Exact Sciences Provides First Look at MRD Test Performance in Triple-Negative Breast Cancer

Original from: genomeweb

Exact Sciences is building evidence on the ability of its Oncodetect minimal residual disease (MRD) test to determine the risk of distant recurrence in breast cancer patients in the hopes of expanding its adoption and reimbursement in this setting.

Researchers led by Marija Balic, a professor at the University of Pittsburgh's hematology/oncology division, shared the first data on the test's performance in triple-negative breast cancer patients from the NSABP B-59 sub-study at the San Antonio Breast Cancer Symposium on Thursday. The sub-study was designed to explore the association between TNBC patients' positive cDNA result after surgery and distant recurrence-free interval — a measure of the time from surgery to occurrence of metastatic disease.

The key findings were that after surgery, TNBC patients who were MRD-positive by Oncodetect were at significantly greater risk of distant recurrence than those who were negative, and most of the patients who were MRD-negative after surgery didn't experience distant recurrence at three years.

"The results demonstrate Oncodetect's ability to help identify patients at higher risk of recurrence and strengthen the growing clinical evidence supporting the test's role in guiding postsurgical treatment decisions," Exact said in a statement. The company and its collaborators, National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation and the German Breast Group, will publish detailed data from this analysis in a peer-reviewed journal. "Exact Sciences will submit the data to MolDx in support of Medicare coverage," the firm added, referring to a program that establishes molecular diagnostic coverage policies for Medicare contractors.

Patients with TNBC have some of the worst outcomes among breast cancer patients. The original NSABP B-59 study was designed to test whether the addition of Genentech's checkpoint inhibitor Tecentriq (atezolizumab) to standard neoadjuvant chemotherapy and continuing single-agent Tecentriq in the post-surgery adjuvant setting improves TNBC patients' outcomes compared to standard neoadjuvant chemo followed by placebo in the adjuvant setting. Data presented last year at SABCS showed that adding perioperative Tecentriq to standard chemo didn't improve event-free survival versus the comparator arm, missing the primary endpoint.

In the MRD sub-study, researchers wanted to see if Oncodetect could provide insights after surgery into how TNBC patients might fare in this trial and included 147 patients out of the more than 1,500 patients in the original trial in their analysis.

Balic, who is also the scientific director of the NSABP Foundation Translational Research Program, noted that this sub-study is one of the largest evaluations of a bespoke MRD assay in prospectively collected serial blood samples from TNBC patients. Researchers collected samples for ctDNA analysis at baseline, at two to four weeks after neoadjuvant treatment, after surgery, and at one and two years follow-up. The median follow-up post-surgery in the sub-study was around three years.

A first look in breast cancer

Oncodetect is Exact's tumor-informed blood test, which is designed to track up to 200 circulating tumor DNA variants identified via tumor-normal whole-exome sequencing for each patient. Oncodetect looks for those somatic mutations in patients' plasma samples and determines cDNA positivity using a proprietary algorithm.

Balic noted that the test successfully sequenced 689 out of 700 plasma samples from study patients for somatic variants, for a 98.4 percent detection rate, and identified between 42 and 200 somatic mutations per patient included in the analysis.

At baseline, before neoadjuvant treatment, 96 percent of 160 patients were cDNA-positive, and only 4 percent were negative. After neoadjuvant treatment, 9 percent of patients were ctDNA-positive and 91 percent were negative. After surgery, the cDNA-positivity rate was slightly lower, at 6 percent, and 94 percent were negative.

Next, researchers looked at how patients' ctDNA status lined up with their pathologic complete response status after neoadjuvant treatment. Patients are deemed to be in pathologic complete response when pathological assessment of the tumor shows no viable cancer cells after neoadjuvant treatment. It's a good sign of long-term treatment benefit.

Most of the 97 patients who achieved pathological complete response, 98 percent, were cDNA-negative; only 2 percent were cDNA-positive. However, 46 out of the 58 pallients, or 79 percent, of those who failed to achieve pathologic complete response were ctNA-negative by Oncodetect, and 21 percent were cDNA-positive.

