Non-small Cell Lung Cancer in Younger Patients May Be More Targetable With Precision Medicine

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Younger patients with non-small cell lung cancer may have a distinct disease, genetically and biologically.
Younger patients with non-small cell lung cancer may have a distinct disease, genetically and biologically.

Researchers now think that younger patients with non-small cell lung cancer may have a distinct disease, genetically and biologically, compared to older patients with NSCLC.1

The new findings suggest that it may be highly advisable to test young patients' NSCLC tissues for the full array of genetic aberrations that can be therapeutically targeted, whether by already-approved drugs or by newer agents being tested in clinical trials.

Researchers found that younger patients were more apt to have genetic subtypes of the disease that can be treated with available targeted therapies.1

The investigators scanned NSCLC tissue from 2237 patients looking for abnormalities in 8 genes that can be targeted by existing drugs or agents under development. They found that alterations in 5 targetable genes (EGFR, ALK, HER2, ROS1, and BRAF V600E) were more frequent in younger patients. Patients diagnosed at age 50 or younger were 59% more likely than older patients to harbor one of these mutations in their tumors.

“Lung cancer in the young is enriched for targetable genomic alterations, yet seems to be associated with a poorer prognosis than expected,” said senior study author Geoffrey Oxnard, MD, who works at Dana-Farber Cancer Institute and Brigham and Women's Hospital and is also an assistant professor of medicine at Harvard Medical School in Boston, MA.

“This means that we can make a big impact for these unique lung cancer patients through tumor genotyping so patients can receive and benefit from appropriate target therapies. Patients with lung cancer at a young age are well suited for comprehensive tumor genotyping, such as with next-generation sequencing (NGS).”

He said performing NGS for a patient with lung cancer has the potential to identify a range of very actionable alterations that can be treated with widely available targeted therapies.

“This can cause dramatic and durable responses which can have a major impact on survival on a case-by-case basis,” Dr Oxnard told Cancer Therapy Advisor.

In this study, investigators looked at a few genes that have been tested for many years and they included EGFR, which is targeted by erlotinib; ALK and ROS1, which are targeted by crizotinib; HER2, which is targeted by afatinib, and BRAF, which is targeted by dabrafenib.

He said NGS also will test for other gene mutations with therapies available or in trials, including MET (crizotinib) and RET (cabozantinib). Dr Oxnard said across all of lung cancer, many of these mutations are rare. However, in younger patients with NSCLC, there is clear enrichment so the chance of finding something targetable is quite good.

The researchers found differences in the biology and behavior of NSCLC in younger and older patients. The differences became apparent when investigators compared survival statistics for the youngest and oldest patients in the study. Even though targetable abnormalities were more common in young patients' tumors, these patients' survival times were shorter than expected when the beneficial effect of targeted therapy was taken into account. The researchers theorized that NSCLC is inherently more aggressive in younger patients.

This is the first study of its kind to include a broad survey comparing the genetic features of younger and older patients' tumors. The researchers found that gene mutations for EGFR and ALK were associated with cancer diagnosis at a younger age. They also found a similar trend for ERBB2 and ROS1. However, that was not the case for BRAFV600E.

Shadia Jalal, MD, who is a medical oncologist at the Indiana University Health Simon Cancer Center in Indianapolis, IN, said genomic sequencing can at times help direct therapy. Dr Jalal said these new study findings come at an important time when newer therapies are coming on the market each month.

“There are ongoing studies that aim to address whether genomic alterations, regardless of where the primary tumor started, can lead to sensitivity to targeted agents and whether this crosses different tumor types,” Dr Jalal told Cancer Therapy Advisor.

“This is an important study. It suggests that young age by itself at the time of lung cancer diagnosis is a good reason to genomically sequence patients as this group is more likely to exhibit targetable mutations. Unfortunately, the study also shows that we need better therapies as younger patients have a poor prognosis.”

Ramaswamy Govindan, MD, who is a professor of medicine in the Department of Oncology at Washington University School of Medicine in St. Louis, MO, said this a well done retrospective that confirms observations made earlier by other investigators and may help better guide clinicians.

“Large scale genomic studies conducted by The Cancer Genome Atlas (TCGA) project have increased our understanding of the molecular aberrations in lung cancer. But more work needs to be done to fully understand the genomic landscape of lung cancer in general and lung cancer in the young in particular,” Dr Govindan told Cancer Therapy Advisor.

Reference

  1. Sacher AG, Dahlberg SE, Heng J, et al. Association between younger age and targetable genomic alterations and prognosis in non–small-cell lung cancer [published online ahead of print December 17, 2015]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.4482.

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