Editor's Note: Treatment strategies for HR+/HER2+ breast cancer have long been a focus of research. On December 11 (Central Time), during the 47th San Antonio Breast Cancer Symposium (SABCS), the results of the TOUCH study (Abstract RF1-02) were released, drawing significant attention. This international, open-label Phase II trial explored the efficacy of a chemotherapy-free approach in the neoadjuvant treatment of early HR+/HER2+ breast cancer. Dr. Feng Jin (The First Hospital of China Medical University), Dr. Diandong Zhang (Zhongshan Hospital, Dalian University), and Dr. Xinmiao Yu (The First Hospital of China Medical University) were invited to provide in-depth commentary on the study.

The TOUCH study demonstrated that a chemotherapy-free regimen (palbociclib + letrozole + HP [trastuzumab and pertuzumab]) achieved a pathological complete response (pCR) comparable to traditional chemotherapy (paclitaxel + HP) with better safety outcomes. This offers a new treatment pathway for patients with HR+/HER2+ breast cancer. Below, we provide a detailed overview of the study and its clinical significance.

1. What is the clinical significance of the TOUCH study?

Dr. Feng Jin: The TOUCH study is the first to confirm that a chemotherapy-free regimen (palbociclib + letrozole + HP) achieves comparable pCR rates to traditional chemotherapy (paclitaxel + HP) in HR+/HER2+ breast cancer. This breakthrough offers a new therapeutic pathway for patients who are unsuitable for or unwilling to undergo chemotherapy, advancing de-escalation strategies.

The study notably improved treatment tolerability in elderly patients, significantly reducing Grade 3–4 adverse events (31.5% vs. 54.1%), particularly chemotherapy-induced diarrhea. Additionally, the chemotherapy-free approach increased breast-conserving surgery rates (82% vs. 67%) in elderly patients, offering more flexible surgical options.

Although the RBsig genetic profile did not significantly predict treatment efficacy, the TOUCH study highlights the need to further explore molecular biomarkers to identify patient subgroups that may benefit most from chemotherapy-free strategies, advancing personalized treatment for HR+/HER2+ breast cancer.

2. What are the advances in neoadjuvant therapy for HR+/HER2+ breast cancer?

Dr. Diandong Zhang: HR+/HER2+ breast cancer is a highly heterogeneous subtype characterized by both hormone receptor and HER2 positivity. The interplay between hormonal and HER2 signaling pathways presents therapeutic challenges. While HR+ tumors are typically sensitive to endocrine therapy, HER2 activation can lead to resistance in some cases.

Currently, neoadjuvant therapy for HR+/HER2+ breast cancer relies on chemotherapy combined with HER2-targeted therapy. However, studies show that pCR rates are generally lower in HR+/HER2+ patients compared to HR-/HER2+ patients. Optimizing endocrine pathway blockade alongside HER2-targeted therapy could provide greater benefits for HR+/HER2+ patients.

Recent advancements include:

• Endocrine Therapy Combined with HER2 Targeting: The PerELISA study demonstrated that patients with a significant reduction in Ki-67 after two weeks of letrozole therapy achieved favorable outcomes with chemotherapy-free regimens (trastuzumab + pertuzumab + letrozole).

The NA-PHER2 study showed that HR+/HER2+ patients receiving palbociclib, trastuzumab, pertuzumab, and fulvestrant achieved a pCR rate of 27% after 16 weeks.

The MUKDEN01 study highlighted the efficacy and safety of pyrotinib combined with a CDK4/6 inhibitor and letrozole in Stage II–III HR+/HER2+ breast cancer.

• Antibody-Drug Conjugates (ADCs): The ADAPT study (WSG-ADAPT-TP) reported promising results for T-DM1 combined with endocrine therapy, achieving pCR rates of 40.5% to 45.8%, significantly outperforming trastuzumab combined with endocrine therapy (6.7%).

These findings support the growing potential of endocrine therapy combined with HER2-targeted agents as a viable chemotherapy-free option for select patients.

3. What is the role of the RBsig genetic profile in comprehensive cancer treatment, and what was its significance in the TOUCH study?

Dr. Xinmiao Yu: The RBsig (RB pathway signature) is a genetic scoring system based on the activity of the E2F pathway, a critical regulator of cell proliferation. The retinoblastoma (RB) protein, a key inhibitor of the E2F pathway, prevents the cell cycle from progressing from G1 to S phase. Dysregulation of this pathway, such as RB loss or hyperactive E2F, leads to uncontrolled proliferation and is a hallmark of cancer.

RBsig scoring stratifies tumors into “high activity” or “low activity” categories. Tumors with high RBsig scores (active E2F pathway) may be more sensitive to therapies targeting proliferation, such as chemotherapy and HER2-targeted treatment. Conversely, tumors with low RBsig scores may require alternative therapeutic approaches.

In the TOUCH study, RBsig scores were used to predict responses to HER2-targeted therapies (with or without chemotherapy). While the association between RBsig scores and treatment outcomes was not statistically significant (P=0.18), the findings underscore the need to refine RBsig as a predictive biomarker.

Future research should explore the interplay between the E2F and HER2 signaling pathways and the combined use of RBsig with other biomarkers like TIL levels and PI3K mutations to improve treatment stratification.

4. What are the limitations and challenges of the TOUCH study?

Dr. Diandong Zhang: Both treatment arms in the study showed relatively low pCR rates, falling short of overcoming the treatment bottleneck for HR+/HER2+ breast cancer. Long-term survival data (DFS, OS) remain pending and will require further follow-up.

Additionally, the study predominantly included older postmenopausal women, limiting its applicability to younger or premenopausal patients. The accessibility and cost-effectiveness of CDK4/6 inhibitors compared to chemotherapy also present challenges for clinical implementation, particularly in resource-limited regions.

5. What are the future research directions for HR+/HER2+ breast cancer neoadjuvant therapy?

Dr. Feng Jin: Future research should focus on:

1. Biomarker Discovery and Validation: Developing predictive biomarkers to tailor therapies for individual patients.
2. Optimization of Chemotherapy-Free Strategies: Providing safe and effective alternatives for specific populations, such as elderly or chemotherapy-intolerant patients.
3. Precision Treatment and Patient Stratification: Personalizing treatment strategies based on molecular and clinical characteristics to enhance efficacy and reduce toxicity.
4. Long-Term Survival Data: Evaluating the impact of different therapeutic approaches on long-term outcomes.

Conclusion

The TOUCH study represents a pivotal exploration of chemotherapy-free strategies in the neoadjuvant treatment of HR+/HER2+ breast cancer, showcasing significant potential in efficacy, safety, and patient-centered care.

While additional evidence is needed to support widespread clinical adoption, the field of HR+/HER2+ breast cancer neoadjuvant therapy is evolving toward precision medicine. Innovative strategies, including CDK4/6 inhibitors, chemotherapy-free regimens, and ADCs, are progressively reshaping the treatment landscape. Future efforts should prioritize biomarker discovery, individualized therapy, and long-term benefit evaluation to improve patient outcomes and quality of life.

Feng Jin

• Professor, Chief Physician, and Doctoral Supervisor
• Chair of the Breast Cancer Committee, Liaoning Anti-Cancer Association
• Vice Chair of the Breast Cancer Group, Chinese Society of Clinical Oncology (CSCO-BC)

Diandong Zhang

• Professor and Doctoral Supervisor
• Vice President, Zhongshan Hospital, Dalian University
• Chair-Elect, Breast Surgery Division, Liaoning Medical Association

Xinmiao Yu

• Associate Professor and Deputy Chief Physician
• Postdoctoral Fellow, University of California, San Francisco (UCSF)