Data continue to show that HPV status matters when it comes to treating patients with head and neck cancers—affecting both clinical behavior and prognosis—especially tumors coming from the oropharynx. That was the conclusion of several studies presented at this year's Multidisciplinary Head and Neck Cancer Symposium.
Commenting on three abstracts presented during a news briefing on the first day of the conference, the session's moderator and the Symposium Chair, David Raben, MD, Associate Professor and Associate Scientist in the Department of Radiation Oncology at the University of Colorado Comprehensive Cancer Center, said: “These cancers are showing some interesting metastatic patterns and interesting failure patterns. And, what we all want to learn and understand is—what is the relevant biology of these patients? How do we stratify and select these patients? Who might be the patients we can treat in a different way?”
Predicting Survival Post-Recurrence
Although it has been known that HPV-positive tumor status is a strong and independent predictor of reduced risk of cancer progression for patients with newly diagnosed, local-regionally advanced oropharyngeal squamous cell carcinoma (OPSCC), data reported in a plenary study show that patients with HPV-positive disease also have increased overall survival after disease progression compared with patients with HPV-negative disease (Abstract 3).
“These findings should be helpful for patient counseling and clinical decision-making,” the study's lead author, Carole Fakhry, MD, MPH, Assistant Professor in the Department of Otolaryngology Head and Neck Surgery at Johns Hopkins Medicine, said via email after the meeting.
“HPV tumor status is independently associated with improved overall survival among OPSCC patients with disease progression. Similarly, surgical salvage is an independent predictor of survival in this patient population.”
She and her colleagues conducted a retrospective analysis of 181 patients with stages III or IV OPSCC who were enrolled in two clinical trials, RTOG 0129 or 0522, with known HPV status, and cancer progression that was local, regional, and/or distant after initial treatment—cisplatin-based chemoradiation (either standard or accelerated fractionation) for patients in the RTOG0129 trial or cisplatin-accelerated fractionation with cetuximab (or without cetuximab) for patients in the RTOG0522 trial.
Patients with HPV-positive OPSCC had significantly improved overall survival rates compared with patients with HPV-negative disease (at two years after recurrence, the rates were approximately 55% vs. 28%).
The data also showed that positive HPV tumor status reduced the risk of death for patients who underwent salvage surgery—72 percent of patients with HPV-positive disease were alive two years after recurrence compared with 45 percent of patients with HPV-negative disease. For the no-surgery group, about 47 percent of patients were alive at two years past recurrence compared with about 21 percent of patients with HPV-negative disease.
Distant Metastatic Failure Patterns in HPV-Positive SCCOP
Another study found that the rates of distant metastases for patients with squamous cell cancer of the oropharynx (SCCOP) were similar regardless of HPV status, but the mean time to develop distant metastases was significantly longer after chemoradiation for patients with HPV-positive disease compared with those with HPV-negative disease.
In addition, those distant metastases for patients with HPV-positive disease tended to involve more subsites, and to more frequently involve sites that are atypical for smoking-related head and neck cancer (Abstract 125).
“This cannot be overstated—HPV-positive squamous cell carcinoma of the oropharynx is a unique disease process with a different etiology, histopathology, and clinical behavior than HPV-negative disease,” the study's lead author, Samuel Trosman, MD, a resident in otolaryngology at the Cleveland Clinic, said in a news briefing at the meeting.
“According to our data, in HPV-positive patients distant metastases seem to occur late and in unusual sites,” he added via email after the meeting.
For the 285 patients with stages III and IV SCCOP treated with chemoradiation between 2002 and 2013, the distant metastatic rate was found to be similar for patients with HPV-positive and HPV-negative disease (11% compared with 20%); but for patients with HPV-negative disease the mean time to develop distant metastases was seven months compared 21.6 months for patients with HPV-positive disease.
For the 37 patients with distant metastases, the average number of metastatic subsites involved was significantly higher for patients with HPV-positive disease than for patients with HPV-negative disease (2 vs. 1.3). Of the 28 patients with HPV-positive disease, nine patients (32%) had disseminated disease involving more than two organ systems compared with one of the patients (11%) with HPV-negative disease.
Regardless of HPV status, the lungs were the most common site of distant metastases. And, patients with HPV-positive disease were more likely than those with HPV-negative disease to have distant metastases in the liver, bone, kidney, muscle, and peritoneum, and in the intra-abdominal lymph nodes.
The findings suggest that patients may need more inclusive follow-up for longer periods of time, and patient-reported symptoms, like non-remitting pain, should not be ignored, Trosman said.
