Search

MAF file for copy number variations identified in the cohort

Treatment history for patients enrolled on the PancSeq protocol.

Supplemental Tables and Figures

Supplementary Figure S1: Overview of workflow and data generation. Supplementary Figure S2: Analysis of neoplastic cellularity. Supplementary Figure S3: Recurrent copy number alterations. Supplementary Figure S4: Mutational signature analysis. Supplementary Figure S5: Analysis of PDAC gene expression signatures. Supplementary Figure S6: Clinically relevant alterations in the cohort.

Supplementary Experimental Methods

MAF file for mutations identified in the cohort

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic.Significance:FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355

PURPOSE With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration–approved label, and consideration of additional or orthogonal molecular testing. RESULTS We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

Background Trifluridine/tipiracil (FTD/TPI) and regorafenib prolong survival for patients with refractory metastatic colorectal cancer (mCRC); limited comparative effectiveness data exist. Materials and Methods A retrospective, longitudinal cohort study of patients with mCRC who initiated FTD/TPI or regorafenib (index therapy) between 2012 and 2017 at a U.S. tertiary oncology center, Dana-Farber Cancer Institute, was conducted. Using best tumor response assessments, real-world overall response rates (rwORR) and disease control rates (rwDCR) were described and analyzed using logistic regression. Survival rate was examined for each month after index therapy using Kaplan-Meier. Overall survival (OS) was assessed using Cox proportional hazards models. Subgroup analyses among patients with index therapy as second- or third-line were performed. Results One hundred twenty-six and 95 patients were treated with FTD/TPI or regorafenib as index therapy, respectively. Patients treated with FTD/TPI versus regorafenib had a better response (rwORR 52.5% vs. 34.2%; adjusted odds ratio [OR] = 2.6; all p value Conclusion Patients treated with FTD/TPI had better tumor response and disease control than patients treated with regorafenib. Subgroup analysis in second- or third-line suggests that early use of FTD/TPI may have clinical benefits. Implications for Practice In this retrospective cohort study, patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil (FTD/TPI) were significantly less likely than those treated with regorafenib to have dose modifications and more likely to have higher real-world objective response rate (rwORR) and real-world disease control rate (rwDCR) while treated. Patients treated with FTD/TPI versus regorafenib had significantly higher odds of having rwORR or rwDCR in adjusted analyses. Monthly survival rates were higher overall in patients treated with FTD/TPI versus regorafenib in the first 6 months of follow-up, particularly at months 3 and 4. This study offers insight into patients' treatment experience in real-world clinical settings.

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic.Significance:FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro, and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic.This article is highlighted in the In This Issue feature, p. 2355

Use of comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC) is limited. We estimated impacts of expanded 1 L CGP, using the Tempus xT test, on detection of actionable alterations and testing budgets in a modeled US health plan over two-years. A decision analytic model was developed to estimate the impact of replacing 20% of usual testing (a mix of CGP and non-CGP) with Tempus xT CGP. Actionable alterations for matched treatments or clinical trial included KRAS, NRAS, RAF, BRAF, deficient mismatch repair (dMMR)/microsatellite instability (MSI), NTRK, RET, EGFR, HER2, MET, PIK3CA and POLE1. Costs included initial and repeat testing, physician-associated and administrative costs. In a hypothetical five-million-member plan, 50% Medicare and 50% commercial, 1,112 new cases of mCRC were expected per year. Of these, 566 (51%) would undergo 1 L molecular testing, with 55 re-tested upon progression. Based on current testing rates, there were an expected 521 missed opportunities for genomically informed treatment (47% of new cases), with 442 missed due to lack of testing and 79 due to testing without CGP. Replacing 20% of usual testing with Tempus xT CGP was associated with up to a $0.003 per member per month testing cost increase (net total cost of $202,102 for the five-million-member plan) and 15.5 additional patients with an opportunity for genomically informed care (12.7 patients for treatment and 2.8 for clinical trial). The testing total cost (initial test, repeat test, biopsy and physician services, and administrative cost) to put one additional patient with mCRC on matched therapy or matched clinical trial was estimated to be $13,005. Number needed to test to identify one actionable alteration with Tempus xT CGP versus usual testing was 7.8 patients. Conservative assumptions were made for inputs with limited evidence. Based on high concordance rates with dMMR/MSI status, tumor mutational burden (TMB) status was not calculated separately. Replacing 20% of usual testing with Tempus xT CGP was associated with a small incremental testing cost and can identify meaningfully more actionable alterations.

OBJECTIVEReconstruction of the mobile spine following total en bloc spondylectomy (TES) of one or multiple vertebral bodies in patients with malignant spinal tumors is a challenging procedure with high failure rates. A common reason for reconstructive failure is nonunion, which becomes more problematic when using local radiation therapy. Radiotherapy is an integral part of the management of primary malignant osseous tumors in the spine. Vascularized grafts may help prevent nonunion in the radiotherapy setting. The authors have utilized free vascularized fibular grafts (FVFGs) for reconstruction of the spine following TES. The purpose of this article is to describe the surgical technique for vascularized reconstruction of defects after TES. Additionally, the outcomes of consecutive cases treated with this technique are reported.METHODSThirty-nine patients were treated at the authors’ tertiary care institution for malignant tumors in the mobile spine using FVFG following TES between 2010 and 2018. Postoperative union, reoperations, complications, neurological outcome, and survival were reported. The median follow-up duration was 50 months (range 14–109 months).RESULTSThe cohort consisted of 26 males (67%), and the median age was 58 years. Chordoma was the most prevalent tumor (67%), and the lumbar spine was most affected (46%). Complete union was seen in 26 patients (76%), the overall complication rate was 54%, and implant failure was the most common complication, with 13 patients (33%) affected. In 18 patients (46%), one or more reoperations were needed, and the fixation was surgically revised 15 times (42% of reoperations) in 10 patients (26%). A reconstruction below the L1 vertebra had a higher proportion of implant failure (67%; 8 of 12 patients) compared with higher resections (21%; 5 of 24 patients) (p = 0.011). Graft length, number of resected vertebrae, and docking the FVFG on the endplate or cancellous bone was not associated with union or implant failure on univariate analysis.CONCLUSIONSThe FVFG is an effective reconstruction technique, particularly in the cervicothoracic spine. However, high implant failure rates in the lumbar spine have been seen, which occurred even in cases in which the graft completely healed. Methods to increase the weight-bearing capacity of the graft in the lumbar spine should be considered in these reconstructions. Overall, the rates of failure and revision surgery for FVFG compare with previous reports on reconstruction after TES.

