Bottom Line: The presence of circulating tumor DNA (ctDNA) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer after they received neoadjuvant treatment and surgery predicted worse outcomes than in those patients without ctDNA, even in patients with a pathologic complete response (pCR).
Journal in Which the Study was Published: Cancer Research Communications , a journal of the American Association for Cancer Research (AACR)
Authors: Lead author Chiun-Sheng Huang, MD, PhD, MPH , professor of surgery and director of the Breast Care Center at National Taiwan University Hospital in Taipei, Taiwan; first author Po-Han Lin, MD, PhD, also of National Taiwan University Hospital
Background: Breast cancer is the most common form of non-skin cancer in the United States, and HER2-positive breast cancer accounts for about 13% of breast cancer cases . According to Huang, however, many of these patients still experience recurrence and metastasis, which he said points to the need for a better biomarker to evaluate patients' risk. ctDNA is shed from tumors into the bloodstream and can provide a noninvasive way to glean insights about a patient's cancer. To do this, researchers measure blood serum levels of DNA with genetic variants that tend to occur in tumors.
"Patients with HER2-positive early breast cancer have a high recurrence rate. After these patients receive neoadjuvant systemic therapy (NAT), pCR has been a surrogate marker of outcomes, but some patients with pCR still experience recurrence or distant metastasis," Huang said. "This highlights the need for a better biomarker to identify which patients may experience disease recurrence. In this study, we aimed to investigate the prognostic role of ctDNA after NAT in patients with HER2-positive early breast cancer."
How the Study was Conducted: Huang and colleagues studied the relationship between ctDNA and disease recurrence through a retrospective analysis of 117 patients with HER2-positive early-stage breast cancer who had received NAT in the form of chemotherapy with single or dual anti-HER2 antibodies. Following surgery, 18 of these patients had received the antibody-drug conjugate therapy trastuzumab emtansine (T-DM1, Kadcyla) as an adjuvant therapy, which has been shown to improve survival in patients who do not have pCR after NAT. Researchers collected blood samples from the patients before starting NAT and after surgery.
Results: Of the total 117 patients, 79 patients (67.5%) were ctDNA-positive before NAT, and 32 of those 79 (40.5%) continued to test positive for ctDNA after NAT. Thirty-eight of the 117 patients (32.5%) tested negative for ctDNA before treatment, and all 38 of them remained ctDNA-negative after NAT.
Overall, 25 patients (21.4%) had a pCR after NAT, compared with 92 (78.6%) who did not. Of the 25 patients with pCR, six (24%) tested positive for ctDNA after NAT. In the 92 patients who did not experience pCR, ctDNA was detected after NAT in 26 (28%) patients.
Among the 99 patients not treated with T-DM1, patients who were ctDNA-positive after NAT were 5.5 times more likely to experience disease recurrence than patients who were ctDNA-negative within the median 4.02 years of follow-up, regardless of pCR status. Further, recurrence-free survival (RFS) was not statistically different between ctDNA-negative patients with pCR and ctDNA-negative patients without pCR, nor between ctDNA-positive patients with and without pCR. This suggested that ctDNA may be a more accurate predictor of disease recurrence than pCR, said Huang.
Because T-DM1 adjuvant therapy is currently recommended for patients without pCR, the researchers investigated ctDNA's potential to further refine the use of T-DM1 adjuvant therapy. If ctDNA may predict risk of recurrence better than pCR, they hypothesized, then it may also be a better measure of potential patient benefit from T-DM1.
Among the patients not receiving T-DM1, 62 patients were ctDNA-positive before NAT. Forty of the 62 patients had ctDNA clearance after NAT, and patients with ctDNA clearance experienced significantly better RFS than patients with ctDNA that persisted after NAT. Of the total 117 patients in the analysis, 18 patients without pCR received adjuvant T-DM1 therapy. During serial tests, adjuvant T-DM1 therapy led to significantly higher ctDNA clearance rates (8/8) than non-T-DM1 therapy (7/12) in patients who were ctDNA-positive after NAT.
The researchers further compared RFS among four patient groups—ctDNA-negative/non-T-DM1 (n=77), ctDNA-negative/T-DM1 (n=8), ctDNA-positive/non-T-DM1 (n=22), and ctDNA-positive/T-DM1 (n=10). Of these, only the ctDNA-positive/non-T-DM1 group experienced a significantly worse three-year RFS than the others. All eight ctDNA-negative patients who received T-DM1 adjuvant therapy lived without any observed recurrence during a median 3.3 years of follow-up.
These results suggest that adjuvant T-DM1 could benefit patients who test positive for ctDNA after NAT and surgery, potentially independently of pCR status, Huang said. Conversely, patients who test negative for ctDNA may not experience any added benefit from adjuvant T-DM1.
Author's Comments: "Our findings indicate that ctDNA could be a better prognostic factor than pCR in patients with HER2-positive early breast cancer after they've received NAT. We believe that this knowledge could be effectively used to guide escalation or de-escalation of adjuvant therapy," said Huang. "However, these implications need to be verified by further large-scale studies or randomized trials."
Study Limitations: The study's limitations include its retrospective design, a limited sample size, and the possibility of confounded ctDNA reads due to the sequencing methods used.
Funding & Disclosures: The study was funded by the Taiwan National Science and Technology Council, the National Taiwan University Hospital, and the Yonglin Foundation. Huang reports receiving research grants from Aston Sci., AstraZeneca, Daiichi Sankyo, EirGenix, Eli Lilly, Gilead, MSD, Novartis, OBI Pharma, Pfizer, Roche, and Seagen. He has also received honoraria and/or advisory fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, and Roche outside the submitted work.
