For several years we have been participating in using Natera ctDNA blood testing to help monitor the status of numerous patients with diagnosed cancers both during and after medical interventions. The following are excerpts from a recent Nature Journal article on this valuable molecular monitoring for various cancers. CtDNA blood testing can monitor patients for the effectiveness of treatment and status post treatment over time.
Nature Journal 7/13/23
Practical recommendations for using ctDNA in clinical decision making
Over the past 20 years, there has been an incremental and consistent improvement in cancer survival rates1, largely attributed to more effective treatments and improved patient management strategies2. Refining the identification of patients who may benefit from adjuvant therapy following definitive management is critical to optimizing patient care. As appropriate interventions may improve outcomes, the judicious use of additional therapy can spare patients at low risk of recurrence from adverse treatment effects and unnecessary costs. The current paradigm of disease management centres around tumour-specific, stage-based recommendations, primarily relying on pathology and imaging results to optimize treatment plans for patients3. Although imaging is the accepted standard method to monitor disease progression or relapse and measure response to treatment, radiological findings are sometimes difficult to interpret correctly, leading to high rates of false positivity and negativity4. Blood-based metabolic tumour markers (for example, carcinoembryonic antigen (CEA), cancer antigen (CA)-125, CA19-9 and lactate dehydrogenase (LDH)) represent a non-invasive approach to evaluate the status of disease. However, many of these established biomarkers are considered unreliable, as they can be elevated due to conditions unrelated to cancer, leading to low sensitivity and specificity.
Although evidence of clinical utility is still emerging, early results from largely observational studies demonstrate that ctDNA is a highly significant prognostic factor compared with other established clinicopathological risk factors. Thus, ctDNA testing may add to the overall patient assessments for risk stratification, wherein postoperative ctDNA-positive status indicates a higher risk of recurrence. Implementation of ctDNA testing can inform prognosis and assist in determining the level of treatment that may be needed to clear existing disease, prevent relapse and improve chances of long-term survival. A potential development from ctDNA-guided decision making is the mitigation of unnecessary treatment and the accompanying side-effects and financial burden to patients, or targeted second-line therapy decisions if first-line therapy does not halt disease progression117,118. Although a number of post hoc analyses, clinical experiences and case series have been published to date, prospective studies to define the utility of ctDNA testing in clinical practice are still needed. We recommend that ongoing and future trials aiming to examine novel therapy approaches consider utilizing ctDNA testing in their study design, to enable stratification to identify those patients who are most likely to benefit from the studied therapeutic intervention. Ultimately, as the specific indications, ctDNA platforms, treatment decision points and therapy implications are refined and validated, it is likely that ctDNA will be incorporated into many aspects of clinical practice. Prospective studies with well-established clinical end points will determine whether ctDNA can supplement or even replace current standard clinical metrics.
Pseudoprogression refers to an initial radiographic increase in size of the primary tumour, followed by radiographically apparent tumour regression107. The phenomenon is defined as tumour’s response to treatment after initial increase in volume, due to the infiltration of tumoral tissue by immune cells. It has been observed to occur in approximately 10% of solid tumours treated with ICB107. Pseudoprogression is problematic for clinicians to determine whether a change in treatment is warranted or whether the patient is responding and needs additional therapy with the same regimen.
Given that ctDNA dynamics provide an early indication of response to NAC, it is recommended that providers consider this information to optimize patient outcomes. For example, in cases where patients are treated with NAC that can have long-term and cumulative effect on survivorship, such as anthracyclines in breast cancer101, ctDNA clearance can provide a rationale for early cessation of therapy. Conversely, early identification of non-responders may enable a timely switch to more effective therapies. This is a novel extrapolation from what is done with interval imaging restaging. In addition, the prognosis of cases with residual disease can further be refined by differentiating cases in which ctDNA persists from those in which clearance is achieved. Furthermore, in MIBC, excellent response to NAC can provide a rationale for avoidance of cystectomy and urinary diversion.
Management of ctDNA-positive patients
Many studies have outlined the role of ctDNA testing in disease management as an early indicator of cancer recurrence18,19,20,23,24,44,46,48,57. However, recent studies have shown that the poor prognosis associated with ctDNA positivity can be modified by effective adjuvant systemic therapy58,59,60. Although on-treatment ctDNA clearance is correlated with a favourable prognosis61,62,63, the current evidence does not suggest that ctDNA clearance alone is sufficient for prediction of long-term survival benefit (disease free survival or recurrence-free survival). Thus, although on-treatment ctDNA clearance is an indicator of treatment response, completion of the full planned course of treatment based on established clinical practice irrespective of on-treatment ctDNA results is still recommended to minimize the chance of a future relapse
Technical aspects of ctDNA detection
MRD is a subclinical disease that is associated with a high risk for recurrence, which cannot be detected by standard imaging techniques. Evaluating MRD using ctDNA enables the detection of micrometastatic disease. It should be noted that a negative ctDNA result suggests a decreased risk of recurrence, rather than a guaranteed lack of recurrence18,19,20,24,34,36,37. SOC post-surgical surveillance is limited to imaging and/or blood-based biomarkers (that is, CEA, CA-125, CA 15-3 and LDH) that are a proxy for ongoing disease, but these have demonstrated poor sensitivity and specificity for assessing MRD6,7,8,9. The addition of ctDNA to standard surveillance can complement the current paradigms and may improve the time to detection of a cancer recurrence.
ctDNA detection subsequent to surgery
When ctDNA is detected (that is, detection of MRD) following definitive surgery, patients have a risk of relapse approaching 100%, varying on the basis of the cancer type, ctDNA assay and whether repeated (longitudinal) testing is performed20,24,37. The frequency at which ctDNA becomes detectable after surgery or treatment with curative intent is dependent on the tumour biology38 and the aggressiveness of the residual disease. For example, patients whose ctDNA is detectable at the MRD timepoint but is undetectable following adjuvant therapy may have improved long-term outcomes compared with those with persistent positivity. This latter scenario suggests resistance to treatment, possibly owing to tumour heterogeneity and clonal evolution, contributing to an eventual relapse