Radiosensitive Variation Key in HPV-Positive Head and Neck Cancer

Kate Johnson

May 01, 2013

GENEVA, Switzerland — Increased radiosensitivity likely contributes to improved outcomes in patients human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCC), according to a new study.

The findings point to a potential new approach that could enhance radiosensitivity further in these tumors, said Thorsten Rieckmann, PhD, from University Medical Center Hamburg Eppendorf in Germany.

The study results, which he presented here at the 2nd European Society for Radiotherapy & Oncology (ESTRO) Forum, were also published online April 19 in Radiation and Oncology.

The work was named 1 of 2 top-scoring abstracts at the ESTRO meeting.

Dr. Rieckmann and colleagues compared a panel of 5 HPV-positive and 5 HPV-negative HNSCC cell lines, and demonstrated a statistically significant difference in average radiosensitivity between the 2 panels.

However, in the HPV-positive cells, "we saw a very high variation in radiosensitivity, so clearly not every HPV-positive cell line is equally highly radiosensitive," Dr. Rieckmann told meeting delegates.

"Therefore, caution should be urged when considering the deintensification of therapy via dose reduction," the researchers write. "Additional stratification within the subentity of HPV/p16-positive HNSCC may be necessary to more precisely predict individual tumor sensitivity."

"Until we have molecular markers to predict radiosensitivity in HPV-positive HNSCC, pack-years of smoking, as suggested by Ang et al [N Engl J Med. 2010;363:24-35], are probably the best option," he told Medscape Medical News.

The study demonstrated that a compromised DNA repair process is likely the reason behind the more favorable prognosis for patients with HPV-positive HNSCC treated with radiotherapy, compared with patients with HPV-negative cancers.

The researchers note "a pronounced and sustained G2-arrest" in the panel of HPV-positive cells, said Dr. Rieckmann.

The G2 (or premitotic) phase of the cell cycle allows cells to repair DNA damage. The data suggest that a compromised DNA repair capacity in HPV-positive HNSCC cells is what leads to their enhanced radiosensitivity, he explained.

"Can we expect something from these findings that will benefit patients?" he asked. "We think we can."

Building on this newly discovered defect in DNA repair, new therapies could make HPV-positive tumors even more radiosensitive, allowing radiotherapy to be deintensified for some patients without compromising outcome, he said.

"Our findings demonstrate that the enhanced radiosensitivity of HPV-positive HNSCC cells comes from a compromised DNA repair process and can be further boosted by the inhibition of cell-cycle arrest mechanisms," he told Medscape Medical News. "The normal function of G2-arrest is to provide time for DNA repair; therefore, its inhibition should confer radiosensitivity," he explained.

With this in mind, his team targeted Chk1, "the master regulator of G2-arrest," and demonstrated that the inhibition of Chk1 leads to the inhibition of G2-arrest in HPV-positive cancer cells.

"In this case, the rationale is not to further reduce DNA repair, but to compromise the G2/M cell-cycle checkpoint that protects the cells from passing mitosis with unrepaired chromosomes. In brief, we reduce the time available for repair," he explained.

"This was true for 4 of 5 cell lines in our panel," and not the case for normal fibroblasts, he added.

Dr. Rieckmann and colleagues report that, to the best of their knowledge, there are no published data that demonstrate the enhancement of radiosensitivity in HPV-positive HNSCC, nor are there any clinical trials based on this phenomenon.

"Several trials aimed at deintensification of therapy for HPV-positive HNSCC have been or are about to be initiated. Some of them utilize the anti-EGFR antibody cetuximab to substitute for cisplatin; however, there are no in vivo or in vitro data that actually demonstrate a radiosensitizing effect in HPV-positive HNSCC."

"This is very exciting work because the investigators identified a mechanism and a target for the enhanced radiosensitivity of HPV-positive HNSCC, said Arlene Forastiere, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who was asked by Medscape Medical News to comment on the findings.

Clinically, we know there is heterogeneity among HPV positive cancers; most do well, but some do not. Our challenge is to identify those subsets based on molecular-genetic characteristics that can then be manipulated. This study moves us in that direction," Dr. Forastiere said.

Dr. Rieckmann and Dr. Forastiere have disclosed no relevant financial relationships.

Radiother Oncol. Published online April 19, 2013. Abstract

2nd European Society for Radiotherapy & Oncology (ESTRO) Forum. Abstract OC-0499. Presented April 22, 2013.


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