Numerous advances in precision oncology have led to better outcomes for patients; however, solid tumors still account for an overwhelming number of cancer-related deaths. The majority of these cancers are diagnosed at an early stage (I–III), where surgical interventions offer the greatest potential of cure. Unfortunately, many patients undergoing surgery for early-stage disease recur as a result of micrometastatic disease that lurks undetected after surgery. These remaining cancer cells, commonly referred to as minimal residual disease (MRD), can become active and multiply, leading to disease relapse.
The ability to detect the presence of micrometastatic cancer cells has been shown to help physicians make better-informed decisions about their patients’ treatment, because early and appropriate adjuvant therapy can greatly improve a patient’s outcome. However, the amount of residual disease can be miniscule with the result that patients often experience no symptoms and the tumor cannot be visualized on a scan. In routine care, post-surgical patients who have a high risk of recurrence are given adjuvant chemotherapy on a ‘just in case’ basis, which is often based on tumor location and anatomy at the time of surgery and not the patient’s disease status after surgery. Detecting MRD requires an appropriately designed and developed test that exhibits exquisite and reliable analytical sensitivity and specificity to robustly and accurately measure circulating tumor DNA (ctDNA) at levels that correlate with disease stage and patient status.
“To avoid the risk of recurrent disease, we often overtreat patients with stage 2 colorectal cancer based on pathological and clinical criteria and physician choice. The clinical benefit for adjuvant therapy for these patients is modest,” said Joshua Cohen, clinician researcher at Johns Hopkins University School of Medicine in Baltimore, Maryland, United States (US). “In stage 3 patients, the benefit of adjuvant treatment is undisputed, but we still need to know how aggressively these patients should be treated, as many receive therapy they don’t need and some don’t receive enough or the appropriate type.”
Testing for minimal residual disease
Treating only those patients who are truly at risk of recurrence because they still have disease present after surgery and prescribing them the right types and duration of treatment can ensure patients receive treatment based on their current disease status. This approach spares patients from the worry and side effects of receiving treatment that may not be necessary or forgoing treatment that can greatly improve their potential to be cured. Ultimately, this can greatly improve the precision of clinical practice, improve the lives of patients and improve the efficiency of the healthcare system.
Detecting MRD with the appropriate test can influence several aspects of care by providing unique insights at critical clinical decision points where accurate information from traditional diagnostic tests is often lacking. Testing for MRD helps physicians to measure the effectiveness of treatments with curative intent, enabling the identification of patients who are at highest risk of relapse and would benefit from receiving additional therapy. After successful treatment, monitoring for MRD has been shown to identify relapses much earlier than radiographic imaging, supporting earlier treatment interventions that have the greatest potential for eradicating an emerging relapse (Fig. 1).
“Every diagnostic is rooted in a biomarker. Many of the non-genetic biomarkers used in cancer aren’t sensitive or specific enough to accurately find all cases,” said Cohen. “Because cancer is genetic at its core, detecting the mutation driving the disease can create a more potent diagnostic.”
MRD detection could also be a powerful tool in the development of future adjuvant therapies, because it can more accurately identify patients who have active disease and thereby reduce the number of patients enrolled in clinical trials, which is often a mixture of patients with disease and those who have already been cured by surgery. Clearly it makes no sense to treat patients who have already been successfully treated.
“Cancer clinical trials can take years. If we can select the patients who have residual disease, we may be able to conduct smaller trials and get faster results,” said Peter Gibbs, Professor of Medicine at The Walter and Eliza Hall Institute (WEHI) of Medical Research in Melbourne, Australia.
Beyond MRD, the same approach could play a role in helping physicians choose the best chemotherapy regimens and immuno-oncology drugs for patients with unresectable disease.
“As an example, in stage 4 melanoma, the test would allow physicians to track the evolution of the tumor, choose treatment based on that patient’s mutations, and see how they respond over time,” said Cohen.
Finally, it allows doctors to reassure patients that the treatment is working, that they are disease-free, or that their disease will be detected in time to apply treatment successfully if it comes back.
Seeing through the noise
The challenge of creating a ctDNA-based diagnostic is that the overall level of tumor DNA is very low in comparison with the level of DNA in the blood from healthy cells. The fraction of tumor DNA to normal DNA can be lower than one in a million, which makes finding the tumor signal within the background noise of normal tissue difficult. Several studies have reported that the overall level of tumor DNA at a given time point is related to the size, stage and location of a patient’s cancer, with later-stage tumors depositing greater quantities of ctDNA into circulation and early-stage cancers depositing the least. Considering a patient with early-stage disease, whose tumor is surgically removed, detecting ctDNA becomes even more challenging.
Haystack Oncology’s Duo technology is a low-error rate, next-generation ctDNA detection chemistry that is the basis for its ultrasensitive and specific personalised MRD testing. The test is personalized to each patient—after the primary tumor is resected, the tissue is sent to Haystack for sequencing, and the personalized test is built while the patient recovers from surgery. The test is available at the first follow-up—approximately four weeks following surgery—to inform the success of the surgery and guide the physician and patient as to the benefit of adjuvant therapy. Blood samples can be obtained during and after treatment and sent to Haystack for measurement of ctDNA levels that provide valuable information about a patient’s response to therapy.
“By taking a tumor sample and sequencing it, we know which specific mutations are there for that individual patient. Once this is done, we can receive a test for those mutations within weeks of the initial treatment and monitor the patient over months and years,” said Cohen. While the initial creation of each patient’s personalized assay requires several workflow steps, each blood test to measure MRD only takes a few days to return results.
Haystack’s technology can detect as few as one mutation in a million DNA molecules, which positions it as the most sensitive ctDNA-based MRD test for use in solid tumors. Additionally, the company captures and archives the patient’s tumor genome at each MRD timepoint for deep genomic mining and to detect actionable resistance mechanisms and novel biomarker discovery (Fig. 2).
The landmark DYNAMIC clinical trial of patients with stage II colon cancer conducted at WEHI in Australia and Johns Hopkins Kimmel Cancer Center in the US represented the first prospective, randomized interventional MRD study to read-out with practice-changing findings reported at the meeting held by the American Society of Clinical Oncology (ASCO) in 2022. In the trial, post-surgery treatment decisions were guided completely by ctDNA results. Outcomes were compared to results of a standard of care arm that was managed according to traditional clinicopathological features. Patients managed with ctDNA after surgery were 50% less likely to receive adjuvant therapy, with no impact on recurrence-free survival when compared to the standard of care arm. The study, which employed Safe-SeqS chemistry developed by researchers at Johns Hopkins to detect ctDNA, demonstrated a clinical benefit of MRD testing for guiding adjuvant chemotherapy. “This was a paradigm-changing clinical trial. It showed that physicians could reduce adjuvant chemotherapy use without compromising survival,” said Gibbs.
Haystack’s Duo technology is based on chemistry developed by Cohen and others in Bert Vogelstein’s group at Johns Hopkins University and represents an evolution of the Safe-SeqS chemistry used in the DYNAMIC study. Regarding Haystack’s technology, Gibbs stated, “Duo has been developed over a number of years and represents the latest advancements in the only MRD [technology] to have been validated in randomised controlled trials.”