Metastatic breast cancer may present clinically either as recurrence after a previous diagnosis of stage I-III disease or as de novo metastatic breast cancer that is also called stage IV disease according to the American Joint Committee on Cancer (AJCC) tumor, node, metastasis classification.¹ Recurrent metastatic disease arises from clinically undetectable distant micrometastases that were already present at the time of diagnosis, were not eradicated by systemic adjuvant therapies, and grew into clinically detectable macrometastasis after a variable duration of tumor dormancy. In this conceptual framework, de novo metastatic breast cancer is a disease where micrometastases have no dormant period or the dormancy has passed before diagnosis. What determines the duration of cancer cell dormancy and how cells emerge from dormancy remain largely unknown.² Approximately 6%-7% of newly diagnosed breast cancers present as de novo metastatic disease in the United States,³ and this proportion is larger in middle-income countries. While this fraction remained stable in the past 20 years, the absolute number of patients diagnosed with de novo metastatic breast cancer is increasing because of a growing population and more sensitive imaging technologies for staging, an estimated 18,000 patients will be diagnosed with stage IV breast cancer in 2023 in the United States.^3,4 As adjuvant systemic therapies become more effective in eradicating micrometastatic disease, metastatic recurrences in stage I-III breast cancers are decreasing, and the proportion of de novo metastatic cancers is increasing. Historically, about 20% of patients with newly diagnosed metastatic breast cancers had de novo disease; in comparison, the contemporary rates are closer to 30%-40%.^5,6 Clinically, a fundamental difference between recurrent and de novo metastatic disease is exposure to prior therapies. Most patients with recurrent metastatic disease have been exposed to prior systemic therapy, and their recurrent disease represents growth of partially treatment resistant cells. Despite a potentially major difference in sensitivity to systemic therapies, current treatment guidelines for metastatic breast cancer do not distinguish between recurrent and de novo metastatic cancers. A further clinical subset within de novo metastatic cancers is oligometastatic disease that could be rendered no evidence of disease (NED) with locoregional and metastases-directed therapy.

Molecular Evolution of Metastatic Breast Cancer

Phylogenetic analysis of primary tumors and metastatic lesions from the same individual revealed three distinct paths to metastatic dissemination with clinical implications.^7–9 First, metastatic spread can occur early from a common ancestor of both the primary tumor and distant metastases, resulting in lesions evolving simultaneously. This phenomenon may explain why small primary tumors could present as micrometastatic disease. Second, metastases may arise from a small subpopulation of cells that develop within the primary tumor, which is consistent with the clinical observation that primary tumors left untreated will eventually metastasize. Finally, metastatic lesions can also give rise to new metastases, which implies that as long as any viable metastatic lesion exists, the potential to disseminate to other distant sites remains. All three types of dissemination can be observed in the same patient; the limited data that exist today suggest that the parallel evolution from a common ancestor to both the primary and the metastasis is the most common path. Another important discovery was that the molecular features of the cancer change over the course of the disease. Metastatic lesions acquire new genomic alterations spontaneously and under selective pressure from therapies.¹⁰ Comparison of primary tumors and metastatic lesions also revealed that synchronous metastases have a more similar genomic architecture to the primary tumors, presumably due to shorter divergence time and lack of therapeutic selective pressure, whereas asynchronous metastases show a larger number of genomic differences compared with the primary tumor.^7–11 This observation raises the possibility that synchronous metastases have similar treatment sensitivities to the primary tumor. This hypothesis is supported by clinical observations including high rates of pathologic complete response (pCR) in biopsy-proven synchronous lymph node metastases in patients who achieve pCR in the breast with neoadjuvant chemotherapy^12,13 and longer progression-free survival (PFS) with initial therapy in patients with de novo compared with recurrent metastatic disease.^6,14–16

