Shifting the Paradigm in Patient Management with Clinically Validated MRD Testing

In the inaugural event of the Global Cancer Movement, initiated by OncoDaily, Dr. Alexey Alishin, General Manager for Oncology at Natera, delves into the groundbreaking role of circulating tumor DNA (ctDNA) in revolutionizing cancer care. The virtual event, held from December 6-8, 2024, brings together global experts to explore how ctDNA testing is transforming early detection, treatment monitoring, and personalized care strategies.

Dr. Alexey Aleshin, General Manager for Oncology at Natera, began his presentation by emphasizing the challenges clinicians face in determining which cancer patients are cured following surgery or definitive treatment for early-stage cancer. Traditional tools like imaging, cancer staging, and biomarkers such as CEA provide some insight but are not definitive. As a result, patients are often treated uniformly with toxic therapies, regardless of their individual risk of recurrence.

Dr. Aleshin introduced circulating tumor DNA (ctDNA) as a transformative tool in oncology. He explained that ctDNA consists of fragments of DNA shed by dying cancer cells into the bloodstream, providing a dynamic and sensitive biomarker. This DNA has a short half-life, allowing clinicians to measure the presence and quantity of cancer in the body with high precision, even at extremely low levels post-surgery.

Natera’s approach, using the Signatera test, involves whole-exome sequencing to identify tumor-specific mutations. A personalized assay is then designed to monitor ctDNA levels throughout the patient’s treatment journey, from pre-surgery neoadjuvant therapy to post-surgery adjuvant therapy and long-term surveillance. This “tumor-informed” method enables unprecedented accuracy in detecting molecular residual disease (MRD) and stratifying patients into those likely cured and those at high risk of recurrence.

Dr. Aleshin highlighted the prognostic power of ctDNA, noting its ability to redefine traditional cancer staging. For instance, a ctDNA-positive stage I patient may have a worse prognosis than a ctDNA-negative stage III patient. This shift towards incorporating ctDNA into staging—termed TNMB staging—represents a significant evolution in cancer care.

He discussed the GALAXY study, part of the Circulate Japan initiative, which prospectively evaluated ctDNA across various treatment phases in over 6,000 colorectal cancer patients. Initial results from approximately 2,000 patients demonstrated the strong prognostic value of ctDNA positivity shortly after surgery, with a hazard ratio of 11.9 to 13 for recurrence risk compared to ctDNA-negative patients. This data challenges traditional risk factors like tumor size and lymph node involvement, positioning ctDNA status as a primary determinant in treatment decision-making.

The study also revealed the therapeutic implications of ctDNA monitoring. Patients who were ctDNA-positive post-surgery experienced significantly improved outcomes with adjuvant chemotherapy. Nearly 40% of these high-risk patients were cured with appropriate treatment, as opposed to almost universal recurrence without it. In contrast, ctDNA-negative patients showed excellent outcomes regardless of receiving chemotherapy, reducing unnecessary exposure to toxic therapies.

Dr. Aleshin emphasized the utility of serial ctDNA testing. Patients whose ctDNA levels dropped and remained undetectable had remarkable outcomes, akin to those who were ctDNA-negative from the outset. Conversely, persistent or recurrent ctDNA positivity indicated a high likelihood of recurrence, prompting considerations for therapy escalation or modification. The temporal dynamics of ctDNA also provided insights into the highest-risk periods for recurrence, with most recurrences occurring within 18 months post-therapy.

He concluded with the story of a 69-year-old man with stage II colon cancer, whose case illustrated ctDNA’s clinical value. Despite appearing low risk based on traditional criteria, the patient’s ctDNA positivity post-surgery identified him as high risk. Adjuvant chemotherapy initially cleared the ctDNA, but its subsequent recurrence facilitated early detection of relapse through imaging. This case underscored ctDNA’s role in guiding personalized treatment and surveillance strategies.

Dr. Aleshin’s presentation highlighted ctDNA’s revolutionary potential to personalize cancer care, minimize overtreatment, and improve survival outcomes. The continued integration of ctDNA into clinical practice promises to refine risk stratification, optimize therapy decisions, and ultimately transform oncology.