Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.

BACKGROUND Biliary tract carcinoma is an aggressive cancer, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A Phase II trial was conducted to study a combination of oral capecitabine and gemcitabine (CapGem) as first‐line therapy in patients with advanced and/or metastatic biliary carcinoma. METHODS Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients had histologically or cytologically confirmed, measurable adenocarcinoma and had not received prior therapy with capecitabine or gemcitabine. Treatment consisted of intravenous (i.v.) gemcitabine (1000 mg/m² on Days 1 and 8) plus oral capecitabine (650 mg/m² twice daily on Days 1–14) every 3 weeks for up to 6 cycles. Tumor response, survival, and safety were determined. RESULTS A total of 44 patients were evaluable. Primary tumor sites were: intrahepatic (n = 14) and extrahepatic biliary duct (n = 16); gallbladder (n = 7); and ampulla (n = 7). Fourteen (32%) patients had a partial response and 15 (34%) patients had stable disease. Median time to disease progression and overall survival were 6.0 (range, 3.8–8.1) and 14 (range, 11.4–16.6) months, respectively. The 1‐year survival rate was 58%. No Grade 4 adverse events were seen. Transient Grade 3 neutropenia/thrombocytopenia and manageable (almost invariably Grade 2) nausea, diarrhea, and hand–foot syndrome were the most common adverse events. CONCLUSIONS CapGem is an active and well tolerated first‐line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma that offers a convenient home‐based therapy. Cancer 2005. © 2005 American Cancer Society.