Presentation by Dr Samuel Klempner, Massachusetts General Hospital Cancer Center
At the 2023 Best of GI Cancer Symposium, Dr Samuel Klempner from Massachusetts General Hospital Cancer Center reviewed the current status of an emerging technology, circulating tumor DNA, or ctDNA, in the setting of GI non-metastatic cancers. ctDNA is already used in patients with advanced (stage IV) GI cancers, but is still largely an investigational technology for detecting early cancer recurrences, evaluating patient’s response to cancer treatments, and/or the possible need for intensified therapy.
In the setting of localized colorectal, and many other cancers, most patients are treated surgically, completely removing their tumor, with a goal of curing their disease (“curative intent therapy”), however, systemic adjuvant treatment may also be used as a means to reduce the risk of recurrence, or regrowth of their cancer. Cancer recurrences can be either at the primary cancer site, at other sites in the body (“distant metastasis”), or both sites. Most cancer recurrences are believed to result from a small number of cancer cells escaping from the primary site (“micrometastatic disease”), and the purpose of adjuvant therapy is to completely kill any such escaping cells, and thereby prevent recurrence. Once a patient has been treated with curative intent therapy such as surgery, the oncologist will usually decide whether or not an “adjuvant therapy”, such as chemotherapy, is needed. This decision is usually based on the specific clinical parameters of the patient and tumor that determine their overall risk for recurrence such as their tumor size, tumor grade, and whether or not there is lymph node involvement. A clinically high-risk patient (e.g., large tumor, high grade, with positive lymph nodes) might therefore receive adjuvant treatment, while a clinically low-risk patient (e.g., small tumor, low grade, and node negative) might not require any systemic adjuvant treatment. The latter, low-risk patient might instead have a “watch and wait” approach, with imaging after surgery, such as a chest X-ray or CT scan, done periodically to monitor for recurrence. Dr Klempner noted, however, that by the time a recurrence is detectable by imaging, even using the most sensitive methods, there is already a large number of tumor cells present that have had time to establish themselves. For example, a cancer recurrence that is detectable on a chest X-ray might correspond to approximately 1 billion cancer cells.
As healthy cells in the body live and die, such as white blood cells, and other types of cells, they release their genetic material, or DNA, into the bloodstream, and the same is true for cancer cells. DNA released into the blood is termed “cell-free DNA” or cfDNA, and one means to detect residual cancer cells in the body is to detect the circulating DNA that belongs to the tumor (ctDNA) among the pool of cfDNA. The benefit of monitoring for ctDNA is that it can detect a much lower amount of residual cancer in the body as compared to that which is visible on, for example, a chest X-ray or CT scan, the idea being that a smaller amount of cancer may be easier to treat. ctDNA monitoring can also allow the detection of a recurrence at a much earlier stage, at which the oncologist can potentially intervene with additional curative therapy. The presence of positive ctDNA test in a patient, before there is any radiologic evidence of a cancer recurrence, is referred to as minimal or molecular residual disease, abbreviated as “MRD”.
Two Types of Assays
There are currently two broad approaches for detecting ctDNA in the blood, both of which can be performed using a simple blood test. “Tumor-informed” ctDNA assays require a portion of a biopsy, or a sample of the tumor tissue, obtained during surgery or clinical biopsy. The DNA in the tumor is then sequenced in order to determine a specific DNA “signature” that is unique to that tumor and to that individual patient. Once the signature has been defined from the biopsy sample or tumor specimen, the blood can be monitored serially, over time, to detect the presence of residual cancer, and no further biopsy is needed. Subsequent testing of the blood in that specific patient will yield either a “yes” result (meaning the ctDNA is present) or a “no” result (meaning the ctDNA is not detected).
Another type of assay, “tumor-uninformed” or “tumor-naïve”, works in essentially the same manner, except that no initial biopsy or tumor specimen is needed, and the signature that is used is not specific to that patient or patient’s tumor, but rather corresponds to a set of specific genetic changes that are commonly associated with a specific tumor type, for example, lung cancer, gastric cancer, etc. Tumor-uninformed ctDNA assays can therefore be useful if no tumor biopsy or specimen is available, and as with the tumor-informed test, the readout is also a ‘yes’ or ‘no’ answer, with ctDNA present, or not present. Because ctDNA represents only a very small portion of DNA in the blood, the sensitivity of both of these tests can also be enhanced by combining them with other tumor cell markers, such as methylation patters within the tumor DNA, or levels of protein biomarkers in the blood, for example, carcinoembryonic antigen (CEA).
What Does a Positive Test Mean?
Results from a number of clinical trials have shown that the presence of ctDNA in the blood after surgery (“ctDNA positive” status) is a poor prognostic factor, meaning that these patients are at a significantly higher risk for a recurrence of their cancer, as compared to those who are deemed as ctDNA negative after surgery. Importantly, Dr Klempner emphasized that ctDNA positive status is one of the strongest predictors for cancer recurrence, even stronger than established clinical risk factors of tumor size, grade, and nodal status. For example, in resected colorectal cancers (CRCs) using a tumor-informed assay, approximately 18% of the resected CRCs were ctDNA positive at 4 weeks after surgery. For patients who were ctDNA negative, the 18-month disease-free survival (DFS) rate was 91% versus 38% for those who were ctDNA positive. Dr Klempner noted that the greatest degree of supportive clinical evidence for using ctDNA to monitor for recurrence is in the setting of colorectal cancer at present, whereas less data is available for some of the less common GI cancers, such as gastric and esophageal cancer.
