Introduction

Breast cancer remains the most common cancer in women worldwide, and the second leading cause of cancer-specific death [1]. Most breast cancer–specific mortality can be attributed to sequelae of distant recurrence/metastasis. About 6% of metastatic breast cancer (MBC) cases arise de novo, and an estimated 20–30% of all early-stage breast cancers recur at distant sites [2]. MBC represents a spectrum of disease, both biologically and clinically in terms of proclivity for certain sites (e.g., bone predominant in hormone receptor-positive disease) and disease burden. A subset of patients with MBC will present with limited disease, often defined as ≤ 5 deposits, termed “oligometastatic” breast cancer (OMBC). Although the incidence of OMBC is not well characterized, there is some data to suggest a significant proportion of all new MBC presents as oligometastatic disease. For instance, one tri-institutional retrospective analysis of 2249 patients with stage I–III disease who had first treatment failure found that 21.9% were characterized as having oligometastasis [3]. This delineation between oligo- and polymetastatic disease is recognized increasingly as far more than an arbitrary differentiation; there are treatment and survival implications. For example, the oligometastatic patients in the review cited above were followed for ≥ 3 years and were found to have significantly longer overall survival (OS) as compared with polymetastatic patients.

Although the term “oligometastatic” has been part of common clinical parlance since its introduction in 1995 by Hellman and colleagues [4••], our conceptualization of this entity continues to evolve. Prior reviews on this subject have focused on outcomes with local techniques, e.g., stereotactic radiation and surgery. In the last decade, novel analytic techniques have led to significant insights into disease biology with the aim of informing next-generation treatment strategies. As such, we aim to bring the reader up to speed on the current molecular understanding of this unique disease entity. Having a deeper biologic understanding of oligometastatic cancer will help conceptualize a framework for treatment options. We also provide a historical perspective on OMBC, a review of the current treatment paradigms, and a discussion on clinical trials evaluating new approaches for treating OMBC.

A Historical Perspective

For over a century, clinicians, surgeons, and scientists have sought to define the mechanism of progression of breast cancer from a localized, curable surgical disease to systemic, incurable disease. William Halstead, a prominent Johns Hopkins surgeon, described breast cancer as a local disease that spread in a contiguous fashion to lymph nodes and then systemically [5, 6]. From this concept, the anatomic staging system was developed in 1959 to aid in selecting patients for surgery [7], which at that time was the Halstedian approach of radical mastectomy [6]. Subsequent to this, a “systemic” model of disease was proposed, whereby cancer was thought of as either localized or systemic at diagnosis, and hence, if patients had positive lymph nodes, the systemic model would assume they had a high probability of metastasis [8]. This model, in turn, gave rise to the now universally accepted concept of adjuvant systemic therapy. In 1995, Hellman and colleagues defined a new entity, oligometastasis, reflecting contemporary insights into carcinogenesis; namely, that cancer progression is a multi-step process, rather than a binary phenomenon of whether or not metastasis is present and widespread [4••]. They proposed that at this stage, the cancer’s full metastatic potential was not yet reached, limiting it to certain sites in the body that were receptive to the cancer, implicating the “seed and soil” theory originally proposed in 1889 by Stephen Paget [8]. Since then, they and others have propelled the field of OMBC forward by attempting to understand this state at the genomic level.

Biologic Basis for Oligometastatic Disease: What We Know

Our biologic understanding of carcinogenesis and evolution from primary tumor through an intermediate “disseminated tumor cell” state to overt metastatic disease continues to evolve as we utilize highly sophisticated analytic techniques to achieve increasingly granular resolution at the single cell genomic level. As we have come to understand, there are several hallmarks of a cancer’s metastatic potential. Genotypic diversity, immortality, and phenotypic plasticity at distant sites are some of the more relevant features [9]. Studies have shown that primary tumors release a subpopulation of genetically immature cells which travel through the blood (also known as circulating tumor cells, or CTCs), and deposit in the bone marrow (referred to as disseminated tumor cells or DTC’s) where they enter a state of dormancy and rely on autophagy among other mechanisms for self-maintenance [10,11,12]. At some later point, they exit dormancy and acquire further genetic changes that enable a more phenotypically plastic cell, thereby allowing it to resist the hostile selective pressures at distant sites. Somewhere in this transit period, the cells presumably have not yet reached their full metastatic potential and can achieve metastasis in a select few sites that provide a more favorable niche [13••].