Oligometastatic Disease

The extent of metastatic disease at the time of diagnosis varies from a single or few metastatic lesions to extensive disease with many lesions in multiple organs. Oligometastatic disease is defined by the European Society for Medical Oncology and by the European Society for Radiotherapy and Oncology and American Society for Radiation Oncology as a disease with up to five lesions each amenable to local therapy aimed at achieving a NED status.^17,18 Approximately 40% of newly diagnosed metastatic breast cancers, including de novo disease, are oligometastatic.^19,20 Multiple studies showed longer overall survival (OS) for oligometastatic de novo metastatic breast cancers, which may be due to (1) slower growth rate and more limited metastatic ability of these cancers, (2) lead time bias (ie, being diagnosed at an earlier time point during the course of the disease), or (3) more aggressive treatment approaches including local ablative therapy in addition to systemic therapy.^21,22 The individual contributions of these potential causes are difficult to distinguish on the basis of current data. In breast cancer, several retrospective studies documented 20-year disease-free survival in a quarter of patients who were rendered NED with multimodality local and systemic therapies.^22–30 Analysis of the National Cancer Database (NCDB) including 12,838 patients with de novo metastatic breast cancer also showed improved survival among patients who received trimodality therapy (ie, surgery, radiation, and systemic therapy) compared with patients who had systemic therapy only.²⁹ These studies indicate that long-term disease control is possible in select patients with oligometastatic cancers; however, these retrospective studies are all subjects to selection bias since patients treated with multimodality therapy were likely younger with fewer comorbidities and better overall prognosis. Two small phase II randomized trials, including mostly recurrent oligometastatic cancers, showed no benefit from stereotactic ablative body radiotherapy (SABR) in breast cancer. The SABR-COMET phase II randomized trial enrolled 99 patients with a variety of cancers and ≤5 metastatic sites; the 5-year OS was improved in the SABR arm, but there was no difference in outcomes in the very small breast cancer subset (n = 18).³¹ The randomized NRG-BR002, that accrued patients with oligometastatic breast cancer (N = 125), that had not progressed on initial systemic therapy within 12 months also found no statistically significant improvement in progression-free survival (PFS), OS, or new metastases rate.³² These results indicate that SABR to stable oligometastatic lesions of recurrent estrogen receptor–positive (ER+) metastatic cancers have very limited (hazard ratio for PFS: 0.92), or no, effect on survival end points. Because 71% of patients in BR002 had recurrent metastatic disease and 80% had ER-positive breast cancer, it is uncertain to what extent these results may be extrapolated to patients with oligometastatic stage IV disease. Among the 25 patients with de novo metastatic cancer, the 24-month PFS rates were 70% and 65% in the SABR plus systemic therapy and systemic therapy alone arms, respectively. These differences were not statistically significant. Several randomized trials continue to examine the value of SABR in oligometastatic breast cancers (Table 1).

Impact of Management of the Primary Tumor in De Novo Metastatic Breast Cancer

Four randomized trials addressed whether surgical removal of the primary tumor is beneficial in de novo metastatic breast cancer. The Tata Memorial trial showed no survival benefit from locoregional therapy,³³ and the ABSCG-28-Posytive trial was terminated early because of low accrual but suggested no benefit.³⁴ By contrast, the MF07-01 trial showed a 34% improvement in OS in the locoregional therapy arm.³⁵ The most recent trial, EA2108, randomly assigned patients who responded or had stable disease after 4-8 months of initial systemic therapy to surgery and radiation to the primary tumor site versus continuing systemic therapy. The trial showed that locoregional progression was less frequent in the locoregional therapy arm (3-year rate: 16.3% v 39.8%; P < .001), but there was no improvement in OS.³⁶ Each of these trials included both oligometastatic and nonoligometastatic cancers; in EA2108, very few participants received ablative therapy to metastatic sites, and systemic therapies were standard-of-care metastatic treatments. Collectively, these studies established that selectively removing some of the cancer (ie, the primary tumor) without ablating all lesions is not beneficial in de novo metastatic breast cancer. Unfortunately, these trials cannot answer whether removing the primary tumor and ablating all detectable distant metastatic lesions, coupled with molecular subtype-specific multidrug systemic therapy, could improve survival of oligometastatic de novo metastatic disease.

