单纯DNA检测不足以识别HPV相关癌症

根据《癌症研究》9月18日在线发表的2项研究，单纯检测人乳头瘤病毒(HPV)DNA，尤其是采用多聚酶链反应(PCR)方法，并不能充分确定头颈部鳞状细胞癌(HNSCC)是否由HPV所致。

确定恶性肿瘤是否与HPV相关非常重要，因为HPV相关性肿瘤的治疗应答效果和结局均更好。鉴于有关这类患者化疗和放疗降阶梯治疗的安全性和有效性评价试验正在进行中，不久或可根据肿瘤HPV状态指导HNSCC治疗。然而，目前最适合用于确认HPV相关性恶性肿瘤的生物标志物尚不清楚。

生物标志物病例分析

在第1项研究中，德国海德堡大学德国癌症研究中心的Dana Holzinger博士及其同事评估了4种生物标志物用于识别HPV相关性HNSCC的可行性。他们检测了1990~2008年确诊的199例口咽部鳞状细胞癌德国成人患者的新鲜冷冻肿瘤活检标本。4种生物标志物分别为HPV-16病毒载量、病毒癌基因RNA (E6 和 E7)、p16INK4a和 类似于宫颈癌特征的RNA模式(CxCa RNA)。

结果显示，肿瘤标本中单纯检出HPV DNA并不是很好的预后指标。这可能是因为HPV DNA通常代表既往HPV感染或最近口腔暴露，而并不反映导致恶性肿瘤的活动性HPV感染(Cancer Res. 2012 Sept. 18 [doi: 10.1158/0008-5472.CAN-11-3934])。

相反，研究者发现高病毒载量和癌症特异性病毒基因表达模式更适合用于识别HPV相关性口咽癌患者。病毒表达模式是该领域一种全新的标志物，在以前几乎不能确定病毒载量。

研究者认为，一旦建立起适于常规临床实验室检测这些标志物的标准化分析方法，精确识别HPV相关性癌肿将成为可能，进而可影响患者预后和治疗。

研究结果支持联合应用2种标志物

在第2项研究中，美国布朗大学的Caihua Liang博士及其同事分析了1999~2003年间在波士顿地区进行的一项大规模研究中的488份HNSCC样本和血清样本。

如同第1项研究，研究者发现仅凭肿瘤组织的HPV-16 DNA并不能准确预测患者总生存率或无进展生存率，尤其是通过PCR方法。相反，研究结果明确表明，HNSCC肿瘤组织HPV-16 DNA连同E6/E7抗体p16免疫染色是识别患者最佳预后的最有临床价值的替代指标(Cancer Res. 2012 Sept. 28 [doi: 10.1158/0008-5472.CAN-11-3277])。

资深作者、布朗大学流行病学系和病理学与实验室医学系教授Karl T. Kelsey博士 指出，PCR方法检测HPV DNA作为生物标志物不能很好预测头颈癌患者结局，与预示HPV暴露和(或)感染的抗体反应结果的相关性也不佳。在需要调整治疗方案时，仅凭此指标难以作出准确和精确诊断。

Holzinger博士的研究得到欧洲委员会、BMBG/HGAF-Canceropole Grand-Est和德国研究基金会部分资助，她的同事报告与Qiagen和罗氏公司存在利益关系。Liang博士的研究由美国国立卫生研究院和空服医学研究所资助，他的一位同事报告与百时美施贵宝公司存在利益关系。

随刊述评：并非如此简单

华盛顿大学/ Fred Hutchinson癌症研究中心的Eduardo Mendez博士指出，上述2项研究均表明，在解读HNSCC HPV DNA状态时应慎重。进一步确认HPV活动性感染的检测方法应得到认可，尤其是在考虑降阶梯治疗时。此外，还应考虑其他预后因素，如肿瘤分级和淋巴结状态(Cancer Res. 2012 Sept. 18 [doi: 10.1158/0008-5472.CAN-12-3285])。

Mendez博士报告与Intuitive Surgical公司存在利益关系。

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By: MARY ANN MOON, Oncology Practice

Testing for the presence of human papillomavirus DNA alone, especially using polymerase chain reaction methods, is not adequate to identify which head and neck squamous cell carcinomas are caused by the virus, according to two studies published online Sept. 18 in Cancer Research.