BACKGROUND Adult spinal deformity (ASD) is a debilitating condition that commonly requires surgical intervention. However, ASD patients may also present with osteoporosis, predisposing them to surgical complications and failure of instrumentation. As a result, proper detection of low bone mineral density (BMD) is critical in order to ensure proper patient care. Typically dual-energy x-ray absorptiometry (DEXA) scans are performed on the hip and spine. Unfortunately, in ASD patients, the latter is often inaccurate PURPOSE In this study, we consider the value of obtaining a forearm DEXA scan in addition to a hip scan in patients suffering from ASD and osteoporosis in order to accurately detect low BMD. STUDY DESIGN Retrospective study. PATIENT SAMPLE Patient data between 2016 and 2018 from a single academic medical center was utilized. Two hundred eighty-six patients met the initial search criteria. OUTCOME MEASURES No outcomes measures related to self-reporting, physiology, or functionality were evaluated in this study. Primary outcome measures analyzed included T-scores across various anatomic locations and diagnoses relating to low bone density (ie, osteopenia and osteoporosis). METHODS This retrospective study examines patients that underwent DEXA studies between 2016 and 2018 and were previously diagnosed with both osteoporosis and adult spinal deformity. For each patient, age, gender, body mass index, and smoking history were noted, as well as whether there was long-term prednisone use. T-scores from both the forearm and hip were recorded and analyzed. Diagnoses from hip DEXA scans were compared with those obtained from forearm scans to identify which region was more sensitive in detecting low BMD. From this data, the frequency of a missed diagnosis, due to reliance on hip or spine T-scores for detection of low BMD, was extrapolated. No external funding source was received in support of this study. RESULTS Two hundred eighty-six patients matched the initial search criteria. Only 68% had one T-score value. However, 24.8% of patients had data for both the hip and forearm, whereas 7.1% had data for the forearm, hip, and spine. Among the 85 patients with more than one anatomical site of study, the forearm was more sensitive than the hip in its ability to detect osteopenia or osteoporosis 41.2% of the time. A two-tailed t test showed no statistically significant difference between hip T-scores and forearm T-scores. However, for more than 17% of patients, the forearm allowed clinicians to detect osteoporosis or osteopenia in a setting where using only the hip data would have missed such a diagnosis. CONCLUSIONS Clinicians need to ensure they survey at least two locations when conducting DEXA studies before precluding a diagnosis of osteopenia or osteoporosis. All ASD patients being evaluated for low bone density should receive DEXA scans that survey at least the hip and the forearm. Misdiagnoses can be costly in the setting of ASD. They occur frequently when only a single hip scan is relied upon to assess BMD.

Background Trifluridine and tipiracil (FTD + TPI) and regorafenib (REG) are approved treatments for the treatment of refractory metastatic colorectal cancer (mCRC). This study assesses adherence and duration of therapy with FTD + TPI versus REG and explores the effect of sequencing on adherence. Materials and Methods Adults diagnosed with mCRC were identified in the IQVIA Real‐World Data Adjudicated Claims: U.S. database (October 2014–July 2017). The observation period spanned from the index date (first dispensing of FTD + TPI or REG) to the earliest of a switch to another mCRC agent, the end of continuous enrollment, or the end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC), and persistence and time to discontinuation (gap ≥45 days) were compared between FTD + TPI and REG users and among switchers (FTD + TPI‐to‐REG vs. REG‐to‐FTD + TPI). Results A total of 469 FTD + TPI and 311 REG users were identified. FTD + TPI users had higher compliance with an MPR ≥80% (odds ratio [OR], 2.47; p < .001) and PDC ≥80% (OR, 2.77; p < .001). FTD + TPI users had better persistence (82.8% vs. 68.0%; p < .001) and lower risk of discontinuation (hazard ratio [HR], 0.76; p = .006). Among switchers (96 FTD + TPI‐to‐REG; 83 REG‐to‐FTD + TPI), those switching from FTD + TPI to REG were more likely to have an MPR ≥80% (OR, 2.91; p < .001) and PDC ≥80% (OR, 4.60; p < .001) compared with REG‐to‐FTD + TPI switchers while treated with these drugs. Additionally, FTD + TPI‐to‐REG switchers had a lower risk of first treatment discontinuation (HR, 0.66; p = .009). Conclusion FTD + TPI users had significantly higher adherence and persistence, and patients who were treated with FTD + TPI before switching to REG also had higher adherence and persistence outcomes. Implications for Practice Trifluridine plus tipiracil (FTD + TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) but have different tolerability profiles. This study assessed real‐world adherence to treatment with FTD + TPI versus REG and compared outcomes among patients who switched from FTD + TPI to REG and vice versa. FTD + TPI was associated with significantly higher medication adherence and longer time to discontinuation than REG. Patients treated with FTD + TPI prior to switching to REG also showed higher adherence outcomes. Findings could help inform decision making regarding the choice and sequencing of treatment with FTD + TPI versus REG in patients with mCRC., This article assesses real‐world treatment patterns and adherence of patients with metastatic colorectal cancer treated with trifluridine plus tipiracil (FTD/TPI) versus regorafenib (REG) and explores the effect of the treatment sequence on adherence among patients who switched from FTD + TPI to REG and vice versa.

