Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

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1 The Oncologist Breast Cancer What Is the Role of Ovarian Ablation in the Management of Primary and Metastatic Breast Cancer Today? TATIANA M. PROWELL, NANCY E. DAVIDSON Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA Key Words. Ovarian ablation. Ovarian suppression Breast cancer Premenopausal Hormone-receptor positive Adjuvant Metastatic Review LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the pros and cons of various methods of ovarian ablation, including oophorectomy, radiation therapy, and luteinizing hormone releasing hormone (LHRH) analogues. 2. Recall the frequency of chemotherapy-related amenorrhea with commonly used regimens in adjuvant breast cancer treatment. 3. Discuss the evidence supporting the use of ovarian ablation in premenopausal women with early-stage breast cancer. 4. Discuss the evidence supporting the use of ovarian ablation in premenopausal women with locally advanced and metastatic breast cancer. CME ABSTRACT Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Ovarian ablation has been used for more than a century in the treatment of breast cancer. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be accomplished medically using luteinizing hormone releasing hormone (LHRH) analogues. In addition, cytotoxic chemotherapy unpredictably produces amenorrhea and primary ovarian failure in 10%-95% of premenopausal women as a function of patient age, cumulative dose, and the specific agents used. In the metastatic setting, ovarian ablation and tamoxifen monotherapies produce comparable outcomes and may be more effective when used together. While many early adjuvant trials of ovarian ablation were methodologically flawed, a more recent meta-analysis by the Early Breast Cancer Trialists Collaborative Group of 12 properly designed randomized trials found significantly greater disease-free and overall survival rates for women under the age of 50, regardless of nodal status, receiving ovarian ablation as a single adjuvant therapy. Several important issues regarding the role of ovarian ablation in the treatment of breast cancer remain unresolved. Data suggest that ovarian ablation followed by some years of tamoxifen produces similar Correspondence: Nancy E. Davidson, M.D., The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 409, Baltimore, Maryland , USA. Telephone: ; Fax: ; davidna@jhmi.edu Received November 10, 2003; accepted for publication April 22, AlphaMed Press /2004/$12.00/0 The Oncologist 2004;9:

2 Prowell, Davidson 508 results to those seen with adjuvant chemotherapy in women with hormone-receptor positive breast cancer; however, the value of combining these modalities is still unclear. Other areas of ongoing investigation include the appropriate duration of therapy with LHRH analogues in the adjuvant setting, the long-term sequelae of ovarian suppression among young breast cancer survivors, and refinement of the population most likely to benefit from ovarian ablation or suppression. The Oncologist 2004;9: INTRODUCTION Ovarian ablation was the original systemic therapy for breast cancer and has been in use for more than a hundred years, producing responses in approximately 30% of unselected women with metastatic breast cancer [1, 2], and in as many as 80% of women with steroid hormone receptor-positive (HR + ) breast cancer [3, 4]. In premenopausal women, the ovaries are the predominant source of estrogen synthesis, with a lesser amount produced by peripheral aromatization of androgens. Thus, oophorectomy and ovarian irradiation have historically been used to achieve the goal of ovarian ablation. More recently, luteinizing hormone releasing hormone (LHRH) analogues, which act on the hypothalamic-pituitaryovarian axis to suppress circulating estrogens to postmenopausal levels, have largely supplanted surgical and radiation-based approaches because of less morbidity and a lower likelihood of permanent amenorrhea, with the potential for restoration of fertility. For the purposes of clarity, this review uses the phrase ovarian ablation/suppression (OA/OS) to refer to the general topic of induction of ovarian failure without regard to technique used. The term ovarian ablation refers specifically to oophorectomy or ovarian irradiation. The term ovarian suppression indicates the use of LHRH analogues. SURGICAL OOPHORECTOMY The first report of surgical oophorectomy for the treatment of advanced breast cancer was published by Dr. George Beatson, a Scottish surgeon, in Dr. Beatson saw a young lactating woman who was found to have advanced breast cancer following excision of a large breast mass. He observed tumor regression after removing both her ovaries, and the patient ultimately survived for 4 more years prior to her death from recurrent disease [5]. His results were subsequently reproduced