Abstract
Background.
Endocrine resistance is a frequent complication, and strategies to reverse it are a high research priority for metastatic breast cancer (MBC) that is hormone receptor positive. Preclinical data suggest re-exposure to estrogen induces tumor regression in tamoxifen-resistant tumors. We conducted a pilot study to determine whether short-term estradiol exposure would reverse endocrine resistance and resensitize tumors
Methods.
Postmenopausal women with estrogen receptor-positive MBC whose disease had progressed after receiving at least one prior endocrine therapy were eligible for the study. Patients were initially treated with 6 mg/day estradiol, and those who had not progressed after 3 months were then switched to exemestane.
Results.
Thirteen patients were evaluable for toxicity and response. No grade 3 or 4 toxicities were observed. Of the 13 patients who initiated estradiol therapy, 6 patients (46%) had not experienced disease progression at month 3 and were switched to exemestane. On exemestane, disease progression was documented in five patients, with one having stable disease as best response. Median progression-free survival for all patients was 4.8 months (range: 0.6–9.5 months).
Conclusion.
Treatment with an estrogen prior to resuming antiestrogen treatments was not effective at reversing hormone resistance; however, low-dose estradiol treatment had measurable clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone-refractory MBC.
Abstract
摘要
背景. 内分泌治疗耐药是激素受体阳性的转移性乳腺癌（MBC）常见的并发症，逆转内分泌治疗耐药的策略已成为研究的重中之重。临床前数据提示，再次暴露于雌激素可诱导他莫昔芬耐药肿瘤再次缩小。我们开展了一项初步研究，旨在明确短期雌二醇暴露能否逆转内分泌耐药以及使肿瘤恢复敏感性。
方法. 入组标准为雌激素受体阳性的绝经后 MBC 患者，且既往接受过至少 1 次内分泌治疗后疾病进展。入组后，初期给予 6 mg/d 雌二醇治疗，3 个月后未发生疾病进展者转换为依西美坦治疗。
结果. 13 例患者毒性反应和缓解率可评估。未观察到 3 或 4 级毒性反应。接受雌二醇起始治疗的 13 例患者中，6 例（46%）在 3 个月时未发生疾病进展，进而转换为依西美坦治疗。接受依西美坦治疗的患者中有 5 例发生疾病进展，其中 1 例最佳缓解状态为疾病稳定。全部患者的中位无进展生存为 4.8 个月（范围：0.6∼9.5 个月）。
结论. 在重新给予抗雌激素治疗之前，使用雌激素并不能有效逆转激素耐药；然而，低剂量雌二醇治疗具有一定的临床活性，毒性反应微乎其微，应考虑作为激素难治性 MBC 的治疗选择之一。The Oncologist 2014;19: 1127-1128
Author Summary
Discussion
Hormonal therapy for the treatment of estrogen receptor-positive metastatic breast cancer is eventually limited by the development of tumor resistance. In the preclinical setting, cycling antiestrogen with estrogen therapy has been shown to prevent tumor cells from developing resistance. In addition, anecdotal reports suggest clinical benefit for patients re-exposed to aromatase inhibitors (AIs) after demonstrating benefit from estradiol therapy [1, 2]. Based on these data, we initiated this pilot trial to test the hypothesis that cycling antiestrogen and estrogen therapies could restore sensitivity to the antiestrogen. We treated patients with estradiol for 90 days (estrogen phase) followed by exemestane (antiestrogen phase). Our results confirm the clinical activity of low-dose estradiol in the antiestrogen-refractory setting, with 46% of patients deriving clinical benefit at 90 days; however, our results suggest little benefit when patients were re-exposed to antiestrogen therapy. Five of six patients (83%) who initially experienced benefit from estradiol therapy experienced disease progression within 3 months of initiating antiestrogen therapy with exemestane. Interestingly, 2 of 4 patients who had disease progression with exemestane re-responded to estradiol after progression on exemestane, obtaining clinical benefit for more than 6 and 12 months, respectively.
Three other groups have reported on the activity of estradiol in patients with metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment [1–3]. Each reported encouraging response rates (28%–55%) and mild toxicities (Table 1). In addition, some trials have included reports of clinical responses after reinitiation of AI therapy following estradiol responses. The number of patients who had re-exposure to AIs and the responses observed were small, precluding definitive conclusions. We did not see sufficient evidence of restoration of sensitivity to estrogen deprivation (i.e., by an aromatase inhibitor) after estradiol exposure for 90 days to pursue a larger phase II trial. Addition of another agent noncytotoxic to estradiol, such as a PI3K/MTOR pathway inhibitor, may be a more effective approach for reversing endocrine resistance, and this could be investigated in future clinical trials.
Table 1.
Published estradiol clinical trials
In conclusion, alternating estrogen with antiestrogen therapy does not appear to prevent endocrine resistance; however, low-dose estradiol has significant clinical activity with minimal toxicity and should be considered as a therapeutic option for patients with aromatase inhibitor- or hormone-refractory metastatic breast cancer.
Supplementary Material
Footnotes
Access the full results at: Chalasani-14-306.theoncologist.com
ClinicalTrials.gov Identifier: NCT01385280
Sponsor(s): Pfizer
Principal Investigator: Robert Livingston
IRB Approved: Yes
For Further Reading:Beverly Moy, Patrick Neven, Fabienne Lebrun et al. Bosutinib in Combination With the Aromatase Inhibitor Exemestane: A Phase II Trial in Postmenopausal Women With Previously Treated Locally Advanced or Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer. The Oncologist 2014;19:346–347.
Abstract
Background. Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC.
Methods. This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned.
Results. Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy's law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0–15.6).
Conclusion. The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.
Author disclosures and references available online.
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