Introduction
Breast cancer is a systemic disease. Only in cases of a true precancer lesion such as atypical ductal hyperplasia or ductal/lobular carcinoma in situ is local therapy curative. All other patients need to undergo systemic treatment to reduce their risk of any type of recurrence. Systemic treatment in combination with surgery [2] as well as radiotherapy [3] increases survival in breast cancer patients having no evidence of distant metastases. However, three prospective trials randomizing with stratification criteria and comparing surgery of the primary cancer with no surgery in combination with systemic treatment in stage IV breast cancer patients demonstrated no survival benefit for local treatment [4‐6].
New techniques such as PET-CT, circulating tumor DNA, circulating tumor cells and MRI are used to earlier find smaller and thus less metastases in breast cancer patients, thus, raising the question of a cut off for the definition of metastatic disease where surgery of the primary may still increase overall survival. This brings the definition of oligometastatic disease back on the scientific debate.
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Oligometastatic breast cancer is a stage were not more than five metastases are visible within not more than two different organs [1]. There are no prospective trials for surgery of the primary cancer in oligometastatic disease but some are in accrual. Regarding radiotherapy, one prospective trial [7] using radiotherapy against distant metastases in metachronous oligometastasized breast cancer patients demonstrated no survival benefit. Several trials are in data accrual regarding this.
This minireview will shed light on local treatment options in oligometastasized breast cancer patients.
Surgery
Surgical treatment can be directed against the primary cancer in synchronous metastasized breast cancer as well as against metastases in synchronous as well as metachronous stage IV disease. While retrospective analyses reported a survival benefit for surgery of the primary tumor in synchronous metastasized breast cancer patients, three prospective trials finally showed no survival benefit with surgical treatment [4‐6]. However, one trial not using stratification criteria and, thus, having a significant imbalance between the two groups regarding important survival factors (triple negative disease and number of metastases) suggested a survival benefit, especially in women with one solitary bone metastasis [8]. This scientific group also prospectively evaluated patients with bone only breast cancer metastases (even not randomized having a similar bias in their groups) showing that surgery of the primary tumor improved survival [9]. As both trials do have significant demographic differences between the two groups, their assumption cannot be taken as a guideline. However, in both trials women with low metastatic burden achieved the highest oncologic effect with surgery of the primary cancer.
In this respect, there is a window of opportunity for women with excellent response to systemic treatment and the possibility of a clear R0 resection including radio-oncologic treatment to the breast as well as the metastases. For example, a 47-year old woman with a luminal B cT2 cN1 breast cancer with several liver metastases as well as bone metastases presented to the clinic. After undergoing first-line treatment with exemestan, abemaciclib and zoladex, all metastatic lesions were PET negative and the breast cancer showed a partial response in the MRI. After discussing this case in the multidisciplinary team conference, we decided to perform breast-conserving treatment and axillary dissection as well as radiotherapy to the breast. The final pathological report showed a ypT1 ypN2 (8/9) L1 cancer. Thereafter, endocrine treatment in combination with abemaciclib and XGEVA has been further applied and all metastases remained PET-CT negative. The initial diagnosis was 2019 and the patient was still PET-CT free of disease in 2024.
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In this respect, we still have to find the right women who might benefit from surgery and radiotherapy in stage IV. Women with metastatic disease which can be treated until PET-CT negativity might be such women. Moreover, we have to take into account treatment-naive synchronously metastasized women with already treated metachronously metastasized patients.
Radiotherapy
No retrospective or prospective trials in metachronously stage IV breast cancer patients demonstrated a survival benefit [7]. Several prospective new trials are on their way (NCT04424732 NCT04646564 NCT02759783); however, the combination between systemic treatment, surgical resection (primary and metastases) as well as radiotherapy have to be tested. The following trials are combining all treatments:
NCT04079049
BreCLIM-2—local treatment for breast cancer liver metastases
Sweden
The purpose of this multicenter randomized clinical trial (RCT) is to evaluate local treatment for breast cancer liver metastases, compared to systemic oncological treatment only. The primary endpoint is time to death from any cause, which will be compared using Cox proportional hazard regression. The secondary endpoints are 3‑year survival, progression-free survival, median overall survival, and quality of life. The aim is also to evaluate overall safety and predictive factors for survival during oncological and surgical treatment.
N = 200; end 2029
NCT04158843
Radical local vs. palliative therapy for ipsilateral humerus or sternum oligometastases
From China, 183 subjects will be randomized divided into two groups (experimental group and control group) at a ratio of 2 to 1. The control group received palliative treatment. No radical surgical resection or radiotherapy is performed in this group, but palliative internal fixation or radiotherapy for pain relief is permitted. Moreover, systemic chemotherapy, endocrine therapy and targeted therapy are allowed. The experimental group received radical local treatment. Radical resection is performed, and the surgical margin is negative, or radical local radiotherapy is feasible (cumulative radiotherapy dose is greater than or equal to 50 Gy). Systemic endocrine therapy and targeted therapy are allowed after radical local therapy.
N = 184; end 2025
NCT03750396
Local treatment plus endocrine therapy in ER-positive/HER2-negative oligometastatic breast cancer (CLEAR)
South Korea
In a multicenter, single-arm, phase 2 trial, local treatment included surgical resection, stereotactic body radiotherapy, palliative radiotherapy, and radiofrequency ablation. Stereotactic body radiotherapy is preferred as a radiation modality. Endocrine therapies with/without target therapy including CDK4/6 inhibitors or mTOR inhibitors are the mainstay of first-line treatment for ER-positive/HER2-negative metastatic breast cancer.
N = 110; end 2025
NCT04698252
Local therapy for ER/PR-positive oligometastatic breast cancer
Sao Paulo
Patients with estrogen receptor/progesterone receptor-positive oligometastatic breast cancer with disease controlled after at least 6 months of systemic therapy will be enrolled in the study. Patients will be randomized to receive local therapy for oligometastatic sites in addition to systemic therapy or systemic therapy alone. Local therapy strategies will include surgery, radiotherapy, and radiofrequency ablation.
N = 74; end 2031
Conclusion
Local treatment in stage IV breast cancer patients should not be routinely offered. Most breast cancer experts, however, believe that there are some stage IV patients who might still benefit from multidisciplinary treatment options. These may be women with the option of a true R0 resection/treatment. However, what does R0 mean, which type of diagnostic work up should be done, and which type of treatment should be offered?
We have to use several new diagnostic techniques such as PET-CT, ctDNA as well as CTCs to find later stages. These new diagnostic methods are not included in the UICC staging atlas but should be included in new prospective trials to identify women who might benefit from local treatment. Thus, I suggest including female and male synchronously as well as metachronously oligometastasized breast cancer patients and start standard palliative treatment. After every 3 months, a PET-CT as well as ctDNA analysis from blood samples should be done. Those with a negative PET as well as negative ctDNA in blood samples should be randomized to undergo local treatment consisting of surgical as well as radiotherapeutic options or not. The question remains who takes the lead and who pays?
Take Home Massage
There is a window of opportunity for women with oligometastastic disease and true R0 resection by treating metastases as well as the primary cancer with systemic as well as local treatment options.
Conflict of interest
F. Fitzal declares that he has no competing interests.
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