Editor's Note: In the field of breast cancer treatment, gene testing for early-stage breast cancer has become a vital component of precision medicine. By deeply analyzing the genetic expression profiles of patients, we can more accurately predict disease progression and develop more personalized adjuvant treatment strategies. However, how is gene testing currently applied in clinical practice, and what challenges remain? Oncology Frontier invited Professor Qiang Zhang from Liaoning Cancer Hospital & Institute to discuss the FLEX study presented at the 2024 ASCO conference.01
Oncology Frontier: Could you give us an overview of the current applications of gene testing for HR+ early-stage breast cancer? How do you use these gene testing results to guide adjuvant treatment strategies?
Professor Qiang Zhang: Among the various subtypes of breast cancer, HR+/HER2- breast cancer is the most prevalent, accounting for about 70% of all breast cancer cases. Compared to other subtypes, HR+/HER2- breast cancer patients generally have a better prognosis, with many early-stage HR+/HER2- cases being managed as chronic conditions, gradually moving towards a cure. Patients with HR+/HER2- breast cancer undergo long-term endocrine therapy, and clinicians aim to find effective, low-toxicity treatment options for these patients while ensuring better adherence to long-term medication.
Chemotherapy is an important adjuvant treatment for early HR+/HER2- breast cancer, but only a subset of patients truly benefit from it. There isn’t sufficient evidence to support intensive chemotherapy for high-risk HR+/HER2- early-stage breast cancer patients, and the possibility of “exempting” low-risk patients from chemotherapy remains a pressing question. Multi-gene testing evaluates the expression levels of specific genes to assess recurrence risk and predict treatment efficacy, thus guiding personalized treatment decisions. Currently, multi-gene testing has become an essential tool for determining the best adjuvant treatment plans for this subtype. Commonly used gene tests in clinical practice include the 21-gene test (Oncotype DX) and the 70-gene test (MammaPrint), both of which are supported by robust clinical research data.
It is worth noting that age is one of the most significant factors influencing gene test results. Generally, a cut-off age of 50 years is used in gene testing, with the guidance being more applicable to patients over 50. Currently, the original Oncotype Dx is not available in China, and the domestic 21-gene test has not been compared with Oncotype Dx for quality control. There might be differences or disagreements between results from different institutions. Therefore, we hope that in the future, domestic 21-gene tests can be compared head-to-head with the original products to verify their practical significance and differences. Additionally, gene test results are somewhat related to ethnicity. We also hope to verify whether the test results for the Chinese population are consistent with those of Western populations through future comparative studies.
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Oncology Frontier: The FLEX study reported at this ASCO conference further explored the correlation between the MammaPrint index and the 3-year prognosis of HR+/HER2- early-stage breast cancer patients receiving chemotherapy (with or without anthracyclines). How do you evaluate this study and its results?
Professor Qiang Zhang: Anthracyclines are cornerstone chemotherapeutic agents. In our previous Onco9735 clinical trial, we compared TC (docetaxel and cyclophosphamide) with AC (doxorubicin and cyclophosphamide) in early HR+/HER2- breast cancer patients, showing that both regimens achieved similar results. Therefore, we believe that anthracycline-based chemotherapy can be exempted in early HR+/HER2- breast cancer patients.
In the preliminary observational FLEX study, patients were tested using the MammaPrint 70-gene test and classified into three groups based on recurrence risk: ultra-low risk, low risk, and high risk (further divided into HIGH 1 [H1] and HIGH 2 [H2]). The results showed that in neoadjuvant treatment, the pCR rates were similar in the H1 group between the TC and AC-T groups (7.7% vs. 7.0%). In the H2 group, the pCR rate was higher in the AC-T treatment group (32.0%) compared to the TC group (0%). This suggests that high-risk early HR+/HER2- breast cancer patients need a combined anthracycline/taxane chemotherapy regimen.
