RET-Positive Lung Cancer: Understanding its Impact on Non-Smokers

Some Facts About RET Fusion Positive NSCLC

RET-positive non-small cell lung cancer is caused by an abnormal re-arrangement or fusion of the RET gene, which codes for a tyrosine protein kinase cell membrane receptor. This alteration leads to abnormal activation of the cell membrane receptor, basically resulting in the “on-off” switch getting stuck in the “on” position and causing tumor growth.

RET gene fusions occur most commonly in lung cancer (non-small cell lung cancer), but other RET alterations like RET mutations are also common in inherited and sporadic medullary thyroid cancer, and can occur in other types of cancers like ovarian, breast, pancreatic, and colorectal cancers, among others.

RET lung cancer accounts for approximately 37,500 lung cancer cases worldwide and 4,000 cases in the U.S.

RET rearranged lung cancers are more frequent in lung cancers, and they occur when the RET gene joins another gene and creates a fusion that leads to uncontrolled cell growth and cancer. There are different types of RET rearrangements, and investigators are currently studying the characteristics of each one in cancer development and treatment.

The most common RET fusion gene partner is KIF5B, and the second most common is CCDC6.

One of the research projects that has been funded by Happy Lungs Project, led by Dr. John Heymach, is focused on the study of the variations in RET fusion partners and how these RET fusions may impact the sensitivity of these tumors to RET inhibition by RET targeted therapies. Establishing a comprehensive landscape of RET fusions and mutations in lung cancer that are associated with selective RET inhibitor resistance will allow clinicians to better determine effective and personalized therapeutic approaches.

Why do non-smokers get lung cancer?
Dr. John Heymach, M.D. Anderson Cancer Center

RET Lung Cancer and Non-Smokers

Some studies have shown that RET rearranged lung cancer patients had more poorly differentiated tumors and tend to be young female patients (≤ 60 years). There is also reported a higher frequency of female non-smokers harboring RET fusions.

In the publication by Wang et al. (1) the investigators showed that RET fusion non-small cell lung cancer patients presented more poorly differentiated adenocarcinoma lung cancer, meaning that the cancer cells looked abnormal and not arranged in the usual way under a microscope when compared to healthy normal cells.

They examined 936 RET fusion non-small cell lung cancer patients and showed that there is a tendency of these RET lung cancer patients to be younger (≤ 60 years; 72.7% of the patients in the study), never-smokers (81.8%) and to have smaller tumors (≤3 cm).

In 2020, Qiu et al. (2) reported that RET non-small cell lung cancer patients have unique genetic characteristics and poor prognosis are found in female patients with lung cancer harboring RET non-small cell lung cancer. As other studies have shown, they reported that RET lung cancer is more frequently found in women.

In a study by Feng et al. (3) involving 167 RET non-small cell lung cancer patients, authors found that RET rearrangement was common in females (65.1%) and never smokers (82.2%).

Genetic and Environmental Risk Factors Contributing to the Development of Lung Cancer in Non-Smokers

According to the American Cancer Society, in the U.S. 20 percent of lung cancers occur in people who never smoked or smoked fewer than 100 cigarettes in their lifetime. Lung adenocarcinoma is the most common lung cancer diagnosed in non-smokers.

Investigators are currently studying the risk factors of lung cancer in non- or never-smokers, but it seems that the cause may be a combination of factors rather than a single cause.

One of the main factors can be a genetic alteration in the tumor, also known as a “somatic” mutation or alteration (meaning, mutations that may occur in a cell that are not inherited,) that drives the development of cancer. Besides RET rearrangements, EGFR, ALK, and ROS1 somatic alterations have been more frequently found in non-smoker lung cancer patients. If any of these somatic alterations are found, then treatment with a targeted therapy – rather than chemotherapy – is preferred.

A large epidemiologic study by Zhang et al.(4) characterized lung cancer in people with no history of smoking. The study found that a majority of these lung cancer tumors arise from the accumulation of mutations caused by natural processes that happen inside the body. They also described different subtypes of lung cancer in non-smokers that could potentially have different approaches for treatment.