The National Comprehensive Cancer Network guidelines do not include distinct treatment recommendations specifically for patients with oligometastatic de novo metastatic breast cancer.³⁷ By contrast, the European Society for Medical Oncology guidelines acknowledge that patients with oligometastatic de novo disease may achieve complete remission after systemic therapy and have a potential for longer survival and hence a multimodal approach including locoregional therapy with curative intent should be considered for selected patients.³⁸ Routine practice in the United States reflects a highly variable approach to the management of patients with de novo oligometastatic breast cancer. Analysis of the NCDB data showed that approximately 52% of patients were treated with systemic therapy only, 22% received systemic therapy plus radiation treatment, 13% had systemic therapy and surgery for the primary tumor, and 12% received multimodality therapy between 2010 and 2015.²⁹

Unanswered Questions and Future Directions

The current therapeutic approach in patients with early-stage disease is based on four decades of clinical trials that have established the critical importance of multimodality therapy in improving survival. Patients at high risk for recurrence are treated with surgical resection of all detectable disease in the breast, resection or radiation of ipsilateral axillary lymph nodes, locoregional radiation therapy to eradicate microscopic residual disease in the ipsilateral breast, and adjuvant, molecular subtype-specific, multidrug systemic therapy that has become increasingly effective in eliminating distant microscopic disease. No prospective randomized trial has tested whether the same multimodality treatment strategy that we apply to stage III breast cancers might also improve survival in de novo oligometastatic breast cancer. The hypothesis that some of these patients may achieve long-term survival with multimodality therapy is supported by several retrospective case series.^39,40 However, the promise of benefit from multimodality therapy have not yet been demonstrated by clinical trials, and enthusiasm must be tempered by the significant short- and long-term morbidity from aggressive local therapies. Surgical removal of the primary tumor is associated with all the risks and costs of a surgical intervention. Although modern SABR techniques are generally safe, a meta-analysis of 21 clinical trials including 948 patients treated with SABR for oligometastatic disease showed that up to 10% of patients may experience acute or late grade 3 or greater toxicity.^21,41 Multidrug regimens that combine the most effective agents into an adjuvant-like treatment administered to patients with de novo oligometastatic disease may also deprive patients from using the same agents sequentially during progression and could limit future treatment options. It is, therefore, crucial to investigate in prospective randomized trials the potential benefits and toxicities of multimodality therapy for oligometastatic de novo metastatic breast cancer. A prospective online registry study (CHLOE) is currently open for patients with stage IV oligometastatic human epidermal growth factor receptor 2-positive breast cancer to collect outcomes with multimodality therapy in the real-world setting.⁴²

In summary, accumulating clinical and molecular data suggests that de novo metastatic breast cancers represent a distinct subset of metastatic disease where distant metastases often share molecular similarities with the primary tumor, and these cancers are all treatment naïve. Among these patients, those with oligometastatic disease represent a unique subset that could be rendered NED, through a combination of surgery and SABR. This clinical setting resembles patients with stage IIIC disease after surgical resection and radiation therapy; in both settings, macroscopic disease was eliminated, but the presence of micrometastasis is very likely, or certain. In stage III disease, adjuvant/neoadjuvant systemic therapies improved survival and reduced distant recurrence rates dramatically in the past 30 years. It is time to test if the same multimodality strategy might also improve survival in oligometastatic de novo breast cancer. Until 2002, supraclavicular lymph node involvement at presentation was considered M1 (stage IV) metastatic disease, and these patients were considered incurable and often received systemic therapies only with palliative intent. However, clinical data indicated that this group of patients when treated with combined modality therapy had long-term survival similar to stage III breast cancers,⁴³ eventually leading to reclassification to N3c (stage IIIC) disease (AJCC edition 7), and today they all receive multimodality therapy with curative intent. Might in one day we consider oligometastatic stage IV breast cancer as stage IIID disease?