Molecular Profiling Reveals Potential Targets in SCLC, Lung NETs

Stephen V. Liu, MD

Molecular profiling has revealed several tumor markers that could be utilized as therapeutic targets for patients with small cell lung cancer (SCLC) or lung neuroendocrine tumors (NETs), according to a presentation at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.¹

The level of gene alterations and protein overexpression observed in the analysis of more than 600 tumor samples highlights the heterogeneous nature of SCLC and NETs. For the two populations, the only consistent highly expressed alteration was found in TP53, with unique drivers identified in each histology. Mutations in EGFR, BRAF, MET, and FGFR2 were among the most promising alterations identified, since therapies targeting these alterations are available, the authors of the study wrote.

"Historically, there has been a lack of clarity surrounding the role of molecular profiling in managing lung NETs and SCLC, due in part to oncologists' limited experience with these less common tumors," senior study author Stephen V. Liu, MD, assistant professor of Medicine in the Division of Hematology/Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center, said in a statement. "Our data support the use of comprehensive molecular analysis for a broader subset of patients with lung tumors. In particular, mutations in EGFR, BRAF, MET, and FGFR2 may have important therapeutic implications for patients with these tumor subtypes."

The analysis examined 607 samples, 375 of which were SCLC and 232 were lung carcinoid, atypical carcinoid, or large-cell NETs. Caris Life Sciences conducted the biomarker testing using its own multiplatform test that combined DNA sequencing, immunohistochemistry (IHC), and in situ hybridization (ISH).

For patients with NETs, several potential therapeutic targets were identified. Next-generation sequencing (n = 32) and Sanger sequencing (n = 68) uncovered alterations in TP53 (34%), PTEN (9%), HRAS (7%), ATM, KRAS, and FGFR2 (5-6% each). Additionally, alterations in APC, EGFR, HNF1A, JAK3, KDR, MLH1, PIK3CA and RB1 were identified in 3% of patients each.

ISH testing identified amplifications in EGFR (12%), cMET (6%), and HER2 (3%) and an ALK translocation in 1 patient (2%). IHC revealed overexpression of cKIT (37%), RRM1 (28%), TOP2A (48%), TOPO1 (43%), and TS (25%). Low expression of PTEN was noted in 36% of patients.

For patients with SCLC, a wide spectrum of potential targets was identified. Next-generation (n = 65) and Sanger (n = 100) sequencing revealed mutations in TP53 (57%), RB1 (11%), ATM, cMET, PTEN (6-7%), BRAF, SMAD4, and KRAS (3-4% each). Other alterations were noted in 1-2% of patients in ABL1, APC, CTNNB1, EGFR, FBXW7, FGFR2, HNF1A, HRAS, JAK3, MLH1, and PIK3CA.

ISH testing identified EGFR amplification in 11% of patients with SCLC but did not detect cMET or HER2. ALK translocations were not identified. IHC revealed overexpression of TOP2A (91%), TOPO1 (63%), cKIT (64%), RRM1 (54%), and TS (46%). Low expression of PTEN was noted in 56% of patients.

“Even cancers that appear to be very similar can be dramatically different at the molecular level, and these differences may reflect unique vulnerabilities that could positively impact therapeutic options and decisions,” Liu said. “We are pleased that this research confirms these rarer subtypes; it calls for additional investigation on a larger scale. Once confirmed, molecular profiling of small cell tumors and NET could become standard, as it is currently for non-small cell lung cancers, which will be especially important as more molecularly targeted chemotherapy agents are developed."

In a separate study presented at the symposium, a large analysis of 6785 non-small cell lung cancer (NSCLC) biomarkers further quantified the level of alterations in these tumors.² This analysis found overlaps in alterations, suggesting the potential for treatment with dual targeted therapies.

In the study, 66% of EGFR-mutated samples also overexpressed MET by IHC and 7% were MET-amplified by chromogenic ISH. Additionally, ALK translocations were detected in 2.8% of patients with NSCLC, with 19% of these patients also harboring an EGFR mutation and 3% with MET amplification.

"The studies presented at the Chicago Thoracic Oncology symposium underscore the importance of comprehensive, multiplatform molecular profiling as a tool to fully characterize and elucidate oncogenic drivers in lung cancers," Sandeep K. Reddy, MD, chief medical officer at Caris Life Sciences, said in a press release. "This is particularly relevant as the NCCN guidelines have been updated this year to reflect the need for multiplex testing as the replacement for simply testing EGFR and ALK alone."

References

1. Feldman R, Astsaturov I, Millis S, et al. Molecular Profiling in Small Cell Lung Cancer and Lung Neuroendocrine Tumors. Presented at: Chicago Multidisciplinary Symposium on Thoracic Oncology; October 30 - November 1, 2014; Chicago, Illinois. Abstract 12.
2. Feldman R, Xiu J, Salgia R, et al. Tumor Biomarker Evaluation Of 6,785 Patients For Combination Treatment Strategies In NSCLC. Presented at: Chicago Multidisciplinary Symposium on Thoracic Oncology; October 30 - November 1, 2014; Chicago, Illinois. Abstract 264.

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