Lung Cancer Molecular Biomarkers
Mutation in epidermal growth factor receptor (EGFR) occurs in ~35% of non-small cell lung cancer (NSCLC) patients of East Asian origin and ~16% in Western populations 1,2. Multiple in-frame deletions in exon 19 and the p.L858R missense mutation in exon 21 comprise 90% of the mutations detected 3.
Studies have confirmed EGFR mutations as a predictive biomarker of treatment response to tyrosine kinase inhibitors (TKIs), Gefitinib and Erlotinib 4,5. As such screening for EGFR mutations in NSCLC patients is deemed necessary before offering these drugs.
Most of the patients who initially responded to Gefitinib and Erlotinib will eventually develop resistance to the drugs. Recently, a third-generation EGFR TKI, which is effective in tumours harbouring the p.T790M EGFR mutation (~50–60% of lung cancer patients 6,7,8), was approved in Australia for patients with NSCLC harbouring the EGFR T790M mutation following progression on an EGFR TKI 9.
In line with the above, a new Medicare item was recently introduced (Item 73351) to test tumour tissue that is derived from a new sample from a patient with locally advanced (Stage IIIb) or metastatic (Stage IV) NSCLC, who has progressed on or after treatment with an EGFR TKI. The test is to be requested to determine the eligibility for accessing “Osimertinib” under the Pharmaceutical Benefits Scheme (PBS) criteria.
Lung cancer therapy continues to follow the genomic testing paradigm. New guidelines recommend ROS1 and PD-L1 testing for all patients with NSCLC at baseline before treatment.
In NSCLC patients, accurate detection of both KRAS and BRAF mutations is therefore of high clinical importance for therapy selection 10,11.
References:
1. Mok TS et al., (2009) N Engl J Med 361(10):947–957.
2. Rosell R et al., (2009) N Engl J Med 361(10):958–967.
3. Pao W Miller VA. (2005) J Clin Oncol 23:2556-2568.
4. Yang CH et al., (2008) J Clin Oncol 26(16):2745–2753.
5. Sequist LV et al., (2008) J Clin Oncol 26(15):2442–2449 .
6. Thress K et al., (2015) Lung Cancer 90:509–515.
7. Wu Y et al., (2017) Br J Cancer 116:175–185.
8. Yu H et al., (2013) Clin Cancer Res 19:2240–2247.
9. AstraZeneca. (2016) TAGRISSO (osimertinib mesilate) product information.
10. Linardou H et al., (2008) Lancet Oncol 9:962–972.
11. Ohashi K et al., (2012) Proc Natl Acad Sci USA 109:E2127–2133.
12. Chao M & Gibbs P (2009) J Clin Oncol 27:e279–e280.
13. Haselmann V et al., (2018) Clinical Chemistry 64 (5):830–842.
Somatic Mutation | Solid Tissue Molecular Profiling in Lung Cancer
Lung Cancer Solid Tissue Gene Panel (DNA)
Mutation in EGFR occurs in ~35% of NSCLC patients of East Asian origin and ~16% in Western populations1,2,3. EGFR mutations are predictive biomarkers of treatment response to tyrosine kinase inhibitors (TKIs), Gefitinib, and Erlotinib4,5. A third-generation EGFR TKI and is effective in patients with tumours harbouring the resistance p.T790M EGFR mutation (~50-60% of lung cancer patients6,7,8) following progression on EGFR TKIs9,10. Detection of KRAS or BRAF mutations (observed in 2-4% of NSCLC patients) is considered a negative predictor of response to anti-EGFR treatment and is associated with poorer survival11,12,13.
Genes sequenced in this panel include:
| EGFR | BRAF |
| KRAS | PIK3CA |
| NRAS | AKT1 |
Test cost: Medicare rebate available if criteria are met.
MET Exon 14 skipping (RNA testing)* is now available.
From November 2022, testing for MET exon 14 skipping mutation (3-4%) should be performed for patients with all types of NSCLC to determine the eligibility for MET inhibitors capmatinib and tepotinib14.
*Provided suitability of sample for testing.
Test cost: Medicare rebate available if criteria are met.
RNA Fusion Test Panel in Solid Tumours
RNA-based fusion testing is recommended for patients with no other oncogenic driver detected by DNA. Approximately 5% of NSCLC patients display a rearrangement in ALK (2-5%), while ROS proto-oncogene 1 (ROS1) and RET proto-oncogene (RET) rearrangements are observed in 1-2% of patients. With variable prevalence, the presence of neurotrophic tyrosine receptor kinase (NTRK) fusions provides a rationale for genomic testing for all solid tumours for patients who may be candidates for TRK-inhibitor therapy. NTRK1-3 fusion is described in 90- 100% of secretory salivary gland carcinomas (also known as MASC). They may also be present in 2-15% of papillary thyroid carcinomas and in less than 1% of other head and neck tumours14.
