Biomarker Stories

The microsatellite is a short piece composite of 1 to 4 DNA base pairs repeated together in a row along the DNA molecule. Each person has hundreds of places in human DNA that contain microsatellites. Alteration in the number of DNA base pairs in the microsatellite may occur and is known as microsatellite instability (MSI). According to the MSI score, we classified cancer into MSI-high (MSI-H), defined as instability in 2 or more microsatellite loci; MSI-low (MSI-L), defined as instability in only one locus; and microsatellite stable (MSS), defined as the absence of any evidence of microsatellite loci instability. MSI-H has been reported in many cancer, with the highest incidence in Uterine cancer, gastric cancer, and colorectal cancer. Several studies showed that MSI-H is a predictor of a better response to immunotherapy.

The neurotrophic receptor tyrosine kinase (NTRK) 1–3 genes fusion has been found in more than 25 different types of adult and pediatric solid tumors, including >80% of breast, salivary gland, and sarcoma patients, 5-25% of certain types of melanoma and thyroid cancer patients, and <5% of cholangiocarcinoma, lung, colorectal, melanoma, thyroid, and head and neck cancer patients. Both entrectinib and larotrectinib received accelerated approval from the US FDA in 2018 and 2019 to be used for the treatment of patients with solid cancer harboring an NTRK fusion gene.

ATM is a tumor suppressor gene that prevents abnormal cell growth and helps repair your cell DNA damage. Alteration in this gene leads to abnormal cell growth and increases the risk of cancer development. Several types of alterations have been reported, including point mutation, gene loss, fusion,..etc. The highest prevalence of ATM gene alterations has been reported in hematological malignancies, including >40% of Mantel cell lymphoma and prolymphocytic leukemia patients. Also, it has been found in many solid tumors, including > 10% of the bladder cancer and 5-10% of prostate, lung, colorectal, gastric, melanoma, and biliary tract cancers. There is no FDA-approved drug for cancer patients harboring ATM gene alteration. However, there are many preclinical, phase I, and II clinical trials, including one for biliary tract cancer patients evaluating the impact of ATR, PARP, immune checkpoint inhibitors, and some chemotherapeutic agents for treating those patients.

Anaplastic lymphoma receptor tyrosine kinase (ALK) is a gene that produces a specific active protein to help cell growth. Several types of alterations in this gene, including mutation, fusion, amplifications,..etc., have been reported. The highest prevalence has been reported in hematological malignancies, including ~44% of myofibroblastic tumors and>22 of large-aplastic cell lymphoma. Also, it has been found in many solid tumors, including > 10% in pediatric neuroblastoma, 5-10% in lung and uterine cancers, as well as skin melanoma, and <5% in the colon, breast, prostate, and hepatobiliary cancers. A couple of ALK inhibitors received an FDA approval for certain ALK-positive hematological and solid tumors but not including cholangiocarcinoma. Currently, there are two ongoing clinical trials for ALK-positive solid tumors, including cholangiocarcinoma patients.

The epidermal growth factor receptor (EGFR, also known as Erb or HER) family consists of 4 types, including EGFR [Erb1 or HER1], Erb2 (HER2), Erb3 (HER3), and Erb4 (HER4). Regardless of the EGFR type, all EGFRs regulate cell growth, proliferation, and survival. EGFR and HER2 are the most reported EGFR pathway alterations in cancer patients, including overexpression, amplification, and mutations. The most common genetic alterations in EGFR are Mutation (5.48%), amplification (2.59%), Exon 19 Mutation (1.75%), and Exon 19 Deletion (1.57%). The highest prevalence of EGFR genetic alterations has been reported in lung cancer and CNS tumors. Also, it has been found in many other solid tumors, including 5-10% in melanoma, stomach, and head and neck cancers and <5% in the colon, breast, bladder, and hepatobiliary cancers. Unfortunately, five randomized controlled trials have not assessed the value of adding EGFR inhibitors, including erlotinib, cetuximab, or panitumumab, to standard gemcitabine and platinum chemotherapy in unselected patient populations or patients without KRAS mutation didn’t show improvement in the survival. Currently, there are two ongoing phases I and II clinical trials for EGFR-altered cholangiocarcinoma patients.

