Even early in situ lung adenocarcinomas (ADCs) come fully equipped with genetic changes that mark highly invasive tumors, a recent study has found. Co-authored by Pierre Massion, M.D., professor of medicine and director of the Cancer Early Detection and Prevention Initiative at Vanderbilt-Ingram Cancer Center, the study is part of an effort to find ways to reduce the overdiagnosis and overtreatment of indolent lung ADCs and appeared in the American Journal of Respiratory and Critical Care Medicine.1
In recent years, widespread lung cancer screening has succeeded in reducing deaths from the disease in smokers, but it can also lead to avoidable surgeries, Massion said. “Our goal is not just to identify more aggressive tumors, but also more indolent ones. The indolent ones may require careful observation rather than immediate surgery.”
“Our goal is not just to identify more aggressive tumors, but also more indolent ones. The indolent ones may require careful observation rather than immediate surgery.”
Forecasting Tumor Progression
“We have a limited understanding of the molecular underpinnings of early adenocarcinoma progression,” the authors wrote. Massion says improved understanding in this realm would be valuable in treatment planning. “Once we know more about which genetic alterations provide hints that a tumor is likely to become aggressive, we can start testing hypotheses about which patients are more likely to benefit from adjuvant therapy.”
The researchers were curious whether the behavior of an early ADC could be predicted based on genetic determinants. They sequenced DNA extracted from 102 ADCs of varying degrees of aggressiveness, drawn from patients for whom they had complete medical histories. The DNA was sequenced at Vanderbilt Technologies for Advanced Genomics.
Twenty-one of the ADCs tested were early, in situ tumors that had not yet broken through basal membranes; 27 were minimally invasive ADCs, and 54 were fully invasive ADCs.
Strikingly, it turned out that even early, in situ tumors came fully equipped with genomic alterations found in highly invasive tumors. “This suggests that the microenvironment for a tumor may play a critical role in its future course,” Massion said.
“Once we know more about which genetic alterations provide hints that a tumor is likely to become aggressive, we can start testing hypotheses about which patients are more likely to benefit from adjuvant therapy.”
Mutations Predict Long or Short Survival
A signature of mutations in five genes – PIK3CA, ATM, EPPK1, EP300 and KMT2C – predicted inferior survival in 10 patients, even in the absence of EGFR, KRAS and TP53 mutations. The researchers also identified mutations associated with longer survival in another 10 patients having ATR, KDM6A or POLQ mutations.
“We found that some genetic alterations give us hints as to whether the tumors are more likely to be aggressive,” Massion said. “I think equipped with this knowledge we can now test new hypotheses for identifying populations with aggressive lung cancers that may benefit from further therapy after surgery.”
Massion plans to further explore the findings in larger studies. “We are gearing up to get a validation set collaborating with others in the Pre-Cancer Atlas program,” he said.