Emerging Treatments for OMBC: Where Are We Now?

Kate M. O'Rourke

Disclosures

August 05, 2021

Metastatic breast cancer has traditionally been considered incurable, with treatments focused on systemic therapies and palliative care. Yet, emerging evidence shows that in some patients with limited metastatic disease, or "oligometastatic disease" (commonly defined as five or fewer metastases diagnosed on imaging), aggressive metastasis-directed therapy with surgery and/or hypofractionated image-guided radiation therapy improves outcomes and may even be curative. This practice is becoming more common as evidence has grown to support the approach and as technology has made it more feasible. Treatment of certain oligometastatic breast cancers (OMBC) in particular (ie, hormone receptor positive and bone-only metastases) may be especially useful in some of these patients.

Igor Makhlin, MD

Recently, Igor Makhlin, MD, an assistant professor in the Division of Hematology & Oncology at the University of Pennsylvania, co-authored an analysis, "Oligometastatic Breast Cancer: Is This a Curable Entity? A Contemporary Review of the Literature." Medscape spoke with Dr Makhlin to discuss the latest advances, research, and treatment strategies for this troublesome disease, for which no standard of care currently exists.

In your article, you aimed to provide an update on OMBC, including both a review of the data around surgery and radiation to oligometastatic lesions, as well as a summary of what we know about the biology of oligometastatic disease across tumor types. Can you provide highlights that most stand out to you regarding your analysis of the literature?

One of the main issues in OMBC is lack of prospective, randomized trials addressing the value of intervening upon individual lesions, though this is changing. Although the literature search for surgical intervention yielded few high-quality trials to draw definitive conclusions, we recently saw Khan et al report the results of the randomized ECOG-ACRIN E2108 trial at the ASCO 2020 meeting, evaluating the value of locoregional therapy to the primary breast tumor following initial systemic therapy in de novo stage IV metastatic breast cancer, which showed no benefit over standard-of-care systemic therapy alone. This was an important result, given mixed data from two prior randomized trials. The data for surgical resection of focal metastatic lesions such as liver or lung metastases stems mostly from retrospective studies, which suggest some benefit over systemic therapy alone in OMBC in carefully selected patients. The data for radiation in OMBC is more robust, with SABR-COMET being the first randomized trial of stereotactic ablative radiotherapy (SABR) to oligometastases with overall survival (OS) as the primary endpoint and showing a significant OS benefit on recent updated longer-term follow-up. In terms of the biology of the oligometastatic cancer, we reviewed work over the past decade exploring miRNAs as regulators of metastatic potential.

Are there open-ended questions in your review?

Our understanding of optimal management of OMBC is still evolving. While we generally think of OMBC as a favorable prognostic factor, the treatment paradigms are still the same as classic polymetastatic disease (eg, site-directed therapy is still mainly employed for symptomatic metastases as a palliative measure). So the open-ended questions right now are whether we can use additional therapeutic strategies to further improve outcomes (such as SABR), whether there are druggable biologic targets underpinning the oligometastatic state, and whether there is a subgroup of patients with OMBC that are truly curable.

Can you elaborate about the presentation by Khan et al regarding the results of the randomized ECOG-ACRIN E2108 trial that you mentioned?

This was a randomized trial addressing the question of whether treating the primary breast tumor with surgery and radiation in a de novo metastatic breast cancer would lead to improved OS, the primary endpoint. Prior data from India and Turkey offered conflicting answers to this question, so this most recent trial sought to offer clarity. This trial enrolled 393 women who received induction therapy tailored to their receptor subtype; of those, 295 had stable disease or response to systemic therapy and were randomized to locoregional therapy (breast-conserving surgery if possible or mastectomy; postoperative radiotherapy as appropriate) vs not. After a median of 5 years of follow-up, although there was improved local control in the early local therapy group, there was no difference in 3-year overall survival rates between the groups. Interestingly, early local therapy also did not improve quality of life. One important caveat is that although we know that roughly half of the participants randomized to early local therapy had "single organ system involved," we don't have subgroup analyses showing how this oligometastatic group fared with early local therapy compared with those who continued with systemic therapy alone. I presume that these data will be reported in the final publication, so that's something we will be waiting for.

What areas of research are meaningful and hopeful in OMBC right now?

I think the preclinical studies looking to decipher the biologic basis for oligometastatic disease as a distinct entity from classic polymetastatic disease are exciting.

Can you describe these preclinical studies in more depth?

There has been some very impressive work, particularly from the folks at the University of Chicago, investigating the role of micro-RNAs (miRs) in oligometastatic disease. This stems from the understanding that certain miRs regulate gene expression and metastatic potential. In one study, Lussier and colleagues performed miR expression profiling on metastatic tumor biopsies from patients with oligometastatic disease receiving radiation therapy (some of whom went on to develop polymetastatic disease and some of whom did not) and, using unsupervised hierarchical clustering, found that oligometastatic and polymetastatic subjects formed discreet clusters. Further validation of miR expression signatures in human datasets identified miR-200c as a potential mediator of metastasis; in mouse xenograft models, injection of oligometastasis-like lung-derived cell lines treated with synthetic miR-200c mimics led to polymetastatic disease, whereas the same cell line treated with control mimics led to the expected development of oligometastasis.