Besides the genetic factors, there are other environmental factors that can increase lung cancer risk, such as exposure to secondhand tobacco smoke, exposure to radon gas, or air pollution. Repeated exposure to carcinogens such as asbestos or heavy metals can also increase the risk of developing lung cancer.

Treatment of Lung Cancer in Non-Smokers

Lung cancers in non-smoker patients frequently present a somatic alteration such as RET, EGFR, ALK or ROS1. A somatic alteration is a genetic mutation that occurs in a cell after conception, driving disease like cancer without being inherited or passed to offspring. If any of these somatic alterations are found, the treatment with a targeted therapy (specific tyrosine kinase inhibitors rather than chemotherapy) is preferred for lung cancers. For the treatment of RET-positive advanced lung cancer, selective RET inhibitors are the preferred first-line treatment option.

Immunotherapy, which involves the use of the immune system cells to fight cancer, has revolutionized lung cancer treatment – but some clinical studies have shown that the treatment tends to work better in smokers than in non-smokers (5). Some explanations of this are that non-smoker tumors present lower immunogenicity, with lower tumor mutation burden and low PD-L1 expression (a molecule that acts as a “brake” to keep the body’s immune responses and is the target of some immune checkpoint inhibitors). If the tumor has low PD-L1 expression, then immunotherapy is not likely to help.

In conclusion, RET-positive lung cancer stands out with its distinct characteristics, particularly in non-smokers, younger patients and women. Understanding these unique genetic markers not only sheds light on the causes of this disease but also paves the way for more effective, personalized treatments.

As research continues to evolve, there’s growing hope for targeted therapies that can improve outcomes and enhance the quality of life for those affected by RET-positive lung cancer. For patients and their loved ones, staying informed about these advancements is crucial in navigating the journey with this complex disease.

For current RET-positive lung cancer patients seeking cutting-edge treatments, exploring ongoing clinical trials could offer new opportunities for personalized care. Learn more and find a match here.

Newly diagnosed with RET-positive cancer? You might also be interested in Steps to take after a RET-positive lung cancer diagnosis.

RET Cancer Links and References

1. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012;30(35):4352-4359. doi:10.1200/JCO.2012.44.1477
2. Qiu Z, Ye B, Wang K, Zhou P, Zhao S, Li W, Tian P. Unique Genetic Characteristics and Clinical Prognosis of Female Patients with Lung Cancer Harboring RET Fusion Gene. Sci Rep. 2020 Jun 25;10(1):10387. doi: 10.1038/s41598-020-66883-0. PMID: 32587276; PMCID: PMC7316706.
3. Feng J, Li Y, Wei B, Guo L, Li W, Xia Q, Zhao C, Zheng J, Zhao J, Sun R, Guo Y, Brcic L, Hakozaki T, Ying J, Ma J. Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients. Transl Lung Cancer Res. 2022 Apr;11(4):617-631. doi: 10.21037/tlcr-22-202. PMID: 35529790; PMCID: PMC9073740.
4. Zhang T, Joubert P, Ansari-Pour N, et al. Genomic and evolutionary classification of lung cancer in never smokers. Nat Genet. 2021;53(9):1348-1359. doi:10.1038/s41588-021-00920-0
5. de Alencar VTL, Figueiredo AB, Corassa M, Gollob KJ, Cordeiro de Lima VC. Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy. Front Immunol. 2022 Aug 24;13:984349. doi: 10.3389/fimmu.2022.984349. PMID: 36091058; PMCID: PMC9448988.
6. CDC.gov
7. https://www.yalemedicine.org/conditions/lung-cancer-in-nonsmokers
8. https://www.cancer.org/cancer/latest-news/why-lung-cancer-strikes-nonsmokers.html
9. https://www.cancer.gov/news-events/press-releases/2021/lung-cancer-never-smokers