Far from a linear pathway, however, genetic evolution in the metastatic process seems to proceed in a branched pattern. In one study, matched samples of patients with primary HER2+ breast cancer, brain metastases, and normal tissue were sequenced and evaluated for both shared and unique mutations in several key oncogenes and tumor suppressors. Although most patients had a set of shared mutations, both the primary tumor and the brain metastases harbored unique mutations, implicating that both primary and metastatic lesions continued to evolve separately once metastasis had occurred [14•].

More recently, micro RNA (miRNA) profiling has allowed a more rigorous examination of the genomic underpinnings of a cell’s metastatic potential. In an elegant study intending to genotypically identify oligo- and polymetastatic disease, Lussier et al. performed miRNA expression profiling of a cohort of patients with oligometastatic disease who underwent radiation therapy and prospectively followed them for progression. While some of these patients went on to develop extensive polymetastatic disease, others had a very stable disease course. Unsupervised clustering analysis of a select panel of miRNAs from the metastatic tumors (but not the primary tumors) revealed a clear clustering of an OM phenotype and a polymetastatic phenotype. Notably, miR-200c was identified as particularly enriched in the metastatic samples, and subsequent mouse xenograft models with oligo- and polymetastatic cell lines with injection of miR-200c vs control showed that this miRNA was able to convert oligometastatic phenotype to polymetastatic phenotype, implicating mi-R200c as a potential mediator for transition from OM to polymetastatic disease [15]. Other studies have also shown differential miRNA expression in slow vs rapid-progressing metastatic disease, with several of the miRNA’s identified in the slow-progressing phenotype shown to regulate cellular adhesion, migration, and invasion [16, 17]. These findings have already led to preclinical work in mouse models demonstrating potential targetability of the miRNA pathways to suppress metastatic potential [18]. Moreover, miRNA expression analysis was able to independently discriminate between OM and polymetastatic breast cancer in a separate cohort of patients with impressive accuracy [19]. Taken together, these data support the notion of OM as a genetically distinct entity rather than just a “transition point” from primary tumor to widespread metastasis.

Further work building on these studies will hopefully yield an array of clinically relevant products, including validated tools for discriminating between true OMBC from polymetastatic breast cancer, an integrated staging system incorporating both genomic and clinical features [20], and appropriate targets (e.g., the miRNA’s described above) for new systemic therapies.

Radiation Therapy in OMBC

Due to the limited extent of disease burden, OMBC lends itself nicely to non-invasive modalities with high precision, such as radiotherapy, and indeed this has been utilized with increasing frequency [21]. Until recently, most data supporting its use came from retrospective and prospective non-randomized, mostly single-arm studies (see Table 1 for list of selected studies) [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. For example, one study prospectively followed 121 patients with various oligometastatic cancers, including a cohort of 39 breast cancers, who underwent stereotactic body radiotherapy (SBRT). OM was defined as ≤ 5 lesions in ≤ 3 organs. For the breast cancer cohort, 2-year overall survival, freedom from widespread metastasis, and local control rates were 74%, 52%, and 87%, respectively [38]. Bone metastases in particular were amenable to radiotherapy, with no lesions recurring as opposed to 10 of 68 lesions in other organs recurring. Another phase II prospective single-arm trial of 52 breast cancer patients with oligometastasis (defined as ≤ 5 metastatic sites) receiving SBRT or intensity-modulated radiotherapy (IMRT) achieved a 53% 2-year progression-free survival and 2-year local control rate of 97%, without incurring any grade ≥ 3 toxicity, supporting the use of radiotherapy as a treatment modality for oligometastatic disease [23].

