The Distinct Molecular and Clinical Profile of Lung Cancer in Young Patients

H. Jack West, MD


January 21, 2016

The field of lung cancer has seen a wide range of dramatic improvements in outcomes over the past decade. Most of these are predicated on tailoring treatment approaches for specific subgroups, rather than offering a default approach to a pooled population that would be more optimally managed as a collection of subgroups, defined by a combination of molecular and clinical features, that receive tailored treatment strategies. We readily recognize pathologic features, such as squamous vs adenocarcinoma and EGFR mutations or ALK or ROS1 rearrangements, as the variables that direct care decisions, but we have also increasingly studied such clinical factors as advanced age and performance status as relevant discriminating variables for developing an optimized treatment approach.

The youngest patients in the spectrum of the lung cancer population may merit consideration as a distinct subgroup, but they have remained virtually unstudied in this capacity.

The youngest patients in the spectrum of the lung cancer population may merit consideration as a distinct subgroup, but they have remained virtually unstudied in this capacity. Although the lung cancers of young patients have been reported as disproportionately more likely to harbor driver mutations, such as EGFR mutations[1] and ALK[2] and ROS1 rearrangements,[3] than those in older patients, such observations have not generally been accompanied by specific management implications.

In this context, a recent publication by Dr Adrian Sacher and colleagues[4] from Dana-Farber Cancer Institute represents an important step forward by systematically studying the frequency of targetable mutations and clinical outcomes of a large cohort of patients with advanced non-small cell lung cancer (NSCLC) as a function of age. The investigators reported on molecular profiles and survival among 2237 patients who had undergone molecular marker testing for EGFR, ALK, ROS1, ERBB2, and BRAF V600E, as well as KRAS mutation testing as a comparator without an identified molecularly directed therapy.

Comparing the frequency of these mutations and overall survival in patients younger than 40, 40-49, 50-59, 60-69, and 70 years or older, Sacher and colleagues reported a significant association of cancer in younger patients with EGFR mutations (P= .02) and ALK fusions (P<.001), a trend toward disproportionate overrepresentation in younger patients for ERBB2 mutations and ROS1 fusions, and no association of BRAF V600E with age. Overall, patients aged 50 years or younger had a 59% increased probability of having a mutation for which a specific treatment was available, whereas young patients without a targetable mutation had a comparably poor survival, indicating that the evidence does not support young age as a favorable independent prognostic factor.

This work is limited by the fact that it represents patients evaluated and treated at a single tertiary care institution, who may not represent the broader lung cancer population. Younger patients may be expected to be particularly proactive about seeking care at an internationally recognized center of excellence that has helped set the pace for clinical research, particularly in such molecularly targeted subgroups, and many patients may have been found to have a targetable mutation at an outside institution and then been referred to Dana-Farber for trials or specific expertise there. It will be critical to determine whether these initial findings can be replicated across a multicenter-based cross-section of lung cancer patients not subject to referral bias.

In the meantime, however, as next-generation sequencing and other multiplex testing efforts become widely incorporated into routine practice, this valuable contribution highlights that NSCLC arising in younger patients may represent a distinct clinical entity with the highest yield for identifying targetable mutations, for whom broad molecular testing is disproportionately likely to direct treatment decisions and improve survival.


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