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Endocrine therapy in breast cancer Dr.Mina Tajvidi Radiation oncologist Endocrine therapy in breast cancer Endocrine therapy for hormone receptor positive early stage breast cancer in premenopausal women Endocrine therapy for hormone receptor positive early stage breast cancer in postmenopausal women Endocrine therapy in metastatic breast cancer Endocrine therapy for hormone receptor positive early stage breast cancer in premenopausal Choice of agent/method Over time, surgical and radiotherapeutic methods of endocrine therapy have been gradually replaced with pharmacologic methods, including blockade of the ER (eg, tamoxifen), suppression of estrogen synthesis by luteinizing hormone-releasing hormone (LHRH) agonists (eg, goserelin) Aromatase inhibitors are generally not used in premenopausal women. The reduced feedback of estrogen to the hypothalamus and pituitary increases gonadotropin secretion, which stimulates the ovary, leading to an increase in androgen substrate and aromatase Sequential administration of AIs may be considered for younger women who become menopausal following adjuvant chemotherapy and tamoxifen chemotherapy-induced amenorrhea may not be permanent in these women. Furthermore, concerns have been raised that the use of AIs in this setting may promote recovery of ovarian function if this approach is used, careful monitoring of ovarian function and frequent assay of serum estradiol levels is needed TAMOXIFEN Tamoxifen, a selective estrogen receptor modulator (SERM), inhibits the growth of breast cancer cells by competitive antagonism of estrogen at the ER Some of the most important information regarding the benefits of adjuvant tamoxifen have come from the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Very young women(ie, those under the age of 35) :The EBCTCG analysis included women under the age of 50 and did not stratify results according to age group., On the other hand, the benefit of adjuvant tamoxifen is uncertain in this group. TAMOXIFEN Tamoxifen also decreases the risk of developing a contralateral breast cancer. Duration : Five years of treatment is considered standard regardless of menopausal status. Three published trials directly compared five years of tamoxifen versus a longer treatment duration (10 years or indefinite) . Two of these, a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial and a Scottish trial, raise the possibility that longer treatment might be associated with worse outcomes(node-negative ) Eastern Cooperative Oncology Group (ECOG) trial,: The initial report of this trial suggested that outcomes with tamoxifen treatment beyond five years were not worse, and in fact, for women with ER+ disease, longer treatment was associated with a significantly better relapse-free survival (RFS) and a trend toward longer overall survival (node-positive ) Longer follow-up of the ECOG trial and two other large randomized trials with relatively short follow-up that have reported only in abstract form (the aTTom, and ATLAS trials ), will hopefully clarify these issues. TAMOXIFEN Timing of tamoxifen and chemotherapy : sequential rather than concurrent therapy has been adopted as standard of care when both chemotherapy and tamoxifen are administered Timing of tamoxifen and RT : some clinical studies suggest the possibility of increased breast and pulmonary fibrosis with concurrent treatment Two cohorts within the treated group were identified retrospectively because RT was allowed either before adjuvant therapy: these data support the view that sequencing of tamoxifen and RT does not substantially affect outcomes. However, the only way this question can truly be answered is with a randomized controlled trial. Summary Tamoxifen (20 mg daily) is a standard adjuvant treatment option for premenopausal women with ER+ early breast cancer. Until more data become available, the recommended duration of therapy is five years. If combined chemotherapy and tamoxifen are given, sequential rather than concurrent administration is recommended OVARIAN FUNCTION SUPPRESSION (OFS) Methods : Surgical oophorectomy , Radiation-induced ovarian ablation (4.5 Gy in one fraction, to 10 to 20 Gy in five to six fractions), pharmacologic methods Benefits of OFS in meta-analyses: The addition of an LHRH analog to tamoxifen, chemotherapy, or both led to smaller but more clearly proven reductions in the risk of recurrence (13 percent, p = 0.02) and death (15 percent, p = 0.04) compared to the same therapy without the LHRH analog. Summary these results support the view that endocrine therapy that includes OFS is a reasonable alternative to adjuvant CMF , and possibly AC, FEC, and FAC chemotherapy for premenopausal women with ER+ breast cancer At least in North