories were T1-2 in 4%, T3 in 87%, T4 in 7%, N0 in 17%, and N1–2 in 80% of patients. MSS/MMR proficient disease was identified in 95% of tumors with status reported (n = 170). CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with capecitabine (n = 176) and FOLFOX (n = 115) as the predominant concurrent and post-operative chemotherapies, respectively. Pathologic complete response at both primary and nodal sites occurred in 15% of all cases and 16% of MSS/MMR proficient cases. There was no difference in sex, tumor category, nodal category, MSS/MMR proficiency status, or pathologic complete response, by age ( < 45 years [n = 111] vs. > 45 years [n = 108]). At a median DFS follow-up time of 5.0 years, there were 11 LRR, 40 DM (including 11 DM detected prior to/at time of TME), and 1 synchronous presentation of LRR and DM. The 5-year rate of DFS was 70.4% for age < 45 years and 85.3% for age > 45 years ( P = 0.02). At an OS median follow-up time of 7.5 years, there were 38 deaths. The 5-year rate of OS was 87.7% for age < 45 years and 94.4% for age > 45 years ( P = 0.126). Two patients developed non-rectal pelvic malignancies. Conclusions: The outcomes reported here from one of the largest single-institution series for young-onset, locally advanced rectal cancer could serve as a benchmark to evaluate newer treatment approaches. Rectal bleeding was the leading presenting symptom, with approximately half-year delay from development of symptoms to diagnosis. Most tumors were MSS/MMR proficient. At 5 years’ follow-up time, the DFS rate was lower for patients age < 45 years when compared to those > 45 years. Secondary pelvic malignancies were a rare occurrence.

4106 Background: Advanced biliary tract cancers (BTC) are lethal cancers with limited treatment options and short survival. Median progression-free survival (mPFS) in the ABC-02 trial was 8.0 months with gemcitabine-cisplatin (GC) and 5.0 m with gemcitabine alone in the front-line setting. The ABC-06 trial showed mPFS of 4.0 m with second-line FOLFOX. TP53 mutation is known to be associated with poor prognosis in other cancers, but its impact on survival in advanced or metastatic BTC has not been detailed. Methods: Mutational profiles were obtained from a retrospective database collected via an institutional DNA/RNA sequencing panel, FoundationOne, or Guardant360. Out of 149 patients with TP53 mutations in BTC, 90 had advanced or metastatic BTC treated at a single institution between 2015 and 2021. These patients were not candidates for surgery, radiation, or liver-directed therapy. Results: Intrahepatic, hilar, distal, and gallbladder cancer diagnoses were confirmed in 66, 11, 10, and 3 patients. Median age was 63, with a male:female ratio of 1:1. Poorly, moderately, and well-differentiated adenocarcinomas were found in 62, 20, and 1 (not available in 7 patients). The most common TP53 mutations were R175H (n = 5) and R248Q (n = 4). Common co-mutated genes included KRAS (n = 15), ARID1A (n = 15), FGFR2 fusion (n = 14), IDH1 (n = 13), BAP1 (n = 10), CDKN2A (n = 9), and HER2 amplification (n = 8). Microsatellite unstable (MSI-H) tumors were found in 3 patients. The median tumor mutational burden was 2.5/Mb. Patients received front-line GC (n = 54), GC-nab-paclitaxel (GAP, n = 14), FOLFIRINOX (n = 3), and GC with targeted or trial therapy (n = 11, e.g. trastuzumab). mPFS with front-line therapy was 5.0 m (n = 90); it was 4.7 m with GC and 5.1 m with GAP. Patients who had co-mutated IDH1 or FGFR2 fusion had longer mPFS (9.5 and 6.9 m, respectively) than those who did not (n = 63, 3.7 m, p < 0.05) from front-line chemotherapy. mPFS after second-line FOLFOX (n = 17) and FOLFIRI (n = 10) was 2.1 and 1.9 m, respectively, and mPFS after third-line FOLFOX/FOLFIRI was 1.8 m (n = 8). The median overall survival (OS) of patients with co-mutated FGFR2, IDH1, or neither was 34.5, 22.0, and 13.1 m, respectively (p < 0.05). TP53-mutated BTC with mutations other than FGFR2/IDH1 did not show statistically significant difference in PFS or OS. Conclusions: Patients with TP53-mutated advanced BTC have shorter PFS than those without TP53 mutation in front and further-line settings. The presence of co-mutated FGFR2 or IDH1 is associated with improved PFS with chemotherapy (not FGFR/IDH1 inhibitors) and longer OS. Other co-mutations do not appear to have a survival benefit. It is crucial for clinicians to take into account the worse prognosis with TP53 mutation before starting front-line therapy in patients with advanced BTC and consider early clinical trial options.

