Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

PURPOSE To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS For human epidermal growth factor receptor 2 (HER2)–negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Background: Although AIs are an effective treatment for HR-positive MBC, whether used alone or in combination with CDK4/6 inhibitors, resistance to therapy and disease progression invariably develops. Therapeutic options for AI-resistant disease include the m-TOR inhibitor everolimus in combination with the steroidal AI exemestane, or the selective estrogen receptor downregulator (SERD) fulvestrant alone. We hypothesized that the combination of fulvestrant and everolimus would be more effective than fulvestrant alone in AI-resistant MBC. Methods: Major eligibility criteria included post-menopausal women with HR-positive, HER2-negative MBC, recurrence or progression while receiving prior non-steroidal or steroidal AI therapy, ECOG PS 0-1, and ≤1 prior chemotherapy regimen for metastases. All patients received fulvestrant (500mg IM q2 weeks for 3 doses, then q4 weeks) plus oral everolimus (10mg) or placebo (1:1 randomization). Prophylactic corticosteroid mouthwash was not used. Tumor assessment was performed at baseline and every 12 weeks. Treatment continued until progressive disease (PD) by RECIST 1.1 criteria. Patients who discontinued everolimus/placebo due to toxicity continued fulvestrant until PD. The primary endpoint was progression-free survival (PFS), defined as time from start of treatment until progression or death. With accrual of 130 patients (120 eligible), the trial had 90% power to detect an improvement in median PFS from 5.4 months to 9.2 months (1-sided stratified log-rank test, type I error rate10%), with analysis planned after 98 PFS events. Results: Of 130 patients treated (64 everolimus, 66 placebo), median age was 61 years (range 35-92), and treatment arms were balanced for stratification factors used in randomization, including ECOG PS 0 vs. 1 (59%/41%), measurable disease (66%), and prior chemotherapy for metastasis (17%). Grade 3/4 AEs were more common in the everolimus arm (53%/3% vs. 23%3%), including hyperglycemia (16%/0% vs. 0%), stomatitis (11%/0% vs. 0%), hypertriglyceridemia (9%/2% vs. 0%), lymphopenia (9%/0% vs. 0%), and pneumonitis (6%/2% vs. 0%). There were 3 grade 5 events (2 everolimus, 1 placebo arm), none of which were attributed to therapy. Selected grade 2 events of interest included fatigue (17% vs. 6%), hyperglycemia (6% vs. 0%), and stomatitis (6% vs. 0%). Everolimus/placebo was discontinued for adverse events, patient withdrawal, or physician discretion in 39% in the everolimus arm and 21% in the placebo arm. After 98 PFS events, median PFS was 10.4 months in the everolimus arm versus 5.1 months in the placebo arm (hazard ratio: 0.61, 95% C.I. 0.40 – 0.92; stratified logrank p= 0.02). Conclusions: The addition of everolimus to fulvestrant significantly improved PFS in post-menopausal women with AI-resistant MBC. Everolimus used without prophylactic corticosteroid mouthwash exhibited a similar rate of oral mucositis and overall AE profile when combined with fulvestrant as when combined with exemestane. Keywords: advanced breast cancer, PrECOG 0102, endocrine resistance, everolimus, exemestane, hormone receptor-positive, mTOR inhibitor, postmenopausal. Citation Format: Kornblum NS, Manola J, Klein P, Ramaswamy B, Brufsky A, Stella PJ, Burnette B, Telli M, Makower DF, Leach J, Truica CI, Wolff AC, Soori GS, Haley B, Nagarajan A, Wassenaar TR, Goldstein L, Miller KD, Sparano JA. PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) resistant to aromatase inhibitor (AI) therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-02.