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A Raloxifene Withdrawal Response

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A Raloxifene Withdrawal Response ICTXXX10.1177/1534735416651329Integrative Cancer TherapiesJordan 651329editorial2016 Editorial Integrative Cancer Therapies April-June 2016: 1 –3 A Raloxifene Withdrawal Response: © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav Translational Research, Definitions, DOI: 10.1177/1534735416651329 and Clinical Applications ict.sagepub.com V. Craig Jordan, OBE, PhD, DSc, FMedSci1 Lemmo1 contributes an interesting case report of a patient after stopping treatment. By contrast, DES is completely with estrogen receptor (ER) and progesterone receptor excreted within days. Be that as it may, the actual explana- (PgR)–positive breast cancer, who was successfully treated, tion is far more complex when acquired resistance develops off label, with adjuvant raloxifene (60 mg daily) for 8 years with tamoxifen. Laboratory studies with ER-positive breast until recurrence (ER/PgR-positive disease). This clinical cancers, retransplanted into tamoxifen treated animals for a case provides an unanticipated opportunity to revisit the decade, show several unique features not seen with any biological rules of anti-estrogenic (aromatase inhibitors, other cancer medicine. tamoxifen and raloxifene) therapy, the manifestation of Acquired resistance to tamoxifen develops under labora- acquired resistance and the “withdrawal response.” This is tory conditions in vivo within 2 years. This is consistent an important topic for the clinician. Breast cancer has the with the treatment of MBC. In the laboratory, breast tumors highest incidence of all cancers in women but the ER target were discovered to grow because of tamoxifen treatment has been the conduit for achieving the highest success in not despite tamoxifen treatment.6,7 The reason that no cancer therapeutics above all others.2 “withdrawal response” is seen with tamoxifen when treat- As a result, and to build upon success, it is important that ment is stopped is because tamoxifen remaining in the efforts to integrate clinical observations with advances in patient’s body continues to stimulate tumor growth for understanding the mechanisms of acquired anti-hormone many months. However, if this is the novel mechanism of resistance, remain a priority to further aid patient survival. acquired resistance to tamoxifen, seen clinically, the labora- The clinical use of the phrase “withdrawal response” was tory observation now created a conundrum: “If tamoxifen promoted through the 1950s and 1960s until the 1970s, to fails to control MBA and experimental tumors for no longer describe the paradoxical pharmacology of high-dose syn- than 2 years, how is adjuvant tamoxifen able to control thetic estrogen therapy, that is, diethylstilbestrol (DES), recurrence of breast cancer, with 5 years of treatment?”8,9 when used for the treatment of metastatic breast cancer The answer lies in the evolution of acquired resistance in (MBC), in women more than 5 years following their meno- cell populations, observed during the retransplantation into pause.3 Thirty percent response rates were routine, but when tamoxifen treated athymic mice for a decade.10 The tamox- recurrent tumor growth resumed, withdrawal of the DES ifen-treated tumors evolve their cell populations through therapy caused a second tumor regression or a “withdrawal selection pressure to expose a vulnerability, after 3 to 4 response.” The synthetic estrogen was now fueling tumor years: estrogen-induced apoptosis. Tumor regression occurs growth. With the advance of tamoxifen in the 1970s,4 which with physiologic levels of estrogen, after tamoxifen treat- replaced high-dose DES therapy, clinicians again observed ment is stopped.11,12 Recent data with acquired anti-hor- 30% response rates in MBA by blocking estrogen action. mone resistant breast cancer cells in vitro illustrate how However, a “withdrawal response” was rarely observed population can change within just a few months under (although one small series was published5). The reasons for this apparent failure with tamoxifen to produce a “with- 1 drawal response,” when it was commonly observed for DES University of Texas MD Anderson Cancer Center, Houston, Dallas/Ft with MBC patients titrated on and off treatment, was not that Worth Living Legend Chair of Cancer Research, Houston, TX, USA it did not exist, but instead the pharmacokinetics of tamoxi- Corresponding Author: fen were radically different than high-dose DES therapy, and V. Craig Jordan, OBE, PhD, DSc, FMedSci, Department of Breast Medical the mechanism of acquired resistance was different. Oncology, University of Texas MD Anderson Cancer Center, Houston, Dallas/Ft Worth Living Legend Chair of Cancer Research, 1515 High levels of tamoxifen and metabolites accumulate in Holcombe Boulevard, Unit 1354, Houston, TX USA. the body and are retained for slow excretion over months Email: [email