America, premenopausal women (especially those with node-positive disease) are more likely to be offered chemotherapy plus endocrine therapy (tamoxifen or OFS) rather than OFS with or without tamoxifen. whether combined endocrine therapy that includes OFS provides superior outcomes over tamoxifen alone, particularly in women who remain premenopausal after adjuvant chemotherapy . This question is currently being addressed in the ongoing SOFT trial Endocrine therapy for hormone receptor positive early stage breast cancer in postmenopausal women TAMOXIFEN five years of tamoxifen was associated with a 41 percent relative reduction in the annual risk of relapse and a 34 percent relative reduction in the annual risk of death among all women with ER+ breast cancer Treatment duration : Timing of tamoxifen: The impact of concurrent aromatase inhibitors and RT is unknown Tamoxifen 20 mg daily is a standard adjuvant treatment option for both premenopausal and postmenopausal women with ER+ early breast cancer. Until more data become available, the recommended duration of therapy is five years AROMATASE INHIBITORS AIs , markedly suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, the enzyme responsible for synthesizing estrogens from androgenic substrates In contrast to tamoxifen, these compounds lack partial agonist activity. AIs are generally avoided in premenopausal women. The reduced feedback of estrogen to the hypothalamus and pituitary increases gonadotropin secretion, which stimulates the ovary, leading to an increase in androgen substrate and aromatase Efficacy at least five randomized trials have explored AIs in the adjuvant setting, either as initial therapy, or sequentially after two to three or five years of tamoxifen In the landmark ATAC trial(Anastrozole, Tamoxifen Alone or in Combination) , anastrozole (1 mg daily) was compared to tamoxifen (20 mg daily) alone or the combination for five years in 9366 postmenopausal women with ER+ (or unknown) breast cancer . At a median follow-up of 100 months, compared to tamoxifen alone, anastrozole was associated with the following benefits Since tamoxifen reduces the risk of contralateral tumors by about 50 percent, this finding suggests that anastrozole might prevent 70 to 80 percent of ER+ contralateral tumors No difference in overall survival has emerged, and there is no advantage for combination therapy over tamoxifen alone Similar benefit for letrozole over tamoxifen was noted in the multicenter BIG 1-98 trial AROMATASE INHIBITORS Similar benefit for letrozole over tamoxifen was noted in the multicenter BIG 1-98 trial, in which 8010 postmenopausal women were randomly assigned to tamoxifen or letrozole for five years, or tamoxifen or letrozole for two years, followed by the alternative agent for three years initial letrozole rather than tamoxifen was associated with significantly better event-free survival (EFS, HR 0.82), but not overall survival . The five-year DFS estimates were 84 versus 81 percent, respectively Both anastrozole and letrozole are approved in the United States for initial adjuvant therapy of postmenopausal women with ER+ breast cancer. Sequential tamoxifen and AIs At least seven trials have compared tamoxifen alone to sequential tamoxifen followed by an AI After five years of tamoxifen :The most important trial examining an SAI after five years of tamoxifen is the NCIC MA 17 trial The optimal duration of SAI therapy after five years of tamoxifen is unknown Women who chose letrozole (approximately two-thirds of the cohort) had a significantly better DFS and distant DFS compared to those who did not, Sequential tamoxifen and AIs The benefit of extending adjuvant endocrine therapy beyond five years with an AI was also addressed in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) At a median follow-up of 62 months, the sequential use of anastrozole was associated with a significant 38 percent reduction in the risk of a new or recurrent breast cancer but no overall survival benefit. the optimal duration of AI therapy after five years of tamoxifen remains uncertain After two or three years of tamoxifen : At least four other trials have studied switching to an AI after two to three years of tamoxifen versus continued tamoxifen, all of which show a significant DFS benefit from switching to an AI the latest reports from two of the trials also suggest an overall survival advantage for this approach Letrozole and exemestane are both approved in the United States for this indication. Summary and ASCO recommendation the available data support the benefit of including an AI as a component of adjuvant endocrine therapy in postmenopausal women with ER+ breast cancer. AI is a reasonable alternative to tamoxifen for initial treatment of postmenopausal women with