In the real-world FLEX registration trial, the 3-year RFS rate for MammaPrint H2, BluePrint Luminal B, HR+/HER2- early breast cancer patients receiving AC-T treatment was higher than the TC group (97.7% vs. 86.4%). For Luminal MP High 1 patients, the 3-year RFS rates were similar between the TC and AC-T adjuvant treatment groups (95.3% vs. 97.1%). These real-world data suggest that MammaPrint H2 HR+/HER2-EBC patients may benefit from adding doxorubicin to the taxane/cyclophosphamide therapy base. However, further validation in other studies is necessary.
The FLEX study categorized HR+/HER2- early-stage breast cancer patients based on gene testing risk, offering new insights for clinicians: for low-risk patients, anthracycline-based chemotherapy can be omitted, while high-risk patients require combined anthracycline/taxane chemotherapy. This study highlights the significance of MammaPrint in guiding chemotherapy for HR+/HER2- early-stage breast cancer patients. In the future, we need to use gene testing to provide individualized treatment for these patients.
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Oncology Frontier: What challenges do you think China faces in using gene testing for HR+ early-stage breast cancer treatment or prognosis assessment? What important areas should be explored in this field in the future?
Professor Qiang Zhang: In recent years, clinical diagnosis and treatment practices for breast cancer patients in China have undergone significant changes, mainly because we have updated guidelines based on the actual situation of Chinese patients while referring to international guidelines, leading to changes in clinical practice. For instance, while the onset age for breast cancer in Western countries is mostly postmenopausal, Chinese breast cancer patients tend to be diagnosed at a younger age. The number of young breast cancer patients under 40 is also higher than in Western countries.
HR+/HER2- breast cancer is the most common subtype, so it is crucial to use gene testing to help these patients receive precise treatment. However, the current gene testing guidelines often use 50 years as the cut-off age, making it difficult for younger patients with low recurrence and metastasis risk to use gene testing to guide their choice of exempting chemotherapy. Therefore, I believe China should conduct multi-center clinical trials focused on premenopausal populations to better utilize gene testing models for guiding precise treatment in these patients.
We also face significant challenges in the neoadjuvant treatment of HR+/HER2- breast cancer patients. Currently, conventional neoadjuvant chemotherapy regimens do not meet the requirements for tumor downstaging and breast-conserving surgery in HR+/HER2- breast cancer patients. The reasons are as follows: first, the pCR rate is not high after neoadjuvant chemotherapy; second, the tumor regression is not significant, or the regression pattern is predominantly sieve-like, making patients unsuitable for breast-conserving surgery after neoadjuvant chemotherapy. Therefore, we hope to identify HR+/HER2- breast cancer patients suitable for neoadjuvant endocrine therapy based on gene testing in the future to achieve tumor downstaging and breast conservation, or to use the neoadjuvant endocrine platform to screen endocrine-sensitive patients for chemotherapy exemption, allowing patients to live longer and better lives.
Professor Qiang Zhang
Director of the Fourth Breast Surgery Ward, Liaoning Cancer Hospital Chief Physician, Doctor of Medicine Graduate Supervisor at Dalian University of Technology, China Medical University, and Dalian Medical University Tier-1 Talent of the “Hundred-Thousand-Ten Thousand Talent Project” in Liaoning Province Chairman-Elect of the Breast Cancer Individualized Treatment and MDT Professional Committee of the Beijing Anti-Cancer Association Member of the Breast Group of the Oncology Branch of the Chinese Medical Association Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Standing Director of the China Medical Education Association Standing Member of the Breast Disease Professional Committee of the China Medical Education Association Deputy Director of the Breast Cancer MDT Study Group of the China Medical Education Association Standing Member of the Breast Disease Branch of the China Medical Promotion Association Deputy Director of the Targeted Therapy Professional Committee of the Liaoning Anti-Cancer Association Has studied at MD Anderson Cancer Center and the European Institute of Oncology (IEO) Breast Department