Unresolved Issues and Caveats of Using ctDNA
One of the primary unresolved issues is what to do with patients who have a positive test after surgery. Based on available evidence in colorectal cancer, for example, patients who have positive ctDNA after surgery can be considered as high-risk for recurrence (even if their clinical parameters might suggest they are low-risk), and as such, one might consider offering adjuvant chemotherapy to such patients. There is also some evidence that using adjuvant therapy in patients who are MRD-positive can clear their blood of ctDNA, and such patients have very good outcomes, similar to those who never had a positive ctDNA test after surgery (i.e., “MRD-negative”). Despite these findings, however, the use of adjuvant therapies such as chemotherapy does entail significant risk to the patient, and decisions should be made jointly with patients. Conversely, a positive ctDNA test after surgery can also be a source of significant worry and anxiety for the patient, due to its adverse prognostic implications, if a “watch and wait” approach is chosen. Dr Klempner emphasized that in these situations, a shared decision-making process with the patient is especially important, and the available evidence for, and against, the use of adjuvant therapy in this setting should be discussed with the patient.
Using ctDNA: A Case Example
To illustrate how ctDNA testing might be utilized in a clinical setting, Dr Klempner considered the case of a 63-year-old female patient who presented with dark stool and anemia, and ultimately was diagnosed with sigmoid CRC. She has no prior history of CRC, and her imaging results show a primary tumor with no evidence of distant metastasis. Her tumor is designated as Stage IIB (pT4aN0cM0), after surgical resection. At 3 weeks after surgery, she is doing well, but is very reluctant to undergo adjuvant chemotherapy, and she opts to undergo ctDNA testing to determine her risk for recurrence. Her post-operative ctDNA test comes back as MRD (ctDNA) positive. Dr Klempner noted that, on average, following a curative intent therapy such as this case, roughly 20% of patients will test positive for ctDNA.
After discussing the results with the patient, she decides to undergo 3 months of adjuvant chemotherapy (CAPOX), and the results of the ctDNA test after this therapy come back as negative. Dr Klempner noted that, based on currently available data, ctDNA testing can reduce the use of chemotherapy for patients with resected stage II disease. Importantly, the reduced use of chemotherapy does not appear to adversely impact the clinically relevant endpoint of relapse-free survival (RFS) at 2-years (93.5% and 92.4%). In addition, Dr Klempner emphasized that patients who are ctDNA negative after surgery do very well without chemotherapy, with a 3-year RFS of 92.5%.
Dr Klempner then posed the question of what to do if, after the patient completes adjuvant chemotherapy, the patient’s ctDNA test comes back as positive, instead of negative. In this regard, he emphasized that there is presently no evidence that acting on the basis of a positive test after adjuvant therapy can improve the patient’s survival, however, multiple trials are underway to answer this very important question.
The case example Dr Klempner provided illustrates the current status and utility of using ctDNA in the setting of colon cancers. He emphasized that, despite the prognostic implications and the utility of ctDNA as a tool to monitor patients during adjuvant therapy, clinical decisions must, in the end, be carefully guided by the supporting data, and shared decision making with the patient. It is also important to fully discuss all possible outcomes with the patient before ordering any test. The field is working hard to generate additional data in non-colorectal GI cancers like pancreatic and gastric/esophageal that may ultimately help shape decision making.
Following curative intent therapy in the post-surgical setting, available evidence has established ctDNA positivity as a poor prognostic factor, even above traditional clinical factors like tumor size, stage, and lymph node positivity. While the vast majority of data at present is in colorectal cancer, the prognostic value of a positive ctDNA test is likely true for all cancers. If the patient undergoes adjuvant therapy and clears their ctDNA from the blood, this is a good prognostic sign, and the patient can continue to be monitored. If, however, sometime after adjuvant treatment, ctDNA again becomes detectable in the patient, this is an indicator of impending recurrence (as well as a source of significant worry and anxiety for patient and clinician), but there is, however, no evidence yet that intervening for the patient with some type of therapy (ahead of a detectable radiological recurrence) will improve their survival. As such, further research is needed, and Dr Klempner noted that both patients and investigators can help in this process, by participating in clinical research and registry studies of ctDNA testing.
Circulating tumor DNA (ctDNA) testing, done using a simple blood draw on the patient, is one means of detecting residual cancer cells that may be present in the body following a curative intent therapy such as surgical removal of the tumor.
The presence of residual ctDNA in the body (a positive ctDNA test) after surgery is a poor prognostic indicator, and has been strongly associated with eventual cancer recurrence.
Conversely, patients who have a negative ctDNA test after surgery have excellent outcomes regardless of whether they undergo any further therapy, such as adjuvant chemotherapy.
It is important for patients to fully understand the utility of ctDNA testing as a means for shared decision-making, and the potential outcomes should be discussed with the patient before ordering the test.
Patients who have a positive ctDNA test after curative-intent surgery may opt to undergo adjuvant treatment (for example, with chemotherapy) as a means to reduce their recurrence risk.
Clearance of ctDNA after adjuvant therapy is a good prognostic indicator, whereas failure to clear ctDNA after adjuvant treatment is a poor prognostic indicator.
There is no evidence as of yet that intervening with any treatment on the basis of a positive ctDNA test after adjuvant treatment (without radiological evidence of disease recurrence) offers any benefit in survival, although studies are currently underway to elucidate this issue.
See more from the 2023 Best of GI Cancer Conference here.
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