e15504 Background: Among patients with anal cancer undergoing chemoradiotherapy, the association between the microbiome and toxicity is not well documented. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) and local microbiome profiles of patients with anal cancer receiving chemoradiotherapy in order to check for potential profiles that can help in predicting toxicity during treatment. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Anorectal swab samples were collected before treatment initiation and at 4 subsequent timepoints. Consequently, PROs were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC). Samples were sequenced using 16S rRNA of the V4 region. Sequence reads were grouped by amplicon sequence variants (ASV’s) representative of unique bacterial species. We then used Linear discriminant analysis Effect Size (LEfSe) with an effect size of 4 to identify taxa at baseline that were differentially enriched in patients with high vs. low toxicity by end of treatment. We compared the EPIC scores with the relative abundance of species identified in the LEfSe using a paired Wilcoxon test. Results: The study included 22 patients (18 women and 4 men), whose median age was 59 years. Most patients were Stage III (59%) with negative HIV status (94%). The majority of patients (91%) received standard of care chemoradiotherapy. Overall toxicity was the highest at week 5 of treatment. At all individual time points, alpha diversity of the microbiome did not correlate with patient-reported GI function, additionally overall baseline diversity was not predictive of eventual GI outcomes. The LEfSe identified that patients with low patient reported toxicity at week 5 had higher of abundance of Selenomonas at baseline, while patients with higher toxicity had high abundance of baseline Actinobacteria, Peptoniphilus, Clostridiales , and Clostridia. When comparing the relative abundance of bacterial species among patients with high and low toxicities, patients with higher relative abundance of Clostridia and Actinobacteria had significantly higher toxicity (p = 0.03). Conclusions: Certain microbiome profiles at baseline are associated with anal cancer patients’ gastrointestinal-related PROs during chemoradiation. Our data provide novel avenues to study the potential uses of the local microbiome as a biomarker in predicting treatment toxicities in anal cancer.

Purpose Standard therapies for localized inoperable intrahepatic cholangiocarcinoma (IHCC) are ineffective. Advances in radiotherapy (RT) techniques and image guidance have enabled ablative doses to be delivered to large liver tumors. This study evaluated the effects of RT dose escalation in the treatment of IHCC. Patients and Methods Seventy-nine consecutive patients with inoperable IHCC were identified and treated with definitive RT from 2002 to 2014. At diagnosis, the median tumor size was 7.9 cm (range, 2.2 to 17 cm). Seventy patients (89%) received systemic chemotherapy before RT. RT doses were 35 to 100 Gy (median, 58.05 Gy) in three to 30 fractions for a median biologic equivalent dose (BED) of 80.5 Gy (range, 43.75 to 180 Gy). Results Median follow-up time for patients alive at time of analysis was 33 months (range, 11 to 93 months). Median overall survival (OS) time after diagnosis was 30 months; 3-year OS rate was 44%. Radiation dose was the single most important prognostic factor; higher doses correlated with an improved local control (LC) rate and OS. The 3-year OS rate for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses (P = .017); 3-year LC rate was significantly higher (78%) after a BED greater than 80.5 Gy than after lower doses (45%, P = .04). BED as a continuous variable significantly affected LC (P = .009) and OS (P = .004). There were no significant treatment-related toxicities. Conclusion Delivery of higher doses of RT improves LC and OS in inoperable IHCC. A BED greater than 80.5 Gy seems to be an ablative dose of RT for large IHCCs, with long-term survival rates that compare favorably with resection.

