Katherine Fero

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors

AbstractBackgroundAbout 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.MethodsWe performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.ResultsWe identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.ConclusionsUsing patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015

Utilization and quality outcomes of cT1a, cT1b and cT2a partial nephrectomy: analysis of the national cancer database

To describe the utilization and compare quality outcomes of partial nephrectomy (PN) for cT1a, cT1b and cT2a renal masses using a large national database.

Surgical Management of Adolescents and Young Adults With Gastrointestinal Stromal Tumors: A US Population-Based Analysis

Importance There is a dearth of population-based evidence regarding outcomes of the adolescent and young adult (AYA) population with gastrointestinal stromal tumors (GISTs). Objectives To describe a large cohort of AYA patients with GISTs and investigate the effect of surgery on GIST-specific survival (GSS) and overall survival (OS). Design, Setting, and Participants This retrospective cohort study of 392 AYA patients and 5373 older adult (OA) patients in the Surveillance, Epidemiology, and End Results (SEER) database with GISTs histologically diagnosed from January 1, 2001, through December 31, 2013, with follow-up through December 31, 2015, compared the baseline characteristics of AYA (13-39 years old) and OA (≥40 years old) patients and among AYA patients stratified by operative management. Kaplan-Meier estimates were used for OS analyses. Cumulative incidence functions were used for GSS analysis. The effect of surgery on survival was evaluated with a multivariable Fine-Gray regression model. Exposure Tumor resection. Main Outcomes and Measures GIST-specific survival and OS. Results This study included 392 AYA and 5373 OA patients diagnosed with GISTs (207 [52.8%] male AYA patients, 2767 [51.5%] male OA patients, 277 [70.7%] white AYA patients, and 3661 [68.1%] white OA patients). Compared with the OA patients, more AYA patients had small-intestine GISTs (139 [35.5%] vs 1465 [27.3%], P = .008) and were managed operatively (332 [84.7%] vs 4212 [78.4%], P = .003). Multivariable analysis of AYA patients found that nonoperative management was associated with a more than 2-fold increased risk of death from GISTs (subdistribution hazard ratio, 2.27; 95% CI, 1.21-2.25; P = .01). On subset analysis of 349 AYA patients with tumors of the stomach and small intestine, small-intestine location was associated with improved survival (OS: 91.1% vs 77.2%, P = .01; GSS: 91.8% vs 78.0%, P = .008). On subset analysis of 91 AYA patients with metastatic disease, operative management was associated with improved survival (OS: 69.5% vs 53.7%, P = .04; GSS: 71.5% vs 56.7%, P = .03). Conclusions and Relevance This study found that AYA patients are more likely to undergo surgical management than OA patients. Operative management is associated with improved OS and GSS in AYA patients, including those with metastatic disease.

Cost-Effectiveness Analysis of Elective Neck Dissection in Patients With Clinically Node-Negative Oral Cavity Cancer

Purpose Recently, a large randomized trial found a survival advantage among patients who received elective neck dissection in conjunction with primary surgery for clinically node-negative oral cavity cancer compared with those receiving primary surgery alone. However, elective neck dissection comes with greater upfront cost and patient morbidity. We present a cost-effectiveness analysis of elective neck dissection for the initial surgical management of early-stage oral cavity cancer. Methods We constructed a Markov model to simulate primary, adjuvant, and salvage therapy; disease recurrence; and survival in patients with T1/T2 clinically node-negative oral cavity squamous cell carcinoma. Transition probabilities were derived from clinical trial data; costs (in 2015 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios, expressed as dollar per quality-adjusted life-year (QALY), were calculated with incremental cost-effectiveness ratios less than

Clinical Impact of Local Progression in Pancreatic Cancer

100,000/QALY considered cost effective. We conducted one-way and probabilistic sensitivity analyses to examine model uncertainty. Results Our base-case model found that over a lifetime the addition of elective neck dissection to primary surgery reduced overall costs by

MP72-09 TRENDS IN UTILIZATION AND QUALITY OUTCOMES OF PARTIAL NEPHRECTOMY IN CT1B AND CT2A RENAL CELL CARCINOMA: ANALYSIS OF THE NATIONAL CANCER DATABASE

6,000 and improved effectiveness by 0.42 QALYs compared with primary surgery alone. The decrease in overall cost despite the added neck dissection was a result of less use of salvage therapy. On one-way sensitivity analysis, the model was most sensitive to assumptions about disease recurrence, survival, and the health utility reduction from a neck dissection. Probabilistic sensitivity analysis found that treatment with elective neck dissection was cost effective 76% of the time at a willingness-to-pay threshold of

PD20-07 ONCOLOGIC AND SURVIVAL OUTCOMES FOR PATHOLOGIC T3A UPSTAGING IN CLINICALLY LOCALIZED RENAL MASSES: DOES PARTIAL NEPHRECTOMY INCREASE ONCOLOGICAL RISK?

100,000/QALY. Conclusion Our study found that the addition of elective neck dissection reduces costs and improves health outcomes, making this a cost-effective treatment strategy for patients with early-stage oral cavity cancer.

Population-Based Epidemiology and Mortality of Small Malignant Gastrointestinal Stromal Tumors in the USA.

