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Younger patients with NSCLC more likely to harbor targetable mutations, experience poor OS
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Younger age appeared associated with an increased likelihood of harboring a targetable genomic alteration in patients with non–small cell lung cancer, according to study results published in JAMA Oncology.
Further, the poor survival of younger patients with NSCLC compared with other age groups suggests disease biology may generally be more aggressive in this cohort.
Geoffrey R. Oxnard
Although young-onset of other cancers — such as breast cancer, colorectal cancer and acute lymphoblastic leukemia — has been linked to a distinct disease biology, NSCLC is rarely diagnosed in younger adults, leading to few data on the clinical characteristics of the disease in this patient population.
Thus, Geoffrey R. Oxnard, MD, assistant professor of medicine at Harvard Medical School and staff physician at Dana-Farber Cancer Institute, and colleagues sought to determine correlations between age, targetable genotypes and disease prognosis in patients with NSCLC.
Between January 2002 and December 2014, Oxnard and colleagues genotyped a cohort of 2,237 patients (median age, 62 years; range, 20-95) with NSCLC at Dana-Farber Cancer Institute.
Researchers divided patients into cohorts based on age, including those aged younger than 40 years (n = 81; 4%), 40 years to 49 years (n = 252; 11%), 50 years to 59 years (n = 597; 27%), 60 to 69 years (n = 697; 31%), or 70 years and older (n = 610; 27%).
The majority of patients (87%; n = 1,939) had histologically confirmed adenocarcinoma, 12% (n = 269) had NSCLC not otherwise specified and 1% (n = 29) had squamous histologic findings.
Sixty-three percent (n = 1,396) of the cohort had stage IIIB or stage IV disease.
Patients underwent genotyping for targetable genomic alterations, including EGFR, KRAS, ALK, ERBB2, BRAF V600E and ROS1.
The frequency of targetable genomic alterations by age, as well as the association of age groups with survival, served as the primary study measures.
Overall, 712 patients (32%) harbored a targetable genomic alteration.
Patients diagnosed with cancer at a younger age appeared more likely to harbor EGFR kinase mutations (P = .02) and ALK rearrangements (P < .001), but less likely to harbor a KRAS mutation (P < .001).
For instance, 32% of patients aged 40 years or younger harbored an EGFR mutation vs. 23% of patients aged older than 70 years, and 19% of the youngest cohort harbored an ALK mutation vs. 1% of the oldest cohort. Conversely, 27% of the oldest cohort harbored a KRAS mutation vs. 9% of the youngest cohort.
There was a trend toward increased expression of ERBB2 and ROS1 mutations among younger patients, but this association did not reach statistical significance.
Among patients tested for all five targetable genotypes (n = 1,325), younger age appeared associated with an increased frequency of a targetable genotype (P < .001), with patients diagnosed at age 50 years or younger exhibiting a 59% increased likelihood of harboring a genomic alteration. Smoking status (P ˂ .001), female sex (P = .02) and Asian race (P = .03) also appeared associated with harboring a mutation; however, after controlling for these factors, the association between age and presence of an alteration persisted (P = .006).
Researchers then evaluated whether prognosis also correlated to age. They found that the shortest median OS occurred among patients aged younger than 40 years (18.2 months; 95% CI, 13.6-25.7) and older than 70 years (13.6 months; 95% CI, 11.4-15.7).
The presence of a targetable mutation treated with a targeted agent appeared associated with improved OS (P ˂ .001). However, even among patients with targetable alterations, the youngest (median OS, 21.4 months; 95% CI, 12.6-47.3) and oldest (median OS, 22.3 months; 95% CI, 16.9-28.6) patient age groups had the poorest outcomes, whereas patients aged 50 to 59 years had the longest median OS (35.4 months; 95% CI, 29.6-41.4).
The researchers acknowledged limitations of their study, including the retrospective design and the limited comprehensive data on patient treatment. Further, they noted that the single-institution recruitment may have caused referral bias.
“Despite the aforementioned limitations, the findings of this study expand the current understanding of the genetics and biology of lung cancer in young patients,” Oxnard and colleagues wrote. “These data suggest that exhaustive genotyping methods such as next-generation sequencing should be used when available for young patients with lung cancer to detect targetable alterations that may guide therapy.”
In an accompanying editor’s note, Howard (Jack) West, MD, medical director of the thoracic oncology program at Swedish Cancer Institute in Seattle, as well as web editor for JAMA Oncology, noted that these findings will move forward research of an underserved population, despite the referral bias.
“While these results and conclusions are limited by the referral bias to a center of excellence to which younger patients and those with an identified mutation likely gravitated, almost certainly creating a skewed study population that is not necessarily generalizable to the broader lung cancer population, this work provides an invaluable early step toward identifying the youngest patients with lung cancer as a subgroup that deserves more study and special consideration as a distinct clinical demographic most likely to benefit from a more extensive search for targeted driver mutations,” West wrote. – by Cameron Kelsall
Disclosure: Oxnard reports consultant roles with and/or honoraria from Ariad, AstraZeneca, Boehringer Ingelheim, Chugai, Clovis Oncology, Genentech and Sysmex. Please see the full study of a list of all other researchers’ relevant financial disclosures. West reports no relevant financial disclosures.
Perspective
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Loretta Erhunmwunsee, MD
The finding that the prognosis of patients aged younger than 40 years is no better than that of patients older than 70 years with non–small cell lung cancer was not expected and suggests that the disease biology is particularly aggressive in this younger group. The data from the study suggest that NSCLC in the young is a unique disease, which is surprising.This study expands the current understanding of the genetics and biology of lung cancer in young patients and suggests that young patients with lung cancer should undergo comprehensive genotyping for better assessment of genetic mutations that can be targeted for treatment. Also, because of these data, providers will be able to more accurately relay the prognosis of patients within this group. The importance of research on new gene mutations, gene sequencing mechanisms and gene-specific therapies is clearer in part due to this study.
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