How Can Next-Generation Sequencing Help Me?
- The goal of Next-Generation Sequencing (NGS) is to identify the exact mutations present in their lung cancer tumor.
- After NGS, the next step is to match these mutations with treatments that are already approved or under investigation in clinical trials.
- A specialized lung cancer team Cone Health Cancer Center can help every patient and their loved one get the treatment that is right for them.
Dr. Mohamed Mohamed, a thoracic medical oncologist at Cone Health Cancer Center in Greensboro, located near Raleigh-Durham, offers his advice for seeking nearby lung cancer treatment.
What is next-generation sequencing?
Read MoreDr. Ronald Natale breaks down how targeted therapy is used for lung cancer.
Lung Cancer Driver Mutations
NGS testing identifies crucial mutations driving lung cancer, known as “driver mutations.” Advanced therapies can target their unique genetic makeup.
The National Comprehensive Cancer Network (NCCN) suggests testing for 9 specific biomarkers (or mutations) before starting treatment for advanced lung cancer. These biomarkers are:
- EGFR (Epidermal Growth Factor Receptor): A protein influencing cell growth and division.
- ALK (Anaplastic Lymphoma Kinase): An enzyme impacting cell growth and development.
- ROS1 (c-ros Oncogene 1): A receptor tyrosine kinase involved in cell signaling.
- BRAF (B-Raf Proto-Oncogene): A gene associated with cell growth and division.
- KRAS (Kirsten Rat Sarcoma Virus): A gene regulating cell division and differentiation.
- MET (MET Proto-Oncogene): A receptor influencing cell growth and regeneration.
- HER2 (Human Epidermal Growth Factor Receptor 2): A protein playing a role in cell growth and repair.
- RET (Rearranged during Transfection): A receptor tyrosine kinase involved in cell growth.
- NTRK (Neurotrophic Tyrosine Receptor Kinase): A receptor affecting nerve cell development.
“For many years, testing for molecular [was] mainly for advanced stage lung cancer like stage three and stage four. But recently, [we] discovered that some of these mutations are present in early type of cancer, like EGFR and ALK. And this could be also used to treat patient in early stage lung cancer,” says Dr. Mohamed.
More on Lung Cancer Mutations That Matter
However, he emphasizes that the majority of patients who benefit from NGS are late stage of lung cancer patients.
Cone Health Cancer Center performs all of the following tests:
PD-L1
Discovered almost 20 years ago, Programmed Death Ligand 1 (PD-L1) is now an integral part of a lung cancer workup.
PD-L1 is a protein on cancer cells that pairs with PD-1, a protein on immune cells. Their connection camouflages the cancer cells from the immune system, preventing immune response and aiding cancer cell growth.
Patients with over 50% PD-L1 expression levels often respond strongly to PD-1/PD-L1 inhibitor immunotherapies such as Keytruda (pembrolizumab), Opdivo (nivolumab), and Tecentriq (atezolizumab).
Conversely, under 50% expression might indicate a less effective response. These inhibitors block the PD-1/PD-L1 interaction, stop cancer cells from deactivating the immune system, and allow it to attack and destroy the cancer cells.
“So the tumor that is rich in PDL-1 actually responds better to the inhibition of that pathway. That’s why we test for PD-L1. Because if we find patient with high PDL-1 expression, we may be able to treat them with just immunotherapy or in combination with chemo,” explains Dr. Mohamed.
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.
Dr. Mohamed describes immunotherapy as an infusion of monoclonal antibodies that counteract the PD-L1 protein, keeping immune cells active to continue attacking the tumor. This approach prevents the tumor from inhibiting our immune system.
“I will simplify this: imagine that you are driving a car that you have to brace the gas but you also have to have a break to stop that car from running so fast,” he says.”Cancer cells are so smart, they understand the mechanism that our immune cells has [on how to] break them.”
EGFR
“Until 2004 we did not have anything [on] lung cancer gene. In 2004 two papers came out at the same time: one from Dana-Farber, the other one from Memorial Sloan Kettering. That was the first discovery of a mutation in lung cancer: called EGFR mutation.” – adds Dr. Mohamed.
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).
Tyrosine kinase inhibitors (TKIs) effectively target EGFR mutations in lung cancer, employing drugs like osimertinib (Tagrisso), erlotinib, and gefitinib.
These TKIs bind to the mutated EGFR protein on the surface of cancer cells, preventing its activation. Their action blocks the molecular signals that lead to uncontrolled cell proliferation, ultimately inhibiting cancer growth and survival.
Osimertinib, shows great promise in treating patients with advanced-stage lung cancers, and recent studies have demonstrated its effectiveness in improving outcomes for early-stage lung cancer patients.
ALK and ROS1 Rearrangement
Anaplastic lymphoma kinase (ALK) is so named because it was first discovered in blood cancers called lymphomas. It 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.
ALK usually switches off before birth. However, sometimes the gene is 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 Xalkori (crizotinib ), Zykadia (ceritinib ), Alecensa (alectinib ), and Alunbrig (brigatinib).
The ROS1 gene is involved in cell growth and differentiation. Like ALK, 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 Zykadia, or Rozlytrek (entrectinib).
KRAS
KRAS is a plentiful protein involved in normal cell function and growth. KRAS mutations, however, can ramp up its signaling and lead to abnormal cell growth, resulting in cancers.
While doctors routinely test for mutations in KRAS in new lung cancer diagnoses, they don’t generally change the initial management of the disease based on test results. But when some lung cancers stop responding to the standard chemotherapies and immunotherapies, patients with a specific KRAS mutation known as KRAS G12C can be treated with the targeted KRAS agent Lumakras (sotorasib ).
BRAF
Another protein that helps regular cellular growth, BRAF, can carry mutations linked to lung cancers. A specific mutation, BRAF-V600, can be treated with a combination of Tafinlar (dabrafenib) and Mekinist (trametinib).
HER2
More well-known in association with breast cancer, HER2 mutations can also be present in lung cancers. Patients with HER2 mutations can be treated with Herceptin (trastuzumab ).
Cone Health Lung Cancer Team
A specialized care team will be there to help you or a loved one when there is a lung cancer diagnosis, Dr. Mohamed says.
“We developed a group of physicians: cardiothoracic surgeons, radiation oncologists, pathologists, radiologists, medical oncologists like me,” he says, adding that Cone Health also has a multidisciplinary clinic, with weekly conferences where experts discuss every case of lung cancer they are treating. This helps shape treatment options for each individual.
“Most of the team members are very familiar with the requirement for molecular testing, so they don’t have to wait for me to order it,” Dr. Mohammad explains. “Most of the time they have already ordered what I need, so that they save me time when I see the patient.”
Questions to Ask Your Doctor at Cone Health
Before you are scheduled for molecular testing, have a conversation with your doctor. Get a good understanding of the process and what to expect. Consider asking the following questions:
- What should I expect with each test?
- How much are these tests going to cost me?
- Which genes will you examine with molecular testing?
- Do I have any genetic mutation that would change the course of my treatment?
- How long does it take to get my NGS testing results?
- How aggressively should my lung cancer treatment be?
- Are there clinical trials available?
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