Understanding how and why RET-positive non-small cell lung cancer (NSCLC) spreads could be the key to transforming how to treat lung cancer and improving outcomes. Discover how this specific cancer type behaves and why understanding its spread is crucial for effective, personalized care.
RET-Positive Lung Cancer is a Type of Non-Small Cell Lung Cancer
RET-positive NSCLC is a type of cancer that is characterized by abnormal gene alterations or gene rearrangements that promote oncogenesis or tumor progression. The most common alterations in RET lung cancer are RET gene fusions, which occur when the RET gene joins another gene and creates a fusion that produces uncontrolled tumor growth.
There are different types of RET fusions depending on the RET gene partner; the gene KIF5B is the most common fusion partner, and the gene CCDC6 is second most common in lung cancer. In addition to this, there are other RET alterations such as gene point mutations that can also cause tumor growth and can be also found in other types of cancers such as medullary thyroid cancer, ovarian, pancreatic, breast, salivary and colorectal. RET fusions or rearrangements appear in about 2% of adenocarcinoma non-small cell lung cancer patients, and they are more prevalent in young patients and patients who never smoked (3-5).
Non-small cell lung cancer accounts for 80% to 85% of all lung cancer cases. This type of cancer can be subdivided in adenocarcinoma, squamous cell carcinoma, and large cell carcinoma – depending on the type of cell of origin. Adenocarcinoma is the most common type of lung cancer and it starts from the epithelial cells of the lining of the lung. The vast majority of RET lung cancers are adenocarcinomas of the lung.
6 Steps: How Non-Small Cell Lung Cancer Spreads
For cancer cells to spread and reach other parts of the body, a series of events occur:
- Local invasion of tumor cells into nearby lung tissues
- Entrance into the circulatory and lymphatic systems (lymph nodes)
- Traveling and survival through the circulatory and lymphatic system to other parts of the body
- Extravasation, or exit from the bloodstream into other normal tissue
- Survival and proliferation causing tumor growing in the normal tissue
- Growing new blood vessels to provide a blood supply to the metastatic tumor
It is important to note that metastatic cancer cells can also remain dormant or inactive at a distant site for a long period of time before they begin to grow again. Investigators are studying these latent cancer cells to design new effective therapeutic options.
Common Sites of Spread in Non-Small Cell Lung Cancer
Tumors can spread to almost any part of the body, but different types of cancer are more likely to spread to certain parts than others. For non–small cell lung cancer, the most common sites are the nearby lymph nodes, brain, bone, liver, adrenal glands, and the other lung.
What Does it Mean When Cancer Spreads (Metastasis)?
The process by which cancer cells disseminate and spread to other parts of the body is called metastasis. When this occurs the cancer is staged as stage IV lung cancer.
The cancer where the metastasis started is called the primary cancer. Unlike normal cells, lung cancer cells of a primary tumor have the ability to enter the bloodstream or lymph system and spread to nearby or distant organs of the body.
The Journey of Cancer Cells : How does Non-Small Cell Lung Cancer Spread?
Metastasis is a complex process by which the cancer cells from a primary tumor spread to other parts of the body. To successfully spread, the metastatic cancer cells acquire features that allow them to disseminate, invade, and continue tumor growth in other parts of the body.
In 2000, professors Robert Weinberg, PhD, FAACR, from the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, and Douglas Hanahan, PhD, FAACR, from EPFL, the Swiss Federal Institute of Technology in Lausanne, described in the ‘Hallmarks of Cancer” publication (6) the complex six biological steps of the development (or acquired capabilities) of human tumors, including tissue invasion and metastasis. Metastasis is a very complex biological process which involves several processes and classes of proteins in the cancer cells and tissues that are altered and allow the abnormal cells to acquire invasive and metastatic potential to promote tumor dissemination and invasion. Characterizing these complex processes can allow the development of effective lung cancer treatment strategies to tackle metastatic disease.
How do Genetic Mutations, like RET Mutations, Impact Lung Cancer Spread?
RET fusion-positive lung non–small cell lung cancers patients often present brain metastasis (approximate 46% of the patients report brain metastasis in their lifetime) (7). FDA-approved targeted therapy based on specific and selective RET inhibitors such as selpercatinib or pralsetinib showed good brain penetrance and activity in patients with brain metastases with intracranial response rates of 70-91% in RET non–small cell lung cancer patients (8-9).
The number of metastatic non–small cell lung cancer patients with brain metastasis was small in these studies. Therefore, these selective RET inhibitors and other classes of novel targeted therapy agents for lung cancer treatment continue to be investigated in clinical trials to treat metastatic disease.
What are the Symptoms of Metastatic Lung Cancer?
Metastatic non-small cell lung cancer (NSCLC) often progresses silently, without causing noticeable symptoms in the early stages. When symptoms do appear, they are frequently mistaken for those of other common health conditions, such as a persistent cough, chest pain, or shortness of breath / trouble breathing. These symptoms are easily overlooked or attributed to less serious issues like respiratory infections.
