Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy

Abstract

Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.

Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies

“…The relative contribution of EGFR expression and signaling to HPV[+] HNSCC development and progression (compared with HPV[−] HNSCC) is not well understood. HPV oncogenes have not been shown to modulate the anti-EGFR antibody responses in HNSCC (6, 8). Others have found that EGFR is selectively overexpressed in HPV[−] HNSCC (9).…”

Targeted Therapy of Head and Neck Cancer

“…The same was found for radiotherapy-based primary treatment of oropharyngeal carcinoma with cetuximab [50]. Similarly, no differences were identified in another small cohort of HNSCC patients treated with cetuximab [47]. Other trials can also be interrogated with regard to EGFR inhibitor response and HPV status, even though these results have to be viewed with caution because of the small sample size.…”

“…However, neither EGFR expression nor amplification have been reported as predictive for clinical outcome after EGFR blockade (see above). Furthermore, in-vivo and in-vitro data could not show an effect of E6/E7 expression or HPV status on cetuximab efficacy [47]. Several clinical analyses have been performed to address this question.…”

Targeting HER (ERBB) signaling in head and neck cancer: An essential update

“…Although, in laboratory settings, E5 has been suggested to enhance EGFR signaling through the inhibition of its internalization, degradation and endosome fusion (Suprynowicz et al, 2010), it is not clear if E6 and E7 also affect EGFR signaling directly. Interestingly, in a recent study, Pogorzelski et al (2014) found that HPV status does not impact cetuximab response in both in vitro and in vivo models of SCCHN (Pogorzelski et al, 2014). Similarly, in the retrospective analysis of the EXTREME trial (Vermorken et al, 2008), the authors found that the "survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status" .…”