BackgroundImmune checkpoint inhibitors have revolutionized cancer treatment, but the benefits in refractory patients with esophageal cancer have been modest. Predictors of response as well as new targets for novel therapeutic combinations are needed. In this phase 2 clinical trial, we tested single-agent pembrolizumab in patients with advanced esophageal cancer, who received at least one prior line of therapy.MethodsPembrolizumab 200 mg every 3 weeks was tested in 49 patients with refractory esophageal cancer: 39 with adenocarcinoma and 10 with esophageal squamous cell carcinoma. Major endpoints were radiological response by Immune-related Response Evaluation Criteria In Solid Tumors and survival. Tumor samples were evaluated for programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and immune contexture by both NanoString mRNA expression analysis and flow cytometry. Peripheral blood mononuclear cells and a panel of circulating chemokines were also analyzed.ResultsThe overall response rate (ORR) was 8% (4 of 49 patients; 95% CI 2.3% to 19.6%). Median overall survival (OS) was 5.8 months (95% CI 4.0 to 9.5). ORR and OS were not associated with histology. For PD-L1-positive patients, ORR was 13.3% (95% CI 1.7% to 40.5%) and median OS was 7.9 months (95% CI 4.7 to 15.5). A trend toward improved OS was observed in seven patients with a TMB ≥10 mut/Mb (p=0.086). Tumors with a PD-L1 Combined Positive Score ≥1 showed enrichment of LAG3 (p=0.005) and IDO1 (p=0.04) gene expression. Baseline levels of circulating CXCL10, interleukin 2 (IL2) receptor α (IL2RA) and IL6 were associated with survival: CXCL10 favorably, (HR 0.37, p=0.002 (progression-free survival); HR 0.55, p=0.018 (OS)); IL2RA and IL6 unfavorably (HR 1.57, p=0.020 for IL6 (OS); HR 2.36, p=0.025 for IL2RA (OS)).ConclusionsPembrolizumab monotherapy was modestly effective in refractory esophageal cancer. Circulating CXCL10 at baseline appeared to be a robust predictor of response. Other T cell exhaustion markers are upregulated in PD-L1-positive patients, suggesting that immunotherapy combinations such as anti-LAG3/programmed cell death protein 1 (PD-1) or anti-IDO1/PD-1 may be of promise in refractory esophageal cancer.

BACKGROUND: MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition. METHODS: This open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS). RESULTS: Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination. CONCLUSION: The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs. TRIAL REGISTRATION: ClinicalTrials.gov NCT03201458. FUNDING: National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI’s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.

Background Context Exposure of unintended levels (defined as a spinal segment outside the intended surgical levels) is unnecessary and potentially adds to operative time and patient morbidity. Wrong-level surgery (defined as decompression, instrumentation, or fusion of a spinal segment not part of the intended surgical procedure) clearly adds to morbidity as well as putting the surgeon at medicolegal risk. Purpose To describe a localization technique for posterior lumbar spine surgery to minimize both unintended-level exposure and wrong-level surgery. Study Design Consecutive case series. Patient Sample One thousand nine hundred and eighty-six consecutive posterior lumbar operations performed from January 2010 to January 2017 using this technique were reviewed. Outcome Measures The primary outcome measure was the incidence of unintended-level exposure and wrong-level surgery. Methods This localization technique was consistently used for determination of skin incision, soft tissue dissection, and identification of spinal levels for all patients undergoing posterior lumbar surgery during the time interval noted. Two spinal needles are inserted under sterile technique 3cm lateral to the midline before incision at the approximate cranial and caudal aspects of the anticipated incision based on external landmarks. A cross-table lateral X-ray before incision is obtained and the actual incision is adjusted based on the location of the spinal needles. Once dissection is carried down to the facet capsules, spinal needles are then placed in adjacent facets, and a second cross-table lateral film is obtained to confirm appropriate levels. A retrospective review of all posterior lumbar cases was performed to determine the incidence of unintended-level exposure and wrong-level surgery using this technique. Results There were no wrong-level surgeries during this time period. There were six (0.30%) cases of unintended-level exposure. Conclusions The technique described provides surgeons with a reliable, accurate, and easily reproducible method for localizing surgical levels during posterior lumbar spine surgery while minimizing exposure of uninvolved areas. This technique offers distinct advantages over previously proposed protocols and may lead to a widely accepted system for intraoperative spinal level identification.

Biliary tract cancers are rare, aggressive neoplasms. Most patients present with advanced/unresectable or metastatic disease at diagnosis, and no second-line regimen has demonstrated clinical benefit. This was a phase 2 study evaluating the efficacy and safety of regorafenib in patients who had advanced/unresectable or metastatic disease after receiving standard therapy.In this single arm-study, patients with advanced/unresectable or metastatic biliary tract cancer who failed at least 1 line of systemic chemotherapy received regorafenib once daily on a schedule of 21-days on/7-days off in a 28-day cycle. Patients initially received a standard 160 mg dose. After toxicity assessments in the first 3 patients, the dose was reduced to 120 mg for subsequent patients, as preplanned. The primary endpoint was progression-free survival (PFS). Secondary objectives included overall survival (OS), the objective response rate, and the disease control rate.Forty-three patients received at least 1 dose of regorafenib, and 34 patients who received at least 1 cycle of treatment were evaluable for tumor response. The median PFS was 15.6 weeks (90% confidence interval, 12.9-24.7 weeks), and the median OS was 31.8 weeks (90% confidence interval, 13.3-74.3 weeks), with survival rates 40% at 12 months and 32% at 18 months. A partial response was achieved in 5 patients (11%), and 19 had stable disease (44%), for a disease control rate of 56%. The toxicity profile was as expected, with grade 3 and 4 adverse events reported in 40% of patients. The most common toxicities were hypophosphatemia (40%), hyperbilirubinemia (26%), hypertension (23%), and hand-foot skin reaction (7%).The current results suggest promising efficacy of regorafenib in patients with chemotherapy-refractory, advanced/metastatic biliary tract cancer, warranting further studies to confirm its clinical efficacy. There is a clear unmet need for effective therapies in patients who have advanced and metastatic biliary tract cancer.