ER+ disease. It is the treatment of choice in a woman with a contraindication to tamoxifen or a desire to avoid the other side effects associated with tamoxifen Postmenopausal women who complete five years of tamoxifen should consider taking an AI for up to five years. Ongoing analyses from the MA17 trial suggest additional benefit gained with each year of letrozole in comparison to placebo Alternatively, postmenopausal women completing two to three years of tamoxifen could consider crossover to an AI, for a total of five years of therapy, It is not known if a longer duration of AI therapy provides further benefit. SUMMARY AND RECOMMENDATIONS five years of anastrozole (1 mg daily) or letrozole (2.5 mg daily) rather than tamoxifen for initial treatment in postmenopausal women with ER+ breast cancer . The role of additional tamoxifen in women who have received an AI for five years is unknown, and we suggest not doing this Endocrine therapy in metastatic breast cancer endocrine therapies are classified: 1-Selective estrogen receptor modulators (ie, tamoxifen and the related agent toremifene) , 2- Steroidal antiestrogens (eg, fulvestrant) , 3- Estrogen-deprivation therapies , 4- Sex steroid therapies, including high-dose estrogen, androgens, 5- and progestins (megestrol, medroxyprogesterone), 6-Sex steroid receptor-independent therapies Endocrine therapy in metastatic breast cancer Over the last 35 years, the selective estrogen receptor modulator (SERM) tamoxifen became the standard of care in much of the Western world for hormone-responsive MBC in both premenopausal and postmenopausal women due to its more favorable safety profile. More recent studies suggest estrogen depletion may be a slightly more effective strategy than tamoxifen, at least for postmenopausal women Selective aromatase inhibitors (SAIs, anastrozole, letrozole, and exemestane, ) are more effective and safer than aminoglutethimide Moreover, randomized trials and a meta-analysis , suggest that SAIs are more effective than tamoxifen for first-line therapy in postmenopausal women whose tumors have not become previously resistant to these drugs Treatment algorithms a trial of endocrine therapy is warranted in a patient with slowly progressive disease, no visceral involvement, and minimal symptoms, even if the breast cancer has low or absent ER expression. Many patients with hormone-responsive MBC undergo sequential endocrine maneuvers for second-line, third-line, and even fourth-line therapy, reserving chemotherapy until all endocrine options have been exhausted Since palliation is the principal goal of therapy for MBC, one can be relatively pragmatic about selection of endocrine agents for individual patients, following certain basic guidelines. Postmenopausal women most clinicians now favor SAIs over tamoxifen as the first choice for advanced disease if a woman has relapsed while receiving adjuvant tamoxifen, if she has not received any adjuvant endocrine treatment, or if she has relapsed more that one year after discontinuing adjuvant tamoxifen or an SAI If she has relapsed during or within 12 months of receiving an SAI in the adjuvant setting, a SERM such as tamoxifen or toremifene, or fulvestrant represent appropriate first-line treatment options The treatment of patients whose tumors are resistant to SAIs has not been adequately studied, and choices are largely based on toxicity, rather than efficacy considerations. Tamoxifen is the most commonly used agent The related agent toremifene appears to have similar efficacy and tolerability as tamoxifen, but it is not effective for tamoxifen-refractory disease For patients with disease progression following an SAI and tamoxifen or toremifene, appropriate agents for third-line endocrine therapy or beyond include fulvestrant, exemestane , megestrol acetate, or estrogen therapy (in carefully selected patients with no history of thrombosis, uncontrolled hypercalcemia or cardiovascular risk factors) Oophorectomy and GnRH agonists are ineffective treatments for postmenopausal women and should not be offered Premenopausal women For premenopausal women, appropriate initial options include tamoxifen (or toremifene) or ovarian function suppression (oophorectomy or a GnRH agonist), or combined ovarian suppression plus tamoxifen. Combined hormone therapy is favored over tamoxifen alone by many clinicians, because it results in higher response rates and a longer time to tumor progression (TTP), and it possibly has a small beneficial impact on overall survival as well For premenopausal women who progress after initial tamoxifen monotherapy, ovarian function suppression is an alternative to chemotherapy An SAI is often introduced immediately following oophorectomy or in conjunction with a GnRH agonist. However, there are no