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Breast Cancer Trial Data Supports Neoadjuvant Use of Natera Liquid Biopsy


NEW YORK – Natera's personalized ctDNA assay technology has shown new potential as a tool to assess the efficacy of breast cancer neoadjuvant chemotherapy and potentially guide decisions regarding further adjuvant treatment after surgery.

In a study in Annals of Oncology late last month, investigators retrospectively analyzed samples from a large neoadjuvant clinical trial called I-SPY 2, concluding that the company's Signatera liquid biopsy approach could predict which patients would go on to show pathologic complete response (pCR) — a term describing there being no discernable tumor cells present when patients receive post-therapy surgery — and that ctDNA testing could identify patients with good outcomes despite a failure to achieve pCR.

Based on the results, authors wrote that use of these types of assays could help fine-tune pCR as a surrogate endpoint of survival in neoadjuvant clinical trials and serve as an immediate tool to help oncologists more precisely treat their patients.

In an interview this week, Natera's Senior Medical Director Alexey Aleshin, who was also an author on the study, said that the company believes that the data — especially coupled with additional confirmatory results from a separate cohort of I-SPY 2 patients being presented this week at the San Antonio Breast Cancer Symposium — are strong enough to support use by clinicians.

Although he said the data needs to be prospectively validated for it to be used to inform broad practice recommendations, "medicine's not black and white," he argued.

"PathCR is the best tool we have to know if a woman has responded or not to neoadjuvant therapy … but the problem right now … is that you give somebody a few months of chemotherapy and only afterward are you finding out whether it worked — after putting a patient through all of this toxicity," Aleshin said.

In this vein, ctDNA status and dynamics during neoadjuvant treatment could offer an earlier readout of whether patients are likely to achieve pCR. "You could use that information to intervene or change therapy earlier if they are not benefiting from it," Aleshin suggested.

More importantly though, he said, the data also suggest that ctDNA could do a better job than pCR at predicting ultimate outcome.

According to the study authors, led by Laura Esserman and Laura van 't Veer, both professors at the University of California San Francisco, about 20 to 25 percent of non-pCR patients will experience metastatic recurrence, while the rest remain cancer free. Without biomarkers to further risk stratify this non-pCR group, most individuals receive additional systemic therapy after surgery, though only a minority stand to benefit from it.

"Obviously not achieving pathCR portends a worse prognosis," but not all women with remaining tumor will recur, Aleshin said. As a result, many women who don't achieve pCR struggle with the decision of how to act on that information. Despite this indicator of higher risk, they may not want to undergo more chemotherapy in the adjuvant setting.

The study analyzed 291 plasma samples from 84 patients who received neoadjuvant treatment in I-SPY 2, including serial blood samples collected before treatment, during treatment, and after treatment but before surgery.

Investigators compared patients' ctDNA status with detailed clinical outcomes data collected up to six years post-surgery.

According to the authors, early clearance of ctDNA during treatment at the first blood draw was significantly associated with an increased likelihood of achieving pathologic complete response. For those who still showed ctDNA at this timepoint, 83 percent failed to achieve pCR compared to only about half of those who did clear their ctDNA early.

Encouragingly, there were no patients who achieved pCR but still showed signs of ctDNA at the final pre-surgery blood draw.

Patients who failed to achieve pCR but were ctDNA-negative after neoadjuvant therapy had a distant relapse-free survival of 93 percent: almost equal to that of those who did achieve pCR. In contrast, among the group that showed evidence of ctDNA and failed to achieve pCR, 67 percent experienced metastatic recurrence.

Other liquid biopsy companies have also investigated their assays in applications that could help direct therapy for patients after neoadjuvant chemo, though under slightly different parameters. Foundation Medicine, for example, has collected data showing that its liquid biopsy platform could help determine which patients who failed to achieve pCR were most likely to recur.

Aleshin argued that Signatera's personalized assay approach offers greater sensitivity to pick up these lingering signals of residual cancer and offers the added ability to provide early assessment of whether neoadjuvant therapy is working or not, before a patient's pCR status has even been established.

Moving forward, Aleshin said the Signatera I-SPY 2 findings establish a potential framework whereby ctDNA can be used to further refine risk over pCR status alone.

"You can imagine three categories," he said. "For the first group, which achieves pathCR and is ctDNA negative, they are going to do great.

"For the second group that does not achieve pathCR but clears their ctDNA, we can say for the first time that these patients are also going to do really well, so maybe they don't need that additional toxic therapy. And for the third group, which is not achieving pathCR and is still ctDNA positive, we can see that this group is going to do really poorly."

"In those borderline situations today where someone is making a complex decision, having that additional information is super helpful because if you're already unsure if you're going to give adjuvant therapy and someone is ctDNA-positive, you can say, 'Well, gosh, I know you have all this toxicity, but you're super high risk so let's kind of push ahead,''' Aleshin said.

If someone is ctDNA-negative that could help justify a choice to avoid adjuvant chemo for women who were already on the fence.

"I think that's probably where this can be helpful today, but I think to make broad blanket statements about … giving standard-of-care adjuvant therapy, [especially de-escalation of that therapy], we need prospective validation and additional studies," Aleshin added.

Finally, for the highest risk group, those with lingering ctDNA and tumor tissue, "maybe we should target more intensive therapies for this [subset], or maybe pharmaceutical companies could focus additional development efforts."

The potential of ctDNA to aid neoadjuvant clinical trials and potentially to serve as a recognized surrogate biomarker in the same way pCR is currently used has been an area of growing attention by researchers and commercial firms like Natera who market liquid biopsy technologies.

"In terms of an exploratory endpoint, it's already here," Aleshin said. "The benefit to trials is that you get a much more granular sense of how the drug is working when it's working."

For example, in the additional data Natera is presenting at the San Antonio Breast Cancer Symposium, investigators analyzed a separate I-SPY 2 cohort treated with Pembrolizumab (Merck's Keytruda) in addition to chemotherapy. Results recapitulated their finding that ctDNA status could predict which patients achieved pCR, as well as improve prediction of overall outcomes over pCR, but researchers were also able to show that liquid biopsy could help identify the impact of added immunotherapy independent of the backbone chemotherapy also being administered.

"In terms of replacing pathCR as a surrogate for overall survival and relapse-free survival, I think that's going to take more time," Aleshin added. "We think probably it's going to be a combination where you use both as a kind of combined surrogate because there is additive benefit from both … and I think the field is moving there. There is already ongoing work with the academic and the regulatory bodies exploring what a strategy like that would look like."