Lung cancer

Traditionally, lung cancer has been divided into small cell and non-small cell types. The latter was further divided into non-squamous and squamous subtypes, with several histological variants within both of these.

Lung cancer is relatively rare before the age of 40, with incidence rising steadily until 80 (females) or 85 years (males) before plateauing. Although currently the commonest cause of cancer death in the UK, the incidence of lung cancer is falling in males and plateauing in females.

The vast majority of cases are associated with smoking. The strength of this association, however, varies according to genetic subtype. For example, the presence of an EGFR mutation enriches for younger, female and never/ex/light-smokers as well as for East Asian ethnicity. The presence of ALK fusions enriches for younger, never/ex/light-smoker patients without enriching for ethnicity. Nonetheless, clinical factors alone are not a reliable guide to driver-mutation status.

Somatic genomics and lung cancer

Advances in genomic sequencing technologies have allowed identification of the genetic drivers behind lung cancer subtypes. A characteristic spectrum of mutations has emerged in both adenocarcinomas and squamous cell cancers, with improved understanding of small cell cancers too.

• In European populations, more than half of lung adenocarcinomas have an identifiable ‘driver’ genomic alteration, with an even higher percentage in East Asian populations. The commonest alterations are found in the KRAS gene (around one-quarter of all adenocarcinomas), with EGFR variants (10%–20% in Europeans, 30%–50% in East Asians) and ALK fusions (4%–5%) being the next most common. Variants in BRAF, MET, PIK3CA and NRAS, and fusions of ROS1, NTRK and RET make up the majority of the rest. Identification of a sensitising driver mutation may have implications for therapy and prognosis.
• These drivers are usually absent in squamous cell cancers. However, in those who are never/ex-/light-smokers they may be present, and such patients may be tested. In those who are current or ex-heavy smokers, identifiable drivers include amplifications of FGFR1, PIK3CA, SOX2 or MET or variants in NRF2, AKT1, DDR or BRAF. There are currently no formal NICE recommendations in lung cancer for the use of drugs that target alterations in these genes*.
• The genetic landscape of small cell cancers is less well understood, but there is interest not only in genetic alterations but also epigenetic modification of genes (for example, gene silencing through promoter hypermethylation).

*In some parts of the UK, combination therapy including a BRAF inhibitor has been permitted for BRAF-positive metastatic lung cancer (non-small cell) instead of chemotherapy to reduce risk of immunosuppression as an interim measure during the Covid-19 pandemic.

Constitutional (germline) genetics and lung cancer

In contrast to our understanding of somatic (tumour) genetic alterations, inherited genetic factors in lung cancer are less well understood. Part of the difficulty is that smoking behaviour, the largest attributable cause of lung cancer, can also be familial, so careful adjustment is needed.

• Several GWAS (genome-wide association studies) have suggested susceptibility loci at chromosome 15q25.1 containing the nicotinic acetylcholine receptor genes (CHRNA5–CHRNA3). These genes may modify smoking behaviour, so the mechanistic link to lung cancer is uncertain. Other studies have identified loci at 5p15 (containing the telomerase (TERT) gene). Overall, the effect of such variants is small.
• Rare families with constitutional (germline) activating variants in EGFR gene (including T790M) have been identified and associated with an increased risk of lung cancer.

Lung adenocarcinoma (particularly broncho-alveolar subtypes) at a young age may also be part of the broad tumour spectrum of the cancer predisposition Li-Fraumeni syndrome, caused by constitutional (germline) pathogenic variants in the TP53 tumour suppressor gene. Patients/families meeting Chompret criteria should be referred to the local clinical genetics service for consideration of genomic testing.

• If a somatic (tumour) driver mutation is identified in an individual with lung cancer, it may have implications for the choice of treatment for their current cancer. For more on this, see our ‘In the Clinic’ articles on the following results scenarios:
  • Results: Patient with lung cancer (non-small-cell) – somatic ALK rearrangement identified
  • Results: Patient with lung cancer (non-small-cell) – somatic BRAF variant identified
  • Results: Patient with  lung cancer (non-small-cell) – somatic EGFR variant identified
  • Results: Patient with lung cancer (non-small-cell) – somatic ROS1 rearrangement identified

For clinicians

• ESMO: Consensus guidelines for treatment of advanced lung cancer (2020) (includes recommendations for molecular testing and treatment) (PDF, 71 pages)
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: NHS England interim treatment options during the COVID-19 pandemic
• NICE: Guidance relevant to lung cancer (many guidelines related to treatments following somatic (tumour) molecular testing)
• World Health Organisation: The 2015 Classification of Lung Cancer (PDF, 18 pages)

References:

• Hirsch FR, Suda K, Wiens J and others. ‘New and emerging targeted treatments in advanced non-small cell lung cancer‘. The Lancet 2016: volume 388, issue 10,048, pages 1,012–1,024. DOI: 10.1016/S0140-6736(16)31473-8

For patients

• Cancer Research UK: Lung cancer resources and organisations