in other women by both Beatson himself, as well as by Lett, who published a series of 99 patients, a quarter of whom had responded to oophorectomy [6]. Although oophorectomy reliably and promptly reduces circulating estrogens to postmenopausal levels in nearly 100% of women, it may require hospitalization and carries potential operative and anesthesia-related morbidity and mortality. Perioperative mortality rates were as high as 5% in some early studies of women with advanced disease [7], though modern surgical practices are associated with considerably less risk. Furthermore, oophorectomy irreversibly induces premature menopause with sequelae including osteoporosis and an increased risk of coronary artery disease, as well as permanent loss of fertility [8]. Surgical castration does have the advantage of simultaneously reducing ovarian cancer risk, which is of particular benefit in women predisposed to the disease. It is also the most cost-effective method of ovarian ablation, which is particularly important in developing countries where resources are limited. OVARIAN IRRADIATION Radiotherapy was first described as a treatment for breast cancer in the adjuvant setting more than half a century ago [9]. Trials evaluating radiotherapy for ovarian ablation have used doses ranging from a single 450 cgy fraction up to 1,000-2,000 cgy divided in five or six fractions [10, 11]. Ovarian irradiation can be easily and inexpensively performed in the outpatient setting, but the efficacy of the procedure is dose- and age-dependent. Standard techniques for targeting the ovaries do not consistently produce a fall in circulating estrogens to postmenopausal levels. One group reported resumption of menses in 13% of women following ovarian irradiation [12], and in younger women, the failure rate may be as high as 35% [13]. Furthermore, the rate of estrogen decline is much slower than that seen with oophorectomy [14]. Finally, concerns about the potential long-term toxicities of pelvic irradiation have limited enthusiasm for this approach in the U.S., although it remains in use in Canada and Western Europe [7]. MEDICAL OVARIAN SUPPRESSION Chemical suppression of ovarian estrogen production can be accomplished via the administration of LHRH analogues, or as a consequence of systemic cytotoxic chemotherapy with resultant primary ovarian failure. Ovarian estrogen production is controlled by the hypothalamic-pituitary-ovarian axis. The hypothalamus releases LHRH in a pulsatile fashion under normal physiologic conditions. LHRH regulates pituitary release of gonadotropins, which in turn stimulate ovarian estrogen production. LHRH analogues have higher binding affinities to pituitary gonadotropin-releasing hormone (GnRH) receptors and greater resistance to degradation than endogenous LHRH. Their chronic administration causes permanent internalization

3 509 Role of Ovarian Ablation in Breast Cancer of pituitary GnRH receptors, thus rendering the gonadotropic cells refractory to endogenous LHRH. LHRH agonists thus cause an initial surge in gonadotropins and estrogen levels, which is thought to be responsible for the tumor flare phenomenon [15], followed by a decline in circulating estrogens to postmenopausal levels within 2-3 weeks of continued use [16]. Examples of LHRH analogues include goserelin (Zoladex ; AstraZeneca Pharmaceuticals; Wilmington, DE), triptorelin, and leuprolide, of which only goserelin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of premenopausal women with advanced breast cancer. Goserelin is generally administered monthly as a subcutaneous implant placed in the upper abdominal wall. Undesired effects of goserelin include menopausal symptoms, injection site reactions, tumor flare, and osteoporosis. The major advantage of LHRH agonists is their potential reversibility, which may help to limit the undesirable longterm sequelae of premature menopause, such as osteoporosis and premature coronary artery disease, and is also of concern to young women desiring preservation of future fertility. It is important to note that return of menses does not ensure restoration of fertility, however [17]. The main disadvantage of the LHRH agonists is a concern that the benefits of ovarian suppression will be lost upon cessation of therapy. Furthermore, there is a theoretical risk of stimulating latent tumor growth with rapidly rising estrogen levels following drug withdrawal [14]. Chemotherapy for breast cancer unpredictably induces amenorrhea and ovarian failure via toxic effects on the ovary in a drug-, dose-, and patient age-dependent fashion. Chemotherapy-related amenorrhea (CRA), primarily due to alkylating agents, on average, affects 68% of women treated with cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy, occurring in 10%-33% of women after a single cycle, 33%-81% after six cycles, and 61%-95% after 12 cycles [18, 19]. Standard