Identifying HPV-driven malignancies is important because they respond better to treatment and have better outcomes than those unrelated to HPV infection. Indeed, treatment of head and neck squamous cell carcinoma (HNSCC) may soon be guided by the tumor’s HPV status, since trials are now underway to determine whether de-escalation of chemo- and radiotherapy is safe and effective in such patients.

At present, however, the biomarkers that are best suited to making this identification are unclear.

Case Series Assesses Biomarkers

In the first study, researchers assessed the usefulness of four biomarkers in determining which HNSCCs in a case series were driven by HPV. They began by examining fresh-frozen tumor biopsy samples from 199 German adults diagnosed as having oropharyngeal squamous cell cancer between 1990 and 2008.

The four biomarkers were HPV-16 viral load, viral oncogene RNA (E6 and E7), p16INK4a, and RNA patterns similar to those characteristic of cervical carcinomas (CxCa RNA), said Dr. Dana Holzinger of the German Cancer Research Center at Heidelberg (Germany) University and her associates.

The simple presence of HPV DNA in a tumor sample was found to be a poor indicator of prognosis, likely because it often signaled past HPV infections or recent oral exposure, rather than active HPV infection that progressed to malignancy, the investigators said (Cancer Res. 2012 Sept. 18 [doi: 10.1158/0008-5472.CAN-11-3934]).

Instead, "we showed that high viral load and a cancer-specific pattern of viral gene expression are most suited to identify patients with HPV-driven tumors among patients with oropharyngeal cancer. Viral expression pattern is a completely new marker in this field, and viral load has hardly been analyzed before," Dr. Holzinger said in a press statement accompanying the publication of these findings.

"Once standardized assays for these markers, applicable in routine clinical laboratories, are established, they will allow precise identification" of cancers that are or are not HPV-driven, which will in turn influence prognosis and treatment, she added.

Results Back Combination Approach

In the second study, Dr. Caihua Liang of Brown University, Providence, R.I., and her associates examined 488 HNSCC samples as well as serum samples collected in a population-based study in the Boston area during 1999-2003.

As in the first study, these investigators found that the mere presence of HPV-16 DNA in these tumors, particularly when detected by PCR analysis, did not accurately predict overall survival or progression-free survival.

Instead, "our study strongly suggests that the combination of detection of HPV-16 DNA in HNSCC tumors [plus] p16 immunostaining with E6/E7 antibodies represents the most clinically valuable surrogate marker for the identification of patients . . . who have a better prognosis," they said (Cancer Res. 2012 Sept. 28 [doi: 10.1158/0008-5472.CAN-11-3277]).

"Assessment of HPV DNA using polymerase chain reaction methods as a biomarker in individual head and neck cancers is a poor predictor of outcome, and is also poorly associated with antibody response indicative of exposure and/or infection by HPV," senior author Dr. Karl T. Kelsey added in the press statement.

"We may not be diagnosing these tumors as accurately and precisely as we need to for adjusting treatments," said Dr. Kelsey, a professor in the department of epidemiology and the department of pathology and laboratory medicine at Brown University.

Dr. Holzinger’s study was funded in part by the European Commission, BMBG/HGAF-Canceropole Grand-Est, and the German Research Foundation. Her associates reported ties to Qiagen and Roche. Dr. Liang’s study was supported by the National Institutes of Health and the Flight Attendant Medical Research Institute, and one associate reported ties to Bristol-Myers Squibb.

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Not So Simple

Both of these studies demonstrate that the HPV DNA status of head and neck squamous cell carcinomas should be interpreted with caution, said Dr. Eduardo Mendez.

"Further testing to confirm HPV active infection may be warranted, particularly in consideration of de-escalation regimens," he said. In addition, other prognostic factors should be taken into account, such as tumor classification and lymph node status.

DR. MENDEZ is at the University of Washington/Fred Hutchinson Cancer Research Center, Seattle. He reported ties to Intuitive Surgical. These remarks were taken from his commentary accompanying Dr. Holzinger’s and Dr. Liang’s reports (Cancer Res. 2012 Sept. 18 [doi: 10.1158/0008-5472.CAN-12-3285]).