Editor’s Note: As 2024 concludes, the year has left us with significant milestones and breakthroughs in oncology. Oncology Frontier invited Dr. Yongmei Yin from Jiangsu Cancer Hospital to summarize the year's advancements in HER2-positive breast cancer research, highlighting the clinical transformations brought by innovative therapies.

HER2-positive breast cancer accounts for approximately 20%–25% of all breast cancer cases and has long been a benchmark for anti-tumor drug research in solid tumors. Over the past two decades, HER2-targeted therapies have undergone significant evolution, from monoclonal antibodies to small molecule tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), each leaving a lasting impact on clinical practice and research.

Advances in Systemic Therapy for Advanced HER2-Positive Breast Cancer

First-Line Treatment

The PHILA Study, presented by Academician Xu Binghe at the 2024 SABCS, reported significant findings from a randomized, double-blind, placebo-controlled phase III trial conducted across 40 centers in China. The study compared pyrotinib combined with trastuzumab and docetaxel (PyroHT group) versus trastuzumab and docetaxel with placebo (HT group) as first-line treatment for HER2-positive advanced breast cancer.

The final progression-free survival (PFS) analysis, with data cutoff on April 30, 2024, showed a median follow-up of 35.7 months in the PyroHT group and 34.3 months in the HT group. Median PFS was 22.1 months in the PyroHT group compared to 10.5 months in the HT group (HR=0.44; 95% CI: 0.36–0.53; P<0.0001). Although overall survival (OS) data were immature, there was a 36% reduction in the risk of death in the pyrotinib group (HR=0.64; one-sided P=0.0038). Four-year survival rates were 74.5% in the PyroHT group versus 64.3% in the HT group.

The EMERALD Study, reported at the 2024 ASCO meeting, evaluated eribulin combined with dual HER2-targeted therapy as a first-line treatment for HER2-positive advanced breast cancer. The study compared eribulin plus pertuzumab and trastuzumab against taxane-based regimens. Median PFS in the eribulin group was 14.0 months, slightly exceeding the 12.9 months observed in the taxane group (HR=0.95; 95% CI: 0.76–1.19; P=0.6817). Although OS data remain immature, the eribulin group demonstrated a longer median treatment duration (28.1 weeks versus 18.1–20 weeks in the taxane group) and lower rates of adverse events, including skin toxicity and edema.

Second-Line and Later-Line Treatment

The DB-03 Study, updated at the 2024 ASCO meeting and published in Nature Medicine, compared T-DXd (trastuzumab deruxtecan) and T-DM1 (trastuzumab emtansine) in patients with HER2-positive metastatic breast cancer.

The study revealed remarkable results, with T-DXd achieving a median PFS of 29.0 months compared to 7.2 months in the T-DM1 group (HR=0.30; 95% CI: 0.24–0.38). At 36 months, PFS rates were 45.7% in the T-DXd group versus 12.4% in the T-DM1 group. OS analysis showed a median OS of 52.6 months in the T-DXd group compared to 42.7 months in the T-DM1 group (HR=0.73; 95% CI: 0.56–0.94), reflecting a 27% reduction in the risk of death.

T-DXd also demonstrated a higher objective response rate (ORR) of 78.9% compared to 36.9% for T-DM1, with complete response rates of 12.6% versus 4.2%. Furthermore, T-DXd offered a longer median duration of response (DoR) of 30.5 months compared to 17.0 months for T-DM1, underscoring its durability and potential to extend patient survival to nearly five years.

The ACE-Breast-02 Study, led by Professor Hu Xichun from Fudan University Cancer Hospital, presented interim results at the 2024 ASCO meeting. This study included patients with advanced HER2-positive breast cancer previously treated with trastuzumab and taxanes. Participants were randomized to receive ARX788 or lapatinib combined with capecitabine (LC).

