Liquid biopsy takes on pancreatic cancer
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Pancreatic cancer is among the deadliest malignancies, and those who specialize in its treatment eagerly embrace any tools that may help extend patient survival.
The notoriously difficult-to-treat disease is well-suited for the integration of liquid biopsy technology into detection and treatment paradigms, Todd C. Knepper, PharmD, associate member in the department of individualized cancer management at Moffitt Cancer Center and a HemOnc Today Editorial Board member, told Healio.
Despite the optimism, Knepper acknowledged unique challenges for liquid biopsy in pancreatic cancer.
Healio spoke with Knepper about current uses for the technology and potential future applications in pancreatic cancer treatment.
Healio: How might clinicians who specialize in pancreatic cancer use liquid biopsy?
Knepper: Liquid biopsies have utility for pancreatic cancer similar to other advanced or metastatic solid tumors without circulating tumor DNA (ctDNA)-based companion diagnostics. A current use case for liquid biopsies in pancreatic cancer is as a tool to identify actionable alterations when genomic testing is indicated, archival tissue is unavailable and new tumor biopsies are not feasible.
Liquid biopsy holds promise as a tool to aid in earlier detection of cancer, including as part of multicancer early detection (MCED) tests and for minimal residual disease (MRD) assessment. Early detection is of particular importance for solid tumors like pancreatic cancers that are disproportionally detected in advanced stages, when they are more difficult to treat effectively.
Because KRAS alterations are present in approximately 90% of pancreatic cancers, they are an obvious marker for MRD assessment. We are seeing evaluation of MRD through liquid biopsies help guide adjuvant treatment decisions in colorectal cancer, and this may make its way into pancreatic cancer in the not-too-distant future.
Another emerging area is around gene fusions, such as those involving NRG1, as well as other targets that occur more frequently in the minority of pancreatic cancers without KRAS mutations.
Healio: Does liquid biopsy have a role in guiding treatment decisions for pancreatic cancer?
Knepper: As there are no pancreatic cancer-specific somatic alterations that provide an indication for a specific therapy in patients with pancreatic cancer, it is important to recognize the genomic markers we are looking for. This includes the “tissue-agnostic” approvals, pembrolizumab (Keytruda, Merck) for tumor mutational burden-high (TMB-H) or microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors, and dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis) for the treatment of patients with noncolorectal cancer solid tumors with BRAF V600E mutations, or those with targetable gene fusions. Although these molecular features are uncommon in pancreatic cancer, they may be more common in KRAS wild-type disease, so it is particularly important that patients with KRAS wild-type pancreatic cancer be considered for comprehensive genomic testing, and in cases where archival tissue is unavailable and new tumor biopsies are not feasible, a liquid biopsy can be useful. Although elevated TMB may provide an indication for treatment with pembrolizumab in patients with solid tumors, the use of TMB assessed through liquid biopsies (bTMB) is an area in need of harmonization with regard to intertest consistency and determination of an optimal cutoff for TMB-H.
Liquid biopsies may also detect deleterious or suspected deleterious BRCA1/2 alterations. Confirmation of these BRCA1/2 alterations as germline may provide an indication for olaparib (Lynparza; AstraZeneca, Merck) as maintenance treatment for patients with metastatic pancreatic adenocarcinoma. Liquid biopsies may also be useful for detection of BRCA reversion mutations in patients treated with platinum-based chemotherapies and/or poly(ADP-ribose) polymerase (PARP) inhibitors. The detection of these reversion mutations is associated with acquired resistance to therapy.
Healio: What is the proper role of this technology within the pancreatic cancer treatment paradigm?
Knepper: Like tissue-based assays, the liquid biopsy can be used when patients may be eligible for a genomic biomarker-linked therapy that a regulatory agency has approved or to meet genomic inclusion criteria for a clinical trial. Its role in treatment of pancreatic cancer is likely to evolve as technology continues to improve the detection of alterations in the tumor, upon refinement of blood tumor mutational burden, within the context of MRD for monitoring of treatment response and, critically, as part of tools to improve the early detection of cancers.
See related cover story, “Liquid biopsy continues its evolution in guiding cancer care”
References:
- Chakravarty D, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02767.
- Fusco MJ, et al. JCO Precis Oncol. 2021;doi:10.1200/PO.20.00265.
- Golan T, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1903387.
- Hackshaw A, et al. Cancer Cell. 2022;doi:10.1016/j.ccell.2022.01.012.
- Kasi PM. Nat Med. 2022;doi:10.1038/s41591-022-01999-6.
- Philip PA, et al. Clin Cancer Res. 2022;doi:10.1158/1078-0432.CCR-21-3581.
For more information:
Todd C. Knepper, PharmD, can be reached at todd.knepper@moffitt.org.
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Chakravarty D, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02767.
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