- Molecular profiling, which identifies genetic alterations driving cancer and guides targeted treatment strategies, has led to significant advances in lung cancer treatment.
- Currently tested “molecules” or mutations with targetable therapies include PD-L1, EGFR, KRAS, BRAF mutations, ALK and ROS1 rearrangements, and HER2 amplification.
- There are new oral treatment options that might be better for patients who have stage-4 lung cancer.
- Many other mutations, such as IDH 1/2, MYC, MET, RET, PTEN, and AKT1, can be tested through NGS. While specific targeted agents may not exist for all, ongoing research aims to uncover targeted approaches for these mutations.
SurvivorNet has put together this piece thinking of you, who live in the D.C. Metro area.Read More
If you live in the D.C. Metro area, Dr. Madan could help you, or a loved one, understand what the importance of these tests are.
What Molecules Are Tested For in Lung Cancer Molecular Profiling?
As investigations into the molecular characteristics and their correlation with the effectiveness of lung cancer treatments evolve, the array of “molecules” being tested continuously expands. A thorough molecular profiling of lung cancer, usually through testing called next-generation sequencing (NGS), and using other methods such as immunohistochemistry nowadays may consist of:
Discovered almost 20 years ago, Programmed Death Ligand 1 (PD-L1) is an integral part of lung cancer workup these days. Dr. Madan expresses, “Nowadays, we do PDL one testing for [all new] lung cancer [diagnoses].”
PD-L1 is a protein expressed on the surface of cancer cells that interacts with a complementary protein, programmed cell death-1 (PD-1), present on the surface of a patient’s native immune system cells. This interaction effectively blinds the immune system to cancer cells, helping them evade detection and continue proliferation.
Increased levels of PD-L1 expression can predict improved response to PD-1/PD-L1 inhibitor class of immunotherapy medications, such as pembrolizumab (brand name: Keytruda), nivolumab (brand name: Opdivo), and atezolizumab (brand name: Tecentriq). These inhibitors block the interaction between PD-1/PD-L1, preventing the cancer cells from turning off the immune system, which attacks and destroys them.
Whatever the PD-L1 expression level, these immunotherapies are used for treatment regardless because of their immense benefit, even in those patients with low levels of PD-L1 expression.
EGFR testing is now done as a routine part of lung cancer workups.
The epidermal growth factor receptor (EGFR) gene produces the EGFR protein, which plays a role in the growth and division of normal cells. Mutant EGFR genes can produce unchecked cell growth and lead to the formation of several types of cancers, including lung cancers, especially non-small cell lung cancers (NSCLC).
“In [patients with EGFR mutations], you can use medications such as osimertinib, erlotinib, gefitinib,” says Dr. Madan.
When present, EGFR mutations can be targeted by drugs called tyrosine kinase inhibitors (TKIs), such as osimertinib (brand name: Tagrisso). This medication has shown great promise in patients with advanced-stage lung cancers. It has also recently been demonstrated to improve outcomes for early-stage lung cancer patients.
“For stage four lung cancer, even in stage one-B onwards, we [check] EGFR mutations. [Having this ]knowledge beforehand [is] in the patient’s best interest,” notes Dr. Madan.
TKIs bind to the mutated EGFR protein on the surface of cancer cells. This prevents the protein from being activated. The molecular signals that lead to uncontrolled proliferation are blocked, ultimately inhibiting cancer growth and survival.
ALK and ROS1 Rearrangement:
Anaplastic lymphoma kinase (ALK), named so because it was first discovered in blood cancers called lymphomas, is a mutation routinely found in NSCLCs. ALK is an essential gene that shepherds the proper development of the gut and the nervous system in embryos. However, it gets turned off before birth.
Sometimes, the gene gets erroneously turned on by fusing with other genes. This errant process, called ALK rearrangement, can lead to unchecked cell growth and cancer development. Knowing the status of ALK rearrangements is essential, especially for metastatic or stage four patients, because they can be targeted with ALK inhibitors, such as crizotinib (brand name: Xalkori), ceritinib (brand name: Zykadia), alectinib (brand name: Alecensa), and brigatinib (brand name: Alunbrig).
The ROS1 gene is involved in cell growth and differentiation. Like ALK rearrangement, ROS1 can be erroneously turned on by fusing with many other genes, leading to cancer development. Stage four lung cancers with such fusions can be targeted by either ceritinib (brand name: Zykadia), or entrectinib (brand name: Rozlytrek).
KRAS is a ubiquitous protein involved in normal cell function and growth. KRAS mutations, however, can ramp up this signaling and lead to abnormal cell growth, resulting in cancers.
While mutations in KRAS are routinely tested for new lung cancer diagnoses, they do not generally change the initial management of the disease. However, some lung cancers may stop responding to the standard chemotherapies and immunotherapies. Such patients with a specific KRAS mutation (KRAS G12C) can be treated with the targeted KRAS agent sotorasib (brand name: Lumakras).
Another protein that helps regular cellular growth, BRAF, can be mutated in lung cancers. A specific form of this mutation, BRAF-V600, “can be treated with [a combination of] dabrafenib [brand name Tafinlar] and trametinib [brand name: Mekinist],” notes Dr. Madan.
Although more well-known in the breast cancer realm, HER2 mutations can also be present in lung cancers. These patients “can be treated with trastuzumab [Herceptin],” per Dr. Madan.
Many Other Mutations:
An ever-increasing number of mutations can be tested through NGS in lung cancer. These include but are not limited to:
- IDH 1/2
While many of these mutations do not have specific targeted agents yet, new research is continuously uncovering targeted ways of exploiting them.
Types of NGS Testing On The Market
There are a number of tests you may encounter, depending on where you are getting treatment and what you are getting treatment for. Here are some of the common ones currently on the market:
- FoundationOne®CDx looks at 324 genes in solid tumors and says it can takes up to 12 days for results. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB) to help inform immunotherapy decisions.
- OmniSeq Insight provides comprehensive genomic and immune profiling for all solid tumors. It looks for 523 different genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB), as well as PD-L1 by immunohistochemistry (IHC).
- Cobas EGFR Mutation Test v2 identifies 42 mutations in exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. It is designed to test both tissue and plasma specimens with a single kit, and allows labs to run tissue and plasma on the same plate simultaneously.
Being a Washington DC resident dealing with lung cancer brings specific questions and concerns. Where can you find the best medical facilities in the DMV area? How does the urban lifestyle affect treatment and recovery? MedStar Health in Washington, D.C., could be an option for you.
You should ask your healthcare team if the brand of molecular testing they are doing is optimal for your cancer type.
Questions to Ask Your Doctor
- Should I have next-generation sequencing testing?
- Do I have any genetic mutation that would change the course of my treatment?
- Am I eligible to receive targeted therapy?
- Is there a clinical trial that would be relevant for me?