The bone healing environment in the posterolateral spine following arthrodesis surgery is one of the most challenging in all of orthopedics and our understanding of the molecular signaling pathways mediating osteogenesis during spinal fusion is limited. In this study, the spatial and temporal expression pattern of Wnt signaling factors and inhibitors during spinal fusion was assessed for the first time. Bilateral posterolateral spine arthrodesis with autologous iliac crest bone graft was performed on 21 New Zealand White rabbits. At 1‐, 2‐, 3‐, 4‐, and 6‐weeks, the expression of sclerostin and a variety of canonical and noncanonical Wnts signaling factors was measured by qRT‐PCR from tissue separately collected from the transverse processes, the Outer and Inner Zones of the fusion mass, and the adjancent paraspinal muscle. Immunohistochemistry for sclerostin protein was also performed. Sclerostin and many Wnt factors, especially Wnt3a and Wnt5a, were found to have distinct spatial and temporal expression patterns. For example, harvesting ICBG caused a significant increase in sclerostin expression. Furthermore, the paraspinal muscle immediately adjacent to the transplanted ICBG also had significant increases in sclerostin expression at 3 weeks, suggesting new potential mechanisms for pseudarthroses following spinal arthrodesis. The presented work is the first description of the spatial and temporal expression of sclerostin and Wnt signaling factors in the developing spine fusion, filling an important knowledge gap in the basic biology of spinal fusion and potentially aiding in the development of novel biologics to increase spinal fusion rates., In this study, the temporal and spatial expression of sclerostin and Wnt signaling factors during a developing posterolateral spine fusion was determined for the first time. Most of the canonical and noncanonical Wnt factors and inhibitors that were assessed were found to have distinct spatial and temporal expression patterns and those patterns were found to differ between successful fusions and nonunions, suggesting new molecular mechanisms for the development of pseudarthroses following spinal arthrodesis. This fills an important knowledge gap in the basic biology of spinal fusion and may aid in the development of novel biologics to increase spinal fusion rates.

OBJECTIVEPosterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) can be associated with significant blood loss. It has been suggested that blood loss is greater in different racial groups. The purpose of this study was to evaluate differences in blood loss between African American and Caucasian patients undergoing PSF for AIS.METHODSA retrospective review was performed of patients aged 10–18 years with AIS who were treated with PSF from 2014 to 2017 at a single children’s healthcare system. Patient demographic, radiographic, and operative data were obtained from medical records. Intraoperative blood loss was calculated using the formula described by Waters et al. Patients who declined reporting their race or had prior spinal surgery, neuromuscular or syndromic diagnoses, a history of cardiac or thoracic surgery, or a bleeding disorder were excluded. Blood loss variables were log-transformed for normality and modeled using multivariable linear regression.RESULTSA total of 433 PSFs for AIS qualified for the analysis. The average age was 14.1 years, and 73.7% of the patients were female. With respect to race, 44.6% identified themselves as African American. There was no significant difference in blood loss (p = 0.31) or blood loss per level fused (p = 0.36) in African American patients. African American patients, however, did have significantly lower preoperative hemoglobin and hematocrit levels and greater operating room time than Caucasian patients (p < 0.001). There was no difference between race and transfusion rate.CONCLUSIONSThere appears to be no relationship between race and blood loss during PSF for AIS. Standardized protocols for minimizing perioperative blood loss can be applied to both Caucasian and African American patients.

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096–111. ©2018 AACR. See related commentary by Collisson, p. 1062. This article is highlighted in the In This Issue feature, p. 1047

Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) prolong survival in refractory metastatic colorectal cancer (mCRC) and have similar indications with different side-effect profiles. The present study compared real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database.Retrospective data from the US Symphony Health Solutions' Integrated Dataverse database were analyzed for adult mCRC patients receiving FTD/TPI or REG from October 2014 to July 2016. The index date was the first FTD/TPI or REG prescription date. The observation period spanned from the index date to the end of data collection, end of continuous clinical activity, or treatment switch. Adherence was assessed using the medication possession ratio and proportion of days covered at 3 months. The time to discontinuation was assessed over the observation period with gaps of 45, 60, or 90 days. Outcomes were compared between the cohorts using logistic regression and Cox proportional hazards models adjusting for baseline characteristic differences.A total of 1630 FTD/TPI patients and 1425 REG patients were identified. The FTD/TPI patients were 80% more likely to have a medication possession ratio of ≥ 0.80 compared with the REG patients (odds ratio, 1.80; P .001) and more than twice as likely to have a proportion of days covered of ≥ 0.80 (odds ratio, 2.66; P .001) at 3 months. The FTD/TPI patients were 37% less likely to discontinue their treatment compared with the REG patients when using the 60-day gap (hazard ratio, 0.63; P .001). Similar results were found using the 45- and 90-day gaps.mCRC patients taking FTD/TPI were significantly more likely to adhere to and comply with therapy compared with those taking REG.

Prospective Cohort Study.The objective of this study is to evaluate and validate a patient-derived version of the modified Japanese Orthopaedic Association (the "P-mJOA") that a patient can complete along with other patient-derived outcome measures.The modified Japanese Orthopaedic Association (mJOA) is a validated instrument widely used in the assessment of cervical myelopathy; however, it is not a patient-derived outcome. If available and reliable, a patient-derived version of the mJOA (P-mJOA) could facilitate research because the data would be immediately available upon patient completion and also remove any potential physician bias. Currently, there is no patient-derived myelopathy survey with the widespread acceptance of the mJOA.The P-mJOA was created by very slightly modifying the verbiage of the mJOA to make it possible for a patient to complete the instrument while maintaining the questionnaire's core structure. A total of 100 consecutive consenting patients with cervical myelopathy were enrolled. After the patient completed the P-mJOA, the mJOA was scored by a physician blinded to the P-mJOA result.The P-mJOA and the mJOA had identical mean scores of 14.7 (mean difference±SD: 0.0±1.5; P=0.89). Several measures of reliability demonstrated agreement between the 2 surveys, including strong agreement with the intraclass correlation coefficient and Spearman ρ (both 0.83) and moderate to substantial agreement with weighted κ values (0.55 to 0.66). In addition, 67% of patients preferred to fill out the P-mJOA themselves, suggesting low patient burden.The P-mJOA provided identical mean scores to the mJOA in assessing myelopathy with moderate to strong agreement. Comprised of the same 4 questions as the mJOA but slightly reworded for patient comprehension, the P-mJOA also demonstrated low patient burden in completing the survey. We believe the P-mJOA is a promising tool in cervical myelopathy research with the benefits of a patient-derived outcome measure and low patient burden.Level II.