randomized trial data of a GnRH agonist versus a GnRH agonist plus an SAI to support this practice. HER2-positive MBC High expression levels identify patients who might respond to therapies targeting HER2, such as trastuzumab and lapatinib Another option for initial treatment of women with ER/PRpositive, HER2-positive MBC is combined trastuzumab plus hormone therapy rather than hormone therapy alone Hormone withdrawal response Prior to the introduction of tamoxifen, it was observed that 25 to 35 percent of patients treated with high-dose estrogens had a secondary response after the estrogen was stopped at disease progression . This same phenomenon has been observed (although less frequently) upon withdrawal of tamoxifen, progestins, and exemestane Convincing withdrawal responses generally occur in patients who have experienced an initial response to hormone therapy. Although usually short lived, some patients may experience disease stability for more than six months Tamoxifen Tamoxifen is an appropriate first-line agent in premenopausal women who have never received tamoxifen or who relapse at least 12 months after completion of adjuvant tamoxifen. It is also appropriate for postmenopausal women who have a disease relapse during or within 12 months of receiving adjuvant therapy with an SAI. expression of HER2 should not be used to select patients who might be resistant to the beneficial effects of tamoxifen or any other endocrine therapy Tamoxifen withdrawal is an appropriate therapeutic maneuver for patients who progress after achieving an objective response to tamoxifen and whose symptoms are minimal at the time of disease progression. OTHER ANTIESTROGENS Several newer SERMs (raloxifene, toremifene, idoxifene) have been evaluated for endocrine therapy of MBC, both in patients who are resistant to tamoxifen and also as primary therapy. only toremifene is commercially available in the United States and approved for treatment of advanced breast cancer Toremifene Toremifene is a SERM that is 40-fold less estrogenic than tamoxifen, an effect that might be expected to improve its side effect profile Several trials and a meta-analysis directly comparing toremifene versus tamoxifen in patients with untreated MBC have concluded that both agents have comparable activity and a similar toxicity profile toremifene is a reasonable alternative to tamoxifen for endocrine treatment of MBC, although it provides no specific advantage over tamoxifen Like raloxifene and idoxifene, toremifene is cross-resistant with tamoxifen and is ineffective as second-line therapy in patients refractory to tamoxifen Pure antiestrogens Fulvestrant (Faslodex®), a "pure" antiestrogen, has a steroid structure that allows it to compete with estrogen for the ER Fulvestrant is also active in women who are refractory to an SAI With respect to first-line endocrine therapy, one trial directly compared fulvestrant versus tamoxifen in 587 women with previously untreated MBC . No significant advantage was shown for fulvestrant in terms of response rates, TTP, or treatment tolerability. No trials have directly compared fulvestrant versus an SAI for first-line therapy. The use of fulvestrant is limited to postmenopausal women A second orally active pure antiestrogen, EM-800, is also active in patients with tamoxifen-resistant breast cancer . EM-800 is not commercially available in the United States. Ovarian ablation/suppression plus tamoxifen Combined therapy with tamoxifen and ovarian ablation/suppression is favored over either approach alone for premenopausal women by many clinicians, because it results in higher response rates, a longer TTP, and possibly has a small beneficial impact on overall survival as well Combined therapy is not necessarily associated with worse side effects a combination of oophorectomy or a GnRH agonist plus tamoxifen as first-line endocrine therapy could be recommended to premenopausal women with MBC who have either never received adjuvant tamoxifen or relapsed more than 12 months after completion of such therapy. since the overall survival gains from combination therapy are small, it is also reasonable to offer patients sequential treatment with tamoxifen initially, followed by either a GnRH agonist or oophorectomy at the time of disease progression. Third-line treatments for premenopausal women with MBC resistant to tamoxifen and oophorectomy or a GnRH agonist include an SAI or fulvestrant (for women who have become menopausal) AROMATASE INHIBITORS IN POSTMENOPAUSAL WOMEN Aminoglutethimide; The benefit of aromatase inhibition for advanced breast cancer was first recognized in patients who received high doses of aminoglutethimide Anastrozole: Anastrozole was the first SAI to be approved in both North America and Europe. Letrozole:Letrozole