Lung Cancer Genetically Distinct, More Aggressive in Younger Patients, Study Finds

Scientists at Dana-Farber Cancer Institute in Boston found non-small cell lung cancer (NSCLC) — the most common type of lung cancer and one that can metastasize to other parts of the body — is a distinct disease in younger people, genetically and biologically, from NSCLC in older patients and could benefit from early and different treatment approaches.

In a study published online before print this week by the journal JAMA Oncology, investigators scanned the DNA of thousands of NSCLC tumor samples for abnormalities. They discovered that younger patients were more apt to have genetic subtypes of the disease that can be treated with available targeted therapies, but that their tumors were also likely to be aggressive. As a result, researchers are beginning a genetic sequencing study of lung cancer in patients under age 40 (more information on the study and possible participation is available through this link and again at the article’s conclusion).

The Original Investigation paper entitled: “Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non Small-Cell Lung Cancer“ (JAMA Oncol. Published online December 17, 2015. doi:10.1001/jamaoncol.2015.4482), is co-authored by Adrian G. Sacher, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, and Geoffrey R. Oxnard, MD of of Dana-Farber and Brigham and Women’s Hospital in Boston, with Suzanne Dahlberg, PhD, of Dana-Farber and the Harvard T.H. Chan School of Public Health; Jennifer Heng and Stacy March of Dana-Farber; and Pasi Jänne, MD, PhD, Director of the Lowe Center for Thoracic Oncology, Scientific Director of the Belfer Institute for Applied Cancer Science, and a Professor of Medicine at Harvard Medical School.

The investigators note that non small-cell lung cancer diagnosed in young patients is rare, and its genomics and clinical characteristics poorly understood. At the same time, diagnosis of other cancers at a young age has been demonstrated to define unique disease biology. In this paper, the co-authors report on an association of young age with targetable genomic alterations and with prognosis in a cohort of 2,237 patients with NSCLC.

All NSCLC patients genotyped at the Dana-Farber Cancer Institute between January 2002 and December 2014 were identified; tumor genotype, patient characteristics, and clinical outcomes were collected and studied at a National Cancer Institute-designated comprehensive cancer center. Multivariate logistic regression was used to analyze relationships between age and mutation status, and multivariate Cox proportional hazard models were fitted for survival analysis and frequency of targetable genomic alterations by defined age categories, as well as by association of age groups with survival. Age categories used in this analysis were younger than 40, 40 to 49, 50 to 59, 60 to 69, and 70 years or older.

Patients diagnosed at 50 years or younger were found to have a 59% greater likelihood of harboring a targetable genotype. While the presence of a potentially targetable genomic alteration treated with a targeted agent was associated with improved survival, the youngest and oldest age groups had similarly poor outcomes even when a targetable genotype was present.

The investigators conclude that diagnosis at younger ages is associated with an increased likelihood of harboring a targetable genotype, and is an underappreciated clinical biomarker in NSCLC. They note that survival of young patients with NCSLC is unexpectedly poor compared with other age groups, suggesting a more aggressive disease biology at work — underscoring the importance of comprehensive genotyping, including next-generation sequencing, in younger patients with lung cancer.

“We discovered that tumor tissue in patients under age 50 was more likely to have alterations in any of five genes that we studied, for which targeted therapies already exist or are in clinical development,” says the study’s lead author, Adrian Sacher, MD, in a release. “We also found differences in the biology and behavior of NSCLC in younger and older patients.”

Those differences became apparent when the investigators compared survival statistics for the youngest and oldest patients in the study, noting that these patients’ survival times were shorter than expected even when the beneficial effect of a targeted therapy was taken into account. The researchers say this suggests that NSCLC is inherently more aggressive in younger patients, and the gain of a targeted therapy is offset by the more virulent nature of their disease.

The investigators observe that their findings reinforce the need to test young patients’ NSCLC tissue for the full array of genetic aberrations that can be therapeutically targeted.

While NSCLC is the most common form of lung cancer, accounting for about 87% of all lung cancer cases, the median age at diagnosis is 70, with fewer than 5% of patients diagnosed prior to age 50. About 9,600 new cases of NSCLC are diagnosed among those under 50 of the 192,000 total new cases diagnosed each year in the U.S., according to the American Cancer Society.

Non-small cell lung cancer begins when epithelial cells, which form the inside lining of the lungs, grow rapidly and uncontrollably. A malignant or cancerous tumor may stay in one place or spread to other parts of the body (metastasis). The bronchi are sometimes also involved in lung cancer. NSCLC is more easily treatable when caught early and localized in the lung. Treatments may include a combination of surgery, radiation, chemotherapy, and/or targeted medications.

The scientists note that while previous research has suggested that certain genetic abnormalities are associated with NSCLC in young patients, no previous study had performed a broad survey comparing genetic features of younger and older patients’ tumors.

“Our findings suggest that younger patients with NSCLC represent a genetically unique subgroup,” says Dr. Sacher. “This has implications for how the disease is treated. Because younger patients are more likely to have a targetable form of the disease, it’s absolutely vital that their tumor tissue undergo comprehensive genetic testing, including all targetable genomic alterations. This will ensure that they reap the full benefit of the targeted therapies that are now coming on line for NSCLC.”

Spurred by the results, the researchers are offering advanced genetic sequencing to all patients under the age of 40 diagnosed with lung cancer. The testing, performed with the FoundationOne genomic profiling system, aims to identify genomic targets in patients tumors and help patients gain access to targeted therapies that may benefit them. Young lung cancer patients willing and possibly able to participate can access information via a study website: www.openmednet.org/site/alcmi-goyl

This international study is led by Geoffrey Oxnard, MD of Dana-Farber and Brigham and Women’s, the senior author of the JAMA Oncology study, and by Barbara Gitlitz, MD, of KeckMedicine at the University of Southern California, and coordinated by the Addario Lung Cancer Medical Institute (ALCMI).

Support for the study was provided by the National Institutes of Health (grants R01CA114465 and P50CA090578), the Conquer Cancer Foundation of the American Society of Clinical Oncology, the Bonnie J. Addario Lung Cancer Foundation, the Canadian Institutes of Health Research, the Canadian Association of Medical Oncologists, the Gallup Research Fund, and the Kaplan Research Fund.