Novel AMBRA1-ALK fusion identified by next-generation sequencing in advanced gallbladder cancer responds to crizotinib: a case report

Abstract

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract with poor prognosis. Several targetable genetic alterations have been identified in GBC; however, responses to targeted therapy are disappointing. We report a case of a 58-year-old Chinese woman with GBC who was detected with a novel ALK genomic rearrangement and received crizotinib after progression from first-line chemotherapy. The patient was diagnosed with stage IV adenocarcinoma of the neck of the gallbladder and received oxaliplatin combined with capecitabine as first-line therapy. After four cycles of this chemotherapy regimen, the patient started to show obstructive jaundice, and progressive disease was evaluated. Biliary drainage surgery was performed to alleviate the symptoms of obstructive jaundice. Upon referral to our department, her archived tissue samples were submitted for next-generation sequencing (Burning Rock Biotech) and immunohistochemistry, which identified the presence of a novel AMBRA1-ALK rearrangement and ALK overexpression, respectively. Oral crizotinib was administered achieving partial response within two cycles of treatment, which lasted for 7 months. AMBRA1-ALK has not been previously reported in any solid tumors and its sensitivity to crizotinib is not well characterized. Moreover, ALK alterations have been rarely reported for GBC. This case suggests that a subset of GBC might be driven by aberrant ALK signaling, which could potentially be explored as a biomarker of therapeutic response to ALK inhibitors in GBC. Moreover, our case report contributes an incremental step in understanding the genetic heterogeneity in GBC and provides clinical evidence of the utility of next-generation sequencing in exploring actionable mutations to expand treatment choices in rare solid tumors including GBC.

Exceptional response to alectinib for duodenal carcinoma with ALK fusion: A case report and literature review

“…However, the role of EML4-ALK as a therapeutic target in these non-NSCLC cancers, including gastrointestinal cancers, is not well understood. From our extensive literature search, we summarize in Table 1 the case series of patients with gastrointestinal cancer who were treated with ALK inhibitors (10)(11)(12)(13)(14)(15)(16)(17). A total of 23 patients with gastrointestinal cancer and ALK fusion were treated with ALK inhibitors.…”

A review of molecularly targeted therapy in biliary tract carcinoma: what is the next step?

“…Sporadic cases of BTCs with ALK rearrangement or alterations and ROS1 fusion are described in few case reports [ 38 , 39 ] and preclinical studies [ 40 – 42 ].…”

The role of molecular diagnostics in the choice of therapy for biliary tract cancers

“…В то же время четыре случая ХК с RETтранслокациями оказались включены в клинические испытания двух препаратов из нового класса селективных RET-ингибиторов -пралсетиниба и селперкатиниба, и в 3/4 (75 %) случаев зарегистрированы частичные ответы на лечение [38,39]. Опубликованы единичные отчеты о клинических случаях опухолей билиарного тракта с ALKи ROS1-транслокациями: применение таргетных ингибиторов киназ ALK и ROS1 в этих случаях сопровождалось выраженными клиническими ответами [40][41][42].…”