Why Lung Cancer Biomarker Testing Matters for RET-Positive Patients

It is not a homogenous disease, and it can be sub-grouped into different types of lung cancer depending on the alterations that the lung tumors present (onco-gene driven alterations such as RET, EGFR, ALK, ROS1, etc.) (1). This distinction is important to determine tailored treatment options for onco-gene driven lung cancer patients.

Biomarker testing is also known as molecular testing or tumor profiling, and it involves analyzing the cancer cells’ DNA, RNA, or proteins to identify specific biomarkers or onco-gene driven alterations present in the tumors (mutations, amplifications, etc). These alterations, called somatic mutations, are genetic alterations that occur in cancer cells during a person’s lifetime and are not inherited. Somatic mutations and the presence of other biomarkers can provide information about the characteristics and behavior of the cancer.

Cancer biomarkers are particularly vital for tailoring personalized treatment plans for lung cancer patients.

Identifying these alterations or biomarkers enables oncologists to select targeted therapies that specifically attack cancer cells with these alterations, often leading to more effective treatment outcomes and fewer side effects compared to traditional chemotherapy.

For example, if a patient’s lung cancer biomarker testing results show an alteration in the RET molecule, the patient may be able to receive a targeted RET therapy. Biomarker testing also analyzes the levels of important proteins in the tumor, such as the immune related PD-L1 protein that may help doctors predict if a patient would benefit from immunotherapies based on PD-L1 inhibitors.

Breakdown of Lung Cancer Biomarker Testing

For lung cancer, it is important to discuss with your doctor comprehensive biomarker testing (4-5). This looks for a large number of genetic alterations and proteins in all the genes known to be associated with lung cancer. The results will show if you have an alteration that can be treated with a targeted therapy or if you are likely to benefit from immunotherapy.

The biomarker testing is done in tumor tissue from a tumor biopsy and can be performed at the hospital where treatment is administered or sent to a certified laboratory.

Next-Generation Sequencing (NGS)

The most common comprehensive biomarker tests for detecting alterations or biomarkers in lung cancer is Next-Generation Sequencing (NGS). This advanced method allows for comprehensive analysis of multiple genes at once, including the RET gene, to identify mutations, fusions, and other genetic alterations that may drive cancer growth. NGS is highly sensitive and can detect a wide range of genetic changes, making it an invaluable tool for personalized cancer treatment.

• How it works: NGS involves extracting DNA or RNA from a tumor tissue sample, sequencing the genetic material, and then analyzing the sequence data to identify any genetic alterations. In the context of RET positive lung cancer, NGS can detect RET gene fusions, mutations, and other relevant genetic changes in cancer cells.
• Benefits: NGS is highly accurate and can analyze numerous genes simultaneously, providing a comprehensive genetic profile of the tumor tissue. This broad analysis is particularly useful for identifying not only RET alterations but also other potential therapeutic targets within the same test.
• Applications: The results from NGS can guide the selection of targeted therapies, such as RET inhibitors, and inform clinical trial eligibility for new treatments.

Fluorescence In Situ Hybridization (FISH)

FISH is a molecular method that can be used to detect chromosomal abnormalities in lung cancer patients. FISH is a well-established method that is highly specific for detecting gene amplifications, deletions, or translocations. This test is useful for lung cancer diagnosis of some types of alterations such MET amplifications in lung cancer patients.

Liquid biopsy test

Liquid biopsy can look for certain biomarkers or genetic alterations in a patient’s blood. It is a minimally invasive method that can detect tumor DNA fragments in the bloodstream (also called circulating tumor DNA or ctDNA). The alterations on these DNA fragments may indicate the most effective treatment options to use. Liquid biopsy can be used for lung cancer diagnosis, prognosis, and predicting treatment response. In addition to helping determine the right treatment for a lung cancer patient, liquid biopsy offers the following benefits:

• Minimally invasive, requiring only a few vials of patient’s blood
• Can be performed frequently to determine whether a cancer is changing in response to treatment

Read Joyce’s story about liquid biopsy and RET cancer.

When should biomarker testing be performed?

Discuss biomarker testing with your doctor preferably before a tumor tissue biopsy is performed. It is also important to discuss the option of performing additional biomarker testing frequently to determine whether the cancer is changing using liquid biopsies, or if there is progression and the cancer returns after therapy.

Importance of Biomarker Testing after Progression for RET Non-Small Cell Lung Cancer Patients

For individuals diagnosed with RET positive lung cancer, biomarker testing is crucial and can significantly impact treatment and prognosis.

Targeted therapies are very effective in eliminating cancer cells, but unfortunately some cancer cells escape the effects of the treatment and survive to proliferate and drive tumor growth.

FDA-approved targeted therapies against RET (selpercatinib (Retevmo) and pralsetinib (Gavreto)) specifically target the RET molecule and showed great responses in RET patients. However, despite initial success, some patients may develop resistance to these cancer treatments over time.

Ongoing monitoring through biomarker testing (liquid biopsy) allows for real-time assessment of how well a treatment is working and whether it has stoped working. This approach ensures the early detection of any resistance to therapy. For patients with RET positive lung cancer, this means a more responsive and adaptive treatment strategy, enhancing their overall quality of life and increasing the chances of long-term survival. For example, if a RET lung cancer patient who has been treated with RET targeted therapies develops a MET amplification as mechanism of resistance to the RET therapy, the biomarker testing would be able to detect those changes in the tumor and the doctor may recommend a change in therapy. Patients should talk to their doctor about frequent comprehensive biomarker testing using liquid biopsy.

What Does Tumor Testing Cost?

Insurance may cover the cost of most lung cancer tumor biomarker tests. Talk with your doctor or medical team about your insurance and the costs for biomarker testing.

Some companies like Tempus offer a financial assistance program, which may help provide access to biomarker tests for patients in financial need. More information here.

Genetic Germline Testing vs Biomarker Testing

Genetic germline testing involves analyzing an individual’s DNA to identify inherited genetic mutations that may increase the risk of developing cancer or that could influence the management of cancer. These mutations are present in every cell of the body and are passed down from parents to their children. The focus is primarily on germline mutations – hereditary changes in genes that a person is born with.

Genetic germline testing identifies inherited risks and helps in preventive measures, while biomarker testing provides critical information on the molecular characteristics or alterations of the tumor tissue.

The National Comprehensive Cancer Network (NCCN) guidelines currently recommend germline genetic testing for all patients (aged < 50 years) diagnosed with pancreatic, ovarian, or colorectal cancer. The NCCN guidelines also recommend germline testing for some patients with breast cancer. Given the low proportion of lung cancer patients carrying pathogenic germline mutations and the lack of studies, genetic germline testing is not yet recommended for lung cancer patients (2,3).

References and Resources

1. Skoulidis F, Heymach JV. Co-occurring genomic alterations in non small cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19(9):495-509. doi:10.1038/s41568-019-0179-8
2. Liu M, Liu X, Suo P, et al. The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility. Transl Lung Cancer Res. 2020;9(3):646-658. doi:10.21037/tlcr-19-403
3. Sorscher S, LoPiccolo J, Heald B, et al. Rate of Pathogenic Germline Variants in Patients With Lung Cancer. JCO Precis Oncol. 2023;7:e2300190. doi:10.1200/PO.23.00190
4. https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing
5. https://www.lungcancerresearchfoundation.org/for-patients/comprehensive-biomarker-testing-for-lung-cancer/
6. National Cancer Institute https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment