A new horizon in cancer care: liquid biopsy

Mehmet Sitki Copur, MD, gives his take on liquid biopsies and how they can be used in gastrointestinal cancer.

With innovations in liquid biopsy platforms over the past decade, the oncology world is witnessing the transformation of precision medicine in cancer care. The first FDA approval of a liquid biopsy test was the CellSearchCTC enumeration platform in 2013, which focused on the detection of circulating tumor cells (CTCs) in the blood.1 In 2016, the FDA approved the first circulating tumor DNA (ctDNA) blood test, the cobas EGFR v2 mutation test, to detect EGFR Genetic mutations in patients with non-small cell lung cancer (NSCLC).2 In 2020, the FDA approved 2 additional full genomic profiling liquid biopsy assays, Guardant360 CDx and FoundationOne Liquid CDx, both of which use next-generation sequencing technology to detect tumor genomic alterations in cDNA without cells in the body. blood.3.4 Although Guardant360 CDx can detect changes in over 60 different genes that are relevant in solid tumors, FoundationOne Liquid CDx can identify mutations or alterations in 300 or more genes.

In this issue of the journal, Christine Chung, DO, and her colleagues5 report on the biological and clinical correlates of genomic alterations in 77 consecutive patients with pancreatic ductal adenocarcinoma (PDAC), using the Guardant 360 CDx blood molecular profiling assay. This timely article reflects the current momentum in the use of liquid biopsies as an alternative to traditional tissue biopsies. The current standard, tissue-based molecular profiling is more invasive, not always easy to perform, and takes longer to produce results.6 Blood-based molecular profiling tests, on the other hand, are fairly recent. Despite recent advances, uncertainties remain; one determines the standardization of the schedule of blood collection and extraction methods, and another determines the test cutoffs for cDNA or CTC positivity.seven There are also possibilities for false positive or false negative results. Currently, the FDA recommends confirmation of negative Guardant 360 CDx or FoundationOne Liquid CDx test results with a tissue biopsy test. Likewise, the National Comprehensive Cancer Network 2021 clinical practice guidelines state that cell-free cDNA testing should not replace histologic tissue diagnosis, unless a patient is medically unfit for invasive tissue sampling. While in most cases a positive mutation, such as BRCA, BRAF, EGFR, Where FGFR, guides the targeted therapeutic decision, confirmation of a negative mutation may also have implications for treatment, as in the case of KRAS Wild-type tumors in colon cancer patients.

Although the guidelines are not well established, the basic principles of tumor biology can help in the decision of fluid vs tissue biopsy. The higher the tumor burden, the higher the yield can be for the detection of ActDNA in blood molecular tests. In a patient with early stage cancer or in a patient with metastatic cancer whose tumor responds well to current treatment, tumor shedding may not be high enough to detect cDNA in the blood. In this group of patients, tissue biopsy may be more appropriate. On the other hand, in a patient with metastatic cancer whose tumor progresses during or soon after treatment, blood-based molecular tests may be more applicable and may provide a rapid response for the next choice of treatment.

In the retrospective examination performed by Chung et al, the initial stage of patients varied from stage I to stage IV; the largest proportion (48%) had stage IV disease at the time of diagnosis. The blood of 35 of 77 (45%) patients exhibited one or more genetic alterations, with a median number of 3 alterations per patient. The gene most often altered was TP53, followed by KRAS, BRCA2, SMAD4, and CDKN2A. Among the patients with alterations, 36% had one or more potentially exploitable mutations, most often BRCA2 (12%); this was followed by STK11, KRAS, PIK3CA, NF-1, EGFR, and FGFR.

The humbling fact is that so far no agent has been approved against the most commonly identified mutations in PDAC other than olaparib, a PARP inhibitor (Lynparza). Clinical trials testing other agents are also limited. In addition to finding targeted treatment options, other valuable uses of liquid biopsy technology may be the application of serial liquid biopsy tests in patients currently undergoing treatment and the quantitative assessment of cDNA. to predict response and long-term clinical benefit. Likewise, monitoring patients who have completed curative treatment using molecular blood tests could be a valuable tool in determining the risk of recurrence.

