Genomic analysis of tumor tissue and healthy tissue from 279 patients with previously untreated head and neck squamous cell carcinomas highlighted 15 genes that were significantly mutated across all tumor samples. Among human papilloma virus–positive samples, the study revealed a 40% to 50% rate of PIK3CA alterations linked with very low rates of EGFR alterations.

Investigators in The Cancer Genome Atlas (TCGA) Research Network have uncovered numerous genomic aberrations involved in head and neck squamous cell carcinomas (HNSCC), which are often caused by tobacco use but have recently been increasingly associated with human papilloma virus (HPV).

“We've found that these tumors are heterogeneous across all patients,” says David Neil Hayes, MD, MPH, a medical oncologist at the University of North Carolina in Chapel Hill, cochair of the TCGA head and neck cancer working group. Hayes presented these findings at the American Association for Cancer Research Annual Meeting 2013 in Washington, DC, held April 6–10.

The study examined tumor and healthy tissue samples from 279 patients with HNSCC. Among the samples from this group, 80% of tumors were associated with tobacco use and 13% were HPV-positive.

For smoking-related cancers, 60% to 70% of patients already have lymph node–positive cancer at the time of diagnosis and typically have 5-year survival rates of about 50%, says Hayes.

The outlook for people with HPV-positive tumors is more optimistic, with at least one study showing a 5-year survival rate of 90%. However, standard treatment—radiation plus chemotherapy—is aggressive and toxic. “There's an incentive to find targeted treatments that cause less toxicity,” notes Hayes.

Among HPV-positive samples, the study revealed that 40% to 50% harbored alterations in PIK3CA. Interestingly, these were linked with very low rates of EGFR alterations. “EGFR has been described as universally expressed in head and neck cancer,” says Hayes. “But these findings suggest there may be a subgroup that does not fit this description.”

He suggested that this finding may raise questions about the efficacy of Erbitux (cetuximab; Bristol-Myers Squibb and Lilly), which has been approved by the U.S. Food and Drug Administration for the treatment of metastatic HNSCC in patients with HPV-positive tumors.

All 279 tumor samples showed 15 significantly mutated genes, among them CDKN2A, TP53, PIK3CA, NOTCH1, HRAS, and NFE2L2.

Of these, PIK3CA stands out because inhibitors for it are already in the works. Activated in approximately 21% of all samples, PIK3CA shows the highest frequency of a druggable mutation found in HNSCC. “PIK3CA inhibitors are being developed for breast cancer,” says Hayes. “Let's see if these drugs work in head and neck cancer.”

Additionally, roughly 5% of samples exhibited HRAS mutations, and those tumors might be vulnerable to farnesyltransferase inhibitors. These drugs have shown disappointing clinical results so far, “but this might be fertile ground for revival,” says Hayes.

The study also revealed that the NOTCH and/or NFE2L2 pathways are altered in 30% to 40% of cases of HNSCC, suggesting that these pathways could be promising targets for new therapies.

Overall, the findings inform the development of a rational HNSCC research strategy, says Hayes. “There are many potential drugs, but only so many patients, and so much time and money,” he says. “If we can design trials around the features of the tumor, that might be a more effective way to make progress.”

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