Outcomes in TN Breast Cancer Predicted by Blood Biomarkers

Pam Harrison

December 16, 2019

SAN ANTONIO – Biomarkers of residual disease detected in the blood at surgery following neoadjuvant chemotherapy can identify which patients with triple-negative breast cancer will have a better outcome at 2 years and which will do much worse, a phase 2 randomized controlled trial indicates.

"What we know with triple-negative breast cancer is that these cancers tend to recur at a very high rate, particularly peaking in the first 3 years after surgery, and this causes an untenable situation for our patients, who live in constant fear and uncertainty of their cancer recurring after chemotherapy and surgery," Milan Radovich, PhD, associate professor of surgery and medical and molecular genetics, Indiana University School of Medicine in Indianapolis, said at a press briefing here at the San Antonio Breast Cancer Symposium (SABCS) 2019.

"We found that the detection of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) in early-stage, triple-negative breast cancer after neoadjuvant chemotherapy is an independent predictor of disease recurrence and represents, we think, an important, novel stratification factor for post-neoadjuvant trials," he added.

The BRE12-158 trial involved 151 patients with early-stage, triple-negative breast cancer in whom there was evidence of residual disease at surgery following neoadjuvant chemotherapy.

"The first marker we focused on was a marker called ctDNA," Radovich noted. As he explained, ctDNA is DNA that is shed from tumors into the circulation, where next-generation sequencing techniques can be used to noninvasively detect the DNA in a simple blood draw.

Investigators also studied CTCs, which are live tumor cells that float in the circulation, where, again, sensitive techniques can be used to detect them in the blood.

"ctDNA was successfully sequenced in 150 patients.... 148 of the 150 sequenced patients had clinical follow-up," the investigators point out.

Genomic or DNA sequencing was conducted by Foundation Medicine using the FoundationOne Liquid assay, which provides profiles for 70 commonly mutated oncogenes.

Following genomic sequencing, patients were randomly assigned to receive either genomically directed therapeutics or the investigative physician's choice of therapy.

Plasma samples of both ctDNA and CTCs were collected at cycle 1, day 1 in the genomically directed therapies arm. In the control arm, they were collected at the patient's first routine visit.

Investigators then correlated the presence of mutated ctDNA with distant disease-free survival (DDFS) and overall survival in both univariate and multivariate analyses.

Striking Results

"Results were absolutely striking," Radovich said.

"Patients who were positive for ctDNA in their circulation after surgery had a significantly inferior DDFS compared to patients who were ctDNA negative," he emphasized.

At 17.2 months' follow-up, the median DDFS rate was almost threefold higher for ctDNA-negative patients, which had not been reached at the time of data analysis, vs a median DDFS of 32.5 months in ctDNA-positive patients.

At 2 years, estimated DDFS rates were 56% for the ctDNA-positive patients vs 81% for ctDNA-negative patients (P = .005).

"The addition of CTC adds complementary information to ctDNA for detection of minimal residual disease," Radovich continued.

For patients who tested negative to both biomarkers, the 2-year DDFS rate was more than fivefold higher, at 89%, compared to 52% for patients who tested positive for both biomarkers (P = .009).

Importantly, for the subgroup of patients who tested negative for both ctDNA and CTCs, outcomes were still significantly superior to those of other groups, even though some of them were at very high risk for relapse, as determined on the basis of standard clinical variables, Radovich emphasized.

The risk for mortality among patients who tested positive for ctDNA was also almost threefold higher than it was for those who tested negative for ctDNA (P = .022), the investigators add.

"At the end of the day, we want to use tests where we can actually act on results," coinvestigator Bryan Schneider, MD, professor of medicine and medical and molecular genetics, Indiana University School of Medicine, and senior author of the study, told Medscape Medical News.

"We already know that the risk of relapse in these patients is really high, so the ability to take that information and understand whether we can act on it in a clinically meaningful way is really important," he added.

Hence, investigators are now planning the BRE18-334 trial, also known as the PERSEVERE trial, another phase 2 study in which patients with triple-negative disease with minimal residual disease at surgery who test positive for ctDNA will be treated with a genomically directed, post-neoadjuvant therapy.

The therapy will target actionable genomic markers detected on sequencing among ctDNA-positive patients. Those who have no actionable tumor targets or who are ctDNA negative will be assigned to standard of care.

"The goal of our trial is not to prolong survival, it is to try and go for cure — we are going to use this ctDNA information and actual germline alternations to improve the cure rate," Schneider said.

"And we feel our patients will be very motivated to participate, especially if they know there is a high risk of their cancer coming back," he added.

Asked to comment on the study's findings, the press briefing moderator, Virginia Kaklamani, MD, UT Health, San Antonio, Texas, said that she does not like disclosing test results to a patient when she can't act on them.

"That is why we do clinical trials," Kaklamani said. "We need this information so we can do clinical research and figure out if we can salvage these patients with our novel therapies and maybe make a difference to their outcomes," she added.

Radovich concurred, saying that although he believes it is important that they now have the technology that can identify which patients with triple-negative breast cancer will do poorly, "I think the more important thing now is that we have to learn how to act on it," he said.

Radovich has received financial assistance from LifeOmic, Macrogenics, Immunomedics, and Arqule. Schneider has disclosed no relevant financial relationships. Kaklamani has received speaker fees from Pfizer, Celgene, Genentech, Genomic Health, Puma Eisai, and Novartis and has served as a consultant for Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex. She has also received research funding from Eisai.

San Antonio Breast Cancer Symposium 2019: Abstract GS5-02. Presented December 13, 2019.

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