e18834 Background: A growing number of genomic alterations inform treatment of advanced/metastatic colorectal cancer (mCRC). However, use of comprehensive genomic profiling (CGP) is limited in the first-line (1L) setting. Based on the Tempus xT next-generation sequencing assay, we estimated the impact of expanded 1L CGP on the detection of currently actionable alterations in mCRC and associated diagnostic testing costs in a modeled US health plan setting. Methods: A decision analytic model was used to compare testing scenarios over a two-year time horizon: current 1L testing with a mix of CGP and non-CGP diagnostics vs. replacing 20% of usual testing with Tempus CGP. The incidence of 1L mCRC, current testing rates, prevalence of actionable alterations, and test sensitivity were drawn from a literature review and clinical expert input. Currently actionable alterations included KRAS, NRAS, RAF, BRAF, dMMR/MSI, NTRK, RET, EGFR, HER2, MET, PIK3CA and POLE1. Cost components included initial and repeat testing, physician-associated and administrative costs. Opportunities for genomically-informed therapy or clinical trials were assessed under each testing scenario. A forward looking scenario, with additional informative alterations, was also explored. Results: In a hypothetical five million-member health plan, with 50% Medicare and 50% commercial insurance, 1,112 incident cases of mCRC (22 per 100,000 patients) are expected in a typical year. Among these cases, 566 (51%) are expected to undergo 1L molecular diagnostic testing, with 55 projected to undergo repeat testing upon progression within the next year. Based on current real-world testing rates, there are an expected 521 missed opportunities for genomically informed treatment (47% of the incident mCRC population), with 442 missed due to lack of testing and 79 due to testing without CGP. Replacing 20% of usual testing with Tempus CGP in the modeled scenario was associated with up to a $0.003 per member per month (PMPM) testing cost increase and an additional 15.5 patients with an opportunity for genomically-informed care (12.7 patients for guideline-recommended treatment and 2.8 for a clinical trial). The number needed to test (NNT) with Tempus CGP versus the usual mix of testing was 7.8 1L patients to identify one actionable alteration. Scenario analyses projecting the advent of additional genomically-informed treatments and clinical trials resulted in smaller numbers needed to test. Conclusions: Replacing 20% of usual testing with Tempus CGP is associated with a small incremental testing cost but can identify actionable alterations for a meaningful number of patients. For every eight 1L mCRC patients tested with Tempus CGP rather than the usual mix of molecular testing, one additional patient is expected to be identified as having currently actionable alterations.

Background: BTCs are aggressive cancers with a poor prognosis. In preclinical models, MEK inhibition modulates the tumor immune microenvironment and enhances responses to programmed death-ligand 1 (PD-L1) inhibition. We report a randomized, open-label, multicenter phase 2 trial of atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor) in BTC (NCT03201458). Methods: Eligible patients had advanced BTC [intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC)], with 1-2 lines of prior therapy in the metastatic setting, measurable disease by RECIST v1.1, and ECOG performance status ≤1. Patients randomized to Arm A received atezolizumab 840 mg IV Q2w. Patients randomized to Arm B received oral cobimetinib 60 mg daily (21 days on/7 days off) plus atezolizumab 840 mg IV Q2w. The primary endpoint was progression free survival (PFS) using the Kaplan-Meier method and compared between groups under the assumption of Cox proportional hazards, stratified for primary tumor site. Secondary endpoints included objective response rate (ORR), safety and tolerability, and overall survival (OS). Results: 86 patients were enrolled at 23 centers in the United States; 77 patients were randomized and received at least one dose of study therapy (Arm A: n=37, ICC=21, ECC=7, GBC=11; Arm B: n=38, ICC=22, ECC=8, GBC=8). Median age was 63 (range 44-86), and 48 (62%) were female. The trial met its primary endpoint, with a median PFS of 3.65 months (cobimetinib+atezolizumab) vs 1.87 months (atezolizumab monotherapy) (p=0.027). OS data are not mature at the time of analysis. There was 1 PR (3.2%), 13 SD (41.9%), and 17 PD (54.8%) in the combination arm and 1 PR (2.9%), 10 SD (29.4%), and 23 PD (67.6%) in the atezolizumab monotherapy arm. Two patients in the combination arm remain on therapy 15+ months from enrollment. One patient in each treatment arm had known mismatch repair deficiency (MMRd), of whom 1 had PD as a best response and the other withdrew prior to response evaluation. Grade 3-4 treatment-related adverse events were similar in both arms, and there were no treatment-related deaths. 4 (10%) of patients receiving atezolizumab monotherapy and 8 (22.2%) receiving cobimetinib+atezolizumab discontinued therapy due to adverse events. Changes in tumor CD8, CD4, FoxP3, PDL1, and MHC expression from paired tumor biopsies will be presented at the conference. Conclusions: We report the first randomized trial of immunotherapy in BTC. The combination of atezolizumab plus cobimetinib met its primary endpoint and significantly prolonged PFS as compared to atezolizumab monotherapy in BTC. The combination of atezolizumab and cobimetinib had manageable toxicity and warrants further investigation in BTC. Citation Format: Mark Yarchoan, Leslie Cope, Robert A. Anders, Anne Noonan, Laura W. Goff, Lipika Goyal, Jill Lacy, Daneng Li, Anuj Patel, Aiwu R. He, Ghassan Abou-Alfa, Kristen Spencer, Edward Kim, Stephanie Xavier, Amanda Ruggieri, S. Lindsey Davis, Autumn McRee, Paul Kunk, Qingfeng Zhu, Andrea Wang-Gillam, Andrew Poklepovic, Helen Chen, Elad Sharon, Gregory B. Lesinski, Nilo Azad. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): A NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT043.

