Why does lung cancer recur? It’s all in the genes, finds new study

Patients with this particular type of lung cancer carry a specific mutation in the Epidermal Growth Receptor Factor (EGFR) gene, and are treated with a class of targeted drugs called “EGFR tyrosine kinase inhibitors” that suppress the unusual growth of the cancerous cells.

But many patients eventually relapse owing to resistance to these therapies.

The Indian team, comprising researchers from the University of Delhi South Campus, Tata Memorial Centre in Mumbai and One Cell Diagnostics in Pune, has found that patients are more likely to experience a relapse when certain tumour suppressor genes (TSGs) undergo mutation alongside the EGFR gene. The study analysed data from 483 lung cancer patients with EGFR mutations, and found that patients who also had mutations in certain TSGs had significantly worse survival rates.

The researchers say their findings, published in the European Society of Medical Oncology Open, could help identify patients at higher risk of relapse and accordingly adjust their treatment.

“The average overall survival for patients with these additional mutations (TSGs) was 51.11 months, compared to 99.3 months for those without them. Similarly, the time before the cancer started progressing again — known as progression-free survival — was also shorter in patients with both types of mutations,” said Amit Dutt, Professor and Tata Innovation Fellow, Integrated Cancer Genomic Laboratory, Department of Genetics, University of Delhi South Campus.

According to a global cancer statistics database compiled by the WHO, India recorded 81,748 new lung cancer cases and 75,031 deaths in 2022.

The study was supported by Science and Engineering Research Board and Indian Council of Medical Research. It was led by Supriya Hait, a graduate student under the guidance of Prof Dutt, and Dr Kumar Prabhash from Tata Memorial Centre, in collaboration with Dr Jayant Khandare, Dr Gowhar Shafi and a team from One Cell Diagnostics.

An infographic made by the first author, Supriya Hait. Depicts the clonal state of evolution across early, intermediate ,and late relapse of the disease. Circles depits the different tumor suppressor genes (TSGs) that when co-occurs with EGFR mutation are associated with early relapse and effects the survival of the patient.

Prof Dutt said the researchers performed detailed genetic sequencing on tumor samples from 16 patients before and after their cancer relapsed to better understand how these genetic changes contribute to disease relapse. “A group of 17 TSGs that were frequently mutated in patients who relapsed early were identified. These genes were found to play a key role in driving resistance to EGFR-targeted treatments.”

An important aspect of this study was its use of liquid biopsy — a blood test that detects cancer-related DNA fragments in the blood using a comprehensive genomic profiling panel developed by One Cell Diagnostics.

By analyzing 200 blood samples from 25 patients over time, the team was able to track how the genetic makeup of the tumors evolved during treatment. They found that in patients who relapsed early (within 10 months of starting treatment), mutations in these 17 TSGs were already present and became more dominant over time, suggesting that these mutations contribute to resistance from the start.

“If doctors can identify patients who have these additional tumor suppressor mutations early on, they may be able to tailor treatments more effectively…” Prof Dutt said.