BETHESDA, MD —Despite the development of new classes of drugs that have increased survival for many types of cancer, pancreatic adenocarcinoma (PDAC) remains one of the deadliest malignancies. PDAC accounts for 90% of all pancreatic cancers, which have an overall five-year survival rate of just 12%.
The mutational changes in pancreatic tumors drive gene instability that may both promote tumor growth and provide some resistance to treatments. Multiple signaling pathway disruption might also play a role in PDAC’s resistance. Further, the malignancy displays substantial genetic heterogeneity between patients and within individual tumors. This high degree of variability has made the identification of effective treatments for a large number of patients with PDAC quite challenging.
Researchers at Walter Reed National Military Medical Center and the Uniformed Services University joined with other investigators to examine and compare the quantitative expression and activation of HER-2/3 and other cancer-related pathways in PDAC, breast, and other solid tumor cancers to determine whether any of them might provide a new target for the development of a more effective PDAC therapy.1
The team presented their results at the 2023 American Society of Clinical Oncology annual meeting in Chicago, June 2-6, 2023.
The team used formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsy specimens from 14 PDAC patients, 14 breast cancer patients, and 40 individuals with other solid tumors. They enriched the epithelium of the tumors using laser microdissection prior to reverse phase protein array analysis (RPPA) to quantify HER-2TOTAL and phosphorylated pHER-2Y1248 and PHER-3Y1289 abundances. Next-generation sequencing of DNA and RNA was also performed.
A 32-marker RPPA panel of the enriched specimens found the levels of HER-2 expression in PDAC tumors were similar to that seen in breast cancer tumors (p=0.0962) and significantly higher than observed in other solid tumors (p=0.0112). Mean HER-2TOTAL abundance was 1.6 in PDAC, 1.3 in breast cancer and 0.9 in all other solid tumor malignancies. In contrast, abundance of activated pHER-2Y1248 and PHER-3Y1289 did not differ between PDAC, breast cancer or other solid tumors (p>0.05).
Of note, RNA sequencing showed ERBB2 overexpression in four PDAC patients but DNA sequencing did not amplify ERBB2 in any PDAC patient samples.
As nearly half of the PDAC cases had a total HER2 expression of 2+ or higher, the researchers suggested that the study could have implications for the development of new classes of HER-2 antibody drug conjugates and should be explored in a larger study.
- Randall J, Cannon TL, Hunt AL, Nutcharoen A, Johnston L, Wang H, Wadlow RC, Winer A, Huynh J, Bateman NW, Davis JB, Corgiat B, Petricoin E, Contrads TP. Proteomic quantification of HER-2 abundance and activation in pancreatic ductal adenocarcinoma tumor specimens using reverse phase protein array. 2023 ASCO annual meeting. June 2-6, 2023. Abst. e16299. J Clin Oncol 41, 2023 (suppl 16; abstr e16299).