4055 Background: Among patients with anal cancer, chemoradiotherapy tends to offer an excellent prognosis but is often associated with undesirable toxicities that diminish quality of life. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) of anal cancer patients receiving chemoradiotherapy in order to improve patient-physician communication and shared decision making. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients reported outcomes were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at 4 subsequent timepoints. We used descriptive statistics to summarize the patients’ characteristics and EPIC scores, then used the paired Wilcoxon test to compare EPIC scores at different timepoints. Results: The study included 21 patients (16 women and 5 men), whose median age was 57 years. Most patients (52%) had T2, and either N0 (38%) or N1 (43%) disease. Most patients (91%) received standard of care chemoradiotherapy. Compared with the patients’ median overall summary score at baseline (66), their median score at 1 week (82) was significantly higher (p = 0.009), whereas their median score at 5 weeks (54) was significantly lower (p = 0.025). However, the patients’ median overall summary score at baseline and at 3 months did not differ significantly (p = 0.919). Three months after radiotherapy, most patients (73%) reported rarely or never having bloody stools, and most (82%) reported rarely or never being bothered by bloody stools. Overall, EPIC scores show initial improvement of all domains, followed by some worsening of symptoms before returning to baseline levels. Conclusions: Anal cancer patients’ gastrointestinal-related PROs tend to fluctuate during radiotherapy but return to baseline by 3 months, at which time most patients report few or no residual side effects. Our data provide a clear timeline of gastrointestinal acute toxicity using sequential PRO measurements that will improve patient-physician communication regarding expectations for cancer treatment and help in shared decision making.

794 Background: Duodenal adenocarcinoma (DA) is a rare cancer with limited data regarding the pattern of disease recurrence following resection. Methods: A retrospective review of 115 patients with Stage I-III DA from 3/1994 to 6/2018, at a single high-volume cancer center was conducted. Only patients (pts) who underwent a potentially curative surgical resection (R0/R1 margins) and had a postoperative follow-up radiographic evaluation were included. Periampullary adenocarcinomas were excluded. Clinicopathologic features and patterns of recurrence were compared across cohorts. Results: Of 76 patients who met inclusion criteria, 7 (9%) were stage I, 25 (33%) stage II, and 44 (57%) stage III. Histologic grade was moderate in 58% and poor in 38%. Median age was 63 years (range, 29-84), 38% were female, and R0 resection was 97%. Neoadjuvant therapy was given to 14% and adjuvant therapy to 61%. Radiation therapy (XRT) as either adjuvant/neoadjuvant therapy was used in 27%. Median follow-up was 44 (6-293) months. Median time to recurrence was 11mo, with 84% of recurrences occurring within 2 years. Median time to local recurrence (LR) vs. distant recurrence (DR) was 11mo vs. 12mo, respectively, p = 0.42. Stage impacted recurrence rate: 0% in stage 1 vs. 50% stage 2 vs. 71% stage 3 (p = 0.002). Median time to recurrence was 16mo for stage II and 11mo for stage III (p = 0.04). In total, 4 (5%) pts had LR only, 8 (10%) had LR concurrent with DR, and 32 (42%) had DR only. Recurrence distribution was similar across stage II (LR 8%, LR+DR 15%, DR 77%) and stage III (LR 10%, LR+DR 19%, DR 71%). LR was similar in patients that received XRT (10%) compared to those who did not (9%). Most common sites of DR were peritoneal (38%), liver (33%), distant lymph nodes (12%), and lung (10%). Conclusions: The recurrence pattern for resected DA is predominantly distant metastatic disease with the majority of recurrences occurring within the first two years. Future therapies should focus on improved systemic therapy, and surveillance should be most intensive in the first two years.

