Mutant-allele tumor heterogeneity, HPV status predicted HNSCC outcomes

Issue: April 10, 2014

Mutant-allele tumor heterogeneity at the time of surgery served as a prognostic biomarker based on HPV status for patients with head and neck squamous cell carcinoma, according to study results presented at the Multidisciplinary Head and Neck Cancer Symposium.

Perspective from Barbara Burtness, MD

James Rocco, MD, PhD, a head and neck surgical oncologist at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary, and the Daniel Miller chair in otology and laryngology at Harvard Medical School, and colleagues used The Cancer Genome Atlas to evaluate exome next-generation sequencing and clinical data from 302 patients.

James Rocco

At a median follow-up of 22 months, 173 surviving patients were available for analysis.

Based on the results of previous studies, Rocco and colleagues limited their analyses to mutant-allele fractions ≥0.075 and set the mutant-allele tumor heterogeneity (MATH) cutoff value at 32.

Overall, they found high tumor MATH at the time of surgery was associated with poor prognosis (HR=2.1; 95% CI, 1.4-3.2).

The 35 patients with HPV-positive tumors exhibited lower average MATH values than patients with HPV-negative tumors (34.2 ± 2.3 vs. 39.8 ± 0.7; P=.007).

Bivariate analyses indicated MATH and HPV status were associated with survival in HNSCC (high-MATH HR=1.8; 95% CI, 1.2-2.8; HPV-positive HR=0.36; 95% CI, 0.18-0.75).

High MATH was still associated with survival in subset analyses stratified for HPV status among patients with negative tumor margins (HR=2.2), N0 nodal classification (HR=2) and American Joint Committee on Cancer stage III to IV disease (HR=1.7).

"Calculating patients’ MATH marker as well as their HPV status is a more reliable predictor of patient survival, and the methodology that we used to measure MATH is simple enough that it could be adopted readily in the clinic," Rocco said in a press release. "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 for our patients. We can try less toxic therapies in patients likely to be cured, and try new or alternate therapies in patients likely to fail. In addition, it may help identify the patients most likely to benefit from clinical trials."

For more information:

Rocco JW. Abstract #7. Presented at: 2014 Multidisciplinary Head and Neck Cancer Symposium; Feb. 20-22, 2014; Scottsdale, Ariz.

Disclosure: The researchers report no relevant financial disclosures.

Perspective

Barbara Burtness, MD

Rocco and colleagues report on patients included in The Cancer Genome Atlas Head and Neck Cancer dataset, correlating outcome with HPV status as well as mutant allele heterogeneity (MATH), a measure of intratumoral genetic heterogeneity. Both HPV-negative status and high MATH score predicted a worse outcome, and unsurprisingly, these were related.

The degree of intratumoral genetic heterogeneity might be expected to rise with greater mutational burden and with loss of tumor suppressor function, and it is well established that overall mutational burden and p53 mutation are strongly inversely associated with HPV positivity. Within predominantly HPV negative cohorts, disruptive p53 mutation predicts for worse survival, even in patients with favorable clinical features (Poeta ML. N Engl J Med. 2007;357:2552-2561. Lindenbergh-van der Plas M. Clin Cancer Res. 2011;17:3733-3741).

It will be interesting to discover if specific genetic mutations predict for higher MATH score, and whether MATH is a stronger discriminator than disruptive p53 mutation. In either case, sufficient evidence exists to support trials of intensification of adjuvant therapy for resected patients with disruptive p53 mutation.

Barbara Burtness, MD

HemOnc Today Editorial Board member

Disclosures: Burtness reports no relevant financial disclosures.