The Sequence 12/4-12/10
Decoding Lung Cancer: Genetics and Screening Guidelines
Image credit: American Lung Association Instagram
Decoding Lung Cancer: Genetics and Screening Guidelines
An estimated 2.2 million people are diagnosed with lung cancer globally each year. After speaking to a friend recently who knew not only the name of the targeted treatment his father had received for lung cancer, but the genetic biomarker the therapy was based on, I knew it was time to brush up on my own knowledge. Here is a rundown on the genetics of lung cancer, the guidelines for lung cancer screening based on risk assessment, and the treatments available. Unfortunately, it’s all too relevant; lung cancer remains the leading cause of cancer deaths in the U.S, taking 136,000 lives each year. Finally, of the 197,000 people who are diagnosed in the U.S each year, more are young women than ever before.
The genetics of lung cancer
The most common type of lung cancer is non-small cell lung cancer (NSCLC), and accounts for ~90% of all lung cancers. Most lung cancers are a subtype called carcinomas, which start in the cells that line the airways of the lungs. Although risk factors for lung cancer are both environmental and genetic, information on genetic susceptibility to lung cancer is limited and is still being understood through GWAS and case-control studies. Much of what we know is about the EGFR gene. Here’s why the EGFR gene is so important:
10-40% of NSCLC is associated with somatic pathogenic variants in EGFR
Somatic variants are genetic variants that were acquired over time and NOT from birth
Of those, 50-63% also carry the variant germline
Meaning, the genetic variants are present from birth
Individuals most commonly found to have EGFR mutations are female nonsmokers or former light smokers
Exon 20 variants account for approximately 1 in 30 lung cancer cases and are more commonly found in nonsmoking and Asian individuals
Other significant genetic biomarkers include genetic variants in HER2, ALK, MET (exon 14), ROS1 fusion, and BRAF (V600E).
Guidelines for lung cancer screening are expanding
Lung cancer is the leading cause of cancer deaths in the U.S and the leading cause of cancer-related death throughout the world. Additionally, more than half of all patients with lung cancer already have metastasis, or spread, at the time of diagnosis. All this to say that those that are at high risk of developing lung cancer are recommended to get screening earlier in order to detect it earlier, when treatment is most successful.
Despite the fact that EGFR as well as other genes are known common drivers of NSCLC, there are no current guidelines or recommendations for screening based on germline genetic findings. NCCN guidelines state ‘…several groups have identified genetic loci that may be associated with an increased risk of developing lung cancer’ and note that ‘Individuals with classic familial cancer susceptibility syndromes (such as retinoblastoma and Li-Fraumeni syndrome) have a substantially increased risk for lung cancer if they also smoke cigarettes', but do not make recommendations for screening. Note that the guidelines do discuss the increased risk for lung cancer if there is a history of lung cancer in a first degree biological relative (think: parent, child, sibling), but it is up to the healthcare provider to define ‘high risk’ based on family history.
Currently, ‘high risk’ individuals include those with several environmental and behavioral risk factors, namely age and pack-years of smoking. Lung cancer screening is recommended in patients 50 years of age or older with a 20 pack-year or more history of smoking cigarettes. The "pack year" measurement is used to quantify very heavy smoking and is calculated as such: someone who smoked two packs a day for 10 years is equivalent to 20 "pack years" and should be screened yearly starting at age 50.
The recommendations are based on recently updated new guidelines, released October 2023, which expand the age range for screening to those between 50 and 80. This significantly expands the pool of current and former smokers who should be screened for lunch cancer every year, starting high risk individuals at age 50 when previously the age range had been 55 to 74. The guidelines can be found here, and an easy-to-follow, patient-friendly version can be found here.
Treatment with precision medicine
Dr. Robert Smith, who leads early cancer detection science at the American Cancer Society (ACS) and is the lead author of the screening guideline report, says the expanded screening recommendations "could make a real difference in saving lives".
It’s true. There are treatments that have proven successful and received FDA approval, like Mobocertinib and Amivantamab, which both target the EGFR Exon 20 variant, and Enhertu which targets variants in HER2. Generally, these work by stopping the overgrowth of cancer cells, whether that be by blocking growth receptors or cell-to-cell signaling.
Finally, the use of liquid biopsy has allowed us to actually see the reduction of circulating tumor cells in the blood after treatment in order to confirm the treatment is working.
What’s the takeaway?
Given the high number of people lung cancer impacts, it’s find it important to have a grasp on what we know about the genetics, who should be screened, and what biomarkers we should be looking to for potential treatment. Although smoking tobacco is still the top risk factor for developing lung cancer, there are complex genetics at play in all populations, but especially in nonmokers and young women. I think there’s room for the guidelines to catch up to the known risks in individuals with family members who have had lung cancer (also considering environmental risk factors) at the very least. Lung cancer has a genetic component, and the guidelines and screening recommendations will grow and change as treatments evolve in the years to come.
Newsletter Sources:
https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf
https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/basics
https://www.cdc.gov/cancer/dcpc/resources/features/lungcancer/index.htm#:~:text=Fast%20Facts,people%20die%20from%20this%20disease.
https://www.nytimes.com/2023/10/12/well/live/lung-cancer-women-screening.html?campaign_id=18&emc=edit_hh_20231019&instance_id=105598&nl=well®i_id=196523837&segment_id=147808&te=1&user_id=bf1f00d650cbb110ffd44289d3b2d4b8
https://www.nccn.org/patients/guidelines/content/PDF/lung_screening-patient.pdf
https://www.genomeweb.com/genetic-research/study-links-lung-cancer-risk-genetic-variants-implicated-alternative-splicing?utm_newsletter_section=personalization-engine&utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Tues%20AM%202023-08-15&utm_term=GW%20Daily%20News%20Bulletin
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