e15609 Background: Locally advanced unresectable intrahepatic cholangiocarcinoma (IHCC) remains incurable. Prior data has shown the effectiveness of hypofractionated radiation therapy (HRT) with biological equivalent doses (BED) greater than 80.5 Gy in improving local control and survival for this patient population. This is an updated report of our IHCC experience with HRT in 15 or 25 fractions using a simultaneous integrated boost technique. Methods: A retrospective analysis of 63 patients (median age 64, range 29-87) diagnosed between 2007-2016 who received HRT was performed. RT dose ranged from 58-90 Gy in 15 fractions and 62.5-100 Gy in 25 fractions, translating to a median BED of 97.5 (range 78.1-144 Gy). Median primary tumor size at diagnosis was 7.8 cm (2.4-17cm). Forty-eight (76%) patients received gemcitabine-based therapy prior to HRT. Results: Median follow up was 31 months (4-110). The 2 year overall-survival (OS), local-progression-free-survival (LPFS), intrahepatic-distant-metastasis-free-survival (IH-DMFS) and extraheptic-distant-metastasis-free-survival (EH-DMFS) were 71% (95% CI 58-82), 67% (95% CI 50-80), 40% (95% CI 28-54) and 40% (95% CI 27-54) respectively. Pattern of failure analysis revealed 16 patients with local failure after HRT, of which only 5 (8% of total) progressed within the high iso-dose field line (BED > 80.5). After HRT, 41 (65%) patients had intrahepatic metastasis that occurred outside the radiation field, and 34 (54%) patients developed extrahepatic metastasis. On multi-variate analysis, T-stage was an independent predictor of OS, LPFS, IH-DMFS, and EH-DMFS. Larger normal liver volume and 15 fraction treatments were independently associated with better LPFS and IH-MFS respectively. There were no significant HRT-related toxicities. Conclusions: HRT demonstrates safety and efficacy for durable local control and prolonged overall survival in patients with unresectable IHCC. Dominant modes of failure are outside the HRT field. Improvements in systemic therapies could further improve outcomes for this patient population.

153 Background: Two trials are currently investigating preoperative chemoradiation (CRT) for localized gastric adenocarcinoma. However, radiation therapy (RT) can be associated with relatively high rates of acute toxicity. Newer techniques, such as intensity modulated RT (IMRT), could reduce toxicity by reducing radiation dose to normal structures. Our goal was to compare rates of toxicity and toxicity-related events in patients treated with IMRT compared to 3D conformal RT (3DCRT). Methods: The records of 202 gastric cancer patients treated with preoperative intent RT at our institution from 1998-2018 were retrospectively reviewed. Demographic data, treatment details, acute and late toxicities (CTCAE 4.0 criteria), progression and survival data were recorded. Patients who had stage IV disease were excluded. Statistical analysis included descriptive statistics, Cox regression analysis, and Kaplan-Meier survival. Results: 54% were male and the median age was 63. 82 patients received 3DCRT and 120 patients received IMRT (median 45Gy, IQR, 45-45Gy in each group). 78% of patients in the 3DCRT group and 91% of patients in the IMRT group received neoadjuvant chemotherapy prior to RT. 99% of patients received concurrent chemotherapy. The rate of grade 3-4 acute toxicity was significantly lower in patients treated with IMRT compared to 3DCRT (53% vs. 73%, p = 0.004). The composite rate of toxicity-related events (hospitalization, feeding tube, IV rehydration, or RT break) was also significantly lower in patients treated with IMRT compared to 3DCRT (80% vs. 91%, p = 0.031). 72% of patients who received 3DCRT and 68% of patients who received IMRT underwent subsequent surgical resection. The 3-year OS rate was 58.1% for patients receiving IMRT and 60.2% for patients receiving 3DCRT (p = 0.649). The 3-year PFS rate was 47.5% for patients receiving IMRT and 52.7% for patients receiving 3DCRT (p = 0.486). Conclusions: Our study indicates a marked reduction in the rates of grade 3-4 acute toxicity and toxicity-associated events in patients treated with IMRT compared to 3DCRT. These findings suggest that IMRT should be considered as the radiation modality in patients treated with preoperative CRT for gastric cancer.

