The future is rapidly approaching; several hundred trials are using circulating tumor DNA detection and quantification for either intervention or observation.
What if there were a test that involved just a blood draw or saliva to determine whether a patient with cancer would likely respond to and benefit from immunotherapy or adjuvant therapy? What about a blood test any oncologist could order that would identify lingering cancer cells months before they might show on imaging? That future is rapidly approaching; several hundred trials are using circulating tumor DNA (ctDNA) detection and quantification for either intervention or observation.1
One advantage ctDNA has over traditional scanning methods is that even if all the disease appears to be eliminated with treatment, ctDNA can show minimal residual disease (MRD). MRD is a biomarker that facilitates prognosis, treatment stratification, and personalization based on tumor profile.1 It also helps identify potential for recurrence of disease.
As a component of cell-free DNA, ctDNA is shed by malignant tumors into bodily fluids such as blood, urine, and saliva. Using MRD for diagnosis and monitoring requires detecting tiny bits of tumor remaining after curative intent treatment. Given that ctDNA levels are usually low, especially for localized disease, highly sensitive assays and detection methods are needed. Investigators have shown that “when a patient has MRD detected after treatment, they have a high chance of relapse that can be mitigated with treatment,” Aadel Chaudhuri, MD, PhD, assistant professor of radiation oncology at Washington University School of Medicine in St Louis, Missouri said in an interview with Targeted Therapies in Oncology. By identifying high-risk patients through MRD detection and then treating them, outcomes can improve, he said.
Although MRD is commonly associated with hematological malignancies, investigators are also exploring the use of liquid biopsies to quantify and analyze MRD in solid tumors through ctDNA analysis. “We haven’t really had good MRD biomarkers for solid tumor malignancies, with the exception of ultrasensitive PSA [prostate-specific antigen] for prostate cancer,” Chaudhuri said.
ctDNA MRD can show residual disease in solid tumors like lung cancer earlier than use of imaging techniques during routine clinical surveillance.1 Although standard imaging can detect macroscopic disease recurrence, it can be difficult to assess disease presence caused by inflammation or fibrosis, which can appear similar to tumor tissue, particularly after radiation therapy. With disease progression, outcomes can be poor in patients with lung cancer. Detecting MRD through ctDNA could make disease recurrence easier to detect and allow for earlier treatment and potentially better clinical results.
Tumor-specific mutations were first found in patients with hematologic malignancies in 1994.2 The potential use of ctDNA involves the detection of specific mutations in plasma or serum of cancer patients, suggesting that it could serve as a real-time marker of disease burden. A recent meta-analysis showed ctDNA’s advantages for specificity in diagnosing hematological malignancies and as a good alternative to biopsy because of noninvasive collection methods. For sensitivity, however, ctDNA did not prove superior to biopsy. Investigators note that the lack of sensitivity could be due to the highly heterogeneous nature of hematologic tumors.2 They recommend a panel-based next-generation sequencing (NGS) approach.
MRD is not widely used outside research as a biomarker for treatment in hematology and solid tumors. “These studies are really opening the door toward new standards of care,” said Chaudhuri. Several commercially available assays are quite sensitive, he said, and are available for clinicians to order and use with patients for testing. “[Some] clinicians are using these to inform treatment decisions and to identify resistance mutations.” However, no MRD guidelines are available for clinical decision-making. “As some of these trials get reported, that will change.”
Some clinicians are relying on trials such as the IMvigor010 trial (NCT02450331) for bladder cancer and other major studies with results reported over the past year, for patients with challenging cases. When unsure whether the patient has residual disease, these investigators are ordering assays and bringing the results to a molecular tumor board to determine whether they can make an informed treatment decision, Chaudhuri said. None of the assays have FDA approval but some have been fast-tracked, he said. “And those are the ones that clinicians have the option to order. Those companies are reaching out to clinicians and trying to make a case that, for challenging cases, ctDNA MRD can help add data.”
Current assays can detect ctDNA levels as low as around 10 or 20 parts per million (ppm), Chaudhuri said. “That’s a level so low it’s almost like finding a needle within a city of haystacks.” Different assay types utilize different methods. Some assays focus exclusively on genomic alterations; others look at methylation signatures, which have been shown to exhibit sensitivity and specificity for cancer, he said. There are also assays with a genome-wide approach to assessing ctDNA MRD, rather than a more targeted approach. Some require a patient tumor sample to generate a personalized assay, whereas others are off-the-shelf and can be applied in a tumor-naive fashion.
Research, including some by Chaudhuri, is also detecting ctDNA with other bodily fluids, albeit at lower levels. When using urine, the assays seem to be more sensitive in malignancies like bladder cancer.3 “The biofluid that is most proximal to the tumor tends to be enriched for the malignancy,” he said. “We were surprised that we were able to detect any ctDNA in urine, following neoadjuvant chemotherapy for oligometastatic colorectal cancer. Levels were extremely low, about 10-fold lower than what they were in plasma.” But as this noninvasive approach using urine is promising, he said, he is also collaborating on research for head and neck cancer using saliva.