At the post-surgery time point, researchers wanted to see how MRD status impacted distant recurrence-free interval - the primary analysis of the sub-study. Balic and colleagues reported that seven out of 138 patients who were MRD-negative after surgery, or 5 percent, developed recurrence. That means 95 percent in this subgroup were free of metastatic disease three years after surgery.

In comparison, seven out of nine patients who were MRD-positive after surgery, or 78 percent, experienced distant recurrence. This translated to a 30-fold higher risk of distant recurrence among MRD-positive patients compared to those who were MRD-negative, Balic highlighted.

Finally, researchers explored the relationship between distant recurrence-free interval and patients' cDNA and pathologic complete response status. They reported that five out of 42 patients who were cDNA-negative and didn't achieve pathologic complete response, or 12 percent, had recurrences, and only 2 percent, or two out of 96 patients, who were cDNA-negative but achieved pathologic complete response had recurrences.

This analysis showed that "patients who didn't achieve pathological complete response but were cDNA-negative moved up to the group with very good outcome," Balic said.

On the other hand, six out of seven patients, or 86 percent, of those who were cDNA-positive and didn't achieve pathological complete response had recurrences. There were only two patients evaluated who were cDNA-positive and achieved pathological complete response, and one of them recurred. "The risk [of recurrence] increased with cDNA positivity in both groups," Balic noted.

After her presentation, when asked if she would change adjuvant treatment for her TNBC patients today based on cDNA results, Balic said she wouldn't at this time. However, she noted this sub-study provides data that can help researchers design interventional trials that could potentially change patients' outcomes.

Evolving reimbursement strategy

Exact is in the midst of being acquired by Abbott, and having an MRD test like Oncodetect in its portfolio likely contributed to Abbott's willingness to buy the firm for $23 billion. However, Exact is still building the evidence base for the MRD test in specific tumor types, including breast cancer.

Over the summer, Exact announced that it had coverage for Oncodetect under the US Centers for Medicare and Medicaid Services' MolDx program for performing serial cDNA testing in patients with stage II, III, and resectable stage IV colorectal cancer in the adjuvant and recurrence monitoring settings over a five-year period. "That decision was based on a substantial body of analytical and clinical validation data in colorectal cancer and reflects growing recognition of the value of MRD testing in solid tumors," Rick Baehner, chief medical officer of precision oncology at Exact Sciences, told GenomeWeb.

Now, the company wants to achieve the same for Oncodetect in breast cancer. "The B-59 sub-study is an important first step," Baehner said, "but it is only one part of a broader development program in breast cancer."

MolDx is a program administered by Medicare administrative contractor Palmetto GBA that establishes coverage policies for molecular diagnostics that other Medicare contractors follow. It has issued a foundational local coverage determination policy, which provides guidance to diagnostics firms on the evidence they need to provide on their MRD tests in specific cancer populations.

Commercial and government payors are reimbursing for MRD testing right now where the data are most mature, like in colorectal cancer. On the commercial payor side, Baehner noted that a few have MRD coverage policies in place in specific tumor types, but many plans reference the MolDx framework, highlighting the program's influence. "Overall, coverage is expanding but remains indication and test specific, which is why generating strong, cancer-specific evidence continues to be so important," he said.

The NSABP B-59 sub-study data will be an "important component" of the evidence package Exact will submit to MolDx in support of Oncodetect's coverage in TNBC, but the firm's "investment in breast cancer MRD goes far beyond TNBC," he said.

The company is expecting to share with MolDx and commercial insurers more detailed analysis from B-59 as well as data from a prospective NSABP B-64 registry study looking at MRD outcomes in 1,800 patients with all three subtypes of breast cancer and real-world data and health economic evidence. (Data from the registry trial will be presented at SABCS on Friday afternoon.) Exact is also working on prospective studies with the West German Study Group looking at the clinical utility of pairing Oncodetect and the Oncotype DX recurrence test in hormone receptor-positive, HER2-negative early breast cancer.

Exact hopes these data will facilitate discussions with payors and guidelines bodies on how Oncodetect MRD results can guide treatment decisions in breast cancer and "expand appropriate access to MRD testing for more breast cancer patients over time," Baehner said.

Source:  Exact Sciences Provides First Look at MRD Test Performance in Triple-Negative Breast Cancer