Foreseeing Breast Cancer Recurrence: Ultrasensitive ctDNA and MRD Analysis

Minimal Residual Disease (MRD) and Ultrasensitive Measurement

Minimal residual disease (MRD) consists of microscopic clusters of cells remaining in the body after surgery and systemic treatment, undetectable by imaging but actually responsible for recurrence. The PREDICT-DNA study used technology that could detect the traces these cells release into the blood (ctDNA) at a sensitivity of fewer than 100 molecules per 1 million (<100 ppm).

Is Pathological Complete Response (pCR) Enough on Its Own?

One of the study's most important findings is the relationship between ctDNA status at the end of preoperative treatment (the T1 time point) and pCR. The results indicate that liquid biopsy alone is not yet sufficient to "cancel" surgery, but is flawless for "managing risk."

*ctDNA negativity does not predict pathological complete response with 100% certainty; it therefore cannot yet replace surgery.

A Striking Reality: Positive ctDNA After Surgery

During follow-up through month 12 after surgery (T2*), ctDNA status created a statistical "chasm" in predicting recurrence. These data attracted considerable attention in oncology, particularly in triple-negative breast cancer.

In triple-negative breast cancer, all patients with detectable postoperative ctDNA in the blood experienced recurrence during follow-up. By contrast, among patients with no detectable ctDNA in the blood, 94% remained disease-free at the end of 5 years. This demonstrates that ctDNA testing functions almost as a "diagnostic tool," rather than merely a "biomarker."

In Summary:

1. 0% Error in "Positive" Results: If the test performed after surgery and adjuvant treatment is "positive" (cancer risk present), it produces a correct result 100% of the time: indeed, cancer recurred in every test-positive patient followed for at least 3 years, without exception.
2. Margin of Error in "Negative" Results: Even if the test is "negative" (clear) after surgery, this does not mean zero error: although 94% of patients remained disease-free for 5 years, cancer recurred in the remaining 6%.
3. Failure to Evaluate Preoperative Treatment (NAT): The test was inadequate for predicting whether cancer cells remained in the body after preoperative treatment, incorrectly returning a "negative" result in 40% of patients who still had tumor.
4. Still Too Early for Clinical Use: Although the test is highly successful at predicting recurrence risk, it is not entirely flawless. Because its lack of 100% accuracy, particularly false-negative results, could deprive patients of treatments they need, routine clinical use may await FDA approval or inclusion in internationally accepted guidelines such as NCCN. In other words, ctDNA may be prognostic, but it has not yet been definitively established as a predictive tool that guides treatment.

Precision Treatment: Escalation and De-escalation

These findings open the way to two critical strategies in breast cancer treatment:

• Treatment De-escalation: In patients whose ctDNA remains persistently negative, even with non-pCR, it may be possible to reduce the doses of toxic adjuvant treatments or avoid them entirely.
• Treatment Escalation: In "high-risk" patients with detectable postoperative ctDNA, more aggressive or novel targeted treatments may be introduced before clinical recurrence develops, through molecular relapse trials.