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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1955-1956 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.4108
Aromatase Inhibitor Withdrawal Response in Metastatic Breast CancerMassachusetts General Hospital, Boston, MA A 31-year-old premenopausal woman was diagnosed with left-sided invasive breast cancer when she presented with breast discomfort and a palpable mass. The patient was in good general health without any medical problems. She had no symptoms and had an excellent performance status. She underwent menarche at 12 years of age and had never been pregnant. She had no family history of breast, ovarian, or other cancers. She had emigrated from Romania, where in 1985, at 16 years of age, she lived 700 miles from the nuclear accident at Chernobyl. She underwent a lumpectomy with axillary node dissection, revealing a 1.7-cm, Bloom-Richardson grade 3 invasive ductal carcinoma, with one of 16 sampled nodes positive for metastatic disease. The tumor stained estrogen receptor–positive, intermediate for progesterone receptor, and did not overexpress Her2-neu. At presentation to the medical oncology team, the patient was noted to have mildly elevated liver function tests (LFTs), with an AST of 83 U/L and an ALT of 243 U/L. Staging evaluations revealed three suspicious liver lesions measuring 1.8 cm, 1.3 cm, and 0.8 cm, which were confirmed as liver metastases on liver biopsy. The patient was initiated on tamoxifen 20 mg/d. After approximately 6 weeks, her LFTs had normalized, but her computed tomography (CT) scan demonstrated slight increase in the size of the liver lesions. She was still menstruating regularly, and luteinizing hormone-releasing hormone agonist therapy (goserelin acetate 3.6 µg intramuscularly monthly) was added to tamoxifen. A repeat CT scan after approximately 2 months of combination therapy revealed marked regression of the liver lesions and normalization of her LFTs. She was subsequently monitored on goserelin acetate and tamoxifen, which she tolerated well. She remained asymptomatic and enjoyed a good quality of life. Remarkably, the patient’s disease continued in a sustained partial remission on combination therapy for almost 4 years, when she was found to have a local recurrence of her breast cancer at the surgical scar site. Imaging studies at that time demonstrated a new bony metastasis in her sternum and increased size of the liver lesions. Her LFTs were noted to have risen. Goserelin acetate was continued, and tamoxifen was switched to the nonsteroidal aromatase inhibitor letrozole (2.5 mg/d by mouth). Three months later, despite remaining asymptomatic, staging CT scans revealed progressive disease with prominent liver lesions. A representative liver lesion is shown in Figure 1. At this time, a decision was made to stop all therapy (both goserelin acetate and letrozole), allow her to resume normal menses (which occurred within one cycle), and monitor her for a response to withdrawal of estrogen-suppressing therapy. Three months later, on no treatment, her LFTs decreased, and imaging studies revealed improvement in the sternal lesion and impressive decreases in the size of the hepatic lesions. An example of a regressed liver lesion is seen in Figure 2. To date, 14 months later, the patient continues to feel well, without new symptoms. Her scans continue to reveal a sustained partial remission of her metastatic cancer on no therapy. A rechallenge with endocrine therapy is envisioned should disease progression occur. Antiestrogen therapies, including tamoxifen, and more recently, aromatase inhibitors, are among the most effective and well-tolerated breast cancer therapies. Unfortunately, their clinical utility is limited by the fact that, even in patients with initial disease response, tumors ultimately develop resistance and progress. Therefore, a current major challenge within the field of breast cancer treatment is to devise methods to prevent disease resistance and to prolong the efficacy of antihormonal therapies. A withdrawal response to antihormonal therapy as described above has been reported in the literature, and usually in association with tamoxifen cessation.1-4 The notion that stopping antihormonal therapy and, in effect, exposing tumor cells to estrogen, can inhibit tumor growth seems at first counterintuitive. Yet, before the routine use of tamoxifen, estrogenic compounds were often used to treat breast cancers.5 It is therefore well recognized that either estrogen withdrawal or estrogen supplementation can effect a clinical response. In fact, there exists growing preclinical data that supports a rationale to use withdrawal of antihormonal therapy in the treatment of breast cancer. Tumor cells exposed to long-term estrogen deprivation become increasingly responsive to low levels of estrogen. This adaptive hypersensitivity response to estrogen therapy has been demonstrated both in vitro and in mouse xenograft models.6,7 For breast cancer cells that have been subject to long-term estrogen deprivation and that are subsequently re-exposed to higher levels of estradiol, an inhibitory effect on proliferation has been observed.8 Mouse models of estrogen receptor–positive breast cancer have demonstrated that with continued estrogen deprivation, tumor cells progress through different stages of hormonal dependence.9,10 In such cells exposed to long-term estrogen deprivation, estrogen therapy demonstrates a cyclic ability to both stimulate and inhibit cell growth. Over time, in these cells, estrogen therapy has been shown to eventually reverse tamoxifen resistance.9,10 The clinical observation of an antihormone withdrawal response coupled with emerging preclinical data provides insight into mechanisms of antihormonal resistance. We plan to translate these observations into novel approaches to hormonal therapy in the treatment of breast cancer.
Authors’ Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
REFERENCES 1. Legault-Poisson S, Jolivet J, Poisson R, et al: Tamoxifen-induced tumor stimulation and withdrawal response. Cancer Treat Rep 63:1839-1841, 1979[Medline] 2. Belani CP, Pearl P, Whitley NO, et al: Tamoxifen withdrawal response: Report of a case. Arch Intern Med 149:449-450, 1989[Abstract] 3. Stein W 3rd, Hortobagyi GN, Blumenschein GR: Response of metastatic breast cancer to tamoxifen withdrawal: Report of a case. J Surg Oncol 22:45-46, 1983[Medline] 4. Bhide SA, Rea DW: Metastatic breast cancer response after Exemestane withdrawal: A case report. Breast 13:66-68, 2004[CrossRef][Medline] 5. Ingle JN: Estrogen as therapy for breast cancer. Breast Cancer Res 4:133-136, 2002[CrossRef][Medline] 6. Masamura S, Santner SJ, Heitjan DF, et al: Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells. J Clin Endocrinol Metab 80:2918-2925, 1995 7. Shim WS, Conaway M, Masamura S, et al: Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo. Endocrinology 141:396-405, 2000 8. Song RX, Mor G, Naftolin F, et al: Effect of long-term estrogen deprivation on apoptotic responses of breast cancer cells to 17beta-estradiol. J Natl Cancer Inst 93:1714-1723, 2001 9. Yao K, Lee ES, Bentrem DJ, et al: Antitumor action of physiological estradiol on tamoxifen-stimulated breast tumors grown in athymic mice. Clin Cancer Res 6:2028-2036, 2000 10. Osipo C, Gajdos C, Cheng D, et al: Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy. J Steroid Biochem Mol Biol 93:249-256, 2005[CrossRef][Medline] This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
