When should we perform biomarker testing?
Biomarker testing is relevant:
- when lung cancer is suspected and a biopsy is recommended
- upon lung cancer diagnosis
- when the cancer recurs after treatment
It’s essential for all lung cancer patients to discuss biomarker testing with their healthcare team.
Biomarker testing involves examining tumor tissue or blood for driver mutations and the presence of the PD-L1 protein, which helps determine suitability for targeted therapy or immunotherapy. Decision-making about biomarker testing should be collaborative and consider various factors.
What biomarkers should patients be tested for?
Guidelines commonly advise testing all patients diagnosed with advanced-stage NSCLC for mutations in BRAF V600, EGFR, KRAS, MET exon 14 skipping, HER2, as well as fusions in ALK, NTRK, RET, and ROS1, along with assessing PD-L1 protein expression, before treatment.
In addition, patients with operable NSCLC should be screened for mutations in the EGFR gene and ALK gene fusions at initial diagnosis and before deciding on pre-surgical treatment.
We should also be aware that driver mutations other than ALK, BRAFV600, EGFR, KRAS, MET exon 14 skipping, NTRK, RET and ROS1 have been found in both adenocarcinoma and squamous cell lung carcinomas.
Beyond the recommended mutations, comprehensive biomarker testing, including additional mutations, is encouraged due to ongoing clinical trials testing drugs targeting these mutations.
Patients with SCLC may undergo PD-L1 expression testing and evaluation for small cell-specific biomarkers like DLL3 for eligibility in specific clinical trials, however no biomarker testing is necessary for routine treatment.
Below is a table with common recommendations for biomarker testing:
Lung adenocarcinoma | Stages I, II, and III | Testing for mutations in the EGFR gene and ALK fusions should be conducted at initial diagnosis before surgery. Testing for the ALK, BRAF V600E, KRAS, MET exon 14 skipping, NTRK, RET, and ROS1 mutations and PD-L1 protein levels at the time of diagnosis and surgical resection is not always recommended but may be considered. The decision should be made on an individual basis with your doctors.
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| Stage IV non-small-cell lung cancer (lung adenocarcinoma or other non-squamous or squamous cell carcinoma, de novo or recurrenent after definitive therapy for initially stage I, II, or III lung cancer) | Tumors should be tested for ALK, BRAF V600E, EGFR, KRAS, HER2 (ERBB2), MET exon 14 skipping, NTRK, RET, and ROS1 at the time of diagnosis. Testing for other biomarkers, such as MET amplifications and NRG1 fusions may be helpful in deciding eligibility for clinical trials and off-label drugs. PD-L1 immunohistochemistry is recommended to determine whether you will benefit from an immunotherapy drug in the first-line (initial treatment) setting. | |
Squamous cell lung cancer | Stages I, II, and III | Currently, biomarker testing is performed only for clinical trials.
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Small cell lung cancer | All stages | Currently, biomarker testing is performed only for clinical trials. |
How is biomarker testing conducted?
Tissue biopsies are crucial for confirming lung cancer and identifying specific mutations which inform treatment decisions. However, in specific cases, liquid biopsies, which analyze blood samples, may also be used by your healthcare team.
Tissue Biopsies
Various techniques are available to obtain tumor tissue, chosen based on tumor location, size, and patient overall health. Your healthcare team will discuss the most suitable options, along with associated risks and benefits. Techniques include bronchoscopy, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), transthoracic needle biopsy, thoracoscopy, thoracentesis, mediastinoscopy, and mediastinotomy.
Regardless of the collection method, patients should confirm with their doctors beforehand to ensure adequate tissue for all necessary biomarker tests. Tissue samples are preserved for additional testing if needed. Biomarker testing can be conducted on primary or metastatic tumors. If tumor samples are limited, priority is given to testing mutations most likely to be present or those with EMA-approved treatments. Common genetic alterations include ALK, BRAF V600E, EGFR, HER2 (ERBB2), KRAS, MET exon 14 skipping, NTRK, RET, and ROS1.
Following collection, tumor tissue is sent to a laboratory for testing. Comprehensive biomarker testing is ideal, assessing mutations in multiple genes simultaneously via next-generation sequencing (NGS). This approach includes mutations without approved treatments, as they may be targeted in ongoing or future clinical trials. Results, typically taking up to four weeks, guide treatment choices.
Liquid Biopsies
Although tissue biopsies are the gold standard for diagnosing lung cancer, liquid biopsies – faster and less invasive – are increasingly used to assess targeted therapy suitability.
Liquid biopsies detect driver mutations by analyzing circulating tumor DNA (ctDNA) released when cancer cells die. A blood sample is drawn from a vein and sent to a laboratory for analysis. Liquid biopsy results are often faster than tissue biopsy results and offer the same comprehensive testing for multiple mutations. Studies have demonstrated their effectiveness in detecting mutations with targeted therapies.
Liquid biopsies aid healthcare teams in determining appropriate targeted therapies at diagnosis, assessing resistance to ongoing treatments, and monitoring treatment response. However, they may not capture all mutations. If a liquid biopsy yields negative results, tissue biopsy results are used for treatment decisions.
Both methods are valuable tools in personalized lung cancer care, enabling tailored treatment approaches based on individual genetic profiles.
Is it necessary to undergo multiple biopsies?
In some cases, an additional biopsy may be advised for various reasons:
- insufficient tissue was obtained during the initial diagnostic biopsy.
- when a targeted therapy previously effective against lung cancer has ceased to be effective and the cancer has recurred. It’s important to test the cancer that has become resistant to treatment for new mutations or rare histological changes, which may warrant special therapeutic maneuvers. This helps doctors adjust the patient’s treatment plan.
- new drugs approved for lung cancer treatment, potentially beneficial for the patient, may necessitate biomarker testing. Hence, a patient’s healthcare team might suggest further biopsies (either tissue or liquid) and biomarker testing at different stages of treatment.
The decision to proceed with another biopsy should be made collaboratively by the patient and healthcare team.