By December 21, 2022, 441 patients had been enrolled, and 240 PFS events were reported. Median PFS was 11.33 months in the ARX788 group compared to 8.25 months in the LC group (HR=0.64; P=0.0006). Although ARX788 showed favorable efficacy, common grade ≥3 adverse events included blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (5.9%).

Brain Metastases (BM) Treatment

DB-12 Study: Presented at the 2024 ESMO conference and simultaneously published in Nature Medicine, the DB-12 study focused on HER2-positive breast cancer patients with brain metastases (BM). The study included adults with advanced HER2-positive breast cancer who had progressed after ≤2 lines of therapy, excluding those with prior tucatinib use or leptomeningeal metastases. Patients were divided into two cohorts: those with stable or active BM (BM group, n=263) and those without BM (non-BM group, n=241).

With a data cutoff of February 8, 2024, the median follow-up was 15.4 months for the BM group and 16.1 months for the non-BM group. In the BM group, the median progression-free survival (PFS) was 17.3 months, with a 12-month PFS rate of 61.6%. Among patients with stable and active BM, the 12-month PFS rates were 62.9% and 59.6%, respectively. For central nervous system (CNS) outcomes, the 12-month CNS-PFS rate was 58.9%, showing comparable results between stable (57.8%) and active BM (60.1%).

The overall response rate (ORR) in the BM group was 51.7%, with a measurable disease ORR of 64.1%. For patients with measurable CNS disease at baseline (n=138), the CNS-ORR was 71.7%, with higher rates in stable BM patients (79.2%) compared to active BM patients (62.3%). In the non-BM group, the ORR was 62.7% overall and 68.4% in patients with measurable disease.

T-DXd (trastuzumab deruxtecan) demonstrated significant and durable activity, both systemically and intracranially, in HER2-positive advanced breast cancer patients with stable or active BM. The 12-month overall survival (OS) rates were comparable between the BM and non-BM groups at 90.3% and 90.6%, respectively. Importantly, no new safety signals were reported, reinforcing T-DXd as a valuable option for this patient population.

Early Systemic Therapy

FASCINATE-N Study: At the 2024 SABCS, Professor Li Junjie from Fudan University Cancer Hospital presented findings from the FASCINATE-N study, which evaluated SHR-A1811, a novel HER2 ADC, in the neoadjuvant setting for HER2-positive breast cancer. A total of 265 patients were randomized into three groups: SHR-A1811 monotherapy (n=87), SHR-A1811 combined with pyrotinib (n=88), and a chemotherapy-based regimen (PCbHP group, n=90).

All groups achieved similar pathological complete response (pCR) rates: 63.2% for SHR-A1811 monotherapy, 62.5% for SHR-A1811 with pyrotinib, and 64.4% for PCbHP. Safety data showed that SHR-A1811 monotherapy had better tolerability, with lower rates of dose reductions and treatment discontinuations due to adverse events.

PHERGain Study: Presented at the 2024 ASCO meeting, PHERGain investigated the predictive value of PET and MRI imaging after two cycles of HP (trastuzumab + pertuzumab) in HER2-positive early breast cancer. The analysis showed a strong correlation between PET response and MRI tumor reduction, with similar rates of pCR and three-year invasive disease-free survival (iDFS) among responders.

For patients lacking both PET and MRI response, three-year iDFS remained poor even with standard neoadjuvant chemotherapy. These findings suggest MRI may serve as an alternative to PET when PET is unavailable, offering a reliable method for guiding treatment decisions.

TRAIN-3 Study: Also highlighted at SABCS 2024, the TRAIN-3 study used MRI to assess treatment response in stage II–III HER2-positive breast cancer. Conducted across 43 hospitals in the Netherlands, patients received up to nine cycles of neoadjuvant therapy (PTC-Ptz: paclitaxel, trastuzumab, carboplatin, and pertuzumab).