Background: The high prevalence of distant metastatic disease among patients with pancreatic cancer often draws attention away from the local pancreatic tumor. This study aimed to define the complications and hospitalizations from local versus distant disease progression among a retrospective cohort of patients with pancreatic cancer. Methods: Records of 298 cases of pancreatic cancer treated at a single institution from 2004 through 2015 were retrospectively reviewed, and cancer-related symptoms and complications requiring hospitalization were recorded. Hospitalizations related to pancreatic cancer were attributed to either local or distant progression. Cumulative incidence analyses were used to estimate the incidence of hospitalization, and multivariable Fine-Gray regression models were used to identify factors predictive of hospitalizations. Results: The 1-year cumulative incidences of hospitalization due to local versus distant disease progression were 31% and 24%, respectively. Among 509 recorded hospitalizations, leading local etiologies included cholangitis (10%), biliary obstruction (7%), local procedure complication (7%), and gastrointestinal bleeding (7%). On multivariable analysis, significant predictors of hospitalization from local progression included unresectable disease (subdistribution hazard ratio [SDHR], 2.42; P<.01), black race (SDHR, 3.34; P<.01), younger age (SDHR, 1.02 per year; P=.01), tumor in the pancreatic head (SDHR, 2.19; P<.01), and larger tumor size (SDHR, 1.13 per centimeter; P=.02). Most patients who died in the hospital from pancreatic cancer (56%) were admitted for complications of local disease progression. Conclusions: Patients with pancreatic cancer experience significant complications of local tumor progression. Although distant metastatic progression represents a hallmark of pancreatic cancer, future research should also focus on improving local therapies.

A population-based study of morbidity after pancreatic cancer diagnosis.

laparoscopic kidney tumor enucleation. The tumor bed parenchyma of 15 mm beyond the pseudocapsule were continuously sectioned and examined to investigate the possible presence of tumor invasion or satellite lesions. RESULTS: The study involved 246 patients, consisting of 148 men (60.2%) and 98 women (39.8%), with a mean age of 60.9 10.3 years. The average tumor size was 5.3 1.7 cm. The histopathologic evaluation revealed that 82.5% of tumors were clear cell RCC, 7.7% were papillary, and 6.5% were chromophobe. The pathological staging showed that 23.2% of tumors were pT1a, 68.3% were pT1b, 3.7% were pT2, and 4.9% were pT3a. On the basis of Fuhrman nuclear grading, 171 lesions (69.5%) were grade 1-2 and 75 (30.5%) were grade 3-4. The incidence of positive surgical margins was 3.3%. For the pathological characteristics of tumor bed, tumor infiltration was detected in 5 cases (2.0%) and satellite lesion was detected in 4 cases (1.6%). In the group of 60 primary tumors 4 cm or less in diameter, 3 (5.0%) were found with residual tumor, 1 with tumor infiltration and 2 with satellite lesion. In the group of 186 primary tumors larger than 4 cm, 6 (3.2%) were found with residual tumor, 4 with tumor infiltration and 2 with satellite lesion. Statistically, there was no significant difference (p1⁄40.809). In the group of grade 1-2, 4 (2.3%) were found with residual tumor, and 5 (6.7%) in the group of grade 3-4 (p1⁄40.195). Median followup was 24 months (range 8-43) with a recurrence rate of 4.1% (10 of 246) and a cancer specific mortality rate of 2.4% (6 of 246). CONCLUSIONS: The risks of tumor infiltration and/or satellite lesions of enucleation tumor bed are relatively low. Tumor enucleation is a histopathologically safe technique for patients undergoing partial nephrectomy.

MP22-02 SYNERGISTIC PROGNOSTIC IMPACT OF ELEVATED DE RITIS RATIO AND RENAL SCORE FOR PREDICTION OF SURVIVAL OUTCOMES IN RENAL CELL CARCINOMA AFTER SURGICAL TREATMENT

continuous and categorical variables, respectively. Outcomes of interest includedestimatedblood loss,warm ischemia time, estimatedglomerular filtration rate at 6 months, length of stay, margin status, Fuhrman grade, tumor size, pathological histology, and symptoms index at presentation RESULTS: Among our cohort, 376 (62%) and 228 (38%) patients with were scheduled for RN and PN, respectively. Of the 228 patients originally scheduled for PN, 12% were converted to RN intraoperatively. A smaller proportion of patients scheduled to undergo PN had clear cell/conventional histology (77% vs 88%; p1⁄40.001) on pathology compared to patients scheduled for RN. Among patients with clear cell or papillary histology, a larger proportion of patients scheduled for PN had lower Fuhrman grade (24% vs 10.3% had FG 1 or 2; p<0.0001) on pathology than patients scheduled for RN. Of our 604 patients, 111 patients died, 33 from kidney disease. The median follow up time for survivors was 2.0 years from surgery. On multivariable analysis, scheduled PN was non-significantly associated with better OS (HR 0.62; 95% C.I. 0.37, 1.03; p 1⁄4 0.064), better CSS (HR 0.51; 95% C.I. 0.18, 1.49; p 1⁄4 0.2), and better RFS (HR 0.56; 95% C.I. 0.29, 1.07; p1⁄40.081). From the estimates of the hazard ratio, we suspect that the bias related to surgeons choosing PN or RN based on low or high risk disease is not appropriately adjusted for in our model CONCLUSIONS: We found no evidence to suggest that PN has poorer outcomes than RN in patients with pT3a tumors. The inherent benefits of PN on renal function preservation make this approach very attractive even in larger and complex tumors