567 Background: Fibroblast growth factor receptor (FGFR) pathway alterations have been identified in approximately 20% of patients (pts) with intrahepatic cholangiocarcinoma (IHCC), most commonly by FGFR2 fusions. Early phase clinical trials have demonstrated encouraging efficacy of FGFR inhibitors in pts with FGFR2-translocated cholangiocarcinoma, but efficacy in pts with other FGFR2 activating alterations is less clear. Methods: Pts with cholangiocarcinoma underwent CLIA-certified next generation DNA sequencing (NGS) to identify actionable alterations. FGFR2 fusions and other FGFR2 genomic events were assessed, with genomic characterization performed before and after treatment with FGFR inhibitors in appropriate pts. Novel extracellular domain in-frame deletions (INDELs) of FGFR2 and apparent resistance mutations were investigated for oncogenic activity and inhibitor resistance in vitro and in vivo. Results: Cholangiocarcinomas from 284 pts (136 male, 148 female; median age, 64 [20-89], including 139 IHCCs, were sequenced. Among the IHCCs, 16 (11.5%) had FGFR2 fusions, with 9 different gene partners. Surprisingly, 5 (3.6%) IHCCs harbored extracellular domain FGFR2 INDELs. Two of these IHCCs harbored an exon 5 deletion FGFR2 p.H167_N173del. Expression of FGFR2 p.H167_N173del in 3T3 cells resulted in oncogenic transformation. In the clinic, two pts with FGFR2 p.H167_N173del were treated with Debio1347, an oral FGFR-1/2/3 inhibitor. Both patients achieved a durable partial response (PR) of 11 months, with one of the pts still on active treatment with Debio-1347. The patient who developed acquired resistance underwent repeat biopsy, and NGS identified a secondary mutation ( FGFR2 p. L617F) in the kinase domain. In vitro studies demonstrated that this mutation confers resistance to Debio1347. This patient was subsequently treated with another FGFR inhibitor and again experienced a PR lasting 17 months. A third biopsy after disease progression demonstrated a previously undetected L597Q BRAF mutation. Conclusions: Extracellular domain FGFR2 in-frame deletions are a novel genomic alteration in IHCC that are transforming and predict clinical sensitivity to FGFR inhibitors.

77 Background: There is an increased use of oral anti-cancer therapies (OACTs) for treatment of gastrointestinal (GI) cancers. While OACTs provide convenience compared to IV agents, they carry similar risks for drug-drug interactions (DDI), toxicities, and unique challenges like adherence and drug access. Patients on OACTs have fewer touch-points with clinicians, requiring more patient ownership of treatment. Pharmacist co-management of pts has been shown to be successful in teaching and monitoring of IV therapy. We sought to assess feasibility of pharmacist co-management for pts prescribed OACTs for treatment of GI cancers. Methods: In 2019, the Dana-Farber GI Cancer Center (GCC) had an embedded pharmacist 8 hrs/week to help with co-management of pts on OACTs. The pharmacist provided (1) in-person and telephone teaching; (2) comprehensive medication reconciliation; (3) DDI review; and (4) supportive care recommendations. Patients were identified by reviewing provider schedules and through provider referrals. The initial teach visit was one-on-one with each patient before initiation, with joint visits with providers thereafter for monitoring and adherence checks. Data were collected to quantify the types of support/recommendation provided by pharmacist and the impact on clinical workflow. Results: After 4 months in the GCC clinic, the pharmacist has co-managed 26 new pts, 61% seen in-person. In initial visits, the pharmacist identified 3 DDI, updated 15 medication lists, and assisted 11 pts/or providers with drug access and drug information. The pharmacist saw 10 of 26 pts for follow up, totaling 21 encounters. The pharmacist assisted in 17 of the 21 encounters with drug access and drug information. Pharmacist spent 20 min/pt on teaching. For follow-up visits, the pharmacist did not additional incur clinic resources as patients were seen with providers. Conclusions: Pharmacist co-management of patients on OACTs is feasible and offers an added safety resource to pts and providers from initial teaching to monitoring. Future research will focus on the impacts of co-management on clinical outcomes, such as the use of emergency/hospital visits, the duration of therapy, and adherence.

Degenerative lumbar stenosis can lead to symptoms of neurogenic claudication and lumbar radiculopathy. Lumbar stenosis can be caused by static compression of the neural elements in the central canal, along the lateral recess, and in the neuroforamen, as well as by dynamic changes to the total area of the central canal and neuroforamen. Previously, surgical options for the treatment of degenerative lumbar stenosis were primarily based on direct posterior open decompressions and fusions. However, novel techniques of indirect decompression have now been developed that restore disc height to increase the area of the central canal and neuroforamen and address the dynamic aspect of stenosis, while avoiding the extensive soft tissue injury involved in posterior open decompressions and fusions. Interbody fusions and interspinous devices are two methods of indirect decompression that are being commonly used. In this study, we provide a broad overview of the advantages, disadvantages, indications, evidence, and complications of ALIF, LLIF, and OLIF, as well as interspinous devices including Coflex. Though there is limited comparative evidence demonstrating that one approach is superior to another in terms of clinical and radiographic outcomes, evidence does show that interbody techniques are effective at treating lumbar stenosis by increasing the total area of the central canal and neuroforamen while having high fusion rates. Though the newer generation of interspinous devices have lower failure rates than their predecessors, they still are not comparable to the interbody devices in terms of long term outcomes. The optimal approach for the indirect treatment of lumbar stenosis therefore depends on multiple variables, including but not limited to the spinal level of disease, the anatomy of the individual patient, the pathology being treated, and the familiarity of the surgeon.

592 Background: FTD/TPI and REG have both demonstrated prolonged survival in refractory mCRC patients (pts) when compared to placebo but limited comparative effectiveness data are available. This study aims to compare outcomes following initiation of FTD/TPI or REG for mCRC at a single academic cancer center. Methods: Retrospective chart reviews were conducted in all pts with mCRC who initiated FTD/TPI or REG between 2012-2017. Analyses of time from index therapy initiation to discontinuation for any reason (TTD), real-world response rates (rwRR) and disease control rates (rwDCR) were performed. Cox proportional hazards models adjusting for demographic and clinical characteristics were performed for overall survival (OS). Results: 126 FTD/TPI and 95 REG pts were included. Baseline characteristics were similar in both groups, though more pts treated with FTD/TPI had right-sided primary tumors compared to REG (30.4% vs. 25.5%, p = 0.43). Treatment patterns pre- and post-index therapy were comparable in both groups. Median observation duration for FTD/TPI and REG was 7.1 and 6.3 months, respectively. Mean TTD was 88.4 days for FTD/TPI pts and 84.2 days for REG pts (p = 0.42). Fewer pts treated with FTD/TPI discontinued due to toxicities than pts treated with REG (8.2% vs. 24.2%, p = 0.001). A higher proportion of FTD/TPI pts had no dose modifications vs. REG pts (84.0% vs. 64.1%, p < 0.001). OS was similar between the two groups (adjusted hazard ratio [HR] FTD/TPI vs. REG: 0.79, p = 0.13). FTD/TPI pts had higher rwRR (52.5% vs. 34.2%, p = 0.01) and rwDCR (64.2% vs. 46.1%, p = 0.01) than REG pts. In the subgroup of pts ≥ 65 years, mean TTD was higher in FTD/TPI pts (105.9 vs. 77.6 days, p = 0.004). Pts ≥ 65 years receiving FTD/TPI had better OS than REG pts (HR: 0.51, p = 0.03). Conclusions: In this single institution study, TTD and OS were similar between pts treated with FTD/TPI and REG. Fewer pts treated with FTD/TPI than REG discontinued due to toxicities or required dose modification. Reported responses rates were higher in FTD/TPI pts. Older pts (≥ 65 years) on FTD/TPI remained on treatment longer and had better OS than REG pts.

