Large population-based study identifies that tumor size and lymph node involvement are associated with risk of death in metastatic breast cancer

Despite significant advances in breast cancer treatment, 5-year survival rate remains low in patients with metastatic breast cancer (1-3). The data prompt us to identify clinicopathologic and treatment factors that predict risks in cancer patients with metastatic disease.

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We studied the overall survival or risk of all-cause death in de novo metastatic breast cancer population with 35812 patients from the Surveillance, Epidemiology, and End Results (SEER) database in the United States enrolled between January 1, 2004, and December 31, 2015. We also estimated independent performance of nodal status and T-stage adjusting for clinicopathological features and treatment factors bymultivariable Cox proportional hazards regression analysis.

We found that death was significantly higher in metastatic breast cancer patients with 1 to 3 nodes, 4 to 9 nodes, ≥10 lymph node involvements, and node status unknown, respectively, than node-negative patients (Figure image). Importantly, the association of nodal involvements with death was independent of age, race, tumor grade, estrogen-receptor status and HER2 status as well as chemotherapy, radiotherapy and surgery. In addition, death was significantly higher in patients with T stage (T) 2, T3, T0, T4, and Tx, respectively, than T1 patients (Figure image). They all but T0 are independent of other clinicopathologic and treatment factors. We also demonstrated the association between T stage or axillary lymph nodes and the death risk in HR+/HER2, HR+/HER2+, HR/HER2+ and triple-negative metastatic breast cancer subtypes.

Furthermore, I’d discuss the potential impact of our results and role of surgery in the management of metastatic breast cancer. Surgery is currently not a standard of care to manage patients with metastatic breast cancer. The surgical procedure is for salvage purpose, e.g., resection of a few numbers of metastases in the brain, lung, liver or other areas or treating open wound in the chest. Nonetheless, we found that patients who underwent surgery despite with palliative intent had a significantly reduced death rate, consistent with many previous studies. In a meta-analysis including 15 studies, surgical removal of the primary tumor in metastatic breast cancer was associated with better survival, with a 31% decreased risk of death (5). This was confirmed by an updated meta-analysis with 19 reports including randomized clinical trials in metastatic breast cancer (6). A randomized phase III (MF07-01) study compared the local treatment followed by systemic therapy to the systemic therapy alone for treatment naive stage IV breast cancer patients at diagnosis (7). This metastatic breast cancer trial demonstrated a significant improvement for 5-year survival rate of 41.6% versus 24.4%.

Mounting evidence revealed that proportions of cancer stem cells and cancer cells resistant to treatment propagated as the tumors grew larger (8, 9); it is conceivable and calculable that bulky tumors increase the treatment burdens (10, 11). Anticancer drugs were likely to be more accessible to cancer cells, and systemic therapies were much more effective after surgical removal of bulky tumors including necrotic and avascular tumor areas (12).

In summary, the risk of all-cause mortality was significantly higher in patients with distant metastasis at diagnosis and exhibited node involvement and larger breast tumors. This is an unbiased population-based study in the context of the SEER data that included all patients who had a survival time one month or greater. It is important to recognize and integrate the tumor size and nodal status, in addition to metastatic cancer sites, into the risk assessment and clinical management in metastatic breast cancer. Our findings may have an impact on other metastatic cancer types, ultimately to substantially reduce the cancer death in the years to come.

References

  1. SEER 18 2011–2017, All Races, Females by SEER Summary Stage 2000 at https://seer.cancer.gov/statfacts/html/breast.html. Accessed on March 12, 2022.
  2. Andreopoulou E, Hortobagyi GN. Prognostic factors in metastatic breast cancer: successes and challenges toward individualized therapy. J Clin Oncol 2008; 26: 3660-3662.
  3. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019; 69: 438-451.
  4. Press DJ, Miller ME, Liederbach E, Yao K, Huo D. De novo metastasis in breast cancer: occurrence and overall survival stratified by molecular subtype. Clin Exp Metastasis 2017; 34: 457-465.
  5. Petrelli F, Barni S. Surgery of primary tumors in stage IV breast cancer: an updated meta-analysis of published studies with meta-regression. Med Oncol 2012; 29: 3282-3290.
  6. Lu S, Wu J, Fang Y, Wang W, Zong Y, Chen X et al. The impact of surgical excision of the primary tumor in stage IV breast cancer on survival: a meta-analysis. Oncotarget 2018; 9: 11816-11823.
  7. Soran A, Ozmen V, Ozbas S, Karanlik H, Muslumanoglu M, Igci A et al. Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01. Ann Surg Oncol 2018; 25: 3141-3149.
  8. Nguyen D, Rubinstein L, Takebe N, Miele L, Tomaszewski JE, Ivy P et al. Notch1 phenotype and clinical stage progression in non-small cell lung cancer. J Hematol Oncol 2015; 8: 9.
  9. Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther 2014; 141: 140-149.
  10. Altrock PM, Liu LL, Michor F. The mathematics of cancer: integrating quantitative models. Nat Rev Cancer 2015; 15: 730-745.
  11. Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 2015; 12: 445-464.
  12. Griffiths CT, Parker LM, Lee S, Finkler NJ. The effect of residual mass size on response to chemotherapy after surgical cytoreduction for advanced ovarian cancer: long-term results. Int J Gynecol Cancer 2002; 12: 323-331.

 

Sherry Yang, MD, Ph.D

Program Director and Medical Officer, National Cancer Institute, NIH

Dr. Sherry Yang’s research is focused on translational research aimed at reducing cancer recurrence and death, particularly in breast cancer. It has overtaken lung cancer as the most diagnosed cancer, with an estimated 2.3 million new cases (11.7%) among 36 cancers in 185 countries. Breast cancer is the leading cancer diagnosis and the second highest cause of cancer mortality in women, largely in the context of stage IV disease. Thus, it is critical to identify risk and prognostic factors to reduce death and improve survival in patients with metastatic disease. Dr. Yang’s team recently identified that locoregional tumor burden is a significant risk factor for mortality in de novo metastatic breast cancer. The finding is a result of, over two decades, implementing the precision medicine approach of identification and validation of predictive and prognosis factors. Focused on the biomarker-driven cancer treatment, she has been an editor of Handbook of Therapeutic Biomarkers in Cancer since 2010. Her team evaluated several biomarkers that are associated with chemotherapy outcomes in large cohort studies. They made the seminal observation that breast cancer subtypes per se may not have prognostic value in patients who did not receive any treatment; It was the treatment that had elicited the differential clinical outcomes intrinsically possessed by distinct molecular subtypes. Her group is the first to report that performance of independent clinical and molecular factors is weighted by treatment modality and nature of clinical end points.

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Go to the profile of Sherry Yang, MD, Ph.D
3 months ago

The findings are important to reduce cancer death.