is a more potent suppressor of aromatase activity than is anastrozole Whether letrozole is superior to anastrozole is unclear. Although from a pharmacokinetic standpoint, letrozole is a more effective aromatase inhibitor AROMATASE INHIBITORS IN POSTMENOPAUSAL WOMEN Vorozole:Vorozole is another third-generation nonsteroidal AI that is not commercially available in the United States There are no trials of vorozole in the setting of first-line therapy. Exemestane and formestane :Steroidal aromatase inhibitors such as exemestane (Aromasin®) and formestane (Lentaron®, available outside of the United States) are androgenic steroids that are resistant to the action of aromatase A response to exemestane can be observed in patients who never responded to tamoxifen (primary tamoxifen resistance) as well as in those who have failed other nonsteroidal aromatase inhibitors such as anastrozole and letrozole Fadrozole”: Like formestane, fadrozole is a second generation , It is effective in patients with tamoxifen-refractory advanced breast cancer, and at least two trials suggest similar efficacy as tamoxifen for first line therapy Summary Several trials and a meta-analysis demonstrate that the SAIs are slightly more effective than other endocrine agents, including tamoxifen, for treatment of hormone sensitive MBC in terms of response rate, delay of disease progression, and even prolongation of survival unless a patient is refractory to SAIs (ie, relapses while receiving an SAI in the adjuvant setting), an SAI (anastrozole, letrozole, or exemestane) should be considered as superior to tamoxifen for first line treatment of postmenopausal women with hormone receptor-positive MBC. ‘/ SEX STEROID HORMONES Patients who have low volume disease that is restricted to bone or soft tissue, few disease-related symptoms, and a history of a response to either tamoxifen or an SAI (or both) may be considered candidates for third or fourth-line endocrine therapy using progestins, androgens, or estrogens Progestins:Megestrol acetate and medroxyprogesterone acetate are progestational agents with significant activity in advanced breast cancer Androgens :Androgens, including testosterone, fluoxymesterone, and the less virilizing agent testolactone, are rarely used to treat MBC Estrogens:Before the advent of contemporary endocrine therapy options, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen, this approach is ineffective before the menopause Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to high dose estrogens RECOMMENDATIONS (Postmenopausal women with ER and/or PR-positive MBC) For postmenopausal women who have not received adjuvant therapy with a SAI or whose disease relapses longer than 12 months after finishing adjuvant SAI, we recommend a SAI rather than tamoxifen as the first choice for advanced disease If disease relapse has occurred within 12 months of receiving an adjuvant SAI, we suggest initiating therapy with tamoxifen rather than an SAI , An acceptable alternative to tamoxifen in this setting is fulvestrant For patients with disease progression following tamoxifen and an SAI, appropriate agents for third-line hormone therapy include fulvestrant or an alternative class of SAIs (eg, if a triazole such as letrozole or anastrozole was used initially, one might try a steroidal agent such as exemestane and vice versa). Options for fourth line therapy and beyond include megestrol acetate or estrogen therapy in carefully selected patients (no history of thrombosis, uncontrolled hypercalcemia or cardiovascular risk factors). Premenopausal women with ER and/or PR-positive MBC For premenopausal women who have never received adjuvant tamoxifen or who relapsed more than 12 months after completion of such therapy, we suggest a combination of a GnRH agonist and tamoxifen as first-line therapy an acceptable alternative approach, particularly for asymptomatic women with slowly progressive disease, is sequential treatment (tamoxifen followed by either a GnRH analog or oophorectomy at the time of progression For women who relapse within 12 months of adjuvant tamoxifen, we recommend ovarian ablation or suppression as initial endocrine treatment For premenopausal women who progress after ovarian ablation/suppression and tamoxifen, options for sequential endocrine treatment include an SAI or fulvestrant (if the woman has become menopausal) or megestrol acetate HER2-overexpressing, ER/PRpositive MBC For women whose breast cancers coexpress HER2 and hormone receptors we suggest trastuzumab plus hormone therapy rather than hormone therapy alone Initiation of trastuzumab may be delayed if the patient does not wish to undergo IV therapy, particularly if the pace of disease growth is slow and there are no rapidly progressing liver or lung metastases.