278 Background: The immune system plays a crucial role in cancer surveillance. Lymphopenia during cancer treatment portends poor prognosis. Here, we aim to quantify lymphocyte count changes during radiotherapy (RT) for patients with hepatocellular carcinoma (HCC) treated with proton or photon RT. Methods: Patients with HCC treated with definitive RT from 2006 to 2016 with ≥3 months follow-up were studied. Patient characteristics, tumor features, treatment specifics were recorded. Serial absolute lymphocyte counts (ALC) were collected and graded according to CTCAE v4.0. Overall survival (OS) and distant metastasis free survival (DMFS) were analysed using the Kaplan-Meier method. To investigate difference in ALC between treatment modalities, we performed a paired cohort analysis (15 proton and 15 photon cases, matched to treatment volume). Results: 110 patients were studied. Median age was 67 years. 70% of the cohort had Child-Pugh A5 liver disease and 54% had venous tumor thrombosis (VTT). 75 (68%) had photon RT and 35 (32%) had proton RT. Median OS was 13 months. Overall, there was a 60% drop in ALC during RT. Splenic volume correlated with Grade 3 (G3) lymphopenia (p < 0.0001). Pre-treatment ALC and splenic volume did not correlate with OS or DMFS. Patients who had G3 lymphopenia during RT had poorer DMFS (14 vs 34 months, p = 0.006) and OS (16 vs 34 months, p = 0.015) than their counterparts. Those who received proton RT had a higher ALC nadir (0.56 vs 0.40 k/ul, p = 0.041), lower rate of ALC drop (0.07 vs 0.05 k/ul/day) and better OS (30 vs 22 months) than those who had photon RT. Paired cohort dosimetric analyses revealed that there was a significantly higher low dose volume in the photon group (V1Gy and V10Gy, p < 0.0001 for both; V5Gy, p = 0.002). Higher volume of low dose bath correlated with lower ALC (r = -0.34, p = 0.06 for V1Gy; r = -0.44, p = 0.01 for V5Gy; r = -0.51, p = 0.004 for V10Gy). Splenic irradiation dose correlated with ALC nadir, and proton cases had significantly less splenic dose (p < 0.0001). Conclusions: G3 lymphopenia during RT portends poorer outcomes for patients with HCC. Protons may mitigate RT-induced lymphopenia. An ongoing phase III trial will compare proton and photon RT for HCC to determine the effect on OS.