Genes sequenced in this panel include:
| RET | ROS-1 |
| ALK | NTRK1 or NTRK2 or NTRK3 |
Test cost: Medicare-rebatable for lung cancer only.
When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Fill out our Somatic Mutation testing request form and tick the Somatic Mutation test panel required.
Turnaround Time: 5-7 business days from the sample receipt date.
Specimen Required: Fresh formalin-fixed paraffin-embedded (FFPE) of 5-10 μm thickness from the tumour tissue.
Test Cost:
Lung Panel DNA (EGFR, KRAS, NRAS, BRAF, PIK3CA & AKT1): Medicare rebate available if criteria is met. If criteria is not met, there is an out-of-pocket fee of $400.
MET Exon 14 skipping (RNA testing): Medicare rebate available if criteria is met. If criteria is not met, there is an out-of-pocket fee of $400.
RNA Fusion Lung Panel: Medicare-rebatable for lung cancer only.
A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<5%).
References
1. Mok TS et al., (2009) N Engl J Med 361(10):947–957.
2. Rosell R et al., (2009) N Engl J Med 361(10):958–967.
3. Pao W, Miller VA. (2005) J Clin Oncol 23:2556-68.
4. Yang CH et al., (2008) J Clin Oncol 26(16):2745–2753.
5. Sequist LV et al., (2008) J Clin Oncol 26(15):2442–2449.
6. Thress K et al., (2015) Lung Cancer 90:509-515.
7. Wu Y et al., (2017) Br J cancer 116:175-185.
8. Yu H et al., (2013) Clin Cancer Res 19:2240–2247.
9. AstraZeneca. (2016) TAGRISSO (osimertinib mesilate) product information.
10. John T et al., (2017) Asia-Pacific J of Clin Oncol 13:296-303.
11. Linardou H et al., (2008) Lancet Oncol 9:962-72.
12. Ohashi K et al., (2012) Proc Natl Acad Sci U S A 109:E2127-33.
13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Non-small cell lung cancer (7 April 2017).
14. Malone E et al., Genome Medicine (2020). Molecular profiling for precision cancer therapies 12:8.
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Aspect ctDNA Liquid Biopsy in Lung Cancer
Australian recommendations along with the NCCN Guidelines advise the use of liquid biopsy for lung cancer patients as an alternate for tissue in initial EGFR T790M testing 1,2. However, if the plasma is negative, then a tissue biopsy is recommended, if feasible.
Lung Cancer ctDNA Gene Panel
The Aspect Liquid Biopsy lung cancer ctDNA gene panel can detect actionable DNA alterations specific to lung cancer as detailed below.
Gene panel includes:
| EGFR (incl. T790M): 43 mutations across exon 19 indels, exon 20 insertions, and substitutions across exons 18, 19, 20, and 21 |
| KRAS: 14 mutations across exon 2 and 3 |
| BRAF: 4 mutations across exon 11 and 15 |
| PIK3CA: 4 mutations across exon 9 and 20 |
When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Health practitioners can order Aspect Liquid Biopsy for cancer patients using the Aspect Liquid Biopsy request form.
Turnaround Time: 5–7 business days from the sample receipt date.
Specimen Required: This test requires TWO 10ml blood samples (special tubes), which can be taken at any of our collection centres.
Test Cost: No Medicare rebate available. An out-of-pocket fee of $550 applies.
A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<2%).
References
1. John T et al., (2017) Asia-Pacific J of Clin Oncol 13:296–303.
2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Non-small cell lung cancer (7 April 2017).
3. Premarket approval P150044 d Cobas EGFR MUTATION TEST V2. Cited 2016; Available from: https://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfpma/pma.cfm?id¼P150044.
4. Calapre L et al., (2017) Cancer Letters 404:62–69.
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The content on our Molecular Cancer Services page is written by Associate Professor Mirette Saad, National Director of Molecular Genetics at Australian Clinical Labs.
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Assoc. Prof. Mirette SaadMBBS (Hons), MD, MAACB, FRCPA, PhD |
Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Director of Molecular Genetics at Australian Clinical Labs. She has a Fellowship with honours in Chemical and Molecular Pathology, with Microbiology sub-speciality, from Suez Canal University, Egypt. A/P Saad received her NHMRC sponsored PhD degree in Cancer Genetics from Melbourne University and Peter MacCallum Cancer Institute. Along with her teaching and research roles, A/P Saad is a registered medical practitioner with AHPRA, a Chemical Pathology Fellow (FRCPA) at the Royal College of Pathologists of Australasia and a Member of the Australasian Association of Clinical Biochemists (MAACB). She is a Chair of the RCPA Chemical Pathology Advisory Committee, Member of the RCPA Genetic Advisory Committee, AACB and a Chair of the Precision Medicine Services at Australian Clinical Labs. At Clinical Labs, A/Prof Mirette Saad leads the Molecular Genetic testing for non-invasive prenatal testing (NIPT), antenatal screening, personalised drug therapy and cancer.