In the Journals

Molecular surgical margin assessment may predict recurrence in head and neck cancers

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May 6, 2015

A panel of gene methylation targets in deep surgical margin imprints appeared to predict postoperative locoregional recurrence in patients with postoperative recurrence in patients with head and neck squamous cell carcinoma, according to results of a prospective study.

“Intraoperative use of molecular margin imprint analysis may assist surgeons in obtaining rigorously negative surgical margins and improve the outcome of head and neck surgery,” Wayne M. Koch, MD, director of the Johns Hopkins Head and Neck Cancer Center and a professor of oncology and otolaryngology — head and neck surgery at Johns Hopkins University, and colleagues wrote.

Wayne M. Koch, MD

Wayne N. Koch

Some patients who have histologically negative surgical margins after head and neck surgery still develop recurrence. Prior research demonstrated the recurrence rate among patients who had negative margins exceeded 40%, suggesting examination of the histologic margin failed to detect either residual cancer cells or precancerous cells in the resection bed, according to study background.

Koch and colleagues assessed quantitative methylation-specific polymerase chain reaction (QMSP) that targeted six genes to amplify bisulfite-treated DNA samples from patients who underwent surgery for head and neck cancers. The targeted genes were DCC, EDNRB, HOXA9, KIF1A, NID2 and NR2B. The researchers evaluated the associations between QMSP status of the deep margin samples and patient outcomes.

The analysis included 73 patients treated at Johns Hopkins Hospital between May 2009 and December 2013. The average time between surgery to assessment was 2.3 years.

Researchers collected margin imprints from 65 patients and margin tissues from 63 patients.

Results demonstrated two-gene methylation combinations among the DCC, EDNRB and HOXA9 genes were associated with shorter OS, RFS and locoregional RFS.

An analysis adjusted for differentiation and pathologic TNM stage showed the combination of EDNRB and HOXA9 most strongly predicted poor locoregional RFS (HR = 3.31; 95% CI, 1.3-8.46). Results of multivariable analysis showed methylation of EDNRB and HOXA9 was associated with a trend toward shorter RFS (HR = 2.74; 95% CI, 0.9-8.33) and OS (HR = 5.78; 95% CI, 0.75-44.7).

Koch and colleagues acknowledged several limitations with their study. They excluded some candidate methylation genes — including p16 — because of low methylation levels in the available tumor samples, and that only 43 of 65 (66.2%) of imprint samples were positive for the most promising EDNRB/HOXA9 combination.

“Because we have already developed an innovative, rapid QMSP pipeline, molecular margin analysis is ready for application in the operating room,” Koch and colleagues wrote. “Although these findings will need to be externally validated in an independent cohort, we have demonstrated that securing not only a histologically negative margin but also a molecularly negative surgical margin ultimately may lead to improved patient outcomes.”

The histologic approach remains effective in the clinical setting, but molecular surgical margin assessment can capitalize on the strong understanding of the genetic basis of head and neck squamous cell carcinoma, Li Mao, MD, professor and chair of the department of oncology and diagnostic sciences at the University of Maryland Marlene and Stewart Greenbaum Cancer Center, and David Clark, BS, a student at the university, wrote in an accompanying editorial.

“The path to developing an effective and clinically applicable assay for molecular surgical margin assessment remains challenging,” Mao and Clark wrote. “Another important issue that we may have to consider is how the information from molecular surgical margin assessment will change our current practice to achieve better outcomes.”

The area from which additional tissue can be removed might be limited in some patients, Mao and Clark wrote.

“It may be necessary to establish a consortium — to include surgeons, pathologists, oncologists, radiologists, geneticists/biologists and engineers — to rapidly develop and advance molecular surgical margin-based assays for use in a clinical setting,” they wrote. – by Anthony SanFilippo

Disclosure: The researchers, Mao and Clark report no relevant financial disclosures.