Tomorrow's Non-Small Cell Lung Cancer Treatment Today

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ROS1 Positive Lung Cancer

ROS1 positive lung cancer refers to cases of lung cancer in which the patient is positive for a mutation of the ROS1 gene. The ROS1 gene is responsible for making the protein ROS1, which signals cells to grow and reproduce. If a lung cancer patient is ROS1 positive, the cancer is usually more aggressive due to the ROS1 protein causing more abnormal cells to drive the growth of the tumor. However, ROS1 positive patients may be eligible for checkpoint inhibitors for treatment, which block the mutation from causing the cancerous cells to rapidly grow and divide. Although rare, the identification of the ROS1 alteration can play a major role in the patient’s treatment plan. Other than lung cancer, the ROS1 mutation has been identified in the following cancer types:

-Glioblastoma multiforme

-Bile duct cancer

-Ovarian cancer

-Colorectal cancer 

Genetic Testing for ROS1

ROS1-positive lung cancer has only been identified in non-small cell lung cancer (NSCLC), and not in small cell lung cancer. Of NSCLC cases, about 2% of them are ROS1 positive. This has led to an increase in testing for NSCLC patients.

In order to be eligible for targeted therapies, cancer patients need a positive test for the ROS1 mutation. Typically, a tissue sample of the tumor is collected by the doctor and it is sent to a laboratory for results. The tests used for the ROS1 mutation include:

-Fluorescence in situ hybridization (FISH): The most common testing method used, locates specific DNA sequences by exposing chromosomes to a probe with a fluorescent molecule attached. A researcher will be able to identify if the ROS1 gene if the fluorescent probe has been bound to it.

-Multiplex real-time PCR assays: Test that covers a range of fusion genes. Inexpensive and quick results compared to other tests. This test uses multiple probes that can be distinguished from the rest of the DNA sequences.

-Immunohistochemistry: Uses antibodies against the ROS1 protein to detect any abnormalities. This test is for screening to diagnose cancers, so it can be used initially to avoid unnecessary FISH tests.

-Next Generation Sequencing (NGS): Looks at the entire human genome in one test to detect any mutation. NGS is the most comprehensive test available, but may be expensive and time consuming compared to other testing methods.

ROS1 Positive Lung Cancer Clinical Trials

The only FDA approved treatments for ROS1 positive lung cancer are Crizotinib (Xalkori) and entrectinib (Rozlytrek). These targeted therapies can locate the abnormalities within cells (mutations) to know which cells to attack. This helps treatment avoid damaging healthy cells to minimize side effects compared to standard treatments.

Common side effects of ROS1 inhibitors include:

-Dizziness

-Diarrhea

-Constipation

-Fatigue

-Changes in vision

There are also ongoing clinical trials evaluating new therapies for ROS1 cancers. There are both clinical trials specifically for the ROS1 mutation, and many others available to treat lung cancer. Talk with your doctor to see if clinical trials could benefit you. Other drugs available for ROS1 lung cancer cases include Lorlatinib and Ceritinib. These therapies are often taken by themselves or in combination with chemotherapy and other treatments.

ALK Fusion Clinical Trials

Anaplastic lymphoma kinase (ALK) fusion is a genetic mutation in the ALK gene that is responsible for making a protein called ALK receptor tyrosine kinase. An ALK fusion is when the rearrangement of the gene EML4 and ALK fuse together, creating an oncogene EML4-ALK. ALK fusions can be a predictive biomarker for the effective use of certain targeted drug therapies, so it is important for patients to know if they have an ALK fusion. Patients without an ALK fusion will likely not respond to targeted ALK inhibitor drug therapies. ALK fusion clinical trials study the ALK inhibiting drugs that are available to treat patients who have this gene alteration.

ALK fusion clinical trials commonly target to treat malignant solid tumors, which are cancerous tumors that do not contain cysts or liquid area. Examples of solid tumors include:

-Sarcomas

-Carcinomas

-Lymphomas

ALK fusion clinical trials are currently studying ALK inhibitor drug therapies. An ALK inhibiting drug inhibits proteins involved in the abnormal growth of tumor cells, which is why these drugs are more effective for patients with this gene alteration. Drug therapies being studied in clinical trials include:

-Alectinib

-Brigatinib

-Crizotinib

-Ceritinib

-Lorlatinib

-Cyclophosphamide

-Ensartinib

-Rituximab

-Doxorubicin

-Nivolumab

Testing for ALK Fusion

Cancer patients will be tested for ALK fusions if their doctor performs Next Generation Sequencing (NGS) to see if they would respond successfully to an ALK inhibitor drug therapy. Genetic testing for cancer patients can be beneficial, as there are many targeted drug therapies for biomarkers other than ALK fusions. Testing for ALK fusions usually coincides with testing for other gene mutations, such as ROS1 and EFGR mutations in non-small cell lung cancer. There are a few methods that are used to test for ALK mutations:

-Next generation sequencing (NGS): detects ALK fusions and the fusion partner gene

-Fluorescent in situ hybridization (FISH): looks for gene rearrangement, and is a common test used to look for ALK fusion

-Immunohistochemistry (IHC): detects the altered ALK protein

-Polymerase chain reaction (PCR): detects known ALK fusions, but not new fusions

Non-Small Cell Lung Cancer Genomic Testing

Non-Small Cell Lung Cancer Genomic Testing helps cancer patients determine which mutations they have inherited that will affect their prognosis.

Non-Small Cell Lung Cancer Genomic Testing expresses the genes displayed by a cancer tumor. Any of these genes may have been mutated. Mutated gene structures help doctors gain insight into tumor behavior and propensity to spread.

What is Non-Small Cell Lung Cancer Genomic Test?

Genomic testing is used to detect changes in the DNA of cancer patients and tumors. Better targeted cancer treatment can be planned, including personalized treatments with the help of genomic tests.

Genetic testing is now an important part of diagnosing and staging patients with non-small cell lung cancer. Some chemotherapy drugs may be more or less effective than others against tumors with certain mutations. Molecular analysis of the tumor helps determine which treatments will benefit the patient the most.

Almost all of the genetic changes in cells are found only in cancer cells, not normal cells. This indicates that it is not possible to pass it on to your children.

Non-Small Cell Lung Cancer Genetic Markers

Currently, genomic abnormalities that are clinically actionable with FDA-approved drugs include changes in EGFR, ALK, ROS1, MET, RET, NTRK1 / 2/3 and BRAF genes. Most of these mutations occur during a patient’s lifetime and only occur in cancer cells.

ALK Fusions:

ALK fusions are seen in younger patients, nonsmokers or light smokers. When the ALK gene combines with another gene, EML4, it can trigger the development of lung cancer. ALK fusions are typically not found in patients with EGFR mutations.

ROS1 Fusions:

ROS1 fusions are usually identified in young nonsmokers. ROS1 can combine with many other genes to create an oncogenic fusion that can lead to lung cancer.

RET Fusions:

Similar to the ALK and ROS1 fusions in lung adenocarcinoma, RET fusions can initiate and sustain the tumor.

Sources:

https://www.cancer.org/lung-cancer

https://www.ncbi.nlm.nih.gov/articles

ALK gene: MedlinePlus Genetics

ALK Fusion – My Cancer Genome

ALK Mutation (Gene Rearrangement) | Lab Tests Online

Definition of solid tumor – NCI Dictionary of Cancer Terms – National Cancer Institute

What is ALK-positive lung cancer? By the ALK Positive Community — ALK POSITIVE