Metastatic breast cancer (MBC) can present as recurrence of a previously treated early stage breast cancer or with an intact primary breast tumor at the time of initial diagnosis, commonly called “de novo” MBC (dnMBC). Approximately 5% of MBC cases are dnMBC, which have a better prognosis than the more common recurrent MBC, possibly due to treatment naivety [1]. Current standard of care treatment does not distinguish de novo from recurrent MBC, with both treated with systemic palliative therapy [2].
The value of surgery to the primary tumor in dnMBC has been a longstanding question [2,3]. Nonrandomized retrospective data have shown superior survival for dnMBC patients who undergo surgery [4]. However, because the patients selected to undergo surgery had confounding characteristics of both tumor and patient associated with longer expected survival, the additive value of surgery to systemic therapy has remained uncertain [2]. Despite a lack of evidence clearly establishing benefit, surgery has frequently been performed for selected dnMBC patients. Lane et al [1] demonstrated in a National Cancer Database (NCDB) analysis of 24,015 women with dnMBC that 41.9% of patients underwent surgery to the primary tumor after systemic therapy. Patients who received surgery were more likely to be earlier in disease progression, younger, have fewer comorbidities, and be treated in an academic institution or comprehensive cancer center.
The Eastern Cooperative Oncology Group has recently reported results of a prospective randomized trial designed to determine if surgery should be offered to dnMBC patients [5]. The E2108 trial randomly assigned dnMBC patients whose disease did not progress with initial systemic therapy to receive local therapy (surgery and/or radiation) or systemic therapy alone. Of 390 patients enrolled between February 2011 and July 2015, 256 underwent randomization to local therapy versus no local therapy in addition to systemic treatment. Of the 125 patients in the local therapy arm, 109 underwent surgery, 87 achieved free surgical margins, and 74 underwent radiotherapy. There was no difference in overall survival between the two randomized groups at 3 years (68.4% with local treatment vs. 67.9% without local treatment, HR 1.09) [1]. These findings in a U.S. population are concordant with those previously reported in an Indian population in which 350 patients were randomized to surgery or not in addition to systemic treatment for dnMBC from February 2005 to January 2013 [6]. There was no difference in overall survival at 2 years (41.9% surgery vs. 43% no surgery) or in median overall survival (19.2 months surgery vs. 20.5 months no surgery). The E2108 trial did not demonstrate a statistically significant difference in overall survival by tumor subtypes including for the 29% of patients whose cancers were HER2+ (n = 79; HR 1.05).
Other prospective randomized trials have been performed to determine the potential benefit of treating dnMBC patients with local therapy followed by systemic therapy versus systemic therapy alone. Results are conflicting. In an Austrian study of 90 dnMBC patients, overall survival favored the non-surgery group by 20 months [7]. Soran et al [8] conducted a similar trial of 274 dnMBC patients in Turkey that demonstrated a 17% improvement in median survival in the surgery group at five years.
While these efforts to define the value of surgery to the primary tumor in dnMBC have been ongoing, systemic therapy advances have significantly improved survival, perhaps most notably in HER2 + disease. The advent of dual anti-HER2 therapy with the addition of Pertuzumab to Trastuzumab has dramatically improved the life expectancy of patients with HER2 + MBC. Prior to Trastuzumab, median survival of HER2 + MBC was less than two years, compared to contemporary median survival of nearly five years with the addition of Pertuzumab [9]. The CLEOPATRA randomized trial of a treatment naïve population (n = 808) has shown that Pertuzumab improves overall survival by approximately 1.5 years. Remarkably, 37% of patients are alive at eight years of follow up and 16% remain free of disease, demonstrating a population of exceptional durable responders to dual anti-HER2 blockade [10].
Patients with dnHER2 + MBC treated with dual HER2 blockade with Trastuzumab and Pertuzumab may represent a patient population who does benefit from surgery to the primary tumor. However, the existing randomized controlled trials are unlikely to answer this question. Pertuzumab was FDA approved in the metastatic setting in 2013 following the first of four total years of enrollment to E2108, so not all HER2 + patients enrolled would have received dual HER2 blockade. In addition, the study’s sample size would not be expected to provide a sufficient number of HER2 + patients to answer this subtype-specific question. The trial conducted by Badwe et al6 from India has previously been criticized in terms of application to a U.S. population due to differences in access to contemporary systemic therapy. The arms were not randomized for HER2 status nor did patients receive HER2-directed therapy.
In an Italian retrospective data set of stage IV HER2 + patients, despite similar response rates and progression-free survival with Trastuzumab-based systemic therapy, surgery was associated with prolonged overall survival in the de novo cohort [11]. This work included 331 total patients of whom 23% or 77 patients had dnMBC. More than half of the dnMBC patients (46/77) underwent surgery to the primary tumor, and these patients had more favorable characteristics. Median survival was 60 months for dnMBC patients who had surgery and 26 months for dnMBC patients who did not undergo surgery (p < 0.001) correlating to a nearly 70% reduction in the risk of death.
In this study, we sought retrospective data in the era of dual HER2 blockade with a larger sample size. We suspect that the systemic therapy advances for HER2 + breast cancer require a reevaluation of the role of curative intent surgery for patients with dnHER2 + MBC. Our question - does definitive local therapy offer cure in select HER2 + dnMBC patients treated with dual anti-HER2 blockade? - is timely and shared by others in the field [9,12].