Excluding skin cancers, breast cancer is the most commonly diagnosed cancer among women in the United States, accounting for about 30% of all new female cancers each year. In 2026, the American Cancer Society estimates that 322,000 new cases of invasive breast cancer and about 61,000 new cases of ductal carcinoma in situ will be diagnosed in women in the United States, and that approximately 42,140 women will die of the disease.
A clinical study investigating the prognostic role of circulating tumor DNA (ctDNA) and its utility in guiding adjuvant therapy for HER2-positive early breast cancer has found that patients who test positive for the presence of ctDNA after they have received neoadjuvant treatment and surgery have worse outcomes than patients who are negative for ctDNA—even in patients who experienced a pathologic complete response. The findings demonstrate that ctDNA is an independent prognostic factor and may serve as an additional marker for guiding adjuvant therapy with ado-trastuzumab emtansine (T-DM1). The study by Lin et al was published in Cancer Research Communications.
Study Methodology
The researchers conducted a retrospective analysis to study the relationship between ctDNA and disease recurrence of 117 patients diagnosed with HER2-positive early-stage breast cancer who had received neoadjuvant systemic therapy. Patients had received chemotherapy with single or dual anti-HER2 antibodies, including at least four cycles of taxane chemotherapy and trastuzumab or dual HER2 blockage (trastuzumab plus pertuzumab). Following surgery, 18 of these patients had received the antibody-drug conjugate T-DM1; in the KATHERINE trial, the agent improved survival in patients who did not experience a pathologic complete response (pCR) after neoadjuvant systemic therapy. The researchers collected blood samples from the patients before they started neoadjuvant systemic therapy.
Results
The study found that of the 117 patients enrolled, 25 achieved a pCR after neoadjuvant therapy, and 92 did not; 6 of the 25 pCR patients were ctDNA-positive. Eighteen patients received adjuvant T-DMI, and 99 patients did not.
Among the non–T-DMI group, ctDNA positivity after neoadjuvant therapy independently predicted cancer recurrence (hazard ratio [HR] = 5.505; 95% confidence interval [CI] = 1.950–15.540; P = .001). Patients with a pCR and ctDNA positivity experienced a shorter recurrence-free survival compared to patients with a pCR and ctDNA negativity after neoadjuvant therapy (P = .008), whereas non-pCR patients with ctDNA-negative tumors experienced a better recurrence-free survival compared with non-pCR patients with ctDNA-positive status (P = .001).
Among the 79 patients who were ctDNA-positive before neoadjuvant therapy, clearance of ctDNA by neoadjuvant therapy was associated with significantly better recurrence-free survival than nonclearance (P < .001). Receipt of adjuvant T-DM1 also significantly improved the ctDNA clearance rate (P = .035) compared with non–T-DM1 therapy in patients with ctDNA positivity after neoadjuvant therapy during serial tests.
The researchers classified the 117 patients as T-DM1/non–T-DM1 and ctDNA-positive/negative, and a significantly shorter recurrence-free survival was observed in ctDNA-positive/non–T-DM1 patients (P = .029) than in the other three groups.
“The presence of ctDNA after neoadjuvant therapy in patients with HER2-positive early breast cancer is associated with a poor prognosis and may indicate adjuvant T-DM1,” concluded the study authors.
Significance
“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 neoadjuvant therapy,” said Chiun-Sheng Huang, MD, PhD, MPH, lead study author and Professor of Surgery and Director of the Breast Care Center at National Taiwan University Hospital in Taipei. “We believe that this knowledge could be effectively used to guide escalation or de-escalation of adjuvant therapy. However, these implications need to be verified by further large-scale studies or randomized trials.”
DISCLOSURE: This study was funded by the Taiwan National Science and Technology Council, the National Taiwan University Hospital, and the Yonglin Foundation. For full disclosures of the study authors, visit aacrjournals.org/cancerrescommun.