Table 1 Summary of radiation therapy trials
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Because of the significant heterogeneity in the small case series/cohort studies in publication, it has been difficult to draw firm conclusions. One systematic review evaluated 41 observational cohort studies and was not able to find any clear signal for improvement in outcomes with locally ablative therapies (though it should be noted that about half were radiation and the other half surgery), further arguing for prospective randomized trials [39].

Until recently, these non-randomized studies were all that clinicians had to aid in clinical decision-making. However, results from a large prospective randomized phase II trial have now been published with encouraging results. Palma and colleagues evaluated the efficacy of stereotactic ablative radiotherapy (SABR) in 99 patients with various cancers, each with up to 5 distant lesions. The majority of cancers were breast, lung, and prostate. The control group received standard of care palliative therapy (systemic therapy and non-SABR radiotherapy as deemed clinically appropriate). With a median follow-up of 25 months, the primary endpoint of overall survival was significantly increased from 28 months in the control arm to 41 months in the SABR arm (HR 0.57, 95% CI 0.3–1.1, p = 0.090, noting a prespecified two-sided alpha of 0.20). Furthermore, progression-free survival was doubled from 6 to 12 months (HR 0.47, 95% CI 0.3–0.76, p = 0.0012). Notably, this treatment did lead to grade 5 toxicity in 3 patients (from pneumonitis, pulmonary abscess, and subdural hemorrhage). Although this trial encompassed several cancers, it should be noted that breast cancer was among the most common subtypes [22••]. Reviewing the experience in oligometastatic lung cancer (OMLC), a prospective randomized phase II trial of 49 patients with OMLC (≤ 4 lesions), whose lesions were considered stable after first-line therapy, compared standard of care treatment with local consolidative therapy (LCT) with radiation. The primary endpoint of progression-free survival was improved with LCT (4.4 months in control arm vs 14.2 months in LCT arm, p = 0.022). Overall survival, a secondary endpoint, was also improved with LCT (41.2 months vs 17 months, p = 0.017) [40]. Yet another phase II randomized trial in a limited metastatic non-small cell lung cancer evaluating SABR plus chemotherapy vs chemotherapy alone, further demonstrated a significant progression-free survival benefit with the addition of SABR [41]. Taken together, these prospective trials utilizing local control of oligometastatic cancer are demonstrating survival benefits. Although conclusive data regarding the role for local radio-ablative treatment does not yet exist specifically for breast cancer, there is an ongoing phase II/III randomized trial by the NRG to answer this question for OMBC [42]. We eagerly await these results, with an estimated primary study closure date of 2022.

Surgery in OM

The role of surgery in MBC has been explored in two fundamentally different approaches: resection of the primary tumor and resection of metastatic deposits (metastasectomy). The majority of data in support of these strategies is retrospective in nature and hence must be interpreted with caution. We review both strategies below.

Primary Tumor Resection

Studies evaluating the role of resection of the primary tumor in the context of MBC and specifically OMBC have produced mixed results. Proposed mechanisms for benefit stem from preclinical mouse model experiments. One such study using an orthotopic breast cancer mouse model showed that reduction in tumor burden via primary tumor resection not only halted further metastatic progression but also resulted in reduced splenic myeloid-derived suppressor cells and increased CD4- and CD8-positive T cells, suggesting an enhanced immune response [43]. To date, however, these data have not been conclusively replicated in humans. For instance, a propensity matched retrospective analysis using Surveillance, Epidemiology, and End Results (SEER) data of 29,916 MBC patients, half of whom underwent primary tumor resection, showed an association with increased overall survival of 16 months compared with no surgery, particularly in patients with limited sites of disease [44]. However, this study looked back as far as the 1980s, before modern-day systemic therapies were in use, thus capturing a population not necessarily reflective of today’s treatment paradigms. By contrast, an analysis of two prospective trials of de novo MBC patients who underwent surgery of the primary tumor (N = 568) showed no difference in progression-free survival (PFS) and OS compared with their non-surgical counterparts [45]. The first cohort reflected an observational trial of HER2-positive MBC receiving trastuzumab ± palliative single agent chemotherapy, while the second cohort represented HER2-negative patients receiving bevacizumab plus taxane as first-line therapy in the metastatic setting. High metastatic tumor burden, defined as ≥ 3 sites of disease, was a poor prognostic marker, suggesting that patients with oligometastatic disease fared better. Another retrospective study of 530 patients with de novo MBC patients who underwent surgery of the primary site within 12 months of diagnosis found improved PFS and OS as compared with those who did not, with ≤ 3 lesions at diagnosis a positive prognostic marker for survival [46]. The retrospective nature of all these analyses does limit our confidence in these associations. One of the few prospective trials on this topic is an RCT comparing locoregional surgery (mainly modified radical mastectomy) vs not in 350 patients with de novo MBC. Approximately 25% of patients had oligometastatic disease with ≤ 3 metastases, and about 60–70% were ER-positive and HER2-negative. Almost all surgical patients had been pretreated with chemotherapy. There was no PFS or OS improvement found by undergoing surgery, and on subgroup analysis, the OMBC patients also did not benefit [47]. Keeping in mind this was a single-institution experience, these findings support the negative results of several pooled analyses on this topic, and hence, there is insufficient evidence to recommend this in routine practice at this time.

