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Epstein-Barr virus DNA may predict treatment efficacy for advanced nasopharyngeal cancer
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Plasma Epstein-Barr virus DNA may serve as the most significant prognostic biomarker for adjuvant therapy selection in patients with nasopharyngeal cancer, according to study results.
Further, the excision repair cross-contaminating group 1 codon 118 (ERCC1 C118T) genotype may help identify a favorable subgroup of plasma Epstein-Barr virus–negative patients who would not benefit from adjuvant therapy, according to the study researchers.
“Cisplatin combined with radiotherapy is the current standard treatment for patients with advanced nasopharyngeal cancer," Anthony T.C. Chan, MD, associate dean of medicine and professor and chairman of clinical oncology at The Chinese University of Hong Kong, and colleagues wrote. “However, the addition of cisplatin leads to added toxicities, which narrow the ultimate therapeutic gain. Therefore, the ability to identify patients who cannot benefit from cisplatin may render a more personalized therapy and maximize the therapeutic ratio.”
Single nucleotide polymorphism (SNP) of the ERCC1 gene may indicate sensitivity to platinum and radiation, according to study background.
Chan and colleagues surmised that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118T (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic for patients with nasopharyngeal cancer who receive radiotherapy alone or with cisplatin.
Researchers evaluated biomarker screening samples from the Hong Kong NPC Study Group 0502, which used post-radiotherapy plasma Epstein-Barr virus (pEBV) DNA levels to screen patients with advanced nasopharyngeal cancer for the use of adjuvant chemotherapy.
The analysis included ERCC1 SNPs from 576 consecutive patients screened by pEBV. Overall, the ECRR1 C118T or C8092A genotypes were not significantly associated with OS or RFS in the study population. Further, researchers observed no correlation between ERCC1 genotype and the ERCC1 protein or messenger RNA expression among patients with available paired biopsies.
However, ERCC1 C118T genotype significantly interacted with post-radiotherapy pEBV status for RFS (P = .0106) and OS (P = .0067). The ERCC1 C118T genotype was significantly associated with RFS (HR = 1.67; 95% CI, 1.07-2.61) and OS (HR = 2.31; 95% CI, 1.22-4.4) in the post-radiotherapy pEBV-negative population, but not in the pEBV-positive population.
“The current results validate the pEBV level as the most significant prognostic biomarker in nasopharyngeal cancer, and it is being used in the first biomarker-based, randomized, controlled clinical trial to select patients with high-risk nasopharyngeal cancer for adjuvant therapy,” Chan and colleagues concluded. “The ERCC1 C118T T/T genotype may help to identify a favorable subgroup (approximately 7%) of patients with pEBV-negative nasopharyngeal cancer who have an excellent prognosis (3-year RFS 96%; OS, 100%) who could be spared the toxicities of additional therapy.”
Patient characteristics may account for some of these outcomes, Wendy Hara, MD, and Quynh-Thu Le, MD, both of the department of radiation oncology at Stanford University School of Medicine, wrote in an accompanying editorial.
“A closer look [at Supporting Table 2 in their article] suggests that patients in the TT genotype group had less advanced lymph node disease and stage IV tumors, which may explain their better outcomes,” Hara and Le wrote. “Although the authors observed no interaction between treatment and ERCC1 C118T genotype, it is still not clear which patients received radiotherapy alone and which received chemoradiotherapy. … These findings have generated a hypothesis that will need validation in future studies, as the authors rightly point out.”
Despite potential limitations, study findings may lead to more effective personalized treatment, Hara and Lee concluded.
“[Hui and colleagues] should be commended for their important work confirming that post-treatment EBV DNA levels remain a strong biomarker for survival in patients with nasopharyngeal cancer in the modern era,” they wrote. “Stratifications of patients by appropriate biomarkers hopefully will lead to more individualized treatments and allow us to spare low-risk patients from excessive therapy while identifying high-risk patients who need treatment intensification.” – by Cameron Kelsall
Disclosure: Chan reports no relevant financial disclosures. One researcher reports receiving personal fees from Novartis and nonfinancial support from Pfizer and SIRTEX. Hara and Le report no relevant financial disclosures.
Perspective
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Barbara Ann Burtness, MD
Epstein-Barr virus (EBV)-associated nasopharynx cancer is a treatment-responsive malignancy with a recognized risk for metastasis, and standard therapy has been radiation with concomitant cisplatin, followed by adjuvant cisplatin-based chemotherapy. A recent meta-analysis from the MAC-NPC Collaborative Group supports this standard, as improved outcomes were found for both concomitant and for adjuvant chemotherapy (Blanchard P, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)70126-9.). The group at the Chinese University of Hong Kong has pioneered quantitation of plasma EBV DNA as a means of risk stratification among patients with clinical complete response to chemoradiation, and demonstrated that clearance of EBV DNA is strongly associated with longer survival. Thus, they have studied the use of post-treatment plasma EBV DNA to select patients for adjuvant therapy, with only observation following chemoradiation for patients with undetectable plasma EBV, and a randomization between adjuvant chemotherapy or observation for those with persistent plasma EBV but no clinically detectable disease. The current study attempts to integrate a biomarker of cisplatin-resistance with plasma EBV to further refine treatment decision making in this setting. The best understood biomarker of cisplatin resistance is ERCC1, the excision repair cross-complementation protein that complexes with XPF in the rate-limiting step of nucleotide excision repair. Overexpression of ERCC1 has been linked to cisplatin resistance, and more recently to radiotherapy resistance as well (Mehra R, et al. Clin Cancer Res. 2013;doi:10.1158/1078-0432.CCR-13-0152.), but the development of a clinical test to guide treatment assignment in clinical trials has been hampered by problematic methodology. Given significant post-translational modification of ERCC1, measurement of protein expression would be optimal; however, the antibody used in the seminal analysis of ERCC1 in the International Lung Adjuvant Trial lost significant specificity with changes in lots over time, and initial data could not be reproduced.
The current study is of interest because of its prospective nature and large sample size; however, there is significant heterogeneity in treatment, with 22% of patients treated with radiation alone, which limits interpretation of the ERCC1 polymorphisms under study as predictors of cisplatin resistance. The authors report no relationship between ERCC1 polymorphism and ERCC1 protein content, but in light of the concerns about ERCC1 antibody performance characteristics, this information is also difficult to interpret without greater detail about methodology. The relationship between ERCC1 codon 118 polymorphism and outcome in patients who clear EBV plasma DNA after radiation or chemoradiation will require confirmation in uniformly treated patients, and should be supported by ERCC1 mRNA and protein levels.
The NRG is currently leading a randomized phase 2/3 trial in this disease, which will randomize patients who have cleared EBV plasma DNA to observation or cisplatin-based chemotherapy (phase 3) and also conduct an exploratory randomization of patients with persistent EBV plasma DNA to conventional adjuvant chemotherapy or to the novel combination of gemcitabine/paclitaxel (NCT02135042). This trial will provide important answers regarding the utility of adjuvant chemotherapy in both cohorts, and may be enriched by analyses similar to those conducted by Hui and colleagues.
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