protected] Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Downloaded from ict.sagepub.com at University of British Columbia Library on June 13, 2016 2 Integrative Cancer Therapies selection pressure. Cells with acquired anti-hormone resis- produce the long-term decreases in CA-15-3 (figure 1 in the tance can change from aromatase and selective estrogen case report).1 receptor modulator (SERM) resistant to become estrogen or We must thank Dr Lemmo for contributing an important SERM-stimulated,13,14 just like the aythmic mouse model6 new piece to the cancer biology puzzle of the “withdrawal and MBC.5 Overall, this was thought to be a unique form of response.” This clinical observation further helps decipher acquired resistance for tamoxifen, that is, tamoxifen-stimu- the paradox of estrogen-induced apoptosis as a general lated tumor growth, until the same form of acquired resis- principle to aid and enhance patient care.24 tance, was found for raloxifene in both cell culture and athymic animal studies,15,16 and now clinically in this case Acknowledgment 1 report. Unlike tamoxifen, the polyhydroxylated raloxifene The author thanks the benefactors of the Dallas/Ft Worth Living does not accumulate and is rapidly excreted within days. Legend Chair of Cancer Research for their generous support. The “withdrawal response” following raloxifene-stimulated growth in the patient occurs because the medicine is Declaration of Conflicting Interests excreted rapidly, to prevent growth but there is another The author(s) declared no potential conflicts of interest with cytotoxic component. respect to the research, authorship, and/or publication of this arti- During the past 20 years, a hypothesis has emerged that cle as a member of scientific advisory board for sermonix and a woman’s own estrogen causes estrogen-induced apopto- stenogen. sis, following the cessation of long-term (5 years or more), 10,11,17 adjuvant anti-hormone therapy. This hypothesis, and Funding supporting laboratory data,11 provides a cytotoxic mecha- The author(s) disclosed receipt of the following financial support nism to explain the decreases in mortality after long-term 8,9 for the research, authorship, and/or publication of this article: This tamoxifen is stopped. What would be anticipated when work was supported by the National Institutes of Health (NIH), the anti-estrogen tamoxifen was stopped, if estrogen- MD Anderson’s Cancer Center support grant CA016672 and induced apoptosis of vulnerable cells did not occur, would Susan G. Komen for the Cure Foundation under award number be estrogen-stimulated recurrences, and death in patients SAC100009, and Cancer Prevention Research Institute of Texas once adjuvant therapy stops. (CPRIT) for the STARs and STARs Plus Awards. It seems to be a fact of cancer biology in patients that 5 years or more of estrogen deprivation is required to trans- References form cell populations that initially grow with estrogen to 1. Lemmo W. Anti-estrogen withdrawal effect with raloxifene? become those that die with estrogen. Estrogen-deprivation A case report. Integr Cancer Ther. 2016;xx:xx-xx. can be achieved in many ways clinically: (a) 5 years after 2. Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, menopause is required for high-dose DES to treat MBC Goodwin PJ, Wolff AC. Past, present, and future chal- sucessfully18; or (b) 10 years after menopause, in the estro- lenges in breast cancer treatment. J Clin Oncol. 2014;32: gen alone trial of the Women’s Health Initiative, that pro- 1979-1986. duces a decrease in the incidence of breast cancer and an 3. Stoll BA. Palliation by castration or hormone administra- increase in survival from breast cancer19; or (c) the exhaustive tion. In: BA Stoll, ed. Breast Cancer Management Early treatment of MBC with anti-hormone therapies for over 5 and Late. London, England: W. Heinemann Medical Books; 1977:133-146. years so that estrogen, now produces a 30% response rate20,21 4. McDaniel RE, Maximov PY, Jordan VC. Estrogen-mediated and does not produce growth. This clinical concept is repli- mechanisms to control the growth and apoptosis of breast cated and supported by estrogen deprivation for breast can- cancer cells: a translational research success story. Vitam 22,23 cer cells in culture, and SERMs therapy (tamoxifen and Horm. 2013;93:1-49. raloxifene) for up to a decade observed in studies with 5. Howell A, Dodwell DJ, Anderson H, Redford J. Response aythmic mice.15,16 after withdrawal of tamoxifen and progestogens in advanced The large body of translational laboratory research, breast cancer. Ann Oncol. 1992;3:611-617. along with consistent clinical results, implicate long-term 6. Gottardis MM, Jordan VC. Development of tamoxifen-stimu- estrogen deprivation as the key to the subsequent cytocidal lated growth of MCF-7 tumors in athymic mice after long-term action of estrogen that has created a rule for cancer biology, antiestrogen administration. Cancer Res.
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