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Mutational profiles of HPV-positive, HPV-negative tumors differ
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CHICAGO — The differences in the genetic profile of HPV-positive and HPV-negative tumors may represent therapeutic targets for cancers of the pharynx and oral cavity, according to findings presented at the ASCO Annual Meeting.
Loss-of-function tumor suppressor gene mutations negatively interfered with the efficacy of adjuvant cisplatin-based chemoradiation, whereas activating driver gene mutations were associated with poor risk in HPV-associated squamous cell carcinomas of the head and neck.
Inge Tinhofer, PhD, of the clinical department for radiotherapy at the Charité University Hospital Berlin in Germany, and colleagues compared mutational patterns of HPV-positive and HPV-negative tumors in samples from 208 patients with carcinomas of the hypopharynx, oropharynx or oral cavity. Patients had been uniformly treated with surgery and adjuvant cisplatin-based radiochemotherapy
Clinicians sequenced 211 exons from 45 genes frequently altered in squamous cell carcinomas of the head and neck. They correlated genetic alterations with HPV status and reported outcomes.
“We have seen significant difference in genetic alteration in HPV-positive and HPV-negative carcinomas, but the effect of those alterations on outcomes is unknown,” Tinhofer said.
The researchers found 412 mutations overall, 308 of which were high-impact mutations and 104 of which were low-impact mutations. The mean number of mutations per tumor was 1.2 (range 0-7).
The most frequent high-impact alterations were found in TP53, CDKN2A and PIK3CA.
“We also observed significant differences in the mutational patterns of HPV-positive and HPV-negative cases,” Tinhofer said.
HPV-negative tumors had significantly more loss-of-function alterations in tumor suppressor genes TP53 (67%), CDKN2A (30%), PTEN (4%) and SMAD4 (3%) compared with HPV-positive tumors (P ˂ .001). HPV-positive tumors were significantly more enriched for activating mutations in driver genes PIK3CA (27%), KRAS (8%), NRAS (4%) and HRAS (2%) than HPV-negative tumors (P = .002).
Results of outcome analysis indicated that the presence of driver mutations in HPV-positive tumors was associated with a trend toward increased risk for locoregional recurrence and death (HR = 3.7, 95% CI, 0.7-20.6). This association was not found in the HPV-negative group.
In the negative group, mutations in tumor suppressive genes were associated with reduced OS.
“No such association was found in the HPV-positive group,” Tinhofer said.
After a median follow-up of 55 months, alterations in tumor suppressor genes significantly increased the risk for death (HR = 2.9, 95% CI, 1.5-5.8), locoregional recurrence (HR 5.4, 95% CI, 1.6-18.1) and distant metastasis (HR 2.3, 95% CI, 1.0-5.1).
“For the first time, we provide evidence that genetic profiles might identify patients with reduced efficacy of adjuvant cisplatin-based chemoradiation,” Tinhofer concluded. – by Rob Volansky
For more information:
Tinhofer I, et al. Abstract 6006. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Tinhofer reports a consultant/advisory role and receiving research funding and travel expenses and accommodations from Merck Serono.