Tumor DNA Clearance Before Breast Cancer Surgery Predicts Response, Metastasis Risk

SAN DIEGO — Clearance of circulating tumor (ct)DNA after neoadjuvant therapy correlated significantly with pathologic complete response (pCR) and distant metastasis in triple-negative breast cancer (TNBC), according to a study reported here.

Whole-exome sequencing-based assessment showed that 95 of 141 patients who were ctDNA negative after neoadjuvant therapy achieved pCR as compared with two of 14 who remained ctDNA positive after neoadjuvant therapy. Among patients who were ctDNA positive before treatment and had ctDNA clearance during neoadjuvant therapy, 85 of 123 (69.1%) achieved pCR as compared with two of 13 (15.4%) who did not have clearance during NAT.

Only 6% of patients with ctDNA negative status before surgery had distant metastasis, as compared with 54% who were ctDNA positive before surgery, reported Marija Balic, MD, PhD, of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation and the University of Pittsburgh, at the American Association for Cancer Research meeting.

“Building on our prior findings, post-neoadjuvant treatment, pre-surgery ctDNA positivity was strongly associated with inferior distant recurrence-free interval … mirroring the negative prognostic impact previously observed for post-surgery ctDNA” said Balic. “ctDNA positivity showed a high positive predictive value for non-pathological complete response, highlighting its potential utility as an early indicator of treatment resistance, risk stratification, and potentially, adaptation of treatment. These studies will help define suitable time points for escalation and de-escalation [treatment] strategies.”

The results are almost identical to those of the I-SPY trial, which showed lack of ctDNA clearance significantly predicted poor response and metastatic recurrence, noted Alice Ho, MD, of the Houston Methodist Academic Institute and O’Neal Comprehensive Cancer Center.

“It seems like we are really looking at a future where we’ll be combining the ctDNA status at the end of therapy along with the surgical results,” said Ho. “I agree with you that we will need very large studies to be able to understand how we can use that to [adapt treatment].”

Kenneth Tanabe, MD, of Mass General Brigham in Boston, wondered whether conversations about escalation and de-escalation of therapy would include surgery. “Theoretically, with pathologic CR, patients don’t benefit from surgery.”

Balic said discussions about potentially adapting treatment to ctDNA results involve several considerations, including the potential to de-escalate the nature and duration of neoadjuvant therapy. Conversely, escalating treatment for patients who remain ctDNA positive is another issue for potential future consideration “to try to salvage them and save their lives.”

In summarizing the data presented by Balic and others at the same session, Tanabe said, “The neoadjuvant window serves as a biological stress test. We’re getting real time readout of how specific tumor biology responds to a specific targeted intervention. Readouts like ctDNA can provide very significant prognostic consequences. This leads to integration of anatomic and biologic staging. The AJCC [American Joint Committee on Cancer] staging remains the foundation of language for staging, but we’re now refining that bedrock through a hierarchy of predictive factors.”

Balic reported findings from a substudy of the NSABP B-59/GBG-96-GeparDouze trial that evaluated neoadjuvant chemotherapy plus immunotherapy or placebo in early TNBC. The substudy evaluated post-neoadjuvant therapy ctDNA as a treatment response decision point, examining whether ctDNA clearance during neoadjuvant therapy predicted pCR and whether post-neoadjuvant therapy ctDNA status predicted distant recurrence.

As Balic noted, the recently reported analysis of post-surgical ctDNA status showed that ctDNA persistence was associated with a 30-fold higher likelihood of distant recurrence. Additionally, 95% of patients who had minimal residual disease-negative status were recurrence free at 3 years.

The current substudy included 155 patients who had preoperative ctDNA assessment. In 136 patients who had baseline and post-neoadjuvant therapy assessments, 90.4% had ctDNA clearance with neoadjuvant therapy. Positive ctDNA status after neoadjuvant therapy had 97.9% specificity for non-pCR and 85.7% positive predictive value for non-pCR.

Post-neoadjuvant therapy ctDNA status also predicted distant recurrence at 3 years. Nine of 141 patients who were ctDNA negative before surgery had distant recurrence versus seven of 13 patients who were ctDNA positive. The difference translated into a hazard ratio of 10.2 (95% CI 3.8-27.3, P<0.0001).

During a discussion that followed the presentation, a member of the audience asked Balic about the two patients who achieved pCR despite being ctDNA positive after neoadjuvant therapy.

“We will have to look into the level of ctDNA positivity for those patients and see whether they cleared with longer follow-up,” said Balic.