A team from Memorial Sloan Kettering Cancer Center (MSK) has identified a new, rare type of small cell lung cancer (SCLC) that has different pathologic characteristics to regular SCLC and primarily affects younger people who have never smoked.
“When we first encountered patients in the study, we were immediately aware of the fact that we were dealing with a highly unusual and possibly unique subtype of SCLC,” said Natasha Rekhtman, MD, PhD, an MSK pathologist specializing in lung cancer and the first author of the paper published in Cancer Discovery.
SCLC is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Yet the patients identified in the current study were never- or light-smokers and most were younger than generally seen in SCLC.
“The first patient we identified with atypical SCLC, and whose case led us to look for more, was just 19 years old and not a smoker,” said Charles Rudin, MD, PhD, deputy director of MSK’s Cancer Center and the study’s senior author.
“In addition, we were finding that these tumors lacked inactivation of RB1 and TP53—the genes that are almost invariably inactivated in SCLC. So, we suspected that these patients had a unique pathogenesis, but at the beginning we did not know what it was,” noted Rekhtman.
The team used next-generation sequencing to analyze tumor samples from 600 patients with newly diagnosed SCLC. Of these, just 20 (3%) had intact copies of RB1 and TP53.
The mean age at diagnosis among this atypical subset was 53 years compared with 67 years in the rest of the group, a statistically significant difference. In addition, 65% were never smokers, while the remaining 35% reported a history of only light smoking (less than 10 pack-years).
To determine the underlying genomic processes leading to atypical SCLC, the researchers carried out whole genome sequencing (WGS) on samples from 11 patients with sufficient residual DNA after targeted NGS. This confirmed the lack of pathogenic RB1 and TP53 alterations in all but one sample.
Surprisingly, they found that 10 of the 11 cases were associated with a phenomenon known as chromothripsis—massive, localized chromosome shattering—typically involving chromosomes 11 or 12. This resulted in extrachromosomal DNA amplification of CCND1 or co-amplification of CCND2, CDK4, and MDM2, which are key oncogenes controlling cell cycle and survival. Conversely, amplifications of these genes were seen only rarely in conventional SCLC.
At present, chromothripsis is established primarily using WGS, and therefore would not typically be detected during clinical target or “panel” NGS assays used in patient care.
“An important aspect of the study was to describe for the first time the feasibility of detecting chromothripsis in panel sequencing,” said Rekhtman. By comparing panel NGS results with gold-standard WGS the researchers identified features in panel sequencing that correspond to chromothripsis. “Although the sensitivity of this approach is approximately 75%, it has excellent specificity. In addition, our study describes several hallmark downstream consequences of chromothripsis that can be detected by targeted NGS and other methods, including high levels of amplification of CCND1, CDK4, and MDM2.”
It is unclear what causes chromothripsis in these patients – none had germ-line mutations or other potential “smoking gun” changes or molecular alterations previously associated with chromothripsis. “In general, in most other tumor types, the cause of chromothripsis remains unknown, and will remain the subject of future research,” Rekhtman remarked.
The study also looked at clinical outcomes and found that patients with atypical SCLC did not respond well to platinum-based chemotherapy – the standard first-line treatment for SCLC. Of the 15 patients with available data, 13% had a complete response to platinum-based systemic therapy and 20% had a partial response, which the researchers say is “well-below,” the historical expected response rates of around 70% for SCLC.
However, a subset of patients with chromothripsis-mediated SCLC appeared to derive particular benefit from temozolomide.
“It may be relevant that we found that chromothripsis-mediated SCLC appears to arise from the underlying lower-grade neuroendocrine tumors known as carcinoids,” said Rekhtman. “Temozolomide is known to be active in both SCLC and lung carcinoids; thus, this agent may be particularly suitable for addressing dual histologic characteristics in these patients.”
Rekhtman, Rudin and colleagues are now planning to continue to identify unusual patients with SCLC, and characterize their genomic, pathologic and clinical features. They will particularly focus on identifying most effective treatment strategies for these patients.
