The 18th St. Gallen International Breast Cancer Conference (SG-BCC 2023) was held in Vienna, the “City of Music,” from March 15 to 18, 2023. Breast cancer experts from around the world gathered at this conference to discuss the most cutting-edge and controversial topics in the diagnosis and treatment of early-stage breast cancer, leading to the formation of the updated St. Gallen International Expert Consensus on Early Breast Cancer every two years. Oncology Frontier invited Dr. Jian Zhang from Fudan University Affiliated Cancer Hospital to have an in-depth discussion with Dr. Nadia Harbeck from the University of Munich on the topic of whether chemotherapy is needed for patients with low genetic risk but high clinical risk (ER+/HER2-) breast cancer.
Oncology Frontier: One of the debates at SGBCC is whether chemotherapy is needed for patients with low genetic risk but high clinical risk (ER+/HER2-) breast cancer. What is your perspective on this issue?
Dr. Nadia Harbeck: Regarding low genetic risk/high clinical risk, defined as luminal-type breast cancer patients with 0-3 lymph node involvements (Editor’s note: The MINDACT study used the 21-gene Oncotype DX test, and it included patients with 0-3 positive lymph nodes) and the debate about whether they should undergo chemotherapy, my answer is a definite no.
Firstly, a lot of data suggest that patients with low genetic risk do not respond well to chemotherapy.
Secondly, I believe that for this patient population, the current data primarily support chemotherapy for younger patients. After the results of the German ADAPT study were published, we had another solution because we not only performed Oncotype testing but also assessed hormone sensitivity (Editor’s note: Ki-67 ≤ 10% after treatment defines hormone sensitivity, and RS 0-11 and RS 12-25 in hormone-sensitive patients receive only endocrine therapy, not chemotherapy). If 4 weeks of hormone therapy were administered before surgery, patients achieved good responses to endocrine treatment. The ADAPT trial results showed a 5-year distant disease-free survival (DDFS) rate of 97%. Therefore, there is no reason to subject these women to chemotherapy.
So, for patients with larger tumors or more lymph node involvement but low genetic risk, could we combine CDK4/6 inhibitors with endocrine therapy? For example, we are currently evaluating the effectiveness of CDK4/6 inhibitors in combination with endocrine therapy versus CDK4/6 inhibitors in combination with chemotherapy in the ADAPT trial. Perhaps in the next St. Gallen conference, I can share some data and results from this study.
Dr. Jian Zhang: For patients with low genetic risk/high clinical risk, we can try to identify those who truly need chemotherapy through genetic testing tools such as the 21-gene or 70-gene (MammaPrint) assays. For clinically high-risk patients, if the genomic testing results indicate low risk, is chemotherapy necessary? Dr. Harbeck’s answer is no, and I believe this is mainly based on some evidence from evidence-based medicine. First, I want to emphasize that different genetic testing tools (e.g., 7, 12, 21, 70 genes) have differences, and the definitions of “genetic high risk/low risk” may have prognostic/risk differences. The inclusion criteria for each clinical trial are also not the same. Therefore, in clinical decision-making, we should still rely on the evidence of evidence-based medicine from different genetic tests, rather than categorically classifying all patients with genetic high risk/low risk.
For example, clinical research results represented by MINDACT suggest that the benefit of chemotherapy is not significant in clinically high-risk patients with low genetic risk (95.9% vs. 94.4%, adjusted HR = 0.78, 95% CI: 0.50-1.21, P = 0.27). The patients that Professor Harbeck first mentioned are those who meet the criteria of the MINDACT study (0-3 lymph nodes), especially young (≤50 years old) clinically high-risk patients with low genetic risk who benefit from chemotherapy (5% improvement in 9-year DMFS). Therefore, it is more accurate to say that chemotherapy exemption for clinically high-risk/70-gene low-risk patients mainly applies to the middle-aged and elderly population (>50 years old), based on the results of the MINDACT study. So, can patients with low genetic risk (21 genes) be exempt from chemotherapy? In fact, the TAILORx study included clinically relatively low-risk patients (lymph node negative); therefore, Professor Harbeck also further introduced their ADAPT study, which used the 21-gene test to stratify treatment for clinically high-risk patients. Patients with low genetic risk (RS 0-11) and intermediate genetic risk (RS 12-25) who are hormone-sensitive (Ki-67 <10% after neoadjuvant treatment) may benefit significantly from endocrine therapy alone, and adding chemotherapy to endocrine therapy may not further increase distant disease-free survival. However, in our subgroup analysis of lymph nodes, the 5-year DDFS of lymph node-positive patients is still relatively low (92.7%), especially in patients with 3 positive lymph nodes, where the 5-year DDFS is only 75.9%. This indicates that clinically high-risk patients with 1-3 positive lymph nodes may still need intensified treatment (chemotherapy or CDK4/6i). In the St. Gallen vote, the majority of experts (77.27%) still support the MonarchE regimen (CDK4/6i) without considering Ki-67. I think the ADAPT study provides a very good idea and is an important trend in the future. Combining CDK4/6 inhibitors with endocrine therapy to avoid chemotherapy meets the needs of clinically high-risk patients who are sensitive to endocrine therapy, and I also look forward to the discussion of CDK4/6i in her mentioned ADAPT study.
△ 5-Year DDFS (Distant Disease-Free Survival) in Different Subgroups of Patients from the ADAPT Study
On the other hand, besides genetic testing and Ki-67, can liquid biopsies also help us select the chemotherapy population? The ISPY-2 study suggests that baseline ctDNA and conversion to negative ctDNA during neoadjuvant treatment are associated with better treatment outcomes. However, there is currently no use of ctDNA to guide stepwise chemotherapy in breast cancer RCT studies, whereas similar studies have already been conducted in the field of colon cancer.
In summary, whether we can find specific subgroups of patients who still need chemotherapy among those who benefit from endocrine sensitivity testing is a direction worth exploring in the future. In our daily work, we often encounter clinically high-risk patients like this, but there are not many risk detection tools based on gene clusters currently, and the widely accepted commercial tool is only MammaPrint in China. The clinical studies mentioned by Professor Harbeck provide some insights for our clinical work. Clinically high-risk/70-gene low-risk patients over 50 years of age are exempt from chemotherapy; clinically high-risk patients who undergo the 21-gene test can decide whether to combine chemotherapy with endocrine therapy based on hormone sensitivity (Ki-67), and lymph node-positive patients may still need intensified treatment. We look forward to the publication of more research data from ADAPT and other studies to provide more evidence for establishing and exempting chemotherapy for clinically high-risk/low genetic risk populations. But I also look forward to finding subgroups of patients who still need chemotherapy through some tools or algorithms in this patient population (including subgroups based on molecular subtypes and molecular subtyping). This will allow us to clarify this issue more clearly and have greater clinical practice guidance significance.
Fudan University Affiliated Cancer Hospital
Director of Breast Center, University of Munich Head of Oncology and Clinical Trials in Breast Cancer
