SGBCC International Dialogue | Wang Jia & Professor William Gradishar: Controversies in Surgical Treatment for Stage IV Breast Cancer Patients at Initial Diagnosis
Editor's Note: There is currently a lack of consensus on whether surgical treatment should be performed for patients with stage IV breast cancer at the initial diagnosis. At the 18th St.Gallen Breast Cancer Conference (SGBCC 2023), a debate titled "Surgery of the primary for stage IV disease" garnered global expert attention. The debate was moderated by Professor William Gradishar from Northwestern University Feinberg School of Medicine in the United States, with Professor Rajendra Badwe from Tata Research in India and Professor Florian Fitzal from ABCSG-28 Research in Austria presenting opposing views on this issue. "Oncology Insight" invited Professor Wang Jia from the Second Hospital of Dalian Medical University and Professor William Gradishar from Northwestern University Feinberg School of Medicine to engage in an in-depth discussion on this topic.
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Oncology Insight: You participated in the debate on "Surgical Treatment for Stage IV Breast Cancer Patients at Initial Diagnosis" at the St.Gallen Conference. Could you share your insights on this topic?
Professor William Gradishar: Previous relevant data have shown that surgical treatment for stage IV breast cancer patients can improve overall survival. This topic will be discussed again in the upcoming conference, and although it has not been confirmed, there may be certain types of patients who could benefit from it.
So far, clinical trials have failed to prove that surgery can improve survival for both HER2-positive and triple-negative stage IV breast cancer patients. Therefore, in the absence of substantial evidence, I do not recommend surgery as a routine treatment.
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Oncology Insight: Combining the debates at this year's St.Gallen Conference, please explain the consensus and controversies surrounding surgical treatment for stage IV breast cancer at initial diagnosis.
Professor Wang Jia: The debate over whether to perform surgery for stage IV breast cancer at initial diagnosis has been a hot topic globally in recent years. There is both consensus and controversy among experts, both domestically and internationally, regarding whether to perform local treatment, such as surgery, for stage IV breast cancer patients.
Regarding consensus, firstly, I believe that a pathological biopsy of the primary lesion in these patients is essential as a diagnostic basis. Secondly, it is crucial to provide precise systemic treatment based on the molecular subtype. Thirdly, for all local treatments, including surgery and radiotherapy, whether they can extend patients' overall survival, from the perspective of evidence-based medicine, there is currently no supporting evidence. Fourthly, concerning the role of surgery in controlling local tumors, especially for stage IV patients, if they develop complications such as infection, bleeding, rupture of the primary lesion, or if the control of other lesions is relatively good, surgery can play a significant role in local control. Fifthly, if patients are not undergoing surgery due to the above-mentioned urgent or quality-of-life-affecting complications, efforts should be made to achieve R0 resection during surgery, as there is evidence supporting different outcomes for patients with negative margins and positive margins.
Regarding controversies, first, what does achieving local control in patients with existing distant metastases mean? Does achieving good local control have no significance? This is a matter of debate. Second, under the premise of effective systemic treatment, which patients benefit from local surgical treatment in terms of overall survival? From retrospective and prospective studies, we seem to see some clues. For example, in ER-positive or HER2-positive patients with solitary bone metastasis, some patients have excellent survival after targeted therapy. It may be possible for these patients to benefit from surgical treatment, but it is still unclear how to select the specific population that benefits from overall survival. Third, for some patients, surgical treatment may worsen their condition and reduce overall survival. So, which patients should not undergo surgical treatment? Fourth, there is significant controversy about how to conduct prospective research on surgical treatment for stage IV breast cancer patients at initial diagnosis and what the design concept should be. This is also a point of widespread concern in this year's St.Gallen Conference debate.
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Oncology Insight: What are the high-level prospective studies currently available, and what are their characteristics?
Professor Wang Jia: Prospective studies for stage IV breast cancer at initial diagnosis include both randomized controlled trials and non-randomized controlled trials. Randomized controlled trials mainly include five: Tata Research in India, MF07-01 study in Turkey, POSYTIVE study in Austria (ABCSG-28 study), ECOG-ACRIN E2108 study conducted jointly by scholars in the United States and Canada, and JCOG107 study in Japan, the results of which have not been published yet. In addition, there are some non-randomized controlled trials, including the TBCRC study in the United States and the MF 14-01 study in Turkey.
These prospective randomized controlled trials have two basic logical designs. The first logic is that patients receive systemic treatment first and are then randomly assigned to two groups: one continues systemic treatment, and the other undergoes local treatment, followed by systemic treatment. The second logic is to randomly assign patients to two groups initially, with one group receiving systemic treatment and the other undergoing local surgery, followed by systemic treatment.
The typical studies based on the first logic include the Tata study in India and the ECOG-ACRIN E2108 study in the United States, both of which reached the same conclusion that, after systemic treatment, there is no additional benefit from surgery for patients who respond to treatment. The typical studies based on the second logic include the ABCSG-28 study in Austria and the MF07-01 study in Turkey. Interestingly, these two studies reached different conclusions.
