Molecular subtypes of lung cancer can help predict patient response to treatment
Researchers at the University of North Carolina have shown that molecular subtypes of lung cancer have distinct genetic changes and can predict patient responses to therapy. Detailed information about these molecular subtypes can help us better understand how lung cancer develops and identify better treatments for individual patients.
Jumpstarted with funding in part from Uniting Against Lung Cancer in 2007, Dr. Neil Hayes and his team have dug deeper into analyzing three district lung adenocarcinoma subtypes (bronchioid, magnoid, and squamoid), classified by specific groups of genes. In their most recent publication in PLoS ONE, Dr. Hayes and his team looked at over 600 lung cancers to identify and validate specific genomic alterations, clinical characteristics, and clinical outcomes in each subtype.
Patients with bronchioid subtypes are more likely to be female and nonsmokers. They are more likely to present with bronchioloalveolar carcinoma and early-stage disease, and to live longer after diagnosis. This molecular subtype is more likely to have theEGFR gene driving tumor growth, and patients with this subtype are more likely to benefit from treatment with EGFR-targeted drugs. Surprisingly, bronchioid lung cancers that had normal, non-mutated EGFR were more sensitive to EGFR-targeted therapies than other subtypes. This implies that other genes associated with this subtype could be influencing response to treatment, and may help uncover additional biomarkers to predict positive responses. (About 25% of patients with normal EGFR receive some benefit from EGFR-targeted treatment.)
The majority of patients with magnoid lung cancers were smokers, and this group included the heaviest smokers by pack-years. Magnoid lung cancers showed the most chromosomal instability, the most DNA methylation (modifications that can control expression of many genes at once), and the highest genome-wide mutation rate. Magnoid lung cancers are more likely to have changes to KRAS, TP53, and STK11 genes. Other genes associated with this subtype include DNA repair genes. Patients with magnoid lung cancers also showed the greatest benefit from chemotherapy. As chemotherapy causes damage to DNA, the inability to repair chemotherapy-induced DNA damage in this subtype may explain the increased benefit from chemotherapy.
Patients with squamoid subtypes had the most high-grade tumors (associated with poorer prognosis). This group had the most mutations to the PTEN gene, but overall had the fewest distinctive genomic alterations. As with magnoid lung cancers, patients with squamoid lung cancers were more likely to be smokers, have poor survival outcomes, and present with late-stage disease.
This research is digging deeper into the genetics of lung cancer, and uncovering additional information (beyond a single driver mutation) that can impact how patients respond to treatment. More research will help doctors better predict prognosis and response to therapy, as well as identify new targets and treatment strategies tailored to each individual patient.
Wilkerson MD, Yin X, Walter V, Zhao N, Cabanski CR, et al. (2012) Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation. PLoS ONE 7(5): e36530. doi:10.1371/journal.pone.0036530