Most Young Lung Cancer Patients Have Actionable Mutations

Barbara Gitlitz, MD

Barbara Gitlitz, MD

A preliminary analysis of an ongoing study shows that most patients diagnosed with lung cancer before age 40 had an increased chance for a targeted genomic alteration, knowledge of which could lead to more effective, targeted treatment.

The data, which were reported at the 2015 World Conference on Lung Cancer (WCLC), showed that 60 of the first 68 patients enrolled in the study had adenocarcinoma. The majority of the participants had metastatic adenocarcinoma, and three-fourths of the tumors had actionable mutations.

The preliminary findings exceeded statistically derived expectations for discovery of actionable mutations in younger patients with metastatic adenocarcinoma, Barbara Gitlitz, MD, reported at the conference.

“We had a 33-year-old male who had a 7-month partial response and at progression, he had increased copy number, which is consistent with emergence of resistance in EGFR mutations, and the transformed mutations were also amenable to tyrosine kinase inhibition,” said Gitlitz, an associate professor of Clinical Medicine at the University of Southern California in Los Angeles.

The results came from the ongoing Genomics of Young Lung Cancer study, which was launched by the Addario Lung Cancer Medical Institute (ALCMI) and aims to determine the genomic profile of lung cancers that occur in younger patients. Studies reported at the WCLC suggested that younger patients account for an increasing proportion of lung cancer incidence. The tumor genomics of that subgroup of patients has received little attention because younger patients historically constituted a relatively modest fraction of the total lung cancer burden.

“Lung cancer at any age is a catastrophic illness, but it is particularly devastating when it affects young adults in the prime of their lives. In other cancers, such as breast cancer and leukemia, research has clearly demonstrated that occurrence at a younger age is associated with a distinct biology that guides treatment,” Bonnie Addario, founder of the Bonnie J. Addario Lung Cancer Foundation (ALCF), said in a statement. “Thus, development of a unique treatment approach for young lung cancer is needed.”

Initiated a year ago, the Genomics of Young Lung Cancer study is enrolling patients at centers in the United States and Europe. Additionally, individuals can register for the study online and receive information about the nearest location that can provide the necessary genomic analysis.

Gitlitz said 30 of the first 68 study participants enrolled online and, in the process, helped expand the number of participating centers. Information about online enrollment is available at https:www.openmednet.org/site/alcmi-goyl.

Initially, the study’s primary objective was to obtain multicenter, prospective genomic data for primary lung cancer in 60 patients younger than 40, an accrual goal that has already been exceeded. With that information, investigators hope to gain insight into lung cancer biology associated with younger patients, as well as facilitate identification of new genome-defined subtypes of lung cancer, expand and speed access to targeted therapies for lung cancer, and provide data that will form the basis for future studies of lung cancer risk and associated genetics.

Investigators in the study have identified seven genomic alterations of interest: EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET. The focus on those mutations was decided on the basis of data from the Lung Cancer Mutation Consortium, an initiative of 16 major US cancer centers that contribute tumor-genomic information obtained from lung cancer patients treated at the centers.

“We felt that our enriched subtype would show an increase in targetable alterations from 35% to 50% and subsequent increase in use of targeted therapy,” said Gitlitz.

The data for the 68 patients enrolled thus far showed a median age at lung cancer diagnosis of 35 (range, 16-39), including 33 men and 35 women. Consistent with the literature on lung cancer, 88% (n = 60) of patients had adenocarcinoma, 10% (n = 7) had squamous-cell tumors, and one patient had small-cell lung cancer.

Gitlitz reported that 54 (79%) of the 68 patients had stage IV disease at diagnosis and the remaining patients had stages I-III. In the subset of patients with adenocarcinoma, 50 (74%) had stage IV disease at diagnosis.

Focusing on the 50 patients with stage IV adenocarcinoma, Gitlitz reported that genomic analysis showed that the driver mutation involved ALK in 22 (44%) patients, EGFR in 13 (26%), and ROS1 in three (6%) patients.

In five cases, data were insufficient to determine the driver mutation. The remaining seven (14%) patients had other types of mutations: EGFR-RAD1, EGFR Dup, HER2, ATM, BRCA2, p53/PTEN, and p53. Only one of these mutations occurred in a woman, suggesting a difference between men and women, as 90% of the women in the stage IV adenocarcinoma subgroup had tumors with ALK, EGFR, or ROS1 mutations.

“Our biggest hope is that this study will serve as the foundation for future discovery of novel targetable genotypes as well as inherited and environmental lung cancer risk factors,” Addario said. “By studying comprehensive genomics on lung cancer tumors from patients diagnosed at age 40 or younger, our team has been able to tap into a new strategy for pinpointing targetable genotypes. Discovering these new genotypes is the first step to developing specific drugs to target and inhibit the mutations that drive the cancer.” Gitlitz BJ. The Genomics of Young Lung Cancer Study. Presented at: 16th World Conference on Lung Cancer; September 6-9, 2015; Denver, CO. Abstract 3632.