Example clinical scenario
When to consider genomic testing
Constitutional (germline) testing
- There is currently no formal indication for constitutional (germline) genomic testing for patients with lung adenocarcinoma, although pathogenic constitutional variants in EGFR have been reported in a small number of families.
- Lung adenocarcinoma at a young age may occur as part of the broad tumour spectrum of the cancer predisposition syndrome, Li-Fraumeni syndrome. Patients with young onset lung cancer should therefore be asked about a family history of Li-Fraumeni-related cancers (such as soft tissue sarcoma, adrenocortical carcinoma, choroid plexus cancer, premenopausal breast cancer, brain cancer and childhood cancer). Those meeting the Chompret criteria may be eligible for genetic testing of the TP53 gene after appropriate counselling.
Somatic (tumour) testing
- Somatic testing is crucial to inform optimal therapy of metastatic lung cancer (non-small cell). All patients with possible, probable or definite adenocarcinoma that is suitable for systemic anticancer therapy should have tumour molecular testing performed (regardless of smoking status). A subset of patients with squamous cell carcinoma, including never or light smokers (such as a >15-pack-per-year history), can also be considered for testing.
- Broad panel genomic testing performed at diagnosis can help access first-line targeted agents and help with treatment sequencing for targeted therapies aimed at detectable tier 1 variants that are accessible in the second-line setting. Current standard of care testing includes immunohistochemical assays (such as PDL1), single gene assays and broader panel next-generation sequencing (NGS) testing via the local Genomic Laboratory Hub (GLH).
- ctDNA analysis is an emerging companion diagnostic that can be performed at baseline/diagnosis and serially to detect mutations that may be targetable. ctDNA can minimise the need for invasive biopsy. Access to ctDNA is currently geographically variable.
- Currently, genomic testing for EGFR and BRAF variants, ALK and ROS1 fusions (and PD-L1 testing via immunohistochemistry) should be performed prior to first-line therapy (unless clinical circumstances preclude). Specific variants in these genes may confer eligibility to targeted tyrosine kinase inhibitors (TKI) as follows:
- EGFR variants: EGFR inhibitors including osimertinib, afatinib, dacomitinib, erlotinib and gefitinib;
- ALK fusion genes: alectinib, brigatinib, ceritinib;
- ROS1 fusion genes: crizotinib or entrectinib;
- BRAF V600E mutation: dabrafenib and trametinib; and
- PDL1 ≥ 50%: checkpoint inhibitor monotherapy.
- Patients who progress on certain first-line EGFR or ALK-specific TKIs may have a repeat biopsy to test for specific EGFR/ALK resistance mutations (such as the EGFR T790M or ALK G1202R variant). Presence of EGFR T790M confers eligibility for second-line treatment with osimertinib. Testing for resistance mutations can be performed via repeat tissue biopsy or ctDNA analysis.
- Certain TKIs are approved for second-line (brigatinib, ceritinib, lorlatinib) and third-line (lorlatinib) treatment of ALK-positive lung cancer (non-small cell), dependent on first- (and second-) line treatments.
Presence of an EGFR exon 20 insertion may confer eligibility for second-line treatment (after first-line platinum chemotherapy) with the EGFR inhibitor mobocertinib, which is being made available by the NHS in England through an early national access agreement following a Project Orbis licence.
- KRAS variants (part of the RAS genes family), splice-site variants or amplifications in MET, and RET fusions may also be tested. Presence of the KRAS G12C variant may confer eligibility for second-line treatment with sotorasib in England via an early national access agreement. Presence of a RET gene fusion may confer eligibility for second-line treatment with selpercatinib via an national early access agreement in England.
- There are no other funded treatments currently targeted at KRAS variants, MET amplifications or RET fusions, but results may have implications for trial enrolment and novel therapies are likely to become available in the future.
- Patients who have failed all standard of care therapies can be tested for NTRK1, NTRK2 and NTRK3 rearrangements. In the future, testing may be done prior to first-line therapy. Detection of NTRK fusions may make patients eligible for NRTK TKI therapy. In the future, testing for NTRK fusion genes is likely to be performed prior to first-line therapy in order to optimise sequencing of therapies.
- In the future, somatic (tumour) testing is likely to be expanded to include larger somatic gene panels. Ultimately, it is likely that paired somatic and constitutional (germline) whole genome sequencing (WGS) will be performed.
- All patients with solid tumours who have exhausted all standards of care testing and treatment are eligible for WGS in order to explore clinical trial options.
What do you need to do?
- Consult with your local GLH to determine which genes may be tested and the corresponding assay-class. The National Genomic Test Directory lists somatic lung cancer-specific tests under the following clinical indication codes:
- M4.1 Multi-target NGS panel – small variant (EGFR, ALK, BRAF, KRAS, MET)
- M4.2 Multi-target NGS panel – structural variant (ROS1, RET, ELM4-ALK, NTRK1, NTRK1, NTRK3, MET)
- M4.3 Multi-target NGS panel – copy number variant (MET)
- M4.4 EGFR hotspot tumour
- M4.5 EGFR hotspot ctDNA
- M4.6 ROS1 rearrangement FISH/RT-PCR
- M4.7 RET rearrangement FISH/RT-PC
- M4.8 RET copy number FISH
- M4.10 EML4-ALK FISH/RT-PCR
- M4.11 ALK hotspot cDNA
- For information on the genes that are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service signed-off panels resource.
- To cover the full spectrum of genes relevant for lung cancer (non-small cell), one or more of the following investigation techniques may be used:
- Individual centres may have their own protocols for testing specific genes. NGTD options for covering the genes listed above include clinical indication M4.1 (multi-targeted NGS panel for EGFR, ALK, BRAF, KRAS and MET) plus M4.2 (panel for ROS1, RET, EML4-ALK, MET, NTRK1, NTRK2 and NTRK3). These tests can all be performed on formalin-fixed tumour samples.
- For ctDNA-based tests, a blood sample is required. Please refer to your local GLH for details of test request forms, which blood bottles to use and where to send samples.
- WGS of solid tumours where the patient has exhausted all standards of care testing and treatment is requested as code M232. This requires access to a fresh tumour sample and a matched blood (EDTA) sample for germline testing. A record of discussion (RoD) must be completed for this investigation. If you have not completed an RoD form before and/or do not have access to one, please review this Knowledge Hub article on how to complete an RoD form. Please discuss with your local GLH before submitting samples for WGS to confirm the local test pathway details.
- ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) – includes recommendations for molecular testing and treatment
- NHS England: National Genomic Test Directory and eligibility criteria (note that somatic (tumour) tests are listed in the directory for cancer, while constitutional (germline) tests are listed in the directory for rare and inherited disease)
- NICE: Guidance on larotrectinib for treating NTRK fusion-positive solid tumours
- NICE: Guidance relevant to lung cancer – many guidelines related to treatments following somatic (tumour) molecular testing
- Cancer Research UK: Testing for gene mutations in lung cancer
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