“Now that distant metastases are considered to be the main location of failure in HPV-positive disease, PET/CT screenings may need to be expanded. For HPV-positive SCCOP—given the late distant metastases—we may need to consider getting another scan later than [is typically done] in other aerodigestive tract malignancies, such as at two years after completion of treatment, or consider getting interval PET/CT scans every two years.”
“These are very provocative, hypothesis-generating studies,” Raben said during the news briefing. “The assumption has been that not many HPV-positive patients fail. But there is a group that does fail, and what do we do with those patients? How do we handle them differently than HPV-negative patients? Should all of them go to surgery? What kind of clinical trial design can we look at for those patients?”
Commenting on Fakhry's and Trosman's studies in an email after the meeting, Raben explained that both studies showed that patients with HPV-positive disease are surviving longer, but developing metastatic disease much later and in more unusual locations.
The protocols should be different for HPV-positive patients, he said—the next steps are to re-evaluate post-therapy guidelines and surveillance approaches.
Using MATH to Predict Outcomes
Another study showed that in addition to considering HPV status to predict outcome, combining patients' Mutant-Allele Tumor Heterogeneity (MATH) score as a biomarker was a more effective indicator of improved patient outcome, compared with using HPV status alone for patients with head and neck squamous cell carcinoma (HNSCC)(Abstract 7).
“Now that we know that both HPV status and intra-tumor heterogeneity matter for patient outcome, we are in a better position to personalize therapy. We can try less toxic therapies in patients likely to be cured, and try new or alternate therapies in patients likely to fail,” the study's lead author, James W. Rocco, MD, PhD, a head and neck surgical oncologist at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary and the Daniel Miller Associate Professor in Otology and Laryngology at Harvard Medical School, said in a news release.
“And, the methodology that we use to measure MATH is simple enough that it could be adopted readily in the clinic.”
The study included 305 patients with head and neck squamous cell carcinoma, whose clinical records were culled through The Cancer Genome Atlas—35 of whom had HPV-positive disease. Genetic heterogeneity of each tumor was assessed by MATH, the percentage ratio of the width to the center of the distribution of tumor-specific mutant allele fractions.
High tumor MATH was found to be a poor prognostic sign, and patients with HPV-positive disease had lower MATH values than patients with HPV-negative disease. Both MATH and HPV were significantly associated with survival. And, when stratified by HPV status, MATH was similarly related to outcome in clinically defined subsets of patients regardless of their clinical characteristics. Median follow-up for the 173 surviving patients was 22 months.
Testing for MATH is easily translatable for use in the clinical setting—and could inform which patients should be treated in a different way, Raben noted. “Even though the follow-up is short, this is exciting information that, combined with HPV status, may allow better design of prospective trials to further customize therapy.”
Relatively New Tumors
Asked to comment for this article, Tanguy Seiwert, MD, Assistant Professor in the Section of Hematology/Oncology in the Department of Medicine and Associate Director of the Head and Neck Cancer Program at the University of Chicago, pointed out that HPV-positive SCCOP/HNC is still a relatively new separate tumor entity and there is still much to learn. These studies are further evidence that it is necessary to determine how to better risk-stratify and optimally treat patients based on HPV status, and now MATH.
“Fakhry demonstrated that overall the timing of recurrence is roughly the same for HPV-positive and HPV-negative tumors. Also interestingly, the Trosman study demonstrated that clinicians need to be aware that distant failures can occur later in HPV-positive tumors—which is particularly important as these are highly curable cancers and clinicians may be less concerned about treatment failure.”
Generally, clinicians consider a patient with HPV-negative head and neck cancers cured two years after treatment is complete, but for HPV-positive tumors, the same may not be true and a more aggressive work-up including biopsy of imaging abnormalities is warranted. And once a tumor does recur, Seiwert added, “It appears that HPV-driven biology continues to determine outcomes.”
Commenting on Rocco's study, Seiwert said that further research is needed to validate the findings, but, he noted: “It certainly is a great candidate biomarker for evaluation in clinical studies, or to potentially use for stratification—I believe that MATH (or similar genomic biomarkers) will only reach their full potential once we apply genomic profiling more broadly to patients, which is probably a few years away.”
The Multidisciplinary Head and Neck Cancer Symposium, which this year had 189 abstracts, was co-sponsored by the American Society for Radiation Oncology, the American Society of Clinical Oncology, and the American Head & Neck Society.