On November 30, 2020 Natera,Inc. (NASDAQ: NTRA), a pioneer and global leader in cell-free DNA testing, reported a new paper published in Annals of Oncology, highlighting the use of its personalized and tumor-informed circulating tumor DNA (ctDNA) assay, Signatera, in monitoring the response to neoadjuvant chemotherapy (NAC) across all breast cancer subtypes (Press release, Natera, NOV 30, 2020, View Source [SID1234572003]). The manuscript can be found here.

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Roughly 275,000 patients are diagnosed with breast cancer every year,1 and many receive NAC — the preoperative treatment of cancer with chemotherapy, radiation therapy, or endocrine therapy — which has become a standard of care for patients with locally advanced breast cancer. The primary goal of NAC is to downstage the tumor and allow for breast conserving surgery in those whose tumors are responsive to treatment. However, according to the National Comprehensive Cancer Network’s clinical practice guidelines,2 "the accurate assessment of in-breast tumor or regional lymph node response to preoperative systemic therapy is difficult."

Furthermore, a minority of patients receiving NAC achieve pathologic complete response (pCR), which occurs when there are no discernable tumor cells in the surgically resected tissue after NAC. These patients are known to enjoy very low risk of metastatic recurrence3 and may avoid additional treatment after surgery. In fact, the FDA considers pCR as a surrogate endpoint for drug efficacy. Among non-pCR patients, however, studies show that 20-25% will experience metastatic recurrence.3 Since there are currently no accurate biomarkers available for further risk stratification, most non-pCR patients receive additional systemic therapy after surgery.

"The I-SPY 2 Trial was designed to use novel biomarkers to help accelerate drug development and improve clinical outcomes," said Laura Esserman, MD, MBA, and Laura van ‘t Veer, PhD, breast cancer specialists, professors at the University of California San Francisco, and co-authors of the paper. "This study shows that personalized ctDNA monitoring is a powerful new tool that can help evaluate novel therapies faster, in conjunction with other biomarkers like pCR and MRI imaging response. This technology may also help guide clinical decisions in the neoadjuvant setting, including the type and timing of surgery and whether to switch treatment modalities."

The study analyzed 291 plasma samples from 84 patients who received neoadjuvant treatment. Serial blood samples were collected before treatment (T0), during treatment (T1, T2), and after treatment but before surgery (T3), with detailed clinical outcomes collected up to 6 years post-surgery. Key findings from the study include:

Early clearance of ctDNA during treatment (at T1) was significantly associated with the increased likelihood of achieving pCR (P = 0.012)
Among the 43 patients who did not achieve pCR, 86% were ctDNA-negative after NAC (T3) and achieved distant relapse-free survival of 93%, almost the same as those who achieved pCR
Among those patients who were ctDNA-positive after NAC (T3), 67% experienced metastatic recurrence
"Breast cancer patients who achieve pCR after NAC have been shown to enjoy a significant survival advantage over those who do not," said Alexey Aleshin, MD, MBA, Natera’s Senior Medical Director of Oncology. "However, predicting early metastatic recurrence in patients who do not achieve pCR remains a significant unmet need. Our study shows that Signatera can be used to monitor the response to NAC in real time, potentially allowing physicians to switch treatments or move to surgery earlier. Signatera may also improve on pCR as a prognostic marker for survival, which may have profound effects on how patients are treated in the adjuvant setting."

About Signatera
Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. The test is available for clinical and research use, and in 2019, it was granted Breakthrough Device Designation by the FDA. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood. Unlike a standard liquid biopsy, Signatera is not intended to match patients with any particular therapy; rather, it is intended to detect and quantify how much cancer is left in the body, to detect recurrence earlier and to help optimize treatment decisions. Signatera test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers. Signatera has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). CAP accredited, ISO 13485 certified, and CLIA certified.