Oligometastatic breast cancer from the perspective of the radiation oncologist

Breast cancer is one of the most frequently diagnosed cancers and a leading cause of cancer death in women in Europe [1]. Up to one quarter of all patients with initially early stage disease suffer from distant relapse, and around 5% of all patients are diagnosed with de novo metastatic breast cancer [2]. Historically, there was a sharp cut between localized and widespread disease. Metastatic breast cancer was originally considered incurable and was usually considered as requiring palliative care. However, in 1995, Hellman and Weichselbaum proposed an intermediate entity called “oligometastasis”, where tumors have only spread to a limited number of sites and, therefore, may raise an opportunity for long-term disease control when treated aggressively with metastasis-directed therapy (MDT) [3].

Together with an evolving understanding of tumor biology, advancements in imaging, surgery, systemic therapies and in the field of radiotherapy, several trials were conducted which intended to show an improvement in prognosis and outcomes of patients with OMD and OPD compared to those with polymetastatic disease in different tumor entities, although there is a biologically different nature in OMD, where metastatic lesions usually show molecular similarity to its source, and OPD, where a resistance mechanism occurs [4‐6]. Since some of these studies showed positive results, there is currently momentum towards treating those patients with local ablative therapies.

In this review, the author wants to give a perspective on treating oligometastatic breast cancer patients from the view of the radiation oncologist.

To the present day, an exact definition of OMD is not available. Generally, it is defined as a metastatic situation with one to five lesions in addition to the primary tumor [7]. OPD describes a situation where only one or a few new metastatic lesions occur during systemic treatment. Specific biomarkers are still lacking. Diagnosis relies on imaging; common sites of metastases in BC are lymph nodes, bones, lung, brain, and liver. Some subtypes show a preference for specific sites, e.g., bones for hormone receptor-positive tumors or brain for HER2-positive disease [8]. Computed tomography (CT) of chest, abdomen, and pelvis is still the main imaging modality when it comes to BC staging. Nevertheless, the National Comprehensive Cancer Network (NCCN) guidelines do not recommend routine systemic staging in asymptomatic early stage BC patients for posttreatment surveillance. For OMD and OPD, guidelines need to be updated considering also modern developments such as liquid biopsy.

However, to be able to treat patients with OMD or OPD, modern imaging is crucial. 18F-FDG PET-CT shows sensitivity and specificity rates of ≥ 95% in detecting involved lymph nodes or distant metastases. The PETABC trial showed superior disease detection rates of BC patients with stage IIB or III compared to conventional staging with CT and bone scans [10]. Unfortunately, it is unclear whether the patients diagnosed with OMD could have benefited from a change in treatment. Interestingly, a new PET tracer called 18-fluoro-16-alpha-fluoroestradiol (FES) showed improved accuracy for detecting estrogen receptor (ER)-positive lesions and helps in assessing the efficacy of ER blockade [11]. Unfortunately, these scans are currently limited in the detection of hepatic metastases due to the excretion of FES through the liver. Nevertheless, the combination of appropriate PET tracers and CT scans is currently the best option in diagnosing OMD or OPD, especially when new tracers, e.g., for HER2-positive disease, can be clinically implemented in a fast manner.

Advancements in both hardware and software have assisted radiation oncologists and medical physicists in the development of modern radiotherapy treatment forms such as stereotactic body radiotherapy (SBRT). This technique offers the possibility to deliver highly conformal ablative radiation doses to distinct lesions such as small primary tumors or metastases in only a few fractions, compared to “conventional” radiation schemes, which often last several weeks. It relies on modern imaging to precisely locate the target lesions for both treatment planning and dose delivery. These advancements lead to lower toxicity profiles than former radiotherapy techniques, although long-term side effects like fibrosis, fractures or fistulas can occur, depending on the treatment site.

Due to low penetration of substances through the blood–brain barrier, local treatments for brain metastases have historically had a high value. Stereotactic radiotherapy for brain lesions has been a standard treatment for quite a while, in addition to surgery and radiosurgery. Improved OS and excellent local control for different tumor histologies have been reported [12].

Alongside technological improvements, radiation oncologists also began to use stereotactic radiotherapy for extracranial primaries and metastases in the lung, liver, bones, and lymph nodes. It did not take long until data showed first improvements in LC and OS for patients with OMD. Long-term results from the randomized phase II trial SABR-COMET showed that patients with OMD from different histologies receiving SBRT to all metastatic lesions had a median OS of 50 months (95% CI 29–83 months) compared to 28 months (95% CI 18–39 months) for patients receiving standard-of-care palliative therapy. Median progression-free survival (PFS) was 11.6 months (95% CI 6.1–23.4 months) with SBRT compared to 5.4 months (95% CI 3.2–6.8 months) in the standard arm. Note: Only 18% of the patients in this trial had breast cancer [13]. Several other phase II trials which investigated OMD in NSCLC, prostate cancer and colorectal cancer showed similar positive results [14‐16]. Different phase III studies for tumors with different histologies are on their way, such as NRG-LU002 (NCT03137771), SABR-COMET‑3 (NCT03862911), and CORE (NCT02759783).