369 Background: Chemotherapy is widely used as a component of treatment of localized pancreatic ductal adenocarcinoma (PDAC). Pre-operative chemotherapy is associated with early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy. For locally advanced (LA) PDAC, induction chemotherapy is standard of care. We evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy in localized PDAC. Methods: Records of pts with localized PDAC who initiated Gem/nab-P at a single institution from 2013-2015 were retrospectively reviewed. Clinicopathologic features, dose and outcomes were evaluated. Pts were staged using our previously published criteria: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (co-morbidities requiring medical optimization), and LA. Co-morbidities were classified using adult comorbidity evaluation-27 score. Overall survival (OS) was analyzed using Kaplan Meier method. Results:99 pts [M/F: 50/49; median age: 70 yrs (range 30-85); PR/BR/LA: 45/14/40] were treated with Gem/nab-P. Clinical staging showed PR+BR-A/BR-B+C: 20/39. BR-B+C included one or more of the following factors: age ≥80 yrs [13%], ECOG PS ≥2 [13%], moderate/severe co-morbidities [55%], CA19-9≥1000 [28%], suspicion for metastatic disease [21%]. Majority of pts received biweekly Gem/nab-P dosing [standard/biweekly/other: 10/80/9] with minimal grade 4 toxicity. 45/99 pts received chemoradiation after Gem/nab-P [30Gy/50.4Gy: 15/30]. 12/20 (60%) PR+BR-A, 2/39 (5%) BR-B+C and 1/40 (3%) LA pts underwent pancreatectomy. 13/15 resected pts received adjuvant chemotherapy. At median follow-up of 26 mo, median OS was 18 (95% CI: 15.6-20.5) mo for all, 17 (95% CI: 14.6-19.5) mo for unresected and not reached for resected pts (p = 0.03). Conclusions: A significant number of pts with resectable PDAC albeit aggressive biology (BR-B) and/or medically inoperable disease (BR-C) received first-line Gem/nab-P; resection rates were lower compared to PR/BR-A pts. Biweekly dosing is being used in localized PDAC and is well tolerated.

684 Background: While carcinoembryonic antigen (CEA) as a tumor marker is frequently used in the management of colorectal adenocarcinoma, its clinical utility in squamous cell carcinoma of the anus (SCCA) has never been reported. Indeed, no tumor markers have been validated for monitoring tumor burden in the course of any HPV-associated malignancy like SCCA. We hypothesized that CEA levels might be preferentially elevated in patients with metastatic SCCA. Methods: Charts from 212 patients with SCCA were reviewed under an IRB-approved protocol for correlations between CEA levels and corresponding oncologic status. Clinical status was categorized as newly diagnosed non-metastatic (D), after chemoradiation with no evident remnant disease (N), recurrent/resectable SCCA (R), locally advanced/unresectable SCCA (U), metastatic SCCA to lymph nodes only (M-LN), or metastatic SCCA to visceral organs (M-V). Mean CEA levels were compared between subgroups via student t-tests, and frequencies of elevated CEA were compared via Chi-squared analyses. Results: 118 SCCA patients had metastatic disease (98 M-V, 19 M-LN). Mean CEA levels by clinical status were 5.4 (D), 2.0 (N), 2.3 (R), 4.6 (U), 6.0 (M-LN), and 22.2 (M-V), with a higher (statistically insignificant) mean CEA level in the M-V relative to other populations. However, patients with visceral metastases were more likely to have an elevated CEA at presentation (40.4%) relative to patients with newly diagnosed, non-metastatic SCCA (17.6%, p = .07) or recurrent SCCA (11.1%, p = .02). For patients with metastatic SCCA, a significant association existed between change in CEA and corresponding change in radiographic tumor dimensions (OR 24, p < 0.0001). Conclusions: Trends in CEA correlate with dynamic changes in tumor burden for patients with metastatic SCCA, and patients with metastatic SCCA were more likely to have an elevated CEA. Given that immune checkpoint blockade agents like nivolumab have proven benefit for metastatic SCCA, these data provide rationale for use of newer generation immunotherapeutic approaches like CEA-T cell bispecific antibodies, which target CEA-expressing tumors, in clinical trials for patients with metastatic SCCA.

228 Background: As pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, biomarkers are needed to identify patients who may benefit from specific therapeutic strategies. We previously described a qualitative computed tomography (CT) based biomarker - delta classification, whereby high delta tumors showed lower stromal content, more aggressive biology and poorer outcomes, than their counterparts. Here, we describe a quantitative method to differentiate these patients and predict outcomes. Methods: We retrospectively identified 101 treatment naïve patients who underwent pancreatectomy as a discovery cohort and 90 patients who underwent preoperative gemcitabine-based chemoradiation for validation. All patients underwent a pre-therapy pancreatic protocol CT and were classified as high or low delta, as described before. We semi-automatically segmented the tumors, chose normal pancreatic (NP) tissue and abdominal fat as references, then measured relative enhancement values using Philips IntelliSpace8 multimodality tumor tracking. We then analyzed the arterial and portal-venous phases separately using ROC and cox proportional hazards. Results: Delta class significantly associated with normalized enhancement values (NEV) in the arterial phase referenced to NP (P