The vague and non-specific nature of these early signs often results in patients being diagnosed only after lung cancer has metastasized, at which point treatment options may be more limited and less effective. Early detection through regular screening, particularly for high-risk individuals, is crucial for improving outcomes in lung cancer cases.
As the cancer spreads to specific parts of the body, additional symptoms may develop. For instance, if lung cancer metastasizes to the bones, it can cause significant pain, particularly in the back, ribs, or hips. When the cancer spreads to the liver, patients might experience swelling or discomfort in the abdominal area, jaundice (yellowing of the skin and eyes), or even unexplained weight loss. If the cancer reaches the adrenal glands, it can lead to hormonal imbalances, resulting in symptoms such as fatigue, muscle weakness, low blood pressure, and a loss of appetite.
Lung cancer can also spread to the lymph nodes, leading to noticeable lumps or swelling in the neck, underarms, or chest area. Metastasis to the brain can cause neurological symptoms like headaches, seizures, difficulty with balance, or changes in vision or speech. Imaging tests, such as CT scans or MRIs, are crucial in detecting the spread of lung cancer to these areas and assessing the extent of metastasis.
Understanding your risk factors, such as a history of smoking or exposure to environmental toxins, can help in early detection and prevention. If you have known risk factors, your doctor may recommend regular imaging tests to monitor for signs of metastasis. Additionally, clinical trials offer promising new treatments for metastatic lung cancer, which may help manage symptoms and improve outcomes. If you are experiencing new or worsening symptoms, it is important to report them to your doctor or treatment team as soon as possible. Early detection and intervention can make a significant difference in managing metastatic lung cancer and improving your quality of life.
Always tell your doctor or treatment team if you’re worried about a symptom.
What is the Role of the Immune System in Controlling Lung Cancer Spread?
The immune system plays a crucial role in controlling the spread of lung cancer, particularly through its interaction with lymph nodes. When lung cancer start to spread, it often travels to nearby lymph nodes, which act as a key defense line. The immune system works to identify and attack cancer cells in these lymph nodes, attempting to prevent the disease from spreading to other parts of the body. However, if the immune response is weakened or the cancer cells manage to evade detection, lung cancer can continue to spread, making it harder to treat. Strengthening the immune system through therapies and interventions can be an important strategy in controlling the spread of lung cancer and improving patient outcomes.
The immune system protects the body against pathogens and infections. It also can help to detect and kill cancer cells along the metastatic journey.
During the metastatic journey, cancer cells are exposed and closely interact with the immune cells in the primary lung cancer tumor microenvironment and also during the steps from the primary tumor to the distant site. Immune cells may recognize the cancer cells, attack specific cancer cells, or restrict tumor growth but some specific cancer cells may overcome the detection and escape the control by the immune system.
The mechanisms by which the cancer cells may evade the immune control are complex and involve several immune cell types (T cells, NK cells, macrophages, dendritic cells, etc). Moreover, the cancer cells that survive and reach a distant site have to find strategies to avoid the new tissue immune cell populations. Occasionally, some of these cells find the way to persist in a quiescent or dormant state for long periods of time evading the immune cell attack.
Scientists are investigating the mechanisms by which cancer cells are able to evade the immune system and are also characterizing these dormant metastatic Non-Small Cell Lung Cancer cells with the aim to design new therapeutic interventions to treat cancer metastatic disease.
Find more information about: radiation therapy, RET clinical trials, targeted therapy drugs, and resistance to cancer treatment.
References and Resources
- https://www.cancer.gov/types/metastatic-cancer
- https://www.cancer.org/cancer/types/lung-cancer/about/what-is.html
- Drilon, A., et al., Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol, 2018. 15(3): p. 150.
- Hess, L.M., et al., Characteristics and outcomes of patients with RET-fusion positive non-small lung cancer in real-world practice in the United States. BMC Cancer, 2021. 21(1): p. 28.
- Parimi V, Tolba K, Danziger N, et al. Genomic landscape of 891 RET fusions detected across diverse solid tumor types. NPJ Precis Oncol. 2023;7(1):10. Published 2023 Jan 23. doi:10.1038/s41698-023-00347-2
- Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. doi:10.1016/s0092-8674(00)81683-9
- Drilon A, Lin JJ, Filleron T, et al. Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers. J Thorac Oncol. 2018;13(10):1595-1601. doi:10.1016/j.jtho.2018.07.004.
- Subbiah V, Gainor JF, Oxnard GR, Tan DSW, Owen DH, Cho BC, Loong HH, McCoach CE, Weiss J, Kim YJ, Bazhenova L, Park K, Daga H, Besse B, Gautschi O, Rolfo C, Zhu EY, Kherani JF, Huang X, Kang S, Drilon A. Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung CancerS on the LIBRETTO-001 Trial. Clin Cancer Res. 2021 Aug 1;27(15):4160-4167. doi: 10.1158/1078-0432.CCR-21-0800. Epub 2021 Jun 4. PMID: 34088726; PMCID: PMC8447251.
- Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial. Griesinger, F. et al. Annals of Oncology, Volume 33, Issue 11, 1168 – 1178
- https://www.cancerresearchuk.org/about-cancer/lung-cancer/metastatic/symptoms
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