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Oncology Insight: MF07-01 study's results differ from other studies, showing a benefit in overall survival for the surgery group. How can we understand this difference?
Professor Wang Jia: To understand why the MF07-01 study differs from other studies, we should first look at the design of the ABCSG-28 study, as mentioned earlier. In this study, patients are initially randomly assigned to two groups: one receives systemic treatment, and the other undergoes surgery, followed by systemic treatment. The study concluded that there is no additional benefit from surgery for any subgroup. Additionally, the issue of quality of life, which everyone is concerned about, did not show improvement in any subgroup. Interestingly, we observed high levels of vascular endothelial growth factor (VEGF) expression in the peripheral blood of patients 12 months after surgery.
The MF07-01 study was comprehensively analyzed during the debate at the St.Gallen Conference. Scholars believe that this study has many design and statistical flaws. For example, the study had between-group imbalances, with significant differences in the proportions of ER-positive patients, patients with osteoblastic bone metastasis, and those with the triple-negative subtype between the two groups. The study did not conduct P-value multiple testing for between-group sample imbalances. When looking at survival data, the surgery group performed better numerically in the single bone metastasis group, but in the multiple visceral metastasis group, the surgery group significantly underperformed the non-surgery group.
Another critical point to consider is the diagnosis of bone metastasis. The study did not use precise biopsy methods to confirm bone metastasis but relied on PET-CT scans. This could lead to a situation where some patients with bone metastasis may not have true stage IV breast
cancer. Moreover, the patient population was relatively small in the MF07-01 study.
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Oncology Insight: Can you elaborate on the role of precision medicine in decision-making for surgery in stage IV breast cancer?
Professor William Gradishar: Precision medicine plays a crucial role in decision-making for surgery in stage IV breast cancer. As we've seen in recent years, our understanding of breast cancer has become increasingly nuanced, with various subtypes identified based on molecular characteristics. This has led to the development of targeted therapies that are tailored to specific subtypes of breast cancer.
In the context of stage IV breast cancer, the decision to perform surgery should be based on a comprehensive assessment of the patient's individual characteristics, including the molecular subtype of the cancer, the extent of metastatic disease, and the response to systemic therapy. For example, in cases where the metastatic disease is limited, and the cancer is driven by a targetable molecular alteration (such as HER2 amplification or hormone receptor positivity), surgery may be considered as part of a multimodal treatment approach.
Precision medicine also extends to the choice of systemic therapies. Patients with HER2-positive breast cancer, for instance, can benefit from HER2-targeted therapies like trastuzumab and pertuzumab. Similarly, patients with hormone receptor-positive breast cancer may benefit from endocrine therapies like aromatase inhibitors or CDK4/6 inhibitors.
Ultimately, the goal of precision medicine is to tailor treatment strategies to the unique characteristics of each patient and their cancer, with the aim of optimizing outcomes while minimizing unnecessary interventions.
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Oncology Insight: How do you envision the future of surgical treatment for stage IV breast cancer? What are the key areas of research and clinical practice that need further development?
Professor William Gradishar: The future of surgical treatment for stage IV breast cancer will likely be shaped by ongoing research efforts and advances in our understanding of the disease. Here are some key areas that need further development:
1. Identification of Patient Subgroups: Research should focus on identifying specific subgroups of stage IV breast cancer patients who are most likely to benefit from surgical intervention. This involves refining our criteria for patient selection based on factors such as molecular subtype, extent of metastatic disease, and response to systemic therapy.
2. Optimizing Multimodal Approaches: Future studies should explore the optimal sequencing and combination of surgery with systemic therapies, radiation therapy, and other treatment modalities. This will require well-designed clinical trials that assess the impact of different treatment strategies on overall survival, quality of life, and disease control.
3. Patient-Centered Outcomes: It's essential to prioritize patient-centered outcomes in research and clinical practice. This includes assessing the impact of surgery on quality of life, symptom control, and functional status. Patient preferences and values should also be taken into account when making treatment decisions.
4. Biomarkers and Predictive Models: The development of biomarkers and predictive models that can help identify patients likely to benefit from surgery is an area of active research. These tools can aid in personalized treatment decisions.
5. Minimizing Morbidity: Efforts should be made to refine surgical techniques and minimize the morbidity associated with surgery in stage IV breast cancer patients. This includes strategies to reduce complications and improve wound healing.
6. Global Collaboration: International collaboration is essential for conducting large-scale, high-quality clinical trials that can provide definitive answers regarding the role of surgery in stage IV breast cancer. Collaborative efforts can help address the challenges of patient recruitment and data collection in this patient population.
In summary, the future of surgical treatment for stage IV breast cancer will likely involve a more nuanced and personalized approach, guided by advances in our understanding of the disease and the development of targeted therapies. Research and clinical practice should continue to evolve to optimize outcomes for these patients.
Professor William Gradishar
Chair of the Breast Cancer Clinical Practice Guidelines at the National Comprehensive Cancer Network (NCCN) in the United States"
Professor Wang Jia
Associate Chief Physician, Graduate Supervisor Department of Breast Surgery, Second Affiliated Hospital of Dalian Medical University, Deputy Director"