NEW YORK – With new data presented Friday at the 2022 San Antonio Breast Cancer Symposium, Exact Sciences has crossed the first hurdle in advancing a gene expression assay to guide the use of radiotherapy in women with early-stage breast cancer.
In a meta-analysis of retrospective biomarker data and clinical outcomes from three independent, randomized clinical trials, investigators were able to assert that Exact's Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) signature was not only prognostic but also predictive of which patients benefited meaningfully from radiotherapy.
Rick Baehner, the firm's chief medical officer of precision oncology, said that radiation, like chemotherapy, has physical, financial, and emotional downsides that make the possibility of personalization attractive. "We've seen this in chemotherapy and targeted therapies. It would be super to see that extend into radiotherapy," he said.
The same sentiment is echoed by radiation oncologists. A recent review by a multi-institute group, for example, argued that given current data, breast radiation therapy is "uniquely poised for a genomically personalized approach," and it urged prospective clinical trials.
The path forward for POLAR in this vein mirrors what took place years ago with the chemotherapy-predictive Oncotype Dx assay, originally developed by Genomic Health, which Exact acquired in 2019.
Baehner said that for Oncotype, Genomic Health was able to follow up early prognostic evidence with a retrospective analysis of larger clinical trial cohorts, showing that the test was not merely prognostic. The new data presented at SABCS is the company's first pitch at doing the same for POLAR with radiation.
Now a 16-gene expression score, POLAR was initially developed by academics led by a team at the University of Michigan. When Exact acquired the assay, its inventors had already completed two of the studies used in the new SABCS presentation. One used data from a Swedish randomized trial in order to train and then test the signature, and another reassessed the score in a similar study led by Toronto's Princess Margaret Hospital.
A third study was in the works using another independent cohort from a Scottish clinical trial, which ultimately confirmed the prior findings, classifying about 25 percent of patients as having a low risk of locoregional recurrence and 75 percent as having a high risk. This study was also featured at the meeting in a poster presentation.
"When you look at the radiotherapy benefit, what you'll notice is in the low-risk group, there was no benefit at all, consistent with the previous two studies. And then in the high-risk group, the risk fell from 21 percent down to 2 percent," Baehner said. "That type of information … made us say, let's do a meta-analysis. I like to describe it as that disproportionate benefit in the high-risk group," he added.
"Since we don't have a great [trial] out there with a randomized cohort with sufficient tissue, we thought, let's do the next best thing. Let's put these three independent studies together [to] ask the question, 'Is the score predictive of radiotherapy benefit?'" Baehner said.
The meta-analysis included 623 patients with lymph node-negative, estrogen receptor-positive, HER2-negative breast cancer who were enrolled in one of three randomized clinical trials, the Swedish SweBCG91RT trial, the Scottish Conservation Trial, and a trial conducted with Toronto's Princess Margaret Hospital. Each trial examined the efficacy of breast-conserving surgery with and without local breast radiation therapy.
Analyzing banked tissue samples, researchers had previously applied the POLAR assay to these cohorts separately, concluding that the score was prognostic, in other words, able to divide patients into subsets with lower or higher risk that their cancer would recur.
By combining the three studies, Exact was able to do a new retrospective calculation, showing ultimately that patients at low risk for local regional recurrence following breast-conserving surgery — about 25 percent of the studies' overall population — did not benefit from radiotherapy.
Among 479 patients with high POLAR scores, those who did not have adjuvant radiation had a 63 percent greater risk of local recurrence compared with those who did. But for the 194 patients with low-risk POLAR scores, there was no significant difference in local recurrence rate when patients got radiotherapy or avoided it.
For POLAR's chemotherapy forebear Oncotype Dx — now a commercial mainstay in the clinical care of patients with early-stage breast cancers — next steps included additional retrospective validation, and ultimately, a prospective trial called TAILORx.
According to Baehner, Exact is hoping to be able to do at least the former for POLAR. "We know this [data] is going to start a large discussion, and we are talking with the groups that are involved in doing radiotherapy studies in the United States [and] in Europe around whether there are retrospective patient cohorts … that either have already accumulated results or are ongoing right now in which we could do a confirmatory study," he said.
The company will also be looking out for interest from the research community in doing a TAILORx-style, large inter-group prospective study.
Baehner said that Exact isn't aware of any potential commercial competitors with radiation predictive assays for early, invasive breast cancer, although PreludeDx offers a test for patients with noninvasive ductal carcinoma in situ that competes with the Oncotype DCIS assay.
He added that there has been a variety of academic work advancing prognostic tools, though none appear to have been pursued commercially. The Oncotype Dx assay itself has been the subject of this type of research. A study published earlier this year in Practical Radiation Oncology showed, similar to the POLAR data, that patients deemed low-risk by Oncotype's 21-gene assay had no significant benefit when given radiation versus not.