Precision Oncology in Biliary Tract Cancer. Are We There Yet?

Dr. Abhishek Pathak

Senior Medical Oncologist,
Eastern Command Hospital, Kolkata

The second most common liver malignancy is biliary tract cancer with an incident of 6/100,000. According to the location, it is classified into intrahepatic cholangiocarcinoma (iCCA), perihilar and distal or extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBCA). Although surgical removal is the primary option, many patients diagnosed with advanced stages among whom surgery or loco-regional therapies are not possible. In some patients, this late diagnosis, high recurrence rates and limited treatment leads to poor prognosis of the disease. The recurrence rate of these carcinoma is very high, with 3 years recurrence-free survival rates are <30%, highlighting the urgency for effective systemic therapies.

Many systemic treatments have been used to increase the recurrence-free survival as well as overall survival rate. The ICCA is developed due to chronic inflammatory damage and micro-environmental changes in the tissue that induces an adverse oncogenic habitat. This in turn promotes malignancy by activating the signaling pathway, responsible for proliferation and inflammation. iCCA with proliferative characteristics shows low chances of survival, compared to inflammatory cancers. Existing research suggests that 40% of iCCA patients show targetable molecular alterations, targeted treatments of which can improve survival. Therefore, several molecular approaches are extensively studied in clinical trials. These therapies include:

1. Fibroblast growth factor (FGF) signaling: FGF is involved in multiple cellular functions like cell metabolism, development and angiogenesis. It has four transmembrane receptors (FGFR1, FGDR2, FGFR3 and FGFR4). It represents potentially druggable targets for iCCA patients. With this approach, recurrence-free survival rate is approximately 6 months, whereas, the overall survival rate is around 2 years. The toxicity profiles are manageable, with hyperphosphatemia occurring in most of the patients. However, co-mutational status of the tumors must be considered as it sometimes interferes with the treatment responses. 
2. Mutations of isocitrate dehydrogenase 1 and 2 (IDH 1 and IDH2): Both of these encode for metabolic enzymes. It induces changes in DNA hypermethylation in the tumors and alters chromatin remodeler’s expression. However, the common adverse effects are fatigue, nausea, diarrhea and abdominal pain.
3. Proto-oncogene B-Raf (BRAF) mutation: BRAF mutation activates the oncogenic MAPK signaling pathway and infers poor prediction of the disease. However, a combination of BRAF inhibitors with MEK inhibitors showed potential positive results in solid tumors.
4. Human epidermal growth factor receptor (HER2) alterations: This is proved to be an essential marker in case of breast and gastric cancer. Mutation or over expression or amplification of HER2 occurs mainly in eCCA, rather than iCCA.
5. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions: It is identified as the oncogenic driver in several adult and pediatric tumors.

Apart from these, use of immunotherapy is also investigated in CCA patients. Application of programmed cell death protein-1 (PD-1) inhibitor resulted in recurrence-free survival and overall survival rate of around 2 and 8 months respectively in biliary tract cancer patients. However, the programmed cell death protein-1 ligand 1 expression is not an equally strong predictor of tumor investigation. Interestingly, patients with tumor-harbored mismatch repair deficiency (dMMR)/ micro satellite instability showed recurrence-free survival and overall survival rate of around 4 months and 2 years respectively. Simultaneously, combinations of immunotherapy and tyrosine kinase inhibitor are also investigated in clinical trials for CCA patients, recurrence-free survival and overall survival rate of which is around 2 years. In contrast, combination of immunotherapy and chemotherapy is also frequently investigated. Promising results have been found using immunotherapy with tyrosine kinase inhibitor and/or chemotherapy. But, till now no clear molecular biomarker is identified that can predict immunotherapy response and therefore, further investigation is required.