Research on several solid tumor malignancies is focusing on ctDNA for MRD assessment, including cancers such as lung, colon, breast, bladder, esophageal, gastric, and melanoma.1
Lung Cancer In a landmark 2017 lung cancer study, Chaudhuri said, investigators detected ultralow levels of ctDNA shortly after intense treatment in patients with local disease and poor outcomes.4 The patients whose disease progressed rapidly and who subsequently died had detectable MRD, whereas those without detectable MRD did well after treatment, he said. The study found that ctDNA identified disease earlier than CT imaging in 72% of patients, a median of 5.2 months earlier than with imaging. This gap presents an opportunity to offer earlier treatment when the patient has a lower disease burden, or to give adjuvant treatment. This research “has informed an entire field, where we now aim to detect ctDNA MRD shortly after treatment, with the goal of intensifying treatment for highrisk patients,” he said.
A 2020 study in locally advanced nonsmall cell lung cancer showed that ctDNA predicted benefits from consolidation immunotherapy.5 The study also showed that patients with detectable MRD after chemoradiation who subsequently underwent consolidation immunotherapy had significantly better outcomes compared with those who did not undergo the consolidation therapy.
After chemoradiation therapy, patients with undetectable ctDNA MRD showed excellent outcomes with or without receiving consolidation immune checkpoint inhibition therapy. The authors concluded that ctDNA analysis can enrich personalized therapy decisions.
Colon cancer is another area with ctDNA MRD trials. An oral abstract from the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting shared results from a multicenter study of 265 patients with stage I to III colorectal cancer, noted to be the largest ctDNA cohort assessed to date.6 Researchers collected plasma samples at different times, with a median follow-up of 28.4 months. In the 9.1% of patients who were MRD-positive postoperatively, 75% relapsed eventually. In the MRD-negative cases, just 13.6% relapsed. Investigators concluded that ctDNA analysis predicted recurrence risk and was a more reliable biomarker to monitor treatment response.
A poster presented at the 2021 ASCO Annual Meeting focused on detecting MRD using personalized assays for stage II to III colorectal cancer (FIGURE).7 Investigators monitored MRD before and after surgery before giving adjuvant chemotherapy. MRD was detected in 13% of patients postoperatively; of these patients, 42.9% relapsed. Of the MRD-negative patients, 8.6% relapsed.
The investigators noted that ctDNA status was the most significant factor associated with recurrence-free survival.
Data presented at the European Society for Medical Oncology Immuno-Oncology Virtual Congress 2020 included a ctDNA exploratory analysis to evaluate clinical benefits of atezolizumab (Tecentriq) versus observation in patients with detectable ctDNA.8 Investigators found positive ctDNA MRD in 37% of patients, associated with nodal status and tumor stage, to a lesser extent. Those with detectable ctDNA MRD showed a substantial disease-free survival benefit with atezolizumab compared with observation, and authors concluded that detecting MRD in an adjuvant setting allowed clinicians to offer personalized treatments. Lead author Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology and lead for Solid Tumour Research, Barts Cancer Institute, and director, Barts Cancer Centre, United Kingdom, said during a presentation of the data that these findings could have practice-changing implications for treatment of bladder cancer as well as other malignancies, in that patients can be selected for adjuvant therapy based on a ctDNA MRD biomarker, which could not previously have been done. Patients with detectable ctDNA MRD had an 80% chance of recurrence.
Chaudhuri said similar studies are being performed in other cancer types, too, which will be important in proving the value of ctDNA MRD as an across-the-board predictive biomarker.
Using ctDNA for MRD still has challenges. In small tumors with a curative resection, detecting ctDNA at low levels is difficult. Low assay sensitivity and false negatives are a challenge, Chaudhuri said. The other issue is noise. “As we get older, we generate mutations in our blood through a process called clonal hematopoiesis that can make it difficult to discriminate solid tumor-derived ctDNA mutations from these similar-looking mutations in blood cells,” Chaudhuri explained.
There is a lot of interest in ctDNA, with its promise for early cancer detection and screening, response monitoring for tumor burden, and potential to identify resistance mutations, Chaudhuri said. “Everyone along that spectrum is excited about ctDNA,” he said. “I think it will be actionable along this entire spectrum. We’re already using it clinically for resistance mutation detection, and we’re going to use it for MRD detection, but the sky’s the limit.”
1. Chin RI, Chen K, Usmani A, et al. Detection of solid tumor molecular residual disease (MRD) using circulating tumor DNA (ctDNA). Mol Diagn Ther. 2019;23(3):311-331. doi:10.1007/s40291-019-00390-5
2. Tan X, Yan H, Chen L, Zhang Y, Sun C. Clinical value of ctDNA in hematological malignancies (lymphomas, multiple myeloma, myelodysplastic syndrome, and leukemia): a meta-analysis. Front Oncol. 2021;11:632910. doi:10.3389/fonc.2021.632910
3. Pellini B, Pejovic N, Feng W, et al. ctDNA MRD detection and personalized oncogenomic analysis in oligometastatic colorectal cancer from plasma and urine. JCO Precis Oncol. 2021;5:PO.20.00276. doi:10.1200/PO.20.00276
4. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer Discov. 2017;7(12):1394-1403. doi:10.1158/21598290.CD-17-0716
5. Moding EJ, Liu Y, Nabet BY, et al. Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer. Nat Cancer. 2020;1:176-183. doi:10.1038/s43018-019-0011-0
6. Henriksen TV, Tarazona N, Reinert T, et al. Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients. J Clin Oncol. 2021;39(suppl 3):11. doi:10.1200/JCO.2021.39.3_suppl.11
7. Anandappa G, Starling N, Begum R, et al. Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC). J Clin Oncol. 2021;39(suppl 3):102. doi:10.1200/JCO.2021.39.3_suppl.102
8. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432-437. doi:10.1038/s41586-021-03642-9