Presentation: Patient with advanced lung cancer (non-small cell)

A 67-year-old woman is diagnosed with stage IV adenocarcinoma of the lung. There is no significant family history of cancer. You wish to undertake genomic testing and are considering which constitutional (germline) and/or somatic (tumour) genomic tests are available and appropriate for her.

Constitutional (germline) testing

• There is currently no formal indication for constitutional (germline) genomic testing for patients with lung adenocarcinoma.
• Pathogenic constitutional (germline) variants in EGFR have been reported in a small number of families. NHS-funded constitutional EGFR testing is not currently available, given the lack of data regarding associated disease risk and lack of consensus regarding management of pre-symptomatic individuals with these variants.
• 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 genomic testing of the TP53 gene after appropriate counselling.
• Some authors suggest that there is an increased lung cancer risk in those with pathogenic variants in BRCA2 or other cancer susceptibility genes, but further data is required to clarify disease association.

Somatic (tumour) testing

• Somatic (tumour) 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). Somatic testing should also be performed on selected squamous cell carcinomas with clinical features consistent with a higher likelihood of genetic variants, including in never or light smokers (such as a fewer-than-15-pack-per-year history) and age <50 years.
• Broad panel genomic testing performed at diagnosis can help facilitate access to first-line targeted agents, and can help with treatment sequencing for targeted therapies aimed at detectable tier-one variants that are accessible in the second-line setting. Current standards-of-care testing includes immunohistochemical assays (such as PDL1), single gene assays and broader panel massively parallel sequencing (sometimes called next-generation sequencing) via the local Genomic Laboratory Hub (GLH).
• Circulating tumour DNA (ctDNA) analysis is an emerging companion diagnostic that can be performed at baseline or diagnosis and serially to detect variants that may be targetable. ctDNA can minimise the need for invasive biopsy. Access to ctDNA is currently geographically variable.
• Currently, genomic testing for EGFR, BRAF, MET and ALK variants 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 for targeted tyrosine kinase inhibitors (TKIs) as follows:
  • EGFR variants: EGFR inhibitors including osimertinib, afatinib, dacomitinib, erlotinib and gefitinib;
  • ALK fusion genes: alectinib, brigatinib and ceritinib;
  • ROS1 fusion genes: crizotinib or entrectinib;
  • MET exon 14 skipping variants: tepotinib;
  • BRAF V600E variant: dabrafenib and trametinib; and
  • PDL1 of ≥50%: immune 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 or ALK resistance variants (such as the EGFR T790M or ALK G1202R variant). Presence of EGFR T790M confers eligibility for second-line treatment with osimertinib. Testing for resistance variants 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.
• KRAS variants (part of the RAS genes family) and RET fusions may also be tested for. Presence of the KRAS G12C variant may confer eligibility for second-line treatment with sotorasib in England via the Cancer Drugs Fund. Presence of a RET gene fusion may confer eligibility for second-line treatment with selpercatinib via the Cancer Drugs Fund in England.
• There are no other funded treatments currently targeting 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 standards-of-care therapies can be tested for NTRK1, NTRK2 and NTRK3 rearrangements. Detection of NTRK fusions may make patients eligible for NTRK TKI therapy.
• All patients with solid tumours who have exhausted all standards-of-care testing and treatment options are eligible for whole genome sequencing (WGS) in order to explore clinical trial options.

• Consult with your local GLH to determine which genes may be tested and the corresponding assay class. The National Genomic Test Directory lists somatic (tumour) 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 fluorescent in situ hybridisation (FISH) or RT-PCR;
  • M4.7 RET rearrangement FISH or RT-PCR;
  • M4.8 RET copy number FISH;
  • M4.10 EML4-ALK FISH or RT-PCR; and
  • M4.11 ALK hotspot cDNA.
• To find out which genes 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:
  • single gene sequencing;
  • gene panel sequencing;
  • multiplex ligation-dependent probe amplification (MLPA); and/or
  • immunohistochemistry.
• Individual centres may have their own protocols for testing specific genes. Test directory options for covering the genes listed above include clinical indication M4.1 (Multi-targeted NGS panel for EGFR, ALK, BRAF, KRAS and MET) and 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 in patients who have 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 constitutional (germline) testing. A record of discussion form must be completed for this investigation. Please discuss the case with your local GLH before submitting samples for WGS to confirm the local test pathway details.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• European Society for Medical Oncology (ESMO): Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up (PDF, 71 pages)
• Li-Fraumeni Syndrome Association: Criteria for LFS
• NHS England: National Genomic Test Directory (note that somatic (tumour) tests are listed in the test directory for cancer, while constitutional (germline) tests are listed in the test directory for rare and inherited disease)
• NICE: Entrectinib for treating NTRK fusion-positive solid tumours
• NICE: Guidance relevant to lung cancer
• NICE: Larotrectinib for treating NTRK fusion-positive solid tumours

For patients

• Cancer Research UK: Tests for lung cancer