The retrospective study used the ADAPT approach to create ssODN libraries from pretreatment tissue samples that were submitted to certified central laboratories. The libraries were enriched using positive and negative selection techniques using tumor tissue of patients who did or did not respond to trastuzumab.
The enriched libraries were then tested against a cohort independent of the initial development cohort and translated into a staining scoring system similar to that used for standard HER2 immunohistochemistry. Once the 2 testing libraries were established — those who benefited and those who did not benefit from trastuzumab — patient samples were stratified according to time to next treatment (TTNT).
Pretreatment tissue from another independent cohort of 61 patients with breast cancer was evaluated using the developed libraries. Positivity with the benefit library was significantly associated with TTNT, with a median event-free time of 429 days for positive cases compared with 129 days for negative cases (hazard ratio [HR], 0.384; 95% CI, 0.21-0.70; P = .001). The ADAPT approach resulted in an ROC-AUC of 0.78 compared with a ROC-AUC of 0.47 with standard HER2 testing.
Dr Spetzler noted that the study assessed a surrogate endpoint for clinical benefit because response rate “is not routinely or robustly captured in EMR systems.”
“From a clinical perspective, it would be difficult for physicians to not give trastuzumab to a HER2-positive patient — we are not suggesting that. It is more looking at a single biomarker–driven population and asking if we can do better by expanding it by understanding the system as a whole,” Dr Spetzler said.
Though the trastuzumab assay should be further validated in a prospective, randomized trial, Dr Spetzler said that further development of this particular assay is not planned, as its use to opt out HER2-positive patients from HER2-targeted therapy may be controversial. He noted, however, that the researchers are “developing a number of different assays using clinical trial samples and going through more formal clinical validation procedures so we have the underlying confidence to make recommendations for treatment of patients.” The next study to be published will be in pancreatic cancer.
Another opportunity for the ADAPT platform is developing assays for clinical trial use, such as identifying a small subset of patients who may benefit from an agent that did not fulfill its primary endpoint in a broader population.
- Domenyuk V, Zhong Z, Stark A, et al. Plasma exosome profiling of cancer patients by a next generation systems biology approach. Sci Rep. 2017;7:42741. doi: 10.1038/srep42741
- Domenyuk V, Gatalica Z, Santhanam R, et al. Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes. Nat Comm. 2018;9:1219. doi: 10.1038/s41467-018-03631-z