Four Small Cell Lung Cancer Subtypes and Their Best Therapies

Walter Alexander

March 01, 2021

Researchers studying a large set of small cell lung cancer (SCLC) tumor samples have identified four SCLC subtypes, and they propose that matching baseline tumor subtypes to SCLC therapy may enhance the depth and duration of response.

Carl M. Gay, MD, PhD, of University of Texas MD Anderson Cancer Center in Houston, and colleagues conducted this research and described their findings in Cancer Cell.

The authors noted that survival rates in SCLC remain dismal despite recent modest gains in progression-free survival and overall survival achieved through adding immunotherapy to platinum-based frontline chemotherapy.

Based on transcription factors indicating which genes are activated, prior research had already identified three possible SCLC subtypes. Many SCLC tumors, however, do not fit into one of these three groups, the authors said.

Inflamed Gene Signature

The four groups were identified using tumor expression data and nonnegative matrix factorization from published sources on 81 SCLC patients, and then validated via the largest SCLC data set available (276 SCLC patients enrolled in the phase 3 IMpower133 trial).

The SCLC subtypes were defined largely by differential expression of transcription factors — subtype SCLC-A by ASCL1, subtype SCLC-N by NEUROD1, and subtype SCLC-P by POU2F3. The fourth subtype, SCLC-I, is characterized by low expression of all three transcription factor signatures and an inflamed gene signature with a high expression of multiple immune genes, including significantly greater levels of genes indicating the presence of CD8-positive cytotoxic T cells.

Because each subtype demonstrates unique vulnerability to investigational therapies, this subtype classification has significant clinical implications.

"We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients," the authors stated.

"Our paper shows that the inflamed group has a distinct biology and environment and tends to be more responsive to immunotherapy," study author Lauren Averett Byers, MD, also of the University of Texas MD Anderson Cancer Center, stated in a press release. "Identifying the inflamed group is very important because, so far, there have not been any validated biomarkers for small cell lung cancer that predict which patients get the most benefit from immunotherapy."

In samples from the other three subtypes, SCLC-A was most responsive to BCL2 inhibitors, SCLC-N to Aurora kinase inhibitors, and SCLC-P to PARP inhibitors.

Treatment Resistance

The tendency of SCLC to develop treatment resistance, even after an initial response, is a known challenge. Using single-cell RNA sequencing to evaluate tumor evolution, the authors observed a tendency of SCLC-A to switch to SCLC-I after chemotherapy treatment, a possible contributor to treatment resistance.

It will be necessary to verify the study findings through further investigations, particularly regarding the therapeutic vulnerabilities for each group.

"Now we can develop more effective strategies for each group in clinical trials, taking into account that they each have different biology and optimal drug targets," Byers said. "As a field, small cell lung cancer is about 15 years behind non–small cell lung cancer's renaissance of biomarkers and personalized therapies. This represents a huge step in understanding which drugs work best for which patients and gives us a path forward for personalized approaches for small cell lung cancer."

"Dr Gay's work is the latest in a growing series of exciting studies demonstrating the utility of defining subtypes of small cell lung cancer based on expression of master transcriptional regulators," commented Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, in an interview.

He added, "While tumors can evolve between some of these categories, the dominant subtype assignment influences therapeutic vulnerabilities. It is an exciting time for those of us engaged in small cell research. Subtyping should help guide more focused and successful clinical trials for patients with small cell lung cancer."

The authors disclosed multiple relationships with companies. The study was supported by the National Institutes of Health/National Cancer Institute, the University of Texas Southwestern and MD Anderson Cancer Center, and a variety of other governmental and nonprofit groups. Rudin is principal investigator of the NCI small cell lung cancer research consortium.

Cancer Cell. Published online January 21, 2021. Abstract

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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