Small cell lung cancer (SCLC), a rapidly progressing form of lung cancer affecting approximately 15% of lung cancer patients, has historically lagged behind non-small cell lung cancer (NSCLC) in terms of treatment advancements. However, recent research classifying subtypes of SCLC is bringing renewed hope for more effective and personalized treatment strategies. These advances promise to tailor therapies based on the unique characteristics of each subtype, potentially improving patient outcomes.
Distinguishing SCLC from NSCLC
While SCLC and NSCLC both originate in the lung, they possess distinct biological characteristics. According to Carl Gay, M.D., Ph.D., a thoracic/head and neck medical oncologist, SCLC does not share much in common with NSCLC other than arising from the lung. Unlike NSCLC, SCLC lacks targetable driver mutations. Instead, diversity in SCLC is driven by epigenetic factors, influencing gene expression through transcription factors and chemical changes to DNA.
Four Subtypes of SCLC
In 2021, researchers identified four subtypes of SCLC:
- SCLC-A
- SCLC-N
- SCLC-P
- SCLC-I
These subtypes are defined by the dominant transcription factor present in the tumor: ASCL1 (A), NEUROD1 (N), or POU2F3 (P). The fourth subtype, SCLC-I, is characterized by inflammatory features and the presence of immune cells within the tumor microenvironment. SCLC-A accounts for approximately half of SCLC cases, SCLC-N for about a fifth, and SCLC-P and SCLC-I each represent between 10-15% of cases.
Blood-Based Assays for Rapid Classification
Traditional methods of classifying SCLC subtypes required gene expression pattern data from approximately 1,300 genes, with a turnaround time of 7-10 days. To expedite this process, researchers developed blood-based assays that analyze methylation patterns of DNA. These assays leverage the fact that SCLC sheds circulating tumor cells and circulating tumor DNA (ctDNA) into the bloodstream. By examining methylation patterns associated with ctDNA, researchers can predict gene expression and classify tumors more rapidly.
Personalized Treatment Strategies
The classification of SCLC subtypes has the potential to guide treatment decisions and improve patient outcomes. For instance, immune checkpoint inhibitors appear to be more effective in patients with the SCLC-I subtype. Clinical trials are planned to assign patients to therapies based on their SCLC subtype, comparing these personalized approaches to the current standard of care. Scientists are also developing new targeted therapies specifically for SCLC, offering unprecedented response rates for a disease that has historically responded poorly to treatment.
The Future of SCLC Treatment
While these new therapies are still years away from becoming standard of care, they represent a significant step forward in the treatment of SCLC. Clinical trials will play a crucial role in connecting subtypes with specific treatments and confirming their safety and effectiveness. According to Dr. Gay, there are many new options that are going to be game changers in treating small cell lung cancer. He also noted that a lot of the data out there on survival and prognosis is outdated, so patients should focus on the last few years of progress and less on historical numbers. We’re finally at a point where we have both the ideas of how to treat small cell lung cancer and the tools to act on them.