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]

284 Background: There is currently no reliable biomarker for assessing the response to therapy of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated how changes in the tumor/parenchyma interface associate with response. Methods: We reviewed pre- and post-therapy scans of patients who received chemotherapy and/or chemoradiation for both localized and metastatic PDAC. We classified the interface between the PDAC tumor and surrounding pancreas parenchyma as stable (remains or becomes well-defined) or unstable (becomes poorly defined) using a novel visual scoring system and quantified changes in enhancement at this interface (Philips Intellispace Portal, quantitative European Association for the Study of Liver [qEASL]). Results: Three retrospective datasets were used to develop this method with consensus visual scoring performed by 3 radiologists. The first dataset included 99 patients with localized PDAC who received neoadjuvant chemoradiation. Patients who were classified as having a stable interface had significantly higher probability of achieving a complete or near-complete pathologic response (21% vs 0%, p = 0.01) and additionally demonstrated an improved median disease-free survival (DFS, 20.9 vs 7.9 mos., p < 0.01) and overall survival (OS, 47.7 vs 19.1 mos., p < 0.01). These results were validated in a separate dataset of 94 patients receiving protocol-based chemotherapy and chemoradiation (chemoRT cohort) and a cohort of 86 patients with stage IV disease. In both cohorts, a stable interface was associated with a significant improvement in progression free survival (PFS, Hazard Ratio [HR] 0.44, p = 0.01 for chemoRT and HR 0.70, p = 0.16 for stage IV) and OS (HR 0.42, p < 0.01 for chemoRT and HR 0.59, p = 0.05 for stage IV). Multivariate analyses for each cohort showed interface stability to be independently associated with both DFS/PFS and OS. Measurements obtained using qEASL were concordant with the visual scoring results. Conclusions: The interface stability of PDAC is an early readout of response to therapy. Integration of this imaging feature into clinical trials for localized and metastatic PDAC may aid in the future development of adaptive treatment strategies.

294 Background: Advances in radiotherapy (RT) techniques and image guidance (IGRT) have enabled ablative doses to be delivered to large liver tumors. We evaluated the effects of RT dose escalation in the treatment of intrahepatic cholangiocarcinoma (IHCC). Methods: 79 consecutive patients with inoperable IHCC were treated between 2002–2014. Median tumor size 7.9 cm (range 2.2–17 cm), 57% had nodes+ and 20% had metastatic disease. 89% received gemcitabine and cisplatin before RT (35–100 Gy, median 58.05 Gy) for a median biologic equivalent dose (BED) of 80.5 Gy (range 43.75–180 Gy). 57% were treated with concurrent capecitabine. CT on rails IGRT with gating were used to deliver higher doses. Results: Median FU was 33 months (range 11–93 ). Median overall survival rate (OS) after diagnosis was 30 months; 1, 2, and 3-year OS rates were 87%, 61%, 44%. The median duration of local tumor control (LC) was 23 months; 1, 2, and 3-year LC rates were 81%, 45% and 27%. RT dose was the most important prognostic factor. Higher doses correlated with improved LC and OS. The 3-year OS for a BED greater than 80.5 was 73% versus 38% for those receiving lower doses (P =0.017). Similarly, 3-year LC was significantly higher (78% versus 45%, P= 0.04). On multivariate analysis, RT dose was significant for LC (P= 0.004) and OS (P= 0.006). The majority of patients (32/36, 89%) whose cause of death could be determined died from liver failure related to intrahepatic disease progression. Only 4 patients (11%) died from distant metastatic disease. There were no significant treatment related toxicities. Conclusions: Higher doses of RT improve LC and OS in inoperable IHCC. A BED > 80.5 Gy appears to be ablative for large IHCCs. Long term survival rates compare favorably to resection. RT schedules that achieve a BED > 80.5, such as 67.5 Gy in 15 fractions and 75 Gy in 25 fractions, should be used. Solutions for internal organ motion and IGRT are necessary for safe delivery of high doses near bowel. These findings support the use of 67.5 Gy in 15 fractions (BED = 97.88 Gy) in the current phase III NRG-GI001 randomized trial evaluating whether the addition of RT to chemotherapy affects survival for inoperable IHCC patients.

