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Minimal Residual Disease Testing Progress in Breast Cancer Highlighted at ASCO


NEW YORK – Recent advancements in liquid biopsy technologies have rapidly created new testing options for oncologists specializing in breast cancer, most notably personalized assays for minimal residual disease (MRD) detection in early-stage patients.

Investigators highlighted progress in the application of some of these new tools in clinical practice during the annual meeting of the American Society of Clinical Oncology in Chicago this week, although speakers cautioned that many questions remain regarding these tests' ultimate utility and impact on patient outcomes.

During a webcast clinical science symposium on Sunday, Dana-Farber Cancer Institute oncologist Heather Parsons said that there is reason to be hopeful that new MRD technologies, in particular, could positively impact patients.

"This is probably the space where there's been the most excitement," Parsons said. "Yet [it's also where] there are the most questions that still need to be answered."

MRD assays are being investigated as tools to tailor adjuvant and neoadjuvant therapy to individual patients, to allow for new kinds of drug trials, to monitor response in later-stage disease, and more.

However, technologies are still evolving, and the proof of clinical utility is still lacking, she added. "So far, no study has shown that intervening on a positive [circulating tumor DNA] test improves outcomes, and no study has shown that stopping therapy based on a negative test is safe."

One of the abstracts highlighted during the session featured data on a relative newcomer to the MRD market, Personalis' whole-genome sequencing-based approach dubbed NeXT Personal.

Isaac Garcia-Murillas from the UK's Institute of Cancer Research presented data from a study employing the test in 78 breast cancer patients enrolled in the ICR's ChemoNEAR study.

Garcia-Murillas and colleagues analyzed 619 plasma samples (a median of eight samples per patient) taken at diagnosis, prior to therapy, during neoadjuvant chemotherapy, after surgery, after neoadjuvant treatment, if used, and at further monitoring time points.

Personalis' NeXT Personal uses upfront whole-genome sequencing of tumor tissue to develop personalized ctDNA sequencing panels for each patient that can include more than 1,000 variants, orders of magnitude more than competing tests from other companies like Natera, Exact Sciences, and others.

Personalis and its commercialization partner Tempus officially launched their comarketed version of the test last week under an agreement first announced last fall.

In the study presented at ASCO, the ICR team found that a positive NeXT Personal test result was associated with high risk of future relapse and shortened overall survival, with a median lead time from ctDNA detection to clinical relapse of 15 months.

Investigators said that MRD was identified in all 11 patients who eventually relapsed. Meanwhile, no patients with a negative test result relapsed during the follow-up period. Discounting serial test results and focusing on a single post-surgery landmark time point, 94 percent of patients who tested negative remained relapse-free.

According to Garcia-Murillas, this landmark negative predictive value, in particular, bodes well for the potential use of the test in de-escalation studies, something that has been an area of interest with the advancement of MRD tests, but has not yet been proven out.

Both de-escalation and escalation studies are now in progress in breast cancer, with the hope that they can demonstrate that acting on MRD results leads to better outcomes for patients.

In the escalation sphere, researchers from France's Institut Curie shared a poster at the meeting describing their newly launched randomized trial, CUPCAKE, which seeks to establish whether MRD monitoring in early-stage triple-negative breast cancer patients leads to better overall survival via earlier detection of relapse.

With data from this and other trials still to come, other efforts have sought to find hints of the impact of MRD testing on patient care in different ways. One such study was presented in an ASCO meeting poster by a team led by investigators from the University of California, Los Angeles.

The multisite study included 464 patients with stage I to III breast cancer tested with Natera's tumor-informed Signatera test in a real-world clinical setting.

In that cohort, 58 patients (13 percent) had a ctDNA-positive test result at one or more post-surgery time points. Seven of these were stage I, 25 were stage II, and 26 were stage III. According to the authors, test results impacted the care plan in 53 of the 58 positive patients, with 45 restaging imaging within a year of a positive result, and 25 showing radiographic evidence of recurrence at that time.

Among 20 patients that were ctDNA-positive despite no radiographic evidence of recurrence, five underwent increased imaging surveillance and at least 14 had repeat ctDNA testing. In nine patients, providers changed therapy based on the MRD test result, including enrolling patients into a clinical trial. Five subsequently cleared their ctDNA, and four remained disease-free with a median follow-up time of 12 months.

Another meeting poster featured data collected by researchers at the Rutgers Cancer Institute of New Jersey, also using the Signatera test.

The small study reviewed test results from 35 patients with stage II to III triple-negative or HER2-positive breast cancer who were monitored during neoadjuvant chemotherapy.

All but two patients had positive MRD test results at diagnosis. The authors wrote that those with early ctDNA clearance, within six weeks of starting treatment, were more likely to have the best surgical outcomes, with either pathological complete response, or tumor shrinkage and lymph node negativity.

Overall, ctDNA positivity post-surgery led to a change in disease management for two patients. The first, who remained MRD-positive despite achieving a pathologic complete response, had a change in their adjuvant treatment plan. For the second, ctDNA positivity led to imaging detection of a confirmed asymptomatic metastatic relapse that was then treated.

During the session featuring Personalis' data, Ohio State University oncologist Daniel Stover stressed that these promising signals of clinical impact don't yet translate into a mortality benefit to patients.

"Does intervening upon ctDNA status change outcomes? We don't know that answer yet," he said.

Furthermore, the field also doesn't know whether there is an impact in using more sensitive assays like NeXT Personal. "I think we need to be cautious because some of the early studies where we're trying to intervene based on MRD have been using … less sensitive assays," Stover said. "We don't want to throw the baby out with the bathwater because these assays are rapidly developing, and an increased sensitivity may have a difference in our ability to successfully intervene upon positive MRD."

"Most of the research and commercial assays currently track 16 to 50 mutations. With this current sensitivity, we know that patients who develop MRD positivity in these assays have a very high likelihood of developing recurrence. However, we also know that tracking more mutations enhances the sensitivity of these assays, potentially by multiple-fold."

Asked about how she is fielding the clinical availability of MRD testing for early breast cancers, Parsons said that it is a growing challenge.

"When I'm asked to order one of these tests, I push back pretty hard," Parsons said. "I do not order these test[s] clinically outside of a clinical trial because I think we don't yet know what the clinical utility is. With a positive test, we don't know what to do with that information. And a negative test, I think, in some ways can be even more pernicious because it can provide false reassurance."

"I'll admit that I do send these sometimes, after shared decision-making with patients," added Stover. "Our patients are burdened with a lot of worry and in some cases it may be helpful to have some reassurance [even perhaps falsely]."

"The challenge that we face is what it really means when the result comes back to us," he said.