Dr Lee said that the 8F1 ERCC1 antibody used in the trial may have been nonspecific to the ERCC1 202 isoform protein. If that was the case, it could have contributed to potential false-positive results and misclassification of patients.
“We examined the obligate XPF partner protein following a new report that 8F1 ERCC1 antibody cross-reacted with an unrelated protein, and we observed that XPF negative derived some benefit from platinum therapy but there was little association in XPF-positive patients,” he said. “Future studies could focus on developing assays that target the functional ERCC1 202 isoform protein with or without obligate XPF protein or focus on new multi-marker approaches.”
In an accompanying editorial, Sophie Postel-Vinay, MD, PhD, and Jean-Charles Soria, MD, PhD, of the Gustave Roussy Cancer Campus, Paris, France, questioned whether optimal tools to evaluate ERCC1 as a predictive biomarker for targeted chemotherapy exist yet. They argued that inconsistent results in commercial panels that test for ERCC1 preclude their use in therapeutic decision making, and said that using them to rule out the use of platinum chemotherapy may do more harm than good. They were, however, optimistic about developing technologies for identifying predictive biomarkers.
“The current lack of reliable techniques that would allow us to specifically assess the functional isoform is of course a limitation, but novel technologies such as the development of RNA sequencing on FFPE [formalin-fixed paraffin-embedded] samples or proteomics using mass spectrometry open promising perspectives,” said Dr Postel-Vinay in an email to Cancer Therapy Advisor. “It is clear that no single biomarker will ever be able to recapitulate all predictive factors for sensitivity to a cytotoxic agent. Therefore, approaches favoring a more global or functional evaluation of DNA repair status might be more relevant.”
RNA sequencing (RNA-seq) technology is a rapidly expanding field, and its application to FFPE samples is promising. A 2015 study found that RNA-seq can successfully obtain microRNA profiles of FFPE samples with performance characteristics comparable to those found in microarrays, even in samples 15 to 20 years old and despite fragmentation of ribosomal and mRNA.4 This method could be used to design studies that examine FFPE samples from large patient cohorts.
The method’s accuracy could be further improved by increasing sequencing depth or reducing ribosomal fragments in FFPE RNA samples. Ongoing efforts to develop benchmark standards, optimize assays for clinical conditions, and demonstrate assay reproducibility could help expand the clinical value of RNA-seq for identifying biomarkers in a variety of applications, including targeted chemotherapy.5
The use of mass spectrometry imaging (MSI) to detect biomarkers in cancer treatment is developing promise. In an abstract presented at the American Association for Cancer Research (AACR) 2016 Annual Meeting in New Orleans, researchers found that MSI allowed for the direct determination of biomarkers in FFPE samples from patients with ALK-positive adenocarcinoma who were treated with an ALK-specific kinase inhibitor.6 Their results suggest that analogous MSI techniques could help guide customized chemotherapy decisions in lung cancer.