Genomic Data May Advance Lung Cancer Precision Medicine

A study of genomic data in patients with advanced small-cell lung cancer provided new insights into the patterns of treatment resistance, potentially paving the way for precision medicine treatments.

The study, led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James), could offer new targets to develop more effective immunotherapies for advanced small cell lung cancer.

Advanced small cell lung cancer progresses quickly and is usually fatal, the team noted. The condition accounts for 15 percent of lung cancer cases worldwide. While the disease often responds well to chemotherapy when first diagnosed, it typically recurs in a lethal, treatment-resistant form.

"Advanced SCLC often does not respond as well to immune therapies that are effective in other types of lung cancer, and the reasons for this are poorly understood," said principal investigator Sameek Roychowdhury, MD, PhD, a medical oncologist and member of the OSUCCC - James Translational Therapeutics Research Program. 

"Our findings suggest that the causes of treatment resistances in advanced small cell lung cancer may be subtype-specific. They also highlight the importance of tumor genomic studies to identify the most effective therapies for these patients and to support development of new therapies for this often-fatal disease."

Oncologists can gather specific genomic information from individual patients to help match patients with the best therapy based on their unique tumor characteristics. This precision medicine approach has critical significance in metastatic and rare forms of cancer where treatment options are often limited.

"Understanding the specific drivers of a person's cancer can help us identify potential alternative treatment options through clinical trials that would not have been possible otherwise," said Roychowdhury.

For the study, researchers analyzed genomic DNA and total mRNA from tumor cells removed from five deceased patients with advanced small cell lung cancer, along with circulating tumor DNA. Researchers obtained the tissue as part of a rapid research autopsy study.

The team collected tissue within 16 hours of each patient’s passing, minimizing the molecular changes that occur in cells after death.

The five patients consented to undergo a research autopsy soon after death to allow researchers to collect and evaluate many tumors. Researchers used sequencing technologies to identify genetic and molecular changes in four small cell lung cancer tumor subtypes. Many of the changes are associated with resistance to immune therapy and other treatments.

Key findings from the study included the feasibility for rapid research autopsy to provide in-depth insights into resistant lung cancers. Additionally, the study showed evidence that tumors have continued to evolve after patients receive treatment. Even a single patient may have six to eight genetically distinct subtypes of their cancer, which could have implications for future drug development.

The most common neuroendocrine small cell lung cancer subtypes showed high expression of the enzyme ARG2, a possible suppressor of immune responses. Finally, the study revealed support for the known association between the Wnt pathway and chemoresistance in advanced SCLC.

"Our results need to be validated by larger studies, but they suggest that subtyping SCLC patients before systemic therapy could someday play a role in drug development and therapy selection," said Roychowdhury.

Researchers are increasingly examining the possibility of leveraging genomics and genetic information to advance precision medicine therapies. The University of Alabama at Birmingham School of Medicine and UAB Hospital laboratories recently launched the Genomic Diagnostics Lab (GDL), an effort to increase genetic testing and advance precision medicine therapies.

“This facility is absolutely required to meet our clinicians’ immediate needs and expectations for molecular testing,” said Alexander “Craig” Mackinnon, Jr., MD, PhD, professor and director, Division of Genomic Diagnostics and Bioinformatics.

“This newly renovated lab is a bridge providing urgently needed space in the immediate near term. The next phase brings in additional partners, including Clinical Genetics and Pediatric Microbiology, as the labs integrate. The GDL will greatly increase the scale, scope, and efficiency of genetic testing at UAB.”