Editor’s Note:
According to the cancer burden data released by the World Health Organization, hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for over 60%. The treatment strategies and survival benefits for first-line and subsequent-line therapy for HR+/HER2- advanced breast cancer have been a hot topic. The TROPION-Breast01 study data, unveiling the promising results of the new ADC drug Dato-DXd in the field of HR+/HER2- advanced breast cancer, were disclosed at this year’s ESMO conference. Professor Zhongsheng Tong from Tianjin Medical University Cancer Hospital, a prominent figure in the field, interprets the findings for Oncology Frontier.
01
Oncology Frontier: Could you please introduce the current treatment landscape for HR+ advanced breast cancer?
Professor Zhongsheng Tong: Currently, HR+ advanced breast cancer accounts for 60% to 70% in China, consistent with international data. Treatment for HR+/HER2- advanced breast cancer primarily involves endocrine therapy (ET), with first-line preference given to targeted combinations with ET. Additionally, if a patient experiences visceral crisis, chemotherapy may be chosen as initial treatment. In summary, CDK4/6 inhibitors + ET have become the first-line standard for HR+/HER2- advanced breast cancer. There is no standardized recommendation for second-line and subsequent-line treatments in both domestic and international guidelines. Several clinical studies have explored AKT inhibitors, HDAC inhibitors, chemotherapy, and ADCs. The option of switching between different CDK4/6 inhibitors is also considered. The treatment landscape for HR+/HER2- advanced breast cancer has entered an optimization stage, showing progress and development that have resulted in progression-free survival (PFS) and overall survival (OS) benefits for patients.
02
Oncology Frontier: Currently, CDK4/6 inhibitors + ET has become the first-line standard for HR+/HER2- advanced breast cancer. According to the ESMO metastatic breast cancer guidelines, could you discuss treatment options after the progression of CDK4/6 inhibitors + ET?
Professor Zhongsheng Tong: CDK4/6 inhibitors + ET is the first-line standard treatment for HR+/HER2- advanced breast cancer. Clinical trials with palbociclib, abemaciclib, and ribociclib in combination with endocrine therapy have consistently shown prolonged median PFS, with some trials also demonstrating extended OS. Studies indicate no significant statistical difference between CDK4/6 inhibitors + aromatase inhibitors (AI) and CDK4/6 inhibitors + fulvestrant. Therefore, CDK4/6 inhibitors + AI is generally preferred in clinical practice, and if a patient progresses, switching to other CDK4/6 inhibitors + fulvestrant can be considered.
According to the ESMO metastatic breast cancer guidelines, there are various treatment options after the progression of first-line CDK4/6 inhibitors + ET. For patients without visceral crisis and a prolonged PFS on prior endocrine therapy, alternative targeted treatments combined with ET can be chosen, including mTOR inhibitors + AI/fulvestrant. Patients with PIK3CA mutations can opt for PI3K inhibitors + fulvestrant, and those with ESR1 mutations can choose selective estrogen receptor degrader (SERD) drugs, including fulvestrant and the latest oral SERD drugs.
In addition, HR+/HER2- includes both HER2 (0) and low HER2 expression patients. Preliminary results from clinical trials suggest that patients with low HER2 expression can benefit from T-DXd. The TROPION-Breast01 results announced at this year’s ESMO conference also brought some surprises. In summary, the subsequent treatment of advanced HR+/HER2- breast cancer is a contested area that requires individualized treatment choices, including chemotherapy, ADC drugs, and other targeted therapies combined with ET. Further exploration is still needed in this field.
03
Oncology Frontier: This year’s ESMO conference reported research data on the new Trop-2 ADC. How do you view the related research results?
Professor Zhongsheng Tong: I am very interested in the TROPION-Breast01 study, and many centers in China, including ours, have participated in this research, contributing eight cases. This clinical trial applied a new ADC drug targeting Trop-2 called Dato-DXd for the treatment of patients.
TROPION-Breast01 is the first global, randomized, open-label, phase III trial for Dato-DXd in the treatment of breast cancer, involving 732 enrolled patients. Patients included those with HR+/HER2- (IHC 0, IHC 1+, or IHC 2+/ISH-) breast cancer who had disease progression after receiving endocrine therapy or were not suitable for endocrine therapy (must have received at least 1-2 lines of chemotherapy), and they were randomly assigned to either the Dato-DXd group or the investigator’s choice chemotherapy (ICC group). The study was reviewed by an independent third-party committee, ensuring higher reliability of the results.
