Epigenetic Assay Could Spare Patients From Additional Biopsies for Prostate Cancer.
A new test that can detect the existence of tumor activity is gaining credibility as a means of confirming the results of prostate biopsies, which have the potential to miss tumor cells. The ConfirmMDx epigenetic assay from MDxHealth, of Belgium, hunts for signs of DNA methylation, and recent study results have confirmed its value. One study in particular, involving African American men, was presented in May at the American Urological Association (AUA) annual meeting and demonstrated strong negative predictive value.1
Prostate biopsies not only are invasive and uncomfortable for patients, but also carry significant risk for patients, who may suffer bleeding, pain, difficult or painful urination, and infection and may have blood in the urine or semen.2 These factors can make it challenging for urologists and patients to decide whether a second prostate biopsy is necessary if the initial test is inconclusive.
Further, prostate biopsies sometimes produce false-negative results due to the limitations of the current standard of care-a 12-core needle transrectal ultrasound-guided biopsy. "The challenge is that it is a relatively random sampling because although they're trying to sample 12 definitive areas of the prostate, the needle may not always end up where it's supposed to be," explained Christopher Thibodeau, chief operating officer and EVP of MDxHealth, in an interview with OncologyLive®.
Although the biopsy is targeted for areas of most probable activity, it can still amount to a proverbial shot in the dark. "We're sampling less than 1% of the prostate, so when we look at the men who are undergoing biopsies, most urologists would argue that there is a chance the biopsy might have missed something," Thibodeau said.
The ConfirmMDx assay is efficient in that it can analyze the same tissue removed during a biopsy and potentially detect cancer even if tumor cells are not present in the sample. Typically, if after a prostate biopsy, a urologist still feels that the patient may be at risk for cancer-for example, based on results of a digital rectal exam or prostate-specific antigen (PSA) test-a second biopsy and perhaps even more could be performed. However, additional biopsies could compound the risk of bleeding and infection, lengthen recovery time for the patient, and cause patients to become frustrated with the process.
ConfirmMDx is an alternative to a string of repeat biopsies and their associated risks. "Around the area where the cancer cells are, there are changes happening," said Wim Van Criekinge, PhD, chief scientific officer of MDxHealth and a professor at the University at Ghent in Belgium. "One of these changes is the DNA gets modified by being near the cancer cells. The cells containing that modified DNA have not [yet] become cancer cells themselves-that's why the biopsy doesn't recognize them as being abnormal. The molecular test can see the changes before they progress to a morphological level."
Specifically, ConfirmMDx tests for methylation of the APC, GSTP1, and RASSF1 genes, which are widely studied prostate cancer biomarkers that give an indication not only of the presence of cancer, but the aggressiveness of that cancer as well. Demonstrating confidence in the assay, the National Comprehensive Cancer Network (NCCN) this year recommended ConfirmMDx as a tool for early detection of prostate cancer. An NCCN panel stated that the assay "can be considered an option for men contemplating repeat biopsy because the assay may identify individuals at higher risk of prostate cancer diagnosis on repeat biopsy."3
Specifically, the NCCN guidelines recommend the test for patients who have had at least 1 prior negative biopsy and are thought to be at higher risk, particularly when assessing their PSA levels. Other options listed for patients with a prior negative biopsy are percent- free PSA, the Prostate Health Index, the 4Kscore test, and a prostate cancer antigen 3 (PCA3) test.3
Improving Diagnosis in African American Men
The recent trial results showing that ConfirmMDx has predictive value among African American men suggest the potential for improved treatment in this population, which is underserved when it comes to prostate cancer diagnosis and therapy. African American males have a greater risk of clinically significant prostate cancer than the general population, and prostate cancer in this racial grouping tends to have a different molecular structure. They are approximately 1.6 times more likely than Caucasians and 2.7 times more likely than Asian Americans to develop the disease.4
Prior study results have shown the clinical utility of ConfirmMDx among other populations, too, but until the study presented at the AUA meeting this year, data were lacking on how the assay would perform specifically in the African American population. Principal investigator Robert L. Waterhouse Jr, MD, MBA, and his colleagues wanted to make sure that the test would help African American patients avoid unnecessary repeat biopsies.