The three-year event-free survival (EFS) and overall survival (OS) rates were exceptionally high across all hormone receptor (HR) subgroups. Patients achieving pCR after 1–3 cycles had the best outcomes, with three-year EFS exceeding 96% in both HR-positive and HR-negative groups. The study demonstrates the potential of MRI-guided therapy optimization to achieve excellent long-term outcomes while reducing treatment toxicity.

ATEMPT Study: Published in JCO in June 2024, the ATEMPT trial evaluated T-DM1 as adjuvant therapy for stage I HER2-positive breast cancer. With a median follow-up of 5.8 years, the five-year iDFS rate was 97.0%, and the five-year OS and breast cancer-specific survival rates were 97.8% and 99.4%, respectively.

Genomic analyses using HER2DX revealed significant differences in outcomes based on molecular risk profiles. Patients with low HER2DX risk scores had better five-year RFI (98.1% vs. 81.8%) and iDFS (96.3% vs. 81.8%) compared to high-risk patients. These findings highlight the potential for genomics-based treatment stratification in HER2-positive breast cancer.

Translational Research

In a significant milestone for translational research, Professor Shao Zhimin’s team published a groundbreaking study titled “Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies” in the journal Cancer Research on August 26, 2024. This study unveiled the “Fudan Classification” for HER2-positive breast cancer, marking a major step forward in personalized treatment strategies.

The single-center retrospective study analyzed data from 191 HER2-positive early breast cancer patients who underwent surgery at Fudan University Cancer Hospital between January 1, 2013, and December 31, 2014. After rigorous screening, 180 eligible cases were selected for analysis. Comprehensive multi-omics profiling of surgical specimens—including genomic, transcriptomic, proteomic, metabolic, and immunological analyses—identified four distinct molecular subtypes of HER2-positive breast cancer:

1. Classical HER2 Subtype (HER2-CLA): Comprising 28.3% of cases, this subtype showed high HER2 activity and significant benefits from anti-HER2 therapies.
2. Immune-Regulated Subtype (HER2-IM): Accounting for 20%, this subtype exhibited an immunoactivated microenvironment, suggesting potential suitability for de-escalation and immunotherapy.
3. Luminal-Like Subtype (HER2-LUM): Representing 30.6%, its molecular characteristics resembled hormone receptor-positive, HER2-negative breast cancer, indicating that endocrine therapy and CDK4/6 inhibitors may be effective strategies.
4. Basal/Stromal-Like Subtype (HER2-BM): Found in 21.1% of cases, this subtype responded poorly to existing dual HER2-targeted therapies but may benefit from tyrosine kinase inhibitors (TKIs).

This study demonstrated that HER2-positive breast cancer can be further subdivided into four molecularly distinct subtypes, paving the way for more individualized precision treatments. The authors emphasized the need for larger, multicenter prospective studies to validate these findings.

Summary

In 2024, the field of HER2-positive breast cancer saw significant breakthroughs across early-stage, advanced-stage, and translational research. Anti-HER2 therapies exhibited unprecedented diversity and progress, including advancements in novel chemotherapies, small-molecule TKIs, and next-generation ADCs. Professor Shao Zhimin’s study on the Fudan Classification introduced a new level of precision in tailoring treatments for HER2-positive breast cancer patients.

Furthermore, the updated National Reimbursement Drug List released at the end of 2024 included several innovative HER2-targeted drugs, such as T-DXd (a novel ADC) and the subcutaneous formulation of pertuzumab and trastuzumab. These developments mark substantial improvements in drug accessibility, enabling standardized and effective treatment options for HER2-positive breast cancer patients in China.

As we look ahead, these advancements not only enhance survival outcomes but also improve the quality of life for patients. In closing, I would like to pay tribute to the breast cancer specialists across China for their dedication and compassion in advancing treatment strategies. I also extend my gratitude to the countless breast cancer patients whose participation has been pivotal in driving the rapid development of clinical oncology in the country. With heartfelt wishes, may we continue to achieve breakthroughs together.