Preliminary results are very encouraging, with a median PFS of 6.9 months for the Dato-DXd group and 4.9 months for the ICC group. The Dato-DXd group showed a significant 37% reduction in the risk of disease progression or death compared to the ICC group (HR 0.63, 95% CI: 0.52-0.76; P < 0.0001). Although the OS data are not yet mature, Dato-DXd is a Trop-2-targeting ADC drug with optimized drug antibodies that balance efficacy and toxicity. The drug can also induce bystander effects, killing tumor cells to a greater extent. In terms of safety, the Dato-DXd group had a lower incidence of bone marrow suppression than the ICC group. Therefore, I am confident and look forward to Dato-DXd presenting more impressive results in the future.
04
Oncology Frontier: What do you think are the reasons for the benefits of Dato-DXd in HR+/HER2- breast cancer patients? Please provide an outlook on the future development of this drug based on its mechanism.
Professor Zhongsheng Tong: Dato-DXd is designed with an ideal ADC structure, featuring a humanized anti-Trop-2 IgG1 monoclonal antibody connected by a cleavable tetrapeptide linker and coupled with a topoisomerase I inhibitor. I believe patients can benefit from Dato-DXd for two main reasons. First, breast cancer patients have rarely been treated with topoisomerase inhibitors in the past, resulting in fewer cases of resistance. Second, the drug antibody ratio of Dato-DXd is only 4:1, allowing Dato-DXd to exert strong anti-tumor effects while maintaining safety.
Taking one patient from our center as an example, the patient received 14 cycles of Dato-DXd treatment, achieving partial remission (PR). The patient’s PFS exceeded 10 months, and adverse reactions observed included leukocyte and neutrophil count decrease (Grade 2-3), transaminase elevation (Grade 1), and neurotoxicity (Grade 2). In summary, the eight patients from our center mainly exhibited bone marrow suppression as adverse reactions, mostly Grade 1-2, indicating good patient tolerance, and a balance between treatment efficacy and toxicity.
Based on the drug’s mechanism of action and the cases from our center, I believe the application value of Dato-DXd in HR+ breast cancer patients will further expand and improve in the future, and the treatment line is expected to progress gradually to the frontline. In addition, in the field of breast cancer, besides the TROPION-Breast01 study results announced at this ESMO conference, updates on the BEGONIA study for triple-negative breast cancer (TNBC) were also reported. In the lung cancer field, results from the TROPION-Lung 05, TROPION-Lung 07, and TROPION-Lung01 studies were also disclosed. I believe Dato-DXd will make breakthroughs in more areas in the future, bringing hope and survival benefits to more patients.
References:
1. National Cancer Center Breast Cancer Expert Committee, Chinese Anti-Cancer Association Tumor Drug Clinical Research Professional Committee. Consensus on the clinical application of CDK4/6 inhibitors in hormone receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer[J]. Chinese Journal of Cancer, 2021, 43(4): 405-413.
2. Chinese Society of Clinical Oncology (CSCO) Breast Cancer Diagnosis and Treatment Guidelines (2023 edition)
3. NCCN Clinical Practice Guidelines: Breast Cancer (2023, version 1)
4. Llombart-Cussac A, Pérez-García JM, Bellet M, et al. Fulvestrant-Palbociclib vs Letrozole-Palbociclib as Initial Therapy for Endocrine-Sensitive, Hormone Receptor-Positive, ERBB2-Negative Advanced Breast Cancer: A Randomized Clinical Trial[J]. JAMA Oncol. 2021; 7(12): 1791-1799. doi:10.1001/jamaoncol.2021.4301
5. ESMO Metastatic Breast Cancer Living Guideline. https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline
6. Aditya Bardia, et al. 2023 ESMO. LBA11.
7. Shimizu T, et al. J Clin Oncol. 2023 Jun 16: JCO2300059.
8. Peter Schmid, et al. 2023 ESMO. 379MO.
9. ESMO Congress 2023 Meeting Calendar. https://www.esmo.org/meeting-calendar/esmo-congress-2023
Professor Zhongsheng Tong
Tianjin Medical University Cancer Hospital
Vice Dean, Binhai Hospital
Chief Physician, Department of Breast Tumor, Tianjin Medical University Cancer Hospital
Standing Committee Member, Chinese Anti-Cancer Association Breast Cancer Professional Committee
Standing Committee Member, Chinese Anti-Cancer Association Targeted Therapy Professional Committee
Committee Member, National Cancer Center Breast Cancer Expert Committee
Deputy Leader, National Anti-Tumor Drug Clinical Application Monitoring Expert Committee Breast Cancer Group
Deputy Chairman, Chinese Geriatrics Society Geriatric Tumor Committee Breast Cancer Professional Group
Chairman, Tianjin Anti-Cancer Association Special Committee on Multiple Primary and Unknown Primary Tumors
Editorial Board Member, Chinese Journal of Oncology, Tianjin Medicine, Chinese Journal of Breast Disease, Chinese Journal of Comprehensive Clinical Medicine, etc.
