The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of sidedness, RAS, BRAF, HER‐2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.

Intrahepatic cholangiocarcinoma (ICC) typically presents at an advanced stage and is associated with a poor oncological outcome. The median survival for metastatic ICC is less than 1 year with standard chemotherapy. ICC is associated with distinct oncogenic drivers including IDH (isocitrate dehydrogenase), HER-2 (human epidermal growth factor 2), and BRAF (v-Raf murine sarcoma viral oncogene homolog B), which may benefit from matching targeted therapies. Hereby we report 2 cases of BRAF V600E refractory ICC treated with dual BRAF and MEK inhibitors (dabrafenib and trametinib) with excellent clinical and radiological response to therapy and with protracted duration of disease control. Our first patient achieved CR (complete remission) at 6 months of treatment with ultimate disease progression at 9 months. The second patient achieved a PR (partial response) at 2 months from starting treatment and remains progression free at 5 months. Our results confirm the activity of dual BRAF and MEK targeting in BRAF mutated ICC, adding further support to 3 additional case-reports in the literature. Dual targeting appears superior to other case reports with BRAF inhibition alone and appear favorable to historic data with cytotoxic chemotherapy.Given the poor outlook and refractoriness of BRAF mutant ICC, future studies should focus on early integration of BRAF/MEK inhibition. In view of her high risk of disease recurrence, she received five 3-week cycles of gemcitabine and cisplatin adjuvant chemotherapy. Repeat imaging after cycle 5 (4 months) revealed a new 1 cm right liver lobe lesion with new periportal and portacaval nodes and a pericardial lymph node enlargement. She underwent radiofrequency ablation (RFA) to the liver lesion and was switched to second line single-agent capecitabine. Repeat computerized tomography (CT) scan following 3 cycles of capecitabine (2 months) revealed new liver lesions and progressive lymph node enlargement in the pericardial region ( Figure 1A,B).Foundation One comprehensive genomic analysis was performed on her original resection specimen and confirmed a BRAF V600E mutation. She was started on dabrafenib 150 mg PO BID (twice a day) and trametinib 2 mg PO QD (once a day) in May 2015. Follow-up imaging studies confirmed a partial response after 6 weeks of treatment and a complete clinical response after 5 months of treatment (RECIST 1.1) ( Figure 1C,D). At 9 months of treatment, CT imaging confirmed recurrence of disease in the pericardial node and periportal/portacaval lymph nodes and new right pleural disease. Treatment with dabrafenib and trametinib was discontinued. Case 2A 71-year-old lady presented with vague right sided abdominal discomfort of 3 to 4 months duration with associated anorexia and weight loss in August 2015. Her past medical history was significant for cardiac dysrythmia requiring pacemaker placement and mild chronic obstructive E100Lavingia and Fakih. Impressive response to dual BRAF and MEK inhibition in BRAF mutant ICC

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