Eligible patients were African Americans who had an initial negative prostate biopsy, without any atypical glands or other findings that would increase the risk of having prostate cancer, and a second prostate biopsy within 30 months of the initial biopsy. The ConfirmMDx test was then performed on the tissue from the first biopsy, and investigators checked the results against the findings from the second biopsy.
For each patient included in the study (n = 211), a median of 12 cancer-negative biopsy cores were analyzed. Upon repeat biopsy, 55% of patients had no prostate cancer detected, while 45% received the diagnosis.1 ConfirmMDx improved the identification of African American men at risk for aggressive cancer missed by the initial prostate biopsy. The assay achieved a negative predictive value of 91.2% for any prostate cancer found on rebiopsy. The negative predictive value for high-grade cancer, defined as Gleason 7 or higher, was 96%. Higher intensities were also observed for men diagnosed with highgrade prostate cancer relative to those men with no prostate cancer detected upon biopsy (P = .001).1
Essentially, Waterhouse said, the results showed that a negative result on the ConfirmMDx test means there is a low likelihood that disease will be found in a second biopsy. "If someone has the test performed to look at methylation of all 3 genes on the initial prostate biopsy tissue, and no methylation is found in any of the 3 genes, in any of the 12-core biopsy specimens, then if they were to undergo a repeat prostate biopsy, they have a less than 9% likelihood that prostate cancer will be found at all and a less than 4% likelihood that high-grade cancer would be found," Waterhouse, a practicing urologist at Carolina Urology Partners in North Carolina, explained.
There may be highly valid reasons for going forward with repeat biopsies, but the results of the trial indicate the strong clinical value of ConfirmMDx. "If the initial prostate biopsy is negative, and we perform this test and it's negative, then we have a greater degree of comfort that a repeat biopsy does not have to be performed," said Waterhouse.
Prior Research Into Clinical Utility
Researchers have also sought to determine the clinical utility of the ConfirmMDx assay to detect occult prostate cancer in negative biopsies. In the MATLOC study, investigators blindly tested archived prostate biopsy needle core tissue samples from 498 subjects in the United Kingdom and Belgium with histopathologically negative prostate biopsies. Initial biopsies were tested with the assay and the second biopsies were used for confirmation of the assay's efficacy.5
The epigenetic assay tested on negative biopsies resulted in a negative predictive value of 90% (95% CI, 87%-93%). In a multivariate model factoring for patient age, PSA level, digital rectal examination results, and histopathological characteristics of the initial biopsies, ConfirmMDx was found to be a statistically significant independent predictor of patient outcome, with an odds ratio of 3.17 (95% CI, 1.81-5.53).5
The investigators also found that ConfirmMDx accurately identified 64% of patients without prostate cancer who could safely avoid a repeat biopsy. Notably, the test correctly identified 68% of men who were harboring undetected prostate cancer at the time of their previous histopathologically negative biopsy. Many of those patients presented with clinically significant cancer upon repeat biopsy that would qualify for aggressive treatment.5
The DOCUMENT study, a multicenter trial in the United States, also validated ConfirmMDx as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. As they did for the MATLOC study, investigators evaluated archived negative prostate biopsy core tissue samples from 350 patients, all of whom underwent a repeat biopsy within 24 months and were found to be positive or negative for cancer.6 The samples from the first biopsies were tested for the GSTP1, APC, and RASSF1 genes. According to Thibodeau, 13% of the participants included in the DOCUMENT study were African American, so this was an early indication that the assay would perform well in this population.
In this trial, the assay demonstrated a negative predictive value of 88% (95% CI, 85%-91%). In multivariate models factoring for age, race, PSA, digital rectal examination results, and histopathological characteristics of the first biopsy, the test proved to be the most significant independent predictor of patient outcome, with an odds ratio of 2.69 (95% CI, 1.60-4.51). These results validated that the assay was a significant independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result.6