Editor's Note: Clinical research into precision breast cancer treatment has continued to advance in recent years. On the one hand, the applications of circulating tumor DNA (ctDNA) testing are expanding beyond pretreatment target identification and treatment selection to include dynamic monitoring throughout treatment and intervention before radiographic disease progression. On the other hand, ADC development continues to evolve, with target design moving from single-target to increasingly diverse approaches, opening up new treatment options, particularly for patients who develop resistance. At the 29th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), Oncology Frontier invited Professor Yanxia Shi of Sun Yat-sen University Cancer Center to discuss the latest international evidence on two cutting-edge topics: ctDNA-guided intervention before radiographic progression and the mechanistic differences among ADCs. She also explored recent advances in precision breast cancer treatment and their implications for clinical practice.Oncology Frontier: At the 2026 ASCO Annual Meeting, the SERENA-6 study reported updated progression-free survival (PFS), final second progression-free survival (PFS2), and ctDNA clearance analyses. The study investigated a strategy for patients with HR-positive/HER2-negative advanced breast cancer receiving first-line endocrine therapy plus a CDK4/6 inhibitor: serial ctDNA monitoring was used to detect ESR1 mutations, prompting a switch to the oral selective estrogen receptor degrader (SERD) camizestrant before radiographic progression occurred. The latest data provide further evidence supporting this approach. How do you view this treatment paradigm of ctDNA-guided intervention before radiographic progression? Is it feasible to extend this strategy from advanced to early-stage breast cancer?
Professor Yanxia Shi: The landmark SERENA-6 study, whose findings were presented at the 2026 ASCO Annual Meeting, provided substantial validation of this treatment approach. The study enrolled patients receiving first-line CDK4/6 inhibitor plus endocrine therapy and monitored ctDNA for ESR1 mutations at regular intervals during treatment. Once an ESR1 mutation was detected, patients switched to the mutation-targeting agent camizestrant before radiographic progression.
The results showed that, compared with standard treatment, this molecularly guided, individualized treatment strategy significantly improved both PFS and PFS2. Based on these findings, camizestrant received approval from the U.S. Food and Drug Administration (FDA), and this novel treatment paradigm has attracted widespread attention across the oncology community.
SERENA-6 has translated the concept of molecularly guided, precision, adaptive treatment into clinical practice for advanced breast cancer. This approach could have far-reaching implications for breast cancer and potentially many other solid tumors. Traditionally, molecular testing has primarily been used before treatment to identify therapeutic targets and guide initial treatment selection based on predicted efficacy. Intervention before radiographic progression represents a shift in this paradigm: it allows clinicians to initiate more proactive treatment when tumor burden remains relatively low and the burden of tumor clones harboring resistance-associated mutations is still limited. Earlier intervention may improve treatment response and, in turn, translate into longer-term survival benefits. Although the final overall survival (OS) results from SERENA-6 have not yet been reported, the PFS2 benefit already provides an important reference point for anticipating potential future OS benefits.
The approval process for this indication also reflects the careful scrutiny that novel treatment paradigms face. Initially, the FDA’s advisory committee expressed a negative view of the study results. Its principal concern was that ctDNA testing every three months during treatment could impose a burden on both individual patients and the healthcare system, increasing medical visits and testing costs. Whether the clinical value justified these additional costs required further consideration. The FDA’s eventual approval therefore represents regulatory recognition of the clinical value of this approach and marks the first formal application of ctDNA-guided intervention before radiographic progression in the treatment of advanced cancer.
As for whether this strategy can be extended from advanced to early-stage disease, a similar concept has already emerged in the adjuvant treatment of early breast cancer through the application of minimal residual disease (MRD) assessment. MRD assessment can involve ctDNA testing to detect residual tumor-derived material in the blood, helping evaluate prognosis and guide subsequent treatment decisions. In several cancer types, MRD-guided approaches have been shown to improve patient outcomes and reduce the risk of recurrence and metastasis. From this perspective, extending this intervention paradigm from advanced to early-stage disease is a natural direction in the development of precision oncology.
Oncology Frontier: At ASCO, the late-breaking abstract (LBA) study PANKU-Breast02 investigated iza-bren, described as the world’s first approved EGFR × HER3 bispecific ADC. Its mechanism differs fundamentally from that of Trop-2-directed ADCs currently used in TNBC. Mechanistically, what distinctive advantages might dual targeting of EGFR and HER3 offer in TNBC? How do you think bispecific ADCs and monospecific ADCs may differ in their ability to overcome drug resistance?
Professor Yanxia Shi: Over the past year, development of novel ADCs has progressed rapidly, and the number of domestically developed ADCs in China has continued to grow. Among the major shifts in ADC development strategies, one of the most noteworthy is the move from single-target to multitarget approaches.
Among the major late-breaking studies presented at the 2026 ASCO Annual Meeting, PANKU-Breast02, which investigated the Chinese-developed agent iza-bren (lungcongrelongtuzumab), is particularly representative. The study enrolled patients with metastatic TNBC receiving second- or third-line treatment. Its results showed that iza-bren significantly outperformed physician’s-choice chemotherapy, delivering benefits in both PFS and OS.
Iza-bren is a dual-target ADC directed against EGFR and HER3. Compared with previously approved ADCs targeting Trop-2 in metastatic TNBC, it represents a major advance in mechanism of action. In the current treatment landscape for metastatic TNBC, approximately 20%–40% of patients have HER2-low or HER2-ultralow expression, in addition to the population eligible for Trop-2-targeted treatment. These HER2-expressing patients include a subset of the population addressed by the DESTINY-Breast04 study. The emergence of iza-bren therefore adds a potential third target for TNBC treatment, alongside Trop-2 and HER2.
This mechanistic differentiation is reflected in two main areas. First, at the drug-design level, this is the first reported ADC employing a dual-target design in metastatic TNBC, representing a further evolution in ADC development. Second, it provides an additional treatment option in clinical practice. As a potential third actionable target, iza-bren may offer a better treatment option for patients who have developed resistance to Trop-2-directed or HER2-directed ADCs, making it a promising approach to overcoming or reversing treatment resistance.
Professor Yanxia Shi
