Editors: Donna E. Hansel, MD, PhD, chair of pathology, Oregon Health and Science University, Portland; Richard D. Press, MD, PhD, professor and director of molecular pathology, OHSU; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; and Andrés G. Madrigal, MD, PhD, assistant professor, clinical, Ohio State University Wexner Medical Center, Columbus.
Employing ctDNA testing to inform the use of adjuvant chemotherapy for colon cancer
August 2022—Surgical resection remains the mainstay of treatment for locally advanced (stages II and III) colorectal carcinoma. Patients with node-positive (stage III) cancer receive adjuvant chemotherapy after surgery. However, the medical community continues to debate whether node-negative (stage II) cancer requires additional treatment. Current guidelines recommend that high-risk stage II patients be treated with adjuvant chemotherapy, but the definition of high risk is inadequate. Moreover, the survival benefit of treatment with adjuvant chemotherapy, even for high-risk patients, is minimal. Liquid biopsy is a promising clinical assay for detecting minimal residual disease for many solid tumors, but it is not widely used. For an assay to become standard of care, it must demonstrate analytical validity, clinical validity, and clinical utility. The analytical validity of liquid biopsies in the setting of colon cancer minimal residual disease detection is well established. Tumor alterations can be detected in a patient’s blood in the form of circulating tumor DNA (ctDNA), often before recurrence is found clinically. The clinical validity of liquid biopsies, or their ability to distinguish clinically relevant groups of patients, has also been demonstrated, as colon cancer patients have a high risk of recurrence when ctDNA is detected after surgery. The study featured herein examines clinical utility—that is, whether using ctDNA assays to guide adjuvant therapy decision-making in stage II colon cancer will benefit patients. For the study, 455 patients with stage II colon cancer were randomized, after surgical resection, to standard management or ctDNA-guided management. The decision of whether or not to proceed with adjuvant chemotherapy for patients in the standard-management group was based on clinicopathological characteristics, such as T4 stage or lymphovascular invasion. Patients in the ctDNA-guided–management group had liquid biopsies performed at four and seven weeks post-surgery. If either biopsy was positive, the patient was treated with adjuvant chemotherapy. If both samples were negative, the patient did not undergo further treatment. The two-year recurrence-free survival for the ctDNA-guided–management and standard-management groups was similar (93.5 percent and 92.4 percent, respectively). Most notable was that only 15 percent of patients in the ctDNA-guided–management group received chemotherapy compared with 28 percent in the standard-management group. The study concluded that using ctDNA testing to guide management in stage II colorectal cancer patients reduced the use of toxic adjuvant chemotherapy without compromising outcomes.
Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022. doi:10.1056/NEJMoa2200075
Correspondence: Dr. Jeanne Tie at tie.j@wehi.edu.au
Use of a panel of plasma proteomic biomarkers to screen for alcohol-related liver disease
Alcohol-related liver disease is a common cause of liver failure and the leading indication for liver transplantation. It typically progresses through a number of phases, including alcohol-related fatty liver, steatohepatitis with inflammation, fibrosis, and, ultimately, cirrhosis. The diagnosis of alcohol-related liver disease (ALD) requires microscopic examination of a liver biopsy, in which a number of histologic markers, such as lobular inflammation, ballooned hepatocytes, steatosis, and fibrosis, are scored. Because liver biopsy is an invasive procedure fraught with potential complications, definitive diagnosis of ALD often occurs late in the clinical course, during the cirrhosis phase. Earlier diagnosis would hasten intervention and treatment for alcoholism, potentially slowing disease progression. There is a clinical need for noninvasive biomarkers of ALD that could be used to screen patients. Unfortunately, however, the current biomarkers have limited accuracy and are only useful in high-risk populations. Molecular pathology traditionally focuses on DNA sequencing, but many other biological molecules have clinical and functional significance. The authors conducted a study that used mass spectrometry-based proteomics to examine the molecular pathogenesis of ALD. This methodology allows for the identification and quantification of thousands of proteins in biological or clinical specimens. The authors examined plasma proteomics for 459 patients with ALD and 137 controls. An expert pathologist assessed liver biopsies, available for a majority of the patients with ALD, for histologic markers of liver disease. Two hundred and twenty-five proteins were significantly differentially abundant across the histologic stages of fibrosis, inflammatory activity, and steatosis. The authors used machine-learning classifiers to identify a subset of proteins that correlated best with disease status and settled on a set of nine proteins that predicted fibrosis, six that predicted inflammatory activity, and 12 that predicted liver steatosis. This panel of biomarkers was more accurate for predicting liver disease than any of 15 other commonly used clinical tests, such as transient elastography for measuring liver fibrosis (FibroScan) or AST/ALT ratio for assessing inflammation. Importantly, the protein panels in plasma were able to exclude fibrosis and inflammation in the healthy control patients. The authors also examined the plasma proteomic panel in an independent validation cohort of 63 patients and confirmed that it predicts liver disease better than other standard-of-care clinical tests. This study not only shows great promise for creating a clinical assay for the early detection of ALD but also highlights the potential for developing proteomic assays informed by machine learning.
Niu L, Thiele M, Geyer PE, et al. Noninvasive proteomic biomarkers for alcohol-related liver disease. Nat Med. 2022. doi:10.1038/s41591-022-01850-y
Correspondence: Dr. Matthias Mann at mmann@biochem.mpg.de