Despite the growing popularity of liquid biopsy tests in cancer care, its current use appears to be primarily limited to late stage patients, as is the case in this study by Chung et al. However, in addition to its potential for diagnosing cancer, guiding treatment decisions, and monitoring resistance to treatment, several studies are currently underway to investigate how commercial liquid biopsy tests might track minimal residual disease. Ongoing research is also exploring the utility of liquid biopsy in early stage cancers as well as in detecting cancers in asymptomatic people at moderate risk. Two liquid biopsy early detection tests are making their way into clinical trials: the LUNAR-2 test is designed to detect colorectal cancer in asymptomatic people at average risk, and the Galleri test can detect more than 50 types of cancer, including including pancreatic cancer.8-10 One advantage of the Galleri test is that it may be able to detect cancers for which we do not have an effective screening test, such as pancreatic cancer. It is encouraging to see that blood-based molecular testing is increasingly being integrated into a variety of pivotal clinical trials, supporting the idea that this technology will be part of the standard of care of tomorrow.

The references

  1. What is the CELLSEARCH Circulating Tumor Cell Assay (CTC)? CellSearch. Accessed October 21, 2021. https://bit.ly/3vyTbd3
  2. The FDA approves the first blood test to detect a genetic mutation associated with non-small cell lung cancer. Press release. FDA; June 1, 2016. Updated March 1, 2019. Accessed October 21, 2021. https://bit.ly/3jr6DLf
  3. Guardant Health Guardant360 CDx, the first liquid biopsy approved by the FDA for the complete profiling of tumor mutations in all solid cancers. Press release. Guardian of health; August 7, 2020. Accessed October 21, 2021. https://bit.ly/3B4SkSK
  4. The FDA approves Foundation Medicine’s FoundationOne Liquid CDx, a comprehensive pan-tumor liquid biopsy test with multiple companion diagnostic indications for patients with advanced cancer. Press release. Medicine foundation; October 8, 2020. Accessed October 21, 2021. https://bit.ly/3Gbt7tC
  5. Chung C, Galvin R, Achenbach E, et al. Characterization of blood molecular profiling in pancreatic adenocarcinoma. Oncology (Williston Park). 2021; 35 (12):XX-XX. doi: 10.46883.ONC.2021.3512.0XXX
  6. Sehayek O, Onn A, Roisman LC, et al. The impact of turnaround time for liquid biopsy versus tissue biopsy in advanced NSCLC. 2020 Thematic Meeting of the International Association for the Study of Lung Cancer: Liquid Biopsy – Global Virtual Event; 2-3 October 2020; virtual. Abstract VP01.33.
  7. Merker JD, Oxnard GR, Compton C, et al. DNA analysis of circulating tumors in cancer patients: a joint review by the American Society of Clinical Oncology and the College of American Pathologists. J Clin Oncol. 2018; 36 (16): 1631-1641. doi: 10.1200 / JCO.2017.76.8671
  8. Beer TM, McDonnell CH, Nadauld L, et al. Interim results of PATHFINDER, a clinical use study using a methylation-based test for the early detection of several cancers. J Clin Oncol. 2021; 39 (suppl 15): abstr 3010. doi: 10.1200 / JCO.2021.39.15_suppl.3010
  9. Klein EA, Richards D, Cohn A, et al. Clinical validation of a methylation-based targeted multi-cancer early detection test using an independent validation set. Anne Oncol. 2021; 32 (9): 1167-1177. doi: 10.1016 / j.annonc.2021.05.806
  10. Lee J, Kim HC, Kim ST et al. Multimodal circulating tumor DNA (ctDNA) colorectal neoplasia test for asymptomatic and early colorectal cancer (CRC). J Clin Oncol. 2021; 39 (suppl 15): abstr 3536. doi: 10.1200 / JCO.2021.39.15_suppl.3536


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