De Novo Stage IV Breast Cancer: A New Look at Treatment Options
"Exploring the role of intensified locoregional treatment in the early stages of de novo Stage IV breast cancer and its potential benefits for survival and quality of life."
Traditionally, the primary goal of surgery for metastatic breast cancer (BC) has been to manage symptoms in specific areas. However, recent research, including institutional and population-based studies and meta-analyses, suggests that incorporating locoregional treatment (LRT) alongside systemic therapy (ST) may extend overall survival and significantly reduce locoregional progression in de novo Stage IV BC.
Several theories aim to explain how removing the primary tumor could improve survival. These include reducing the overall tumor load, decreasing the number of circulating tumor cells, enhancing the body's immune response, improving the effectiveness of systemic treatments, targeting breast cancer stem cells, preventing the spread of new metastases, and minimizing the development of treatment-resistant cancer cells.
While these studies may have inherent biases due to their retrospective design, tumor removal has shown to improve survival in other metastatic cancers. Furthermore, some institutional studies indicate that early intervention on primary tumors may improve survival in patients treated with systemic therapy who show no evidence of disease progression.
How Often Breast Cancer Is Diagnosed at a Distant Stage
From 2019 to 2023, about 2 in 3 female breast cancer cases were diagnosed at a localized stage, about 1 in 4 at a regional stage, and 6% at a distant stage, according to the CDC. Stage IV, also called metastatic breast cancer, means breast cancer cells have spread to other parts of the body; they remain breast cancer cells even after spreading through the bloodstream or lymphatic system. The CDC’s Female Breast Cancer Stat Bite also covers diagnoses, deaths, stage at diagnosis, and five-year survival rates.
From Halsted’s Mastectomy to Breast-Conserving Surgery
A review of breast cancer treatment milestones identifies Halsted’s mastectomy in the 1880s as the beginning of modern treatment. About a century later, breast-conserving surgery became another milestone; the review reports equivalent survival with better aesthetic outcomes than mastectomy. The broader history spans treatment and understanding from ancient civilizations through the Middle Ages and the 18th and 19th centuries, though the cited historical chapter notes that its milestone list is not comprehensive.
MF07-01 Trial: A Randomized Study
The MF07-01 trial was a phase III, multi-center, randomized controlled clinical trial. It compared locoregional treatment (LRT) at the time of diagnosis with primary systemic therapy (ST) in patients newly diagnosed with Stage IV breast cancer (de novo). The results align with existing literature. The risk of death was 34% lower in the LRT group compared to the ST group.
- Benefit: 34% lower risk of death with LRT.
- Survival: 41.6% alive after 5 years in LRT group vs. 24.4% in ST group.
- Factors: Solitary bone metastasis, younger age, ER/PR-positive tumors benefit more from LRT.
- Risk: Multiple liver/lung metastases had worse outcomes with initial surgery.
- Safety: No increase in 30-day mortality with primary tumor resection.
Limits of Evidence for Local Therapy
The EA2108 trial report says its findings were limited by an incomplete response rate, while noting support from the POSYTIVE trial. It also reports that locoregional therapy did not relieve patients’ worry about local tumor growth, despite a substantial symptomatic impact of that therapy. POSYTIVE itself was stopped early because of poor recruitment. Separately, a systematic review and meta-analysis cautions that retrospective studies may overstate a survival benefit from surgery because of selection bias, including the possible overrepresentation of patients with excellent systemic-therapy responses or limited disease.
Randomized Trials Report Different Survival Results
In the 10-year follow-up of the MF07-01 randomized clinical trial, median survival was 46 months with local therapy (LRT) and 35 months with systemic therapy (ST); the hazard of death was 29% lower in the LRT group (HR 0.71; 95% CI 0.59–0.86; p = 0.0003). By contrast, the JCOG1017 (PRIM-BC) randomized trial found no statistically significant overall-survival difference (HR 0.86; 90% CI 0.69–1.07; one-sided p = 0.13), with median overall survival of 69 months in arm A and 75 months in arm B. These trial results differ, so the MF07-01 finding should not be treated as a result shared by both studies.
The Future of Stage IV Breast Cancer Treatment
While a single study cannot provide all the answers, the MF07-01 trial offers a valuable option to discuss in tumor boards and with patients who meet the study criteria. It's important to recognize that not all metastatic breast cancers are the same. There appears to be a subgroup of patients who experience longer survival with intensified locoregional treatment early in the course of de novo Stage IV BC.
Treatment Options and Clinical Trials
Metastatic breast cancer remains incurable, but new treatment options have been developed, and the treatment landscape for HR+/HER2− metastatic breast cancer is rapidly changing. Guidelines recommend multiple lines of endocrine therapy, with or without targeted treatments, until options are exhausted. For metastatic disease, clinical trials may test newer treatment approaches or ways to manage symptoms and improve quality of life.
Whole-Body Treatment and Local Disease Concerns
Because stage IV breast cancer has spread to other parts of the body, systemic treatment—which acts throughout the body—is often a main form of treatment. One systematic review and meta-analysis describes two possible reasons to consider breast surgery even without an overall-survival benefit: an effort to render selected oligometastatic patients clinically disease-free, and prevention of quality-of-life deterioration from local tumor overgrowth. Such overgrowth can cause pain, ulceration, bleeding, and infections. The cited review presents these as potential arguments, not established survival benefits.
Intensifying LRT in the early treatment of de novo Stage IV BC is a reasonable approach for selected patients. Factors such as patient age, performance status, other health conditions, tumor type, and extent of metastasis should be carefully considered to determine the most appropriate treatment strategy.
Further research is needed to address remaining questions, such as the optimal approach to treating the primary tumor and axilla (surgery vs. radiation therapy), the best timing for surgery after systemic therapy, whether to include patients who don't respond to systemic therapy in randomization, the most effective systemic therapy regimens, interventions for specific metastatic sites, and whether solitary bone metastasis should be considered a distinct category from other de novo Stage IV BC. Ongoing studies evaluating primary breast surgery after patients respond to systemic therapy may provide answers to some of these questions.