Liver Metastasectomy

Resection of isolated focal metastases to the liver has been shown to improve outcomes in other tumor types, such as colon cancer [48, 49]. In metastatic breast cancer, 15% of patients are estimated to present with liver involvement [50], prompting consideration of local therapy as an adjunct to systemic therapy. Unfortunately, there have been no prospective randomized trials to inform the benefit of such an approach. However, several cohorts and case series have been published, and a number of systematic reviews have summarized those data [51,52,53]. An extensive systematic review of treatment of liver metastases identified 43 studies (all retrospective) encompassing 1686 patients of varying histology, clinical presentation, and sample sizes. Sixty percent were ER-positive and 25% were HER2-positive. All underwent liver metastasectomy. Median overall survival was 36 months, 5-year survival rate was 37%, and 30-day post-operative mortality was 0.7% [54]. Because this review was limited by extreme heterogeneity in patient population and differing trial designs, we interpret this analysis with some caution. Still, some interesting nuances emerged on deeper analysis of the trials, including one case control study of 51 patients undergoing concurrent systemic chemotherapy and liver metastasectomy and 51 matched non-surgery patients. Patients had ≤ 4 liver lesions, and bone metastases were allowed in addition to the liver metastases. Multivariate analysis revealed a 3-fold higher risk of death when surgery was not performed [55]. Further, the 3-year survival rate was 50% in the non-surgery cohort, and 80% in the surgery cohort. Factors that predicted poor prognosis were > 1 course of chemotherapy and presence of bone metastases. These data do suggest that liver resection has particularly favorable results in the oligometastatic population. In unresectable or high-risk surgical patients, alternatives to resection include radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) [56,57,58]. Both forms seem to be relatively safe with low adverse events rates. Head to head trials are lacking, though there is some evidence that the combination appears to be safe and superior to RFA alone [59]. A meta-analysis of 14 studies evaluated the efficacy of RFA compared with hepatic resection and found the latter group to be more efficacious (combined OR for 5 year OS 0.38, p < 0.001) [60].

Pulmonary Metastasectomy

As with the literature for hepatic resection, there are no high-quality prospective data upon which to base a decision for or against recommending pulmonary metastasectomy. However, several cohort studies and case series have been published with 5-year overall survival rates ranging from 36 to 62% [61,62,63,64,65,66,67]. Pooling the available literature, a recent systematic review and meta-analysis of 16 cohort studies comprising nearly 2000 patients sought to describe the outcomes of patients undergoing local resection with or without concurrent systemic therapy [68]. All but one were retrospective, and few had a follow-up longer than 5 years. The pooled 5-year overall survival rate was 46%, and solitary pulmonary metastasis was found to be a significant prognostic factor favoring improved OS. It should be noted that the individual study populations, while heterogenous, did seem to be highly enriched for the oligometastatic phenotype in that several studies excluded patients with extra-pulmonary metastases or even bilateral pulmonary metastases. One should also appreciate the fact that many of these studies predated modern radiation techniques and targeted systemic therapy.

