Circulating Tumor DNA After Neoadjuvant Chemo May Determine Risk of Recurrence in TNBC

December 18, 2019

Patients with early-stage triple-negative breast cancer who did not have circulating tumor DNA in their blood experienced superior outcomes to chemotherapy followed by surgery.

Patients with early-stage triple-negative breast cancer (TNBC) who did not have circulating tumor DNA (ctDNA) in their blood experienced superior outcomes, compared to those with the biomarker, after chemotherapy was given as a first step to shrink their tumors before surgery, according to trial results presented at the San Antonio Breast Cancer Symposium (SABCS).

The new data suggested that ctDNA, which is DNA shed from tumors that circulates in the bloodstream, could be a powerful predictor of survival in women with TNBC, a considerably more aggressive form of breast cancer that has not benefitted from recent advancements in hormonal targeted therapies seen in other types of breast cancers, according to Dr. Milan Radovich, associate professor of surgery at the Indiana University School of Medicine.

“We know with TNBC that patients with this cancer have their disease recur at a very high rate, particularly peaking in the first three years after surgery,” Radovich said during a press conference at SABCS, held Dec. 10-14, in San Antonio, Texas. “This causes an untenable situation for our patients, who live in constant fear and uncertainty of their cancers recurring after chemotherapy and surgery, (which is the current standard of care).”

When treated with neoadjuvant chemotherapy followed by surgery, about one in three patients will have a pathologic complete response, an absence of residual disease of the resected breast. In these cases, long-term survival rates are quite high.

But two in three patients have residual disease after chemo and surgery, with very poor long-term survival rates. Radovich and colleagues focused on this residual disease population in their study and harnessed the power of circulating tumor markers like ctDNA and circulating tumor cells (CTC), which are living tumor cells floating in the circulation that can be detected with simple blood draws.

“The question is if we detect the ctDNA and CTCs in patients who have completed neoadjuvant chemotherapy and surgery, are they at high risk of their cancers coming back? Again, these patients after chemotherapy and surgery are disease-free. We don’t detect any cancer, can’t see it, can’t feel it, can’t scan for it. But in a proportion of them, we know that their cancer will come back anyway,” he said.

Radovich and colleagues analyzed samples from the BRE12-158 clinical trial, designed to evaluate genomically-directed therapy compared with physician’s choice of treatment after neoadjuvant chemotherapy in 196 patients with TNBC. ctDNA was sequenced in 142 patients, and two-year disease-free survival was evaluated as a primary endpoint of the study presented at the symposium.

At two years, ctDNA-negative patients demonstrated superior disease-free survival, compared with ctDNA-positive patients (81% vs. 56%).

“The results are absolutely striking,” Radovich said. “Patients who have ctDNA in their circulation after surgery have significantly inferior distant disease-free survival (DDFS) compared to patients who are ctDNA negative.”

Next, Radovich and colleagues sought to find out whether the combination of ctDNA and CTC in the blood could become an even more powerful indicator of two-year DDFS. They observed a stepwise gradation in the outcomes: If patients came up negative for both ctDNA and CTCs, they had exceptionally superior outcomes; if they were positive for one marker or the other, they had intermediate outcomes; and if they were positive for both CTC and ctDNA, they had inferior outcomes.

The two-year disease-free survival for patients who were positive for both ctDNA and CTC was 52%, compared with 89% among those who were negative for both.

“This population that is ctDNA-negative and CTC-negative had a two-year DDFS of 89% even though based on standard clinical parameters, they’re at very high risk of relapse,” Radovich said. “When you look at their detailed clinical data, many of these patients had large tumors greater than 5 centimeters, several had lymph node involvement, yet they were biomarker-negative for both and have now had exceptional long-term outcomes.”

Although the trial is still ongoing, Radovich and colleagues announced that they’d take their findings a step further by launching a new trial, known as PERSEVERE, which will help further stratify patients who have residual disease after standard therapy.

“These results might be applicable to other types of breast cancer,” Radovich said. “But in TNBC, we think this represents the greatest opportunity.”


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