you may have heard referred to as “molecular testing” or “genomic testing,” is done by obtaining a small amount of tissue (called a biopsy) from a patient’s tumor
Biomarker testing, which you may have heard referred to as “molecular testing” or “genomic testing,” is done by obtaining a small amount of tissue (called a biopsy) from a patient’s tumour, or by drawing a blood sample.
The tissue or blood sample is tested at a lab, which can provide information about a patient’s tumour. Results from biomarker testing help to develop a personalized treatment path, including whether targeted therapy is appropriate for the patient.
The Foundation (USA) teamed up with Bayer Pharmaceuticals to share eight patient stories for whom biomarker testing positively impacted.
A list of known biomarkers and how prevalent they are in cancers is provided for your review. Additional information and resources are also provided.
View our Biomarkers Matter (Page)
Cholangiocarcinoma Patient Matt Reidy’s Biomarker Story
Cholangiocarcinoma Patient John Pierce’s Biomarker Story
Cholangiocarcinoma Patient Sharon Hockenberry’s Biomarker Story
Cholangiocarcinoma Patient Julie Thole’s Biomarker Story
Lung Cancer Patient Gina Hollenbeck’s Biomarker Story
Lung Cancer Patient Ivy Elkins’s Biomarker Story
Lung Cancer Patient Hadley Recor’s Biomarker Story
Thyroid Cancer Patient Ben Lazcano’s Biomarker Story
Some common biomarkers
The acronym ALK, which stands for Anaplastic lymphoma receptor tyrosine kinase, is a gene that produces a specific active protein to help cell growth.
Several types of alterations in the ALK gene have been found.
It has been found in many solid tumours, including 5-10% in lung and uterine cancers, as well as skin melanoma, and less than 5% in the colon, breast, prostate, and hepatobiliary cancers.
Two ALK inhibitors have received FDA approval for certain ALK-positive hematological and solid tumours but not including cholangiocarcinoma so far.
Currently, there are ongoing clinical trials for ALK-positive solid tumors, which include cholangiocarcinoma patients (NCT02568267).
ATM is a tumor suppressor gene that, when working properly, prevents abnormal cell growth and helps repair your cell DNA damage.
An alteration in this gene leads to abnormal cell growth and increases the risk of cancer development.
Several types of alterations in ATM have been found, with ATM D2320N being one of the common mutations.
ATM alteration has been found in many solid tumors, including 5-10% of cholangiocarcinoma patients.
Currently, 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 cholangiocarcinoma patients, that are evaluating whether patients with ATM gene alteration are more sensitive to drugs targeting ATR and PARP as well as immune checkpoint inhibitors, and some chemotherapeutic agents.
BRAF, which encodes a protein called 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 common BRAF mutations that is found in more than 70% of hairy cell leukemia and more than 35% of thyroid cancer and melanoma patients.
It has also been found in many other solid tumors, including more than 10% of colorectal cancer patients and around 5% of cholangiocarcinoma, breast, and bladder cancer patients.
Currently, there are established targeted therapy for BRAF-V600E-mutant melanoma, colorectal cancer, anaplastic thyroid cancer, and non-small cell lung cancer.
A phase 2 multi-center clinical trial formulated as a basket trial, a system in which each patient receives the same treatment assessed the use of dabrafenib (BRAF inhibitor) in combination with trametinib (MEK inhibitor) for BRAF V600E mutated solid tumors, including advanced and metastatic cholangiocarcinoma patients. In this trial, 36% of cholangiocarcinoma patients achieved a partial response with 9.2 months median progression-free survival and 11.7 months median overall survival.
The acronym EGFR stands for Epidermal Growth Factor Receptor; it is also known as Erb or HER.
There are 4 different types of EGFR (Erb, HER) genes. Regardless of the EGFR type, all EGFRs regulate cell growth, proliferation, and survival.
The most common alterations in the EGFR pathway are EGFR1 and HER2.
The highest prevalence of EGFR genetic alterations has been found in lung cancer and brain tumors. It has also been found in many other solid tumors, including 5-10% of melanoma, stomach, head, and neck cancers, and less than 5% in the colon, breast, bladder, and hepatobiliary cancers.
Currently, there are several ongoing phases I and II clinical trials for EGFR-altered cholangiocarcinoma patients (NCT02836847, NCT03768375, NCT02465060).