In another interesting study, Uppal and colleagues uncovered four specific miRs encoded in the 14q32 locus that were overexpressed in patients harboring oligometastatic disease. They then demonstrated functional significance of these miRs in vitro by overexpressing them in a polymetastatic triple-negative breast cancer cell line which led to reduced adhesion and invasion potential in Matrigel assays. They then showed that injection of these cell lines, transfected with each of the four miR-mimics, into NOD/SCID mice led to significantly fewer lung metastases in three of the four transfected miRs. In a complementary series of experiments, they were able to reproduce these findings in vitro and in vivo by suppressing the 14q32 miR target genes TGFBR2 and ROCK2. Essentially, they were able to take traditional polymetastatic cell lines and weaken their invasive potential through manipulation of certain putative oligometastatic-associated miRs or their downstream targets.

These two studies are great examples of the bedside-to-bench work being done to develop better understanding of drivers of oligometastatic disease, with the hope that this will lead to new therapies that can curtail development and progression of polymetastatic disease.

Can you elaborate on the significance of these particular areas of research?

It's promising to see a number of new and interesting randomized studies launching to test whether oligometastatic-directed therapy can improve survival rates and, possibly, cure patients who have a locally advanced cancer with oligometastatic disease at diagnosis. Some of these studies are in other cancer types, but we may learn a great deal and apply these principles to breast cancer. Examples include a trial out of Mumbai offering local consolidation radiotherapy to standard-of-care EGFR or ALK-specific TKI in EGFR- or ALK-positive oligometastatic non–small cell lung cancer, and a phase 1 study evaluating the role of stereotactic ablative radiotherapy (SABR) followed by 6 months of anti-PD1 therapy with pembrolizumab in OMBC.

Variations in radiation techniques in oligometastatic disease are also being tested, such as a recently published report demonstrating superiority of ultra-high-dose (24 Gy) single-fraction radiation compared with multiple-fraction SBRT in OMD, without additional toxicity.

With the recent advances in "liquid biopsy" technologies (eg, circulating tumor DNA and circulating tumor cells), there is increasing data showing the prognostic value of ctDNA and circulating tumor cells in metastatic and oligometastatic disease. Accordingly, new randomized trials testing therapies for OMD are incorporating liquid biopsy as a translational component to better prognosticate these patients and develop predictive biomarkers that may further refine the selection of patients most likely to benefit from local therapy to OMD (per SABR-COMET).

Part of the translational work in progress also focuses on host and tumor immune microenvironments, which may be particularly relevant in cancers where immunotherapy is a standard of care. For instance, recent work published by Yang and colleagues reported on whole exome and RNA sequencing of paired primary pancreatic cancer and synchronous oligometastatic liver lesions, finding that the liver lesions exhibited an immunosuppressive tumor microenvironment with increased proportion of immunosuppressive M2 macrophages and upregulation of C1q complement factor, with in vitro data demonstrating C1q as a promoter of migration and invasion in pancreatic cancer cell lines.

Regarding the SABR-COMET-3 and SABR-COMET trials that you highlighted, can you provide additional details regarding the significance of these studies?

SABR-COMET is a randomized phase 2 clinical trial designed to evaluate the impact of local therapy with SABR on OS (primary endpoint) and other secondary measures, such as progression-free survival and quality of life. Oligometastatic disease (OMD) was defined as one to five lesions, all amenable to SABR. The trial randomized 99 subjects in a 2:1 fashion to standard of care plus SABR or standard of care alone. The most common cancers represented included breast, prostate, colorectal, and lung, and most subjects (92%) had one to three lesions, with bone and lung being the most common locations for metastases. The trial initially reported a 13-month OS benefit for the SABR arm after a 28-month median follow-up. However, a recent updated analysis with a median follow-up of 51 months demonstrated a statistically significant 22-month OS benefit (28 months vs 50 months; P = .006), with a hazard ratio of 0.47 — meaning that the addition of SABR conferred a 53% relative risk reduction for death compared with standard of care alone. Furthermore, quality of life was no different between arms. Of note, nine patients in the SABR arm also received salvage SABR during follow-up for occurrence of new metastatic lesions, which may have additionally impacted survival.

The positive results in this phase 2 have now paved the way for phase 3 confirmatory trials, which will test the value of SABR in subjects with one to three lesions (SABR-COMET-3) and four to 10 lesions (SABR-COMET-10). The design is similar to SABR-COMET, with the addition that randomization is also stratified by histology, which will be important to better understand clinical utility by cancer subtype (eg, breast, colon, etc.). Importantly, these phase 3 trials also build in translational correlative studies through liquid biopsies taken at enrollment and subsequent time points, focusing on circulating tumor DNA (ctDNA), circulating tumor cells, and host immune markers. These will ideally enhance our understanding of the underlying biology of OMD and help identify predictive biomarkers to allow better identification of patients likely to benefit from SABR. Lastly, the phase 2 SABR-COMET trial had three deaths (4.5%) that were possibly associated with SABR, so it will be important to follow this in the larger phase 3 trials and see if this toxicity rate holds.

How do you envision the landscape of OMBC evolving throughout the next 10 years?

I'm optimistic that this next decade will see important gains in both our understanding of oligometastatic breast cancer as well as our ability to intervene with new treatment strategies that will translate into longer periods of disease control and, hopefully, real cures for our patients.

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