Surgery of the Primary Tumor in De Novo Metastatic Breast Cancer Confers No Survival Benefit: Author’s Reply

Abstract

We appreciate the thoughtful commentary from MuraliNanavati and colleagues. With respect to their point about the differences in survival found between our study and the four randomized trials they cited, these trials had relatively short follow-up on survival, which could have limited the ability to detect longer-term survival benefits. Indeed, the important trial conducted by Soran et al. showed survival advantage of surgery with longer followup time (median 40 months), even though the survival benefit did not reach statistical significance at a shorter follow-up time (36-month survival). Second, the results on the overall survival of the Tata Memorial, ECOGACRIN, and ABCSG-28 POSYTIVE trials were all found not to reach statistical significance and therefore definitive statements about locoregional therapy not improving survival in stage IV breast cancer cannot be drawn. It is important to not make definitive statements about the results when statistical significance was not reached. Third, although randomized controlled trials are considered the gold standard in evidence-based medicine, they are not completely immune to bias. Given the challenges of smaller sample sizes and shorter follow-up time with clinical trials, observational studies offer the advantage of much larger sample sizes and longer follow-up time, allowing for more statistically significant results to be obtained. We acknowledge that we incorrectly stated that only 10% of the Tata Memorial trial population received primary systemic therapy, when in reality 100% received this. Thank you for bringing this to our attention and we apologize for this misrepresentation of our data. We concur that there are active discussions and debates on whether removal of the primary tumor results in differences in the number of circulating tumor cells and the effect this may have on overall survival. While MuraliNanavati et al. argue that the ABCSG-28 POSYTIVE trial reported that locoregional therapy is associated with a significantly worse time to distant progression-free survival, this trial was stopped early secondary to poor recruitment, and their results were not statistically significant. The Tata Memorial trial similarly suggested that locoregional treatment might be detrimental to distant progression-free survival; however, the follow-up time for the above result was only 3 years. Ultimately, there is extensive literature on the multiple mechanisms and causes of metastatic spread, and unfortunately none of these have been definitively proven. Systemic therapy is the primary driver of prognosis and outcome in stage IV disease. We do not suggest that all women with stage IV breast cancer should undergo surgical treatment of the primary disease, however we do propose that surgery should be considered on a case-by-case basis in stage IV breast cancer patients with relatively low tumor burden who have received systemic therapy and are treatment responsive. We are happy to participate in this vigorous dialog with the shared goal of expanding our knowledge about optimal treatment for metastatic breast cancer patients.