The acronym ERFFI1 stands for ERBB receptor feedback inhibitor 1.
This gene cancels the function of EGFR family members. There is no available data about the approximate prevalence and types of genetic alteration of this gene in cholangiocarcinoma patients.
IDH2 is known as isocitrate dehydrogenase 2.
Several types of alterations in IDH2 have been found, with IDH2 R172K being one of the common mutations.
Genetic alterations in this gene were found in more than 10% of patients with acute myeloid leukemia and certain types of T-cell lymphoma and brain tumors and 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 (NCT03212274, NCT04521686, NCT03878095).
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, TP53 is decreased, so, TP53 can’t inhibit cancer cell growth leading to a poor prognosis.
Treatment with an 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.
MSi – Microsatellite Instability
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), is defined as instability in only one locus; and
- Microsatellite Stable (MSS), is defined as the absence of any evidence of microsatellite loci instability.
MSI-H (high) 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 NOTCH1 gene produces a protein called Notch 1, which increases cell proliferation, differentiation, and survival.
When NOTCH1 gene mutations are found, this leads to uncontrolled cell growth and division, which can result in the development of cancer.
NOTCH1 genetic alterations have been reported in more than 10% of chronic lymphoblastic leukemia, head and neck cancers, and less than 5% of bladder, colorectal, breast, and hepatopancreatic biliary cancers.
Currently, there are several NOTCH1 targeted therapies being examined in cholangiocarcinoma cell lines and animal models. So far, none of them have moved forward into a clinical trial.
The acronym NRG1 stands for Neuregulin 1 gene.
NRG1 gene encodes a protein that binds to the HER/ERBB family receptors and activates this pathway leading to tumor cell proliferation leading to their activation.
NRG1 has been found, with the most common one being NRG1 fusions.
The NRG1 fusions have been found in multiple solid cancer but are extremely rare, with an incidence of around 0.5%. The use of Seribantumab (NCT04383210) and Zenocutuzumab (NCT02912949), which inhibit HER2 and HER3 led to favorable tumor response and was tolerable in NRG1 fusion tumors, including cholangiocarcinoma patients.
There is an acronym NTRK which stands for neurotrophic receptor tyrosine kinase.
NTRK gene fusions lead to abnormal proteins called TRK fusion proteins, which may cause cancer cells to grow.
NTRK 1, 2, and 3 genes fusion have been found in more than 25 different types of adult and pediatric solid tumors. This includes more than 80% of breast, salivary gland, and sarcoma patients, 5-25% of certain types of melanoma and thyroid cancer patients, and less than 5% of cholangiocarcinoma, lung, colorectal, melanoma, thyroid, and head and neck cancer patients.
Both larotrectinib and entrectinib are NTRK inhibitors that received accelerated approval from the US FDA in 2018 and 2019, respectively, to be used for the treatment of patients with solid tumors harboring an NTRK fusion gene, including cholangiocarcinoma.
PIK3CA is a gene that plays a critical role in cell growth, proliferation, and survival.
Mutations in the PIK3CA gene may cause the PI3K enzyme to become overactive, which may cause cancer cells to grow.
Several types of alterations in PIK3CA have been found, with PIK3CA E542K being one of the common mutations.
PIK3CA has been reported in around 7% of cholangiocarcinoma patients. Currently, there are no available data on the prevalence of different genetic alteration subtypes.
The ROS1 gene is a proto-oncogene (a group of genes that cause normal cells to become cancerous when they are mutated).
Alterations can result in uncontrolled growth/cancer.
The highest prevalence of ROS1 gene alteration has been found in melanoma patients, while the prevalence is <5% in hepatobiliary, lung, breast, bladder, and many other solid tumors.
Currently, there is one trial for solid cancers, including cholangiocarcinoma harboring ROS1 genetic alterations (NCT02568267).
Tumour mutational burden (TMB) is measured by counting the number of genetic alterations/mutations (density)in a tumour sample.
These alternations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children; it also can but does not always cause cancer or other diseases.
TMB can be measured in molecular profiling tests using tumour tissue samples or via liquid biopsy.
Depending on the number of alterations (mutations), tumours are classified into low, intermediate, or high-TMB.
Several studies showed that TMB-high is a predictor of good treatment response, and patients with TMB-high have a better response to immunotherapy.