DISCUSSION

Generally, BM in breast cancer is associated with a poor prognosis.15 The outcome of patients with BCBM remains poor even after chemotherapy and radiotherapy. The response of BCBM to antiestrogens (particularly tamoxifen) has been reported in a few cases.6–14 Previous studies of patients with BCBM treated with hormonal therapy were all reported before 2000, and the responses, then, were evaluated by CT, which did not provide a clear manifestation of BM. Here, we report a patient who responded completely to MPA and another patient with an endocrine-resistant tumor who gained a transient reduction in BM from fulvestrant after multiple-line treatments.

In general, most patients with BCBM are not suitable for hormonal therapy. The majority of these patients are characterized with rapid growing, hormone receptor-negative, and/or Her-2–positive tumors, and concurrently with visceral metastases. However, some cases with hormone-dependent tumors may benefit from hormonal treatments. Cases presented in Table 1 were rare after the year 2000, because of the vigorous development of radiological and radiation therapy technology, with hormonal therapy not regularly used thereafter. Most patients who responded to hormonal treatment had long disease-free intervals and had non-visceral involvement. The first patient that we reported who was responding well to MPA exhibited similar characteristics.

(To view a larger version of Table 1, click here.)


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Both the intracranial and extracranial lesions responded to hormonal treatment, and the response duration time of all reported cases was around 1 year. For the first case, the long-term control of intracranial and extracranial lesions with letrozole suggested that the patient had an estrogen-dependent tumor. The difference in the level of tumor regression between the lung metastases and breast tumors (PR) and the BMs (complete response) after MPA therapy could reflect the changes in ER levels among metastatic lesions or diversity in the concentration of the drug between different organs, and the nature of tumor heterogeneity. MPA has several mechanisms of action that may account for its antitumor effect in patients with metastatic tumors. MPA downregulates the expression of ER and decreases the levels of estrogen, which could inhibit tumor growth directly. A noticeable transient reduction in the sizes of BMs in case 2 suggested that fulvestrant or its metabolites entered the brain by crossing the BBB in extensive amount. The disruption of the BBB by metastases could have allowed the intracranial penetration of the agent. Because case 2 showed a stable response on MRI and the metastatic lesions apparently diminished (not achieved a PR response according to the Response Evaluation Criteria in Solid Tumors) after the single treatment with fulvestrant, we drew a preliminary conclusion that fulvestrant instigated the reduction in tumor size. That the intracranial tumor shrank implies a potential response of BM to fulvestrant after multiple-line treatments. The response did not last and failed to continue possibly as a result of multiple endocrine therapy–resistant mechanisms. While fulvestrant is expected to be beneficial during the management of peripheral diseases, the ability of the drug to cross the BBB is currently an uncharted territory. Abemaciclib, a CDK4/6 inhibitor, is reportedly distributed across the BBB and is efficient against brain metastatic tumors.16 The JPBO study (NCT 02308020) demonstrated that the unbound concentrations of abemaciclib in the plasma and tumor tissue were comparable to and consistent with the CSF concentrations of each patient and 2 of 23 BCBM patients achieved PR (8.7%).17 A further outcome on clinical trials is expected in the near future. There are currently no case reports on BMs responding to fulvestrant, because the RT and/or chemotherapy are preferred choices of treatment for patients with BCBM, meaning clinicians usually do not come to the conclusion we established.

There were conflicting follow-up intervals of BM from breast cancer in the reported cases, and the range of interval was from 3.5 to 18 months (Table 1). In our first case, the follow-up MRI image was performed 10 months after oral endocrine therapy and complete remission of BM was demonstrated. Outstandingly, the reduction of BM in our second case was occasionally found on the positioning MRI after only 1 month of administering the first dose of fulvestrant. It is, hence, suggested that more frequent follow-up imaging is vital to assess periodic and accurate responses. Another suggestion is that, to have an indication of progression, local treatment should be added immediately when BMs appear. At least, an early image assessment, 1–2 months after treatment, should be mandatory.

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Lien et al18 reported that the concentration of tamoxifen and its metabolites was up to 46-fold higher in brain tissues and BMs compared with the concentration in serum. The high levels of the drug and its metabolites in metastatic tumor could be demonstrative of the association between healing agents and the receptors of tumor tissues. Antiestrogen receptors include ERs, cytochrome P-450, protein kinase C, calmodulin, histamine-like receptors, muscarinic receptors, and dopamine receptors. Tamoxifen and its metabolites may bind to these receptors, but may also partition into the myelin layer of the brain.18 However, there is no such data available to show for MPA or fulvestrant so far. Despite the promising findings, our study requires more in-depth studies.

CONCLUSION

The two reported cases suggest that hormone therapy could play a role in the single therapy of selected cases of BMs from patients with disseminated breast cancer who had non-rapidly life-threatening BMs and ER-positive or hormone-dependent carcinoma.

Acknowledgment

Qian Wang and Bing Sun are co-first authors for this study.

Author contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.


Qian Wang,* Bing Sun,* Chao Liu, Sanzhong Shi, Lijuan Ding, Jiannan Liu, Shikai Wu

Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China

*These authors contributed equally to this work.


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Source: OncoTargets and Therapy.
Originally published February 19, 2019.