354 Background: The use of chemoradiation (CXRT) for locally advanced pancreatic cancer (LAPC) is controversial. Delivery of high doses of RT capable of leading to local tumor control is challenging. We reviewed outcomes of treatement with dose-escalated IMRT with curative intent. Methods: Of 211 patients treated from 5/2006 to 8/2014 with CXRT for LAPC, 49(23%) had tumors > 1 cm from the luminal organs ere selected for dose-escalated IMRT using integrated boost (SIB) technique, inspiration breath hold, and computed tomographic (CT) image guidance. Fractionation was optimized for coverage of gross tumor (GTV,Table 1). A 2-5mm margin on the GTV, was treated as an SIB within a microscopic dose. Forty-seven (96%) patients received a median of 4.0 months of induction chemotherapy and 45 (92%) received concurrent capecitabine or gemcitabine. Results: Mean GTV coverage was 86% (95% CI 78% to 94%). Median FU was 32 mo. Median OS and 1, 2, 3 and 5 year OS rates were 22.6mo (95% CI 16.4 to 43.9mo), 83%, 49%,38%, and 18% from the date of diagnosis and 17.8mo, 63%, 38%, 33%, and 18% from the start of RT. Degree of GTV coverage and Biological Equivalent Dose (BED) did not appear to affect outcome. Freedom from progression at 3 y were 40.6% (local) and 37.1% (distant). Acute toxicity was uncommon: grade 2 pain, diarrhea, anorexia, nausea or fatigue in 18 (37%), and grade 3 diarrhea in one patient (2%). Four patients (13%) required transfusion for anemia. One patient had a GI bleed possibly related to treatment. Conclusions: Dose-escalated IMRT across a BED range of 70-100Gy for inoperable patients selected with induction chemotherapy appears well tolerated and may improve the likelihood of long term survival. These results are similar to the best outcomes reported for patients after surgical resection. Incomplete high-dose GTV coverage does not appear to be detrimental. A randomized phase II trial is testing IMRT (RTOG 1201, 63Gy/28fx, with stratification by SMAD4 expression). [Table: see text]

8584 Background: The management of melanoma has evolved rapidly with the identification of activating mutations in the majority of patients (pts). We reviewed characteristics and outcomes of molecularly characterized melanoma pts with brain metastasis (BM) to help design and interpret future clinical trials. Methods: We reviewed clinical and pathologic features of melanoma pts with known BRAF and NRAS mutation status and BM. Pt demographics, intra- (IC) and extra-cranial (EC) tumor characteristics, and IC/EC disease treatments were correlated to BM treatment outcomes (local and distant brain control [LC, DC]) and overall survival (OS). Univariate and multivariate analyses were performed to identify significant associations between mutation status and outcome. Results: We identified 296 pts with melanoma BM and known BRAF/NRAS mutation status diagnosed from 2005 to 2011. Mutation prevalence was BRAF 57%, NRAS 17%, and wild-type for both genes (WT) 26%. The initial treatments given for BM were surgery/radiosurgery (SRS) 60%, surgery/SRS + whole brain radiation (WBRT) 7%, WBRT alone 19%, systemic therapy alone 9%, and no treatment 5%. Mutation status was not significantly associated with sex, performance status, EC disease status, number of brain lesions, or BM treatment. Pts with mutations were younger (p