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).
This conclusion is based on results from a study by Chiun-Sheng Huang, MD, PhD, MPH, professor of surgery and director of the Breast Care Center at National Taiwan University Hospital in Taipei, Taiwan, and first author Po-Han Lin, MD, PhD, also of National Taiwan University Hospital.
The study, funded by the Taiwan National Science and Technology Council, the National Taiwan University Hospital, and the Yonglin Foundation, was published in Cancer Research Communications, a journal of the American Association for Cancer Research (AACR).[1]
HER2-positive Breast Cancer
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. [2] According to Huang, however, many of these patients still experience recurrence and metastasis, which he argues indicates the need for a better biomarker to assess 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.[3]
“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 explained.
“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,” he added.
Study design
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 (ADC) trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche) as adjuvant therapy, which has been shown to improve survival in patients without pCR after NAT. Researchers collected blood samples from patients before NAT initiation and after surgery.[4]
Study outcomes
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.
- Among the 92 patients who did not achieve pCR, ctDNA was detected after NAT in 26 (28%).
- Among the 99 patients not treated with trastuzumab emtansine, 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.
Furthermore, recurrence-free survival (RFS) did not differ statistically between ctDNA-negative patients with pCR and those 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,” Huang noted.
Because trastuzumab emtansine adjuvant therapy is currently recommended for patients without pCR, the researchers investigated ctDNA’s potential to further refine the use of this 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 trastuzumab emtansine, 62 patients were ctDNA-positive before NAT. Forty of the 62 patients achieved ctDNA clearance after NAT, and patients with ctDNA clearance had significantly better RFS than those with ctDNA that persisted after NAT. Of the total 117 patients in the analysis, 18 patients without pCR received adjuvant T-DM1 therapy. In serial tests, adjuvant trastuzumab emtansine therapy achieved 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-trastuzumab emtansine (n=77), ctDNA-negative/trastuzumab emtansine (n=8), ctDNA-positive/non-trastuzumab emtansine (n=22), and ctDNA-positive/trastuzumab emtansine (n=10). Of these, only the ctDNA-positive/non-trastuzumab emtansine group experienced a significantly worse three-year RFS than the others. All eight ctDNA-negative patients who received trastuzumab emtansine adjuvant therapy lived without any observed recurrence during a median 3.3 years of follow-up.
These results suggest that adjuvant trastuzumab emtansine 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 trastuzumab emtansine.
“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,” he added.
Study Limitations
The study’s limitations include its retrospective design, small sample size, and potential confounding of ctDNA reads by the sequencing methods employed.
Highlight of prescribing information
Trastuzumab emtansine (T-DM1, Kadcyla®; Genentech/Roche)[Prescribing Information]
Reference
[1] Lin PH, Tsai LW, Lo C, Kuo SH, Ni CC, Yu CH, Huang CS. ctDNA Detected after Neoadjuvant Therapy for HER2-Positive Breast Cancer Is Associated with Inferior Outcomes and May Inform Adjuvant Therapy. Cancer Res Commun. 2026 Jan 1;6(1):105-114. doi: 10.1158/2767-9764.CRC-24-0234. PMID: 41543393; PMCID: PMC12802552.
[2] Cancer Stat Facts: Female Breast Cancer Subtypes. NationalCancer Institute (NCI). Online. Last accessed on January 14, 2026.
[3] Pancholi NJ. Examining Diverse Uses for Liquid Biopsies, American Association for Cancer Research (AACR). Online. last accesses on January 14, 2026.
[4] Phase III KATHERINE Clinical Trial Crossed Early Reporting Boundary and Met its Primary Endpoint, American Association for Cancer Research (AACR). December 5, 2018. Online. last accessed on January 14, 2026.
Featured image: 2017 – 2026 © Fotolia/Adobe. Used with permission.
DOI
 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).){kind=link}