Primary resistances to EGFR inhibitors (EGFRi) in HPV-positive and -negative oropharyngeal squamous cell carcinoma (OSCC).

Abstract

10591 Background: HPV-positive and negative OSCC, despite a common EGFR expression, have a distinct biology and clinical behaviour, thus we hypothesize different mechanisms of primary resistance to EGFRi. Methods: PI3KCA, PTEN, HER2 and IGF-1R status was investigated in 17 HPV16-positive and 57 HPV16-negative fixed untreated OSCCs through FISH, sequencing, cDNA relative quantification by means of real-time PCR (method 2-ΔΔCt) and immunohistochemistry. Results: PI3KCA gene amplification involved only HPV16-negative (13%) cases, while a gain of PI3KCA gene copy number similarly occurred in HPV16-positive (29%) and negative (25%) OSCC. Activating mutations play a marginal role both in HPV16-positive (6%) and negative (2%) OSCC. An higher occurrence of PI3KCA transcript values, 31 folds > than the lower one, was found in HPV16-positive (60%) compared with negative (27%) OSCC (p=0.05). PTEN gene loss was restricted to HPV16-positive (12%) cases, while PTEN mutation similarly involved both HPV16-positive (9%) and negative (10%) OSSC. Overall, PI3KCA and PTEN alterations was more frequent in HPV16- positive (70%) than negative (44%) OSCC. Despite a statistically significant higher occurrence of an increased HER2 gene/chromosome 17 copy number in HPV16-negative (46%) than positive (18%) OSSC (p<0.004), no case showed HER2 expression. IGF-1R cytogenetic analysis revealed a statistically significant higher frequency of increased IGF- 1R/chromosome 15 copy number in HPV16-negative (41%) than positive (7%) OSCC (p=0.02). This is in keeping with the higher occurrence of IGF-1R transcript values, 30 folds > than the lower one, detected in HPV16-negative (73%) than positive (15%) cases (p<0.001). Most OSCC showed expression of the cognate ligands IGF1 and IGF2, however HPV16-negative cases expressed higher IGF1 levels than HPV16-positive OSCC. Conclusions: PI3KCA/PTEN alterations could be responsible to primary EGFRi resistance particularly in HPV16-positive tumors, while IGF-1R could be associated with resistance mainly in HPV16-negative OSCC. HER2 seems not to be involved. Based on our results, resistances to EGFRi should be tackled differently according to HPV tumor status. No significant financial relationships to disclose.