For breast cancer, data are more limited. There are some retrospective, single-arm trials of SBRT in breast cancer with OMD or OPD which could show positive results with median OS ranging from 14–53 months and median PFS ranging from 7–11 months [17, 18]. There are also some prospective, single-arm trials [19‐21]. Trovo et al. treated 54 patients with synchronous (74%) and induced (26%) OMD breast cancer with SBRT for lesions in lung, lymph nodes, and bones; median OS und PFS were not reached and approximately 28 months, respectively. Toxicity was low in this study. Milano et al. treated 48 patients with synchronous (17%) and metachronous (83%) OMD, 25% were treated for bone metastases with the other patients being treated to liver, lung, lymph nodes, and adrenals. For bone-only metastases, median OS was not reached with the other patients having a median OS of 3.2 years. Both groups showed high local control of the treated lesions. Bone-only OMD is known as a favorable setting and is backed by the study of David et al., who treated 15 patients with 24 bone-only metastases. Median follow-up was 24 months; median PFS was not reached with a 2-year PFS of 65% and a LC of 100%. Generally, toxicity was low in all studies, which was also shown by Franceschini et al. [22].

The only randomized phase IIR/III trial for MDT (surgery or SBRT) in newly diagnosed OMD breast cancer, NRG-BR002 did not show any OS or PFS benefit [23]. This study randomized patients to standard-of-care systemic therapy according to NCCN guidelines with or without MDT, and 93% of patients in the MDT arm received SBRT. After median follow-up of 30 months, median PFS was 23 months (70% CI 18–29 months) with systemic therapy alone, while MDT arm had median PFS of 19.5 months (70% CI 17–36 months). Median OS was not reached in either arm. Three-year OS in the MDT arm was 68.9% (95% CI 55.1–82.6%) compared to 71.8% (95% CI 58.9–84.7%) for systemic therapy alone (p = 0.54). Local control was better in the MDT arm with 6.7% compared to 29.2% in the systemic treatment arm. All treatments were well tolerated.

For OPD, there is even less data. With CURB, there is a phase II, open-label, randomized controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or nonsmall cell lung cancer (NSCLC) after having received at least first-line systemic therapy [24]. In all, 106 patients were randomly assigned to standard of care (n = 51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n = 55; 24 patients with breast cancer and 31 patients with NSCLC). In the breast cancer group, no benefit in PFS could be observed (median PFS 18 weeks with SBRT vs. 19 weeks with palliative standard-of-care). In NSCLC, there was a significant difference in the PFS benefit for the SBRT group. A reason for this may be the fact that BC patients had received more lines of systemic therapy upfront compared to the NSCLC group and that the BC group had a smaller percentage of de novo metastatic disease compared to the NSCLC group. Toxicity was acceptable for all groups.

The AVATAR trial, a single-arm, phase II prospective trial, enrolled ER+/HER2− patients on endocrine therapy with CDK4/6 inhibitors at time of oligoprogression [25]. Primary endpoint was event-free survival, defined as change in systemic treatment or progression within 6 months of enrollment. The results of the study were positive; 47% (15/32) of patients remained on their therapy for ≥ 6 months.

There are several prospective trials ongoing for BC patients in the OMD or OPD setting. STEREO-SEIN (NCT02089100) is a phase III trial with the primary endpoint of PFS including HR+/HER2any patients using SBRT as local ablative therapy. CLEAR (NCT03750396) is a phase II single arm trial also aiming for PFS in HR+/HER2− patients. Next to SBRT, surgery and RFA is also allowed. LARA (NCT04698252) is a randomized phase II trial was similar settings. For OPD, AVATAR (ACTRN 12620001212943) is still ongoing. There are even more prospective studies investigating various tumor entities besides breast cancer.

This review showed the complex landscape of dealing with OMD and OPD breast cancer patients given the limited and heterogeneous nature of the current data. New concepts challenge the conventional view on metastatic disease as being incurable and aim to provide benefit in disease control and overall survival. However, negative results such as NRG-BR002 and CURB tell us that currently there is still a strong need in proper patient identification and evaluating subgroups that may profit from MDT. Furthermore, addition of new immune checkpoint therapies may be another promising possibility to reach for better results.