Taking a New Look at Primary Resection in Distant Metastatic Breast Cancer

Anees B. Chagpar, MD, MSC, MPH, MA, MBA

Associate Professor of Surgery

Assistant Director of Global Oncology

Yale Comprehensive Cancer Center

New Haven, Connecticut

Patients with distant metastatic disease at presentation constitute 3% to 10% of patients with breast cancer. Historically, these patients have been considered to have systemic disease that cannot be treated with surgery for curative intent. This is often a devastating diagnosis for a patient, who is faced with only palliative options.

The rate of resection of primary breast cancer in the setting of distant metastatic disease has fallen dramatically over the past decade,¹ but results from recent studies may alter this trend. Particularly with the more widespread use of effective systemic therapy, the potential to bring patients to the point of “no evidence of disease” via resection of the primary tumor is greater now than ever before.

Further, several authors have hypothesized that resection of the primary tumor may eliminate tumor stem cells and remove a source of tumor-induced immunosuppression, such that resection of the primary tumor may not only reduce tumor burden locally but also help in the clearance of systemic disease.

Conflicting Data in Trials

Although a number of retrospective studies have found that resection of the primary tumor in such patients is associated with improved survival, this is not uniformly the case. Nonetheless, a recent meta-analysis found that surgical resection of the primary tumor was associated with a hazard ratio (HR) for death of 0.63 (95% CI, 0.58-0.70).² It is unclear, however, whether this improvement in overall survival (OS) represents the true effect of debulking or is simply reflective of the inherent selection bias favoring healthier patients with a lower tumor burden as surgical candidates.Randomized controlled trials to elucidate the true impact of surgery in the setting of metastatic disease have produced seemingly conflicting results. Badwe et al reported the findings of an Indian trial (NCT00193778) in which 350 patients with metastatic disease were treated with systemic therapy and subsequently randomized to receive surgery or not.³ In this study, there was no significant difference in OS at 2 years of follow-up between the 2 groups (41.9% vs 43.0%, respectively; HR, 1.04; 95% CI, 0.81-1.34; P = .79). Although patients treated with surgery in this study tended to have a lower rate of locoregional recurrence, they had a higher rate of progression to distant metastases.

Soran et al, on the other hand, in their trial of 274 Turkish patients who presented with metastatic disease, randomized patients to surgical resection versus no resection prior to systemic therapy.⁴ Their results were similar to those of the Indian trial in terms of OS when patients were followed to 3 years (OS, 68% vs 51%; P = .79), but with 5 years of follow-up, investigators found a significant improvement in OS associated with surgery (41.6% vs 24.4%; HR, 0.66; 95% CI, 0.49-0.88; P = .005).

There are a number of factors that may help to reconcile the disparate outcomes of these 2 studies. First of all, the Turkish study had a longer follow-up: At 3 years, its findings were similar to those of the Indian trial. Secondly, in the Turkish trial, patients had surgery first; in the Indian trial, patients were treated with systemic therapy first.

Given the results of the National Surgical Adjuvant Breast and Bowel Project B-18 trial in the nonmetastatic setting, which showed no difference in survival in patients treated with neoadjuvant therapy followed by surgery versus surgery followed by adjuvant therapy, it is difficult to surmise how this could account for the difference, particularly when the response to treatment may be an indicator of improvement in survival with surgical resection (a question being posed by the ongoing ECOG trial).

Additional Factors to Consider

Third, the patients in the 2 trials varied in their clinicopathologic features. The Indian trial had significantly more patients who had more than 3 metastatic sites at presentation (74% vs 40%), and patients were less likely to be estrogen receptor—positive (60% vs 80%). Finally, the use of targeted therapy varied in the 2 trials, with only 28% of HER2-positive patients receiving trastuzumab (Herceptin) in the Indian trial versus nearly 100% in the Turkish trial.A number of studies have found that factors such as younger age, fewer comorbidities, fewer metastatic sites, bone-only disease, and a good response to chemotherapy are all associated with improved outcomes in patients undergoing surgery of the primary tumor. It may be the case, therefore, that surgery for the primary tumor is efficacious only in a certain subpopulation of patients with metastatic disease; but this cohort remains to be well defined.

In addition, any potential benefit of surgery in the setting of metastatic disease must be balanced against the risks of operative intervention. There are data to suggest that surgery in the setting of metastatic disease is associated with a higher 30-day morbidity than in the nonmetastatic setting, elevating risks of complications such as bleeding requiring transfusion and thromboembolic events, such as deep vein thrombosis and pulmonary embolism.⁵

Currently, most patients with metastatic disease are treated with palliative intent, with surgery reserved for local wound control. However, there are several randomized controlled trials that are still ongoing to evaluate the impact of surgery for the primary breast cancer on OS in patients with metastatic disease. Further studies are required to assess surgery’s impact on quality of life. As our understanding of tumor biology improves and our armamentarium of effective systemic therapies grows, it is quite possible that, at least for a select group of patients with otherwise well-controlled metastatic disease, surgical resection of the primary tumor may become standard of care in the future.

References

1. Thomas A, Khan SA, Chrischilles EA, Schroeder MC. Initial surgery and survival in stage iv breast cancer in the United States, 1988-2011. JAMA Surg. 2016;151(5):424-31. doi: 10.1001/jamasurg.2015.4539..
2. Headon H, Wazir U, Kasem A, Mokbel K. Surgical treatment of the primary tumour improves the overall survival in patients with metastatic breast cancer: a systematic review and meta-analysis. Mol Clin Oncol. 2016;4(5):863-867. doi: 10.3892/mco.2016.778.
3. Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial. Lancet Oncol. 2015;16(13):1380-1388. doi: 10.1016/S1470-2045(15)00135-7.
4. Soran A, Ozmen V, Ozbas S, et al. A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer. J Clin Oncol. 2016;34(suppl; abstr 1005). meetinglibrary.asco.org/record/122669/abstract.
5. Cordeiro E, Jackson TD, Elnahas A, et al. Higher rate of breast surgery complications in patients with metastatic breast cancer: an analysis of the NSQIP database. Ann Surg Oncol. 2014;21(10):3167- 3172. doi: 10.1245/s10434-014-3959-0.