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Prognostic Pancreatic Cancer Biomarkers Uncovered in Prospective Proteomics Study

NEW YORK – A research team from China and France has tracked down a pair of proteomic biomarkers offering prognostic clues for pancreatic ductal adenocarcinoma (PDAC) patients receiving adjuvant chemotherapy after surgery, while demonstrating the possibility of putting together broader proteomics-based prognostic models.

"Collectively, our datasets and findings illustrate the feasibility of proteomics-guided prognosis and biomarker-aided PDAC adjuvant chemotherapy," co-first author Shulin Zhao, a physician and researcher at Shanghai Jiao Tong University School of Medicine's Ruijin Hospital, and his colleagues wrote in Nature Medicine on Monday.

For their observational prospective study, the researchers profiled tumor proteomic patterns in Chinese PDAC patients treated with pancreatectomy surgery at Ruijin Hospital between 2018 and 2020. They were searching for protein modules and individual proteins that tracked with overall survival (OS) and other clinical outcomes of interest in that cohort.

"Compared to transcriptome sequencing, proteomic profiling offers a rich resource for deciphering molecular alterations and their clinicopathological implications in disease or treatment prediction," the authors noted.

Using reversed-phase liquid chromatography and liquid chromatography-tandem mass spectrometry, the team profiled 191 treatment-naïve PDAC tumor samples and 90 corresponding tumor-adjacent tissue samples, uncovering a 14-protein prognostic model.

That model could distinguish between patients with better or worse overall survival and disease-free survival when tested in 50 more PDAC patients who had frozen tumor tissue assessed with a targeted proteomics method called parallel reaction monitoring, the researchers explained.

Beyond the general prognostic model, their analyses also led to two protein markers — NDUFB8 and CEMIP2 — that were linked to response to adjuvant chemotherapy after surgery.

"[W]e identified not only a prognostic model, we also proposed two robust biomarkers to predict adjuvant chemotherapy benefits," Zhao said in an email.

While adjuvant chemotherapy appeared to be particularly beneficial in cases with high levels of the CEMIP2 protein in the tumor compared to tumor-adjacent tissue, for example, lower levels of tumor NDUFB8 corresponded to increased survival probability after adjuvant chemotherapy.

The team subsequently validated the NDUFB8 and CEMIP2 biomarkers with immunohistochemistry profiling on samples from 466 PDAC patients from a Fudan University Shanghai Cancer Center cohort and 230 PDAC patients from a multicenter cohort in France, along with IHC testing on another 386 independent cases from the Ruijin Hospital cohort.

"Although NDUFB8 demonstrated higher statistical significance, the predictive power of CEMIP2 is still worth noting and can aid in informing patients about the potential benefits of chemotherapy," the authors concluded, noting that "[f]urther prospective studies are warranted to validate these findings and explore their utility in guiding personalized therapeutic decisions."

To begin untangling the mechanisms behind the proposed biomarkers, the team went on to perform a series of functional assays in PDAC cell lines and patient-derived organoid models lacking the NDUFB8 or CEMIP2 proteins.

The researchers plan to expand on the current findings by assessing potential proteomic markers in PDAC cases receiving neoadjuvant chemotherapy prior to surgery and in individuals with metastatic pancreatic cancer. Depending on the outcomes of further validation efforts, Zhao explained, they expect to pursue multicenter Phase III studies on the predictive value of such proteomic markers in hopes of making them a part of routine clinical management for PDAC.

More generally, the authors suggested, findings from the study "provide insights into the clinical, biological, and therapeutic understanding of PDAC."