ERFFI1 is known as ERBB receptor feedback inhibitor 1. This gene negatively regulates the function of the EGFR family members. There is no available data about the approximate prevalence and types of genetic alteration of this gene in cholangiocarcinoma patients.

BRAF (serine/threonine-protein kinase B-raf kinase) is an essential gene that plays a crucial role in cell proliferation. BRAF V600E is one of the commonly reported BRAF mutations found in >70% of hairy cell leukemia and >35% of thyroid cancer and melanoma patients. Also, it has been found in many other solid tumors, including >10% of colorectal cancer patients and ~5% of cholangiocarcinoma, breast, and bladder cancer patients. Currently, there are established targeted therapeutic therapy for BRAF-V600E-mutant melanoma, colorectal cancer, anaplastic thyroid cancer, and non-small cell lung cancer. A phase 2 multicenter basket trial assessed the use of dabrafenib (BRAF inhibitor) in combination with trametinib (MEK inhibitor) for BRAF V600E mutated solid tumors, including advanced and metastatic biliary tract cancer patients. In this trial, 36% of patients achieved a partial response with 9.2 months median progression-free survival and 11.7 months median overall survival.

ROS1 is a proto-oncogene receptor tyrosine kinase that plays a crucial role in regulating cellular growth and differentiation. The highest prevalence has been found in melanoma patients, while the prevalence is <5% in hepatobiliary, lung, breast, bladder, and many other solid tumors. Currently, there is only one trial for solid cancers, including cholangiocarcinoma harboring ROS1 genetic alterations.

NOTCH1 gene produces a protein called Notch1, which promotes cell proliferation, differentiation, and survival. NOTCH1 genetic alteration has been reported in >10% of chronic lymphoblastic leukemia, head and neck cancers, and <5% of the bladder, colorectal, breast, and hepatopancreaticobiliary cancers. Currently, there are several NOTCH1 targeted therapies examined in cholangiocarcinoma cell lines and animal models. Still, none of them have moved forward into a clinical trial.

IDH2 is known as isocitrate dehydrogenase 2. The most-reported genetic alterations in IDH2 are Mutation (1.14%), Exon 4 Mutation (0.79%), Codon 140 Missense (0.48%), R140Q (0.52%), and R172K (0.32%). Genetic alterations in this gene were found in >10% of patients with acute myeloid leukemia and certain types of T-cell lymphoma and brain tumors. While, it was found in less than <5% of patients with breast, lung, prostate, cholangiocarcinoma, and many other solid tumors. Currently, there are 3 ongoing clinical trials recruiting patients with solid cancer harboring IDH2.

PIK3CA is one of the family members’ lipid kinase genes that play a crucial role in cell growth, proliferation, and survival. The most common reported genetic alterations in PIK3CA are Mutation (12.16%), Codon 1047 Missense (3.28%), Codon 545 Missense (2.88%), H1047R (2.93%), and E545K (2.61%). PIK3CA has been reported in ~7% of cholangiocarcinoma patients. Still, there is no available data about the prevalence of different genetic alteration subtypes.

MDM2 (Mouse double minute 2 homolog) is an important inhibitor of the p53 tumor suppressor gene (TP53), which induces cancer cell death. MDM2 binds to p53, leading to its degradation or breakage. In tumors where there is a high level of MDM2 gene copy number, p53 is decreased. So, p53 can't inhibit cancer cell growth leading to a poor prognosis. Treatment with MDM2 inhibitor has been shown to induce tumor regression, and a clinical trial for cholangiocarcinoma patients who have MDM2 gene copies equal to or more than 8 with no mutations in the TP53 gene will start soon.