doxorubicin/cyclophosphamide (AC) chemotherapy produces somewhat lower rates of amenorrhea, on average, affecting 43% of women, again in a dose- and age-dependent nature [20]. Addition of a taxane to the regimen appears to increase the likelihood of developing amenorrhea. One study found that 75% of women (and 60% of women under the age of 45) treated with four cycles of standard AC chemotherapy followed by paclitaxel experienced CRA [21]. On average, as many as 40% of women under the age of 40 and 90% of women over the age of 40 become irreversibly menopausal due to primary ovarian failure after receiving cytotoxic chemotherapy for breast cancer [19]. Some trials have found, retrospectively, that CRA is associated with a lower recurrence rate and improved survival [22, 23]; however, this has not been confirmed in all studies and is currently a topic of ongoing investigation. COMPARISON OF EFFICACY OF APPROACHES TO OA/OS The relative efficacies of oophorectomy, ovarian irradiation, and medical ovarian suppression have, unfortunately, never been studied in large randomized clinical trials. Oophorectomy and ovarian irradiation have generally been regarded as equally effective based on indirect comparisons, including in the Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis that combined these patient groups. This assumption may be problematic when extrapolated to the adjuvant setting because of the higher failure rate of ovarian irradiation versus oophorectomy. Limited data from two trials performed in women with metastatic breast cancer comparing LHRH analogues to surgical or radiation-induced ovarian failure suggest that LHRH analogues have similar efficacy to these other treatment modalities. In the first trial, premenopausal women with estrogen-receptor-positive (ER + ) metastatic breast cancer were randomized to receive either goserelin or oophorectomy. No significant differences in failure-free or overall survival rates were seen; however, the trial was closed because of low accrual and, thus, may have been underpowered to detect a subtle difference between the groups [24]. A second trial, which randomized premenopausal women with metastatic ER + or ER status unknown breast cancer in a 2 2 factorial design to oophorectomy or ovarian irradiation (OA) with or without tamoxifen versus goserelin with or without tamoxifen, reported a nonsignificant trend toward longer survival in the oophorectomy arm. Although the majority of patients were ER +, the receptor status of one-third of the participants was unknown, with a higher percentage of women of unknown receptor status in the oophorectomy group, which may have confounded the results. Unfortunately, this trial was also closed early due to poor accrual and was, therefore, underpowered as well [25]. Extrapolation of these limited data to women with earlystage breast cancer is problematic because the optimal duration of ovarian suppression in the adjuvant setting has not been established. Trials of adjuvant ovarian suppression have generally used either 2 [23] or 3 [26] years of treatment with an LHRH analogue, which produces comparable, and possibly even superior, outcomes to those obtained with CMF polychemotherapy in premenopausal HR + patients. The greater reversibility of medical castration with LHRH analogues is likely to impact both efficacy and long-term sequelae when compared with other methods of ovarian ablation. OA/OS AS TREATMENT FOR METASTATIC BREAST CANCER Ovarian ablation has long been established as an effective therapy for premenopausal women with metastatic breast

4 Prowell, Davidson 510 cancer, with response rates ranging from 14%-70% in various studies [27]. Both the presence and degree of HR expression are strongly predictive of response to hormonal manipulation, with responses seen in approximately 60% of women having both ER + and progesterone-receptor positive (PgR + ) tumors, versus 30% in patients with either ER + or PgR + status alone [28]. Fewer than 10% of women with receptor negative (ER /PgR ) disease respond to endocrine therapies [29]. Given the goal of palliation and the high likelihood of response to endocrine therapies, hormonal manipulation is often preferable to chemotherapy for first-line treatment of premenopausal women with metastatic HR + breast cancer, especially those with clinical features known to correlate with response to endocrine therapy, such as a long relapse-free interval and nonvisceral metastases [30, 31]. Tamoxifen Versus OA/OS in the Metastatic Setting After the development of tamoxifen in the 1970s, it was often favored over surgical or radiation-induced ovarian ablation in premenopausal women with metastatic disease because of the ease of its oral administration and a relatively low incidence of side effects [32]. Following the introduction of goserelin, a number of phase II trials of the monthly injections were conducted in premