HER2 Mutated Lung Adenocarcinoma Is a Distinct Molecular and Clinicopathologic Entity
Jeanne Shen, Krishan Taneja, Wanghai Zhang, Deborah A Dillon, Leena Gandhi, Lynette M Sholl. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Charlton Memorial Hospital, Fall River, MA
Background: Lung adenocarcinomas (ACA) often contain identifiable “driver” mutations. Recognition of mutation-specific clinicopathologic features has important implications for patient selection for targeted therapy. HER2 is mutated in ∼3% of lung ACA, but little is known about the clinicopathologic or molecular features of these tumors.
Design: 70 lung ACA with known mutations were selected from a patient cohort that had undergone clinical tumor genotyping; 19 of these contained HER2 exon 20 insertions, and the other 51 contained non-HER2 mutations in EGFR (n=18), KRAS (n=15), BRAF (n=12), and/or PIK3CA (n=13). HER2 FISH and immunohistochemistry (IHC) using Herceptest were performed on each HER2 mutated case and interpreted according to ASCO/CAP criteria for breast cancer. Non-parametric analyses were used to test the association between HER2 mutation status and other characteristics. A 2-tailed α=0.10 criterion was used, given the small sample size. Kaplan-Meier survival analysis was used to evaluate overall survival, adjusted for clinical stage.
Results: HER2 mutation status was independent of gender, race, and age, but associated with never or limited-smoker status (p=0.07) and higher clinical stage (p=0.05). HER2 mutated tumors were predominantly acinar, papillary, or solid-subtype, but not significantly associated with any pattern. The tumor cells tended to exhibit coarse chromatin (p=0.07) and columnar shape (p=0.04), and frequently contained eosinophilic hyaline mucin droplets (so-called “targetoid cells”) (OR=12.65, p<0.0001). Of the HER2 mutant tumors, 8 (42%) showed copy number (CN) gain, of which 4 (21%) were amplified. 16 HER2-mutated cases had material available for IHC; 7 (44%) showed 1+ and 4 (25%) showed 2+ staining. Only 2+ staining correlated with CN gain (p=0.02). There was no significant difference in survival time between patients with HER2 mutations and those with non-HER2 mutations (p=0.80).
Conclusions: Compared with other mutated lung tumors, HER2 mutated ACA represents a distinctive subset of tumors that tends to present at higher stage in nonsmokers, has unique morphologic features, including “targetoid cells”, and shows frequent HER2 CN gain in the absence of strong protein expression. These findings lend insight into the biology of HER2 mutation in lung cancer and begin to define a subset of patients who may be amenable to therapy with HER2 inhibitors.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 297, Tuesday Morning