Future Directions

It should be readily apparent at this point that there is a paucity of high-quality published data regarding treatment of OMBC. Even the systematic reviews and meta-analyses are limited by the quality and heterogeneity of their individual studies. However, there is reason for optimism. Given increasing awareness and interest in the OM phenotype, several prospective phase II/III randomized controlled trials are underway, evaluating novel treatment strategies for OMBC (see Table 2 for a list of selected ongoing trials utilizing SBRT). A phase III study in the Netherlands (NCT01646034) is assessing the role of high-dose chemotherapy with carboplatin, thiotepa, and cyclophosphamide in homologous recombination-deficient oligometastatic breast cancer, with the hypothesis that these tumors are particularly sensitive to alkylating agents designed to disrupt double-stranded DNA. Multiple trials are evaluating the use of SABR and/or traditional surgery in addition to standard of care systemic therapy in the first-line setting for newly diagnosed OMBC (e.g., CLEAR, NCT03750396; STEREO-SEIN, NCT02089100; NCT02364557). A novel pilot phase I study in Australia is evaluating the role of SABR followed by 6 months of anti-PD1 therapy with pembrolizumab, with a goal of showing both safety and enhanced immune activation (BOSTON-II, NCT02303366). This strategy is of particular interest, given its recent success in lung cancer where a phase 2 single-arm study showed a 13-month PFS benefit compared with historical controls in OM non-small cell lung cancer [69]. In diseases other than breast cancer, novel prospective trials are looking to collect detailed genomic data in the form of CTCs, circulating tumor DNA, and circulating T cell repertoires as they relate to site-directed therapy, such as the phase II ORIOLE trial in castrate-sensitive metastatic prostate cancer [70]. This design would serve as an excellent model for further investigating OMBC. Not only are these trials prospective and many of them randomized, they also comprise patient populations exposed to modern, guideline-based systemic therapies, e.g., endocrine-CDK4/6 inhibitor or mTOR inhibitors. One critical ongoing challenge, however, is the varying definitions of “oligometastatic” in the inclusion criteria, which ranges from two to five based on the particular trial. To facilitate comparison of trial results and uniformity in future trial designs, it would be prudent to employ a universal definition of “oligometastatic” within the breast cancer investigative community.

Table 2 Summary of ongoing clinical trials
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Conclusion

The “oligometastatic state” has gained increasing visibility and attention as we have come to appreciate the incredibly complex biologic diversity among primary and metastatic tumors. Novel insights into the molecular alterations and unique miRNA expression signatures of oligometastatic disease as compared with polymetastatic disease lend credence to the concept of the oligometastatic state being a unique, distinct entity. Future directions at establishing measurable biomarkers with which we can track the virulence of metastasis will potentially open up new treatment strategies.

With an increasing spotlight on this disease state, data from the first randomized prospective trials in OM are now becoming available. Thus far, increases in PFS and OS in SABR-COMET are promising and we await confirmatory results from phase III clinical trials. However, an improved PFS and even OS do not necessarily equate to “cure.” And so, the most essential question remains: is oligometastatic disease curable? In the breast cancer population, where a considerable portion of patients are at risk of early recurrence (as in HER2+ and triple negative disease) as well as late recurrence (as in hormone positive disease) [71], answering this question is vital as it may help navigate treatment decisions that have the potential to spare toxicity and still produce long-term remissions.

With the exception of rare case reports and series noting extraordinary durations of response to local treatments [72], there is not yet any consistent data to suggest that oligometastatic disease is truly curable. This may well change in the next decade as prospective randomized controlled trials report their results. Still, the literature to date does make a compelling argument that OMBC behaves more favorably than widespread metastatic disease. One major question the breast cancer community will need to address is whether we can utilize local therapies in lieu of systemic chemotherapy up front to prolong progression-free survival and extend the totality of treatment options available to our patients while minimizing toxicity. With the pace at which the scientific community is moving to understand and translate the biology of this disease into human trials, we can only imagine what a review paper in 10 years will look like.