MSK Scientists Identify Rare (Rb-Proficient) Subtype of Small Cell Lung Cancer

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MSK pathologist Natasha Rekhtman and physician-scientist Charles Rudin

MSK pathologist Natasha Rekhtman and physician-scientist Charles Rudin

Researchers at Memorial Sloan Kettering Cancer Center (MSK) have used DNA testing and other methods to identify a previously uncharacterized subtype of small cell lung cancer (SCLC). As they report in a study published July 6, 2022, in the journal Clinical Cancer Research, the new subtype may be vulnerable to specific targeted therapies.

According to Natasha Rekhtman, the MSK pathologist who co-led the study, what distinguishes the subtype is the presence of a normal version of a protein called retinoblastoma (Rb). “The conventional wisdom in the field is that mutation and loss of Rb is a key step in the development of small cell lung cancer,” Dr. Rekhtman says. “But what we found is that about 6% of SCLC cases retain a normal version of the Rb protein.”

This Rb protein, she explains, is associated with increased aggressiveness and resistance to conventional chemotherapy. At the same time, these “Rb-proficient tumors” have several distinct molecular characteristics that may make them vulnerable to specific targeted therapies, including drugs called CDK4/6 inhibitors. These FDA-approved agents are already being used to treat other types of cancer and therefore could be a possible treatment approach.

Because of its clear link with this subtype, Rb status could potentially be used as a biomarker to identify this subset of tumors, allowing doctors to tailor treatment accordingly. However, there are challenges to identifying Rb status with conventional methods, so other approaches are needed, as the authors explain.

Finding Hidden Differences in Small Cell Lung Cancer

Dr. Rekhtman and her colleagues analyzed 208 samples of SCLC tumors with MSK’s standard genetic test called MSK-IMPACT® and immunohistochemistry — a type of tissue staining that can detect the physical presence of the Rb protein in the tumor.

They found that 14 of 208 SCLC samples, or 6%, contained a normal Rb protein. The remaining 194/208 (94%) SCLC samples did not contain a normal Rb. Of these, 184 tumor samples had complete loss of Rb, while 10 samples had a present but mutated Rb protein. This mutated Rb protein was nonfunctional, and the tumors were otherwise identical to those entirely lacking Rb.

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Rb as a Biomarker

In order for Rb status to be a useful biomarker for clinicians, it must be technically feasible to measure it. Dr. Rekhtman’s team showed that conventional genetic testing with MSK-IMPACT may miss certain mutations in the RB1 gene because of where these mutations appear (in the introns, or noncoding regions, versus the exons, or coding regions, of the gene). For example, 29% of the 184 samples with complete loss of Rb had no identifying mutation by MSK-IMPACT testing. Identifying these hidden mutations therefore requires additional, manual effort — but it could well be worth the extra work, say the researchers.

“Rb-proficient tumors are very aggressive,” says Charles Rudin, a physician-scientist at MSK who is the co-corresponding author on the study. “If it’s confirmed that these tumors can be targeted with CDK4/6 inhibitors, that would be a very exciting development as this would offer a new treatment possibility for these patients.”

The scientists are planning further laboratory studies and clinical trials of these drugs for patients with this subtype of Rb-proficient tumors.

 

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This work was supported by the Ning Zhao and Ge Li Family Initiative for Lung Cancer Research and New Therapies, the Fiona and Stanley Druckenmiller Center for Lung Cancer Research, the National Cancer Institute (grants U24CA213274, R35CA263816, P30 CA008748), the Molecular Diagnostics Service in the Department of Pathology at MSK, and the Marie‐Josée and Henry R. Kravis Center for Molecular Oncology.