11 Background: Adherence to oral chemotherapies is a critical but difficult to measure factor in the care of patients with advanced cancer. FTD/TPI and REG have both demonstrated prolonged survival in patients with refractory mCRC, but with notably different side effect profiles. This study utilizes real-world data to assess adherence and discontinuation of patients treated with FTD/TPI or REG and explore the effect of sequencing on adherence. Methods: Adults diagnosed with mCRC were identified using the nationally representative IQVIA Real-World Data Adjudicated Claims – US database (10/2014–07/2017). The first dispensing date of FTD/TPI or REG (if after FTD/TPI approval [10/2015]) was defined as the index date and the 3 months before as the baseline period. The observation period spanned from the index to the earliest date of a switch to another mCRC agent, end of continuous enrollment, or end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC) at 3 months, and discontinuation (i.e., allowable gap≥45 days) were compared. Logistic (odds ratio [OR]) and Cox proportional hazards (hazard ratio [HR]) regressions, adjusting for baseline characteristics, were used to compare adherence and discontinuation, respectively. A subgroup analysis was conducted among switchers (FTD/TPI to REG vs REG to FTD/TPI). Results: A total of 469 FTD/TPI and 311 REG users were identified. FTD/TPI users had higher compliance with an MPR ≥ 80% (OR = 2.47; p < 0.001) and PDC ≥ 80% (OR = 2.77; p < 0.001). FTD/TPI users had lower risk of discontinuation (HR = 0.76; p = 0.006). Among switchers (96 FTD/TPI to REG; 83 REG to FTD/TPI), those switching from FTD/TPI to REG were more likely to have an MPR ≥ 80% (OR = 2.91; p < 0.001) and PDC ≥ 80% (OR = 4.60; p < 0.001) compared to REG to FTD/TPI switchers. Additionally, FTD/TPI to REG switchers had a lower risk of first treatment discontinuation (HR = 0.66; p = 0.009). Conclusions: In this study, FTD/TPI users had significantly higher compliance, lower discontinuation rate, and switchers treated first with FTD/TPI had better compliance, demonstrating that claims data can provide insight into oral chemotherapy adherence patterns in mCRC.

e16072Background: There are limited treatment (tx) options for metastatic esophageal cancer patients (pts). We sought to determine the safety and efficacy of pembro among US pts with previously tre...

666 Background: FTD/TPI and REG both prolong survival in refractory mCRC and have similar indications with different side effect profiles. This study compares real-world treatment patterns with FTD/TPI and REG for mCRC in a large, representative US claims database. Methods: Retrospective data from 10/2014 to 7/2016 from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for patients receiving FTD/TPI or REG. The index date was the date of first FTD/TPI or REG prescription. Patients were included if: 1) age ≥18 years old, 2) ≥1 CRC diagnosis, 3) no diagnosis of gastric cancer or gastrointestinal stromal tumor, and 4) continuous clinical activity for ≥3 months before and after index date. The observation period spanned from index date to end of data, end of continuous clinical activity, or switch to another mCRC treatment. Adherence was assessed using medication possession ratio (MPR) ≥0.80 and proportion of days covered (PDC) ≥0.80 at 3 months. Compliance was assessed using time to discontinuation over the observation period using allowable gaps of 45, 60, or 90 days. Patients who never discontinued therapy were censored at the end of the observation period. Outcomes were compared between FTD/TPI and REG using multivariate logistic regression and Cox proportional hazards models, adjusting for demographic and clinical baseline characteristics. Results: A total of 1,630 FTD/TPI patients and 1,425 REG patients were identified. Mean ± standard deviation (SD) age of FTD/TPI patients was 61.0 ± 11.0 compared to 62.8 ± 10.9 for REG patients (p < 0.001). FTD/TPI patients were 80% more likely to have a MPR ≥0.80 compared to those on REG (Odds Ratio [OR] = 1.80, p < 0.001) and more than twice as likely to have a PDC ≥0.80 (OR = 2.66, p < 0.001) at 3 months. FTD/TPI patients were 37% less likely to discontinue their treatment compared to those on REG when using gaps of 60 days (Hazard Ratio = 0.63, p < 0.001). Similar results were found with 45 and 90 days. Conclusions: In this retrospective study of mCRC patients, patients on FTD/TPI were significantly more likely to adhere and comply with therapy compared to those on REG.

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth-leading cause of cancer-related death in the United States and is projected to become the second leading cause by 2030. Most patients present with advanced disease and die within 12 months of diagnosis. Recent genomic studies of primary pancreatic cancer resection specimens have identified several molecular alterations and genomic subtypes of the disease that may guide precision medicine approaches to clinical management. However, the molecular landscape of metastatic PDAC has been less well characterized. Moreover, biopsy-driven studies in metastatic PDAC have been historically very challenging due to the aggressive course of this disease as well as the low-volume and heterogeneous nature of biopsies that makes deep molecular characterization difficult. Insufficient genomic analysis of a patient’s tumor early in their disease course is a major barrier to enrollment on clinical trials of targeted therapies. To address these limitations, we have implemented a multi-disciplinary clinical and research biopsy protocol to enable real time comprehensive molecular characterization of metastatic PDAC biopsy specimens. We have performed core needle biopsies of metastatic lesions in the liver or peritoneal cavity in 42 patients at the time of initial presentation. A low rate of complications was observed, with only a single patient having a self-limited hemorrhagic complication after liver biopsy. On average, 4-6 separate biopsy specimens were collected from each patient for histopathology and genomic analysis. Whole exome sequencing (WES) was performed in a CLIA-certified laboratory and a comprehensive molecular report of somatic alterations and selected pathogenic germline variants was returned to the referring clinician with a typical turn-around time of 3-5 weeks. We observed a striking incidence of recurrent germline and somatic alterations in DNA-damage repair genes, such as BRCA2, ATM and CHEK2. We also observed alterations in genes with known therapeutic implications, such as BRAF, RNF43, STK11 and ROS, and in select cases, these results guided choice of second or third line therapy. In parallel to WES, we performed RNA sequencing on bulk tumor tissue and readily identified expression signatures defining multiple subtypes of tumor and stroma that may have prognostic or therapeutic implications for tumor- or stroma-directed therapies. Collectively, these results demonstrate the feasibility and value of real-time genomic characterization of metastatic PDAC and provide a path forward for improved stratification and enrollment of PDAC patients on molecularly defined clinical trials. Citation Format: Andrew J. Aguirre, Scott Carter, Nicholas Camarda, Arezou Ghazani, Jonathan Nowak, Annacarolina Da Silva, Lauren Brais, Dorisanne Ragon, Devin McCabe, Lori Marini, Kristin Anderka, Karla Helvie, Nelly Oliver, Ana Babic, Paul Shyn, Douglas Rubinson, Anuj Patel, James Cleary, Nadine McCleary, Matthew Kulke, Thomas Clancy, Leona Doyle, Jason Hornick, Christine Ardito-Abraham, Ruth Yu, Michael Downes, Ronald Evans, Richard A. Moffitt, Jen Jen Yeh, William C. Hahn, Charles Fuchs, Robert Mayer, Nikhil Wagle, David Tuveson, Levi A. Garraway, Brian M. Wolpin. Real-time genomic characterization of metastatic pancreatic cancer to enable precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3036. doi:10.1158/1538-7445.AM2017-3036

e15000 Background: FTD-TPI and REG both prolong survival in refractory mCRC. Both agents have the benefit of oral administration but with distinct side effect profiles. This study aims to compare real-world treatment patterns following initiation of FTD-TPI or REG for mCRC in a large, nationally representative US claims database. Methods: Retrospective data from 10/2014 to 7/2016 from the US Symphony Health Solutions’ Integrated Dataverse (IDV®) database were analyzed for patients (pts) receiving FTD-TPI or REG. The index date was the date of first FTD-TPI or REG prescription. Pts were included if: 1) age ≥18 years old, 2) ≥1 CRC diagnosis, 3) no diagnosis of gastric cancer or gastrointestinal stromal tumor, and 4) continuous clinical activity for ≥3 months before and after index date. The observation period spanned from index date to end of data, end of continuous clinical activity, or switch to another mCRC treatment. Medication adherence was assessed by medication possession ratio (MPR), with MPR ≥80% as the defined threshold for adherence, as well as by proportion of days covered (PDC) at 3 months. Between treatment groups, binary endpoints were compared using Chi-square tests and mean and median time to treatment discontinuation (TTD) were compared using t-test and Wilcoxon test, respectively. Results: The study population consisted of 1,630 FTD-TPI pts and 1,425 REG pts. Mean ± standard deviation (SD) age of FTD-TPI pts was 61 ± 11 and REG pts was 63 ± 11 (p < 0.01). Mean ± SD length of observation period in days was 161 ± 59 for FTD-TPI pts and REG pts was 212 ± 113 (p < 0.01). 84% of FTD-TPI and 74% of REG pts reached MPR ≥80% (p < 0.01). FTD-TPI pts had higher mean PDC (71% vs 59%, p < 0.01) than REG pts. Mean and median TTD were significantly longer for FTD-TPI than REG pts (mean: 101 vs. 88 days, p < 0.01; median: 97 vs. 69 days, p < 0.01). Conclusions: In this analysis of real-world medication utilization for mCRC pts, those pts started on FTD-TPI had significantly higher medication adherence and longer TTD than those on REG.

4081 Background: Biliary adenocarcinoma/cholangiocarcinoma is a rare but aggressive neoplasm. Most patients present with unresectable or metastatic disease with 5-year survival rate ~5%. No second-line regimen has demonstrated clinical benefit in this disease. Regorafenib is an oral multi-kinase inhibitor with potent antitumor activity. This single arm phase II study evaluates the efficacy and safety of regorafenib as a single agent in advanced or metastatic biliary carcinoma/cholangiocarcinoma pts who failed systemic chemotherapy. Methods: Patients with ECOG PS 0-1and adequate liver, kidney and bone marrow function were given regorafenib orally once daily, 21 days on and 7 days off in a 28-day cycle. The initial dose of 160 mg was given to the first 3 patients. After toxicity assessment, the dose was reduced to 120 mg for the subsequent pts. The primary endpoint is PFS with the null hypotheses of 2.0 months, and median PFS ≥3.5 months as evidence of the study drug activity (α = 0.10, 80% power). Secondary objectives include OS, RR, and DCR. Results: Thirty-seven patients received at least one dose of regorafenib, of whom 28 were evaluable for efficacy. All had previous gemcitabine/cisplatin treatment. The mean age was 62.5 (34.5-82.8) with 17 (46%) females. PR was achieved in 3 (10.7%), SD in 18 (64.3%, with DCR of 75%), and PD in 7 (25%). For all 37 patients, median PFS was 3.55 months (95% CI = 2.1- 5.72) and mOS was 5.55 months (95% CI = 4.04 -NA) with survival rate of 42 % at 12 months, and 38% at 18 months. Medan PFS and OS of 30 patients who had ≥1 cycle were 3.91 months (95% CI = 3.55-9.79) and 13.4 months (95% CI = 5.06 - NA), respectively. The overall toxicity profile was as expected, with G3/4 AE’s of 40.5%. The most common toxicities were HTN, hypophosphatemia, hand-foot skin reaction, and increased serum bilirubin. Dose modification was required in 11 (30.6%) patients. Tumor samples were collected in 80% of patients, with planned correlative studies underway. Conclusions: This study showed promising efficacy of regorafenib in chemotherapy refractory advanced/metastatic cholangiocarcinoma. Further studies to confirm the clinic efficacy are recommended. Clinical trial information: NCT02053376.

The Prostatron device, which provides simultaneous microwave heating of the prostate and conductive cooling of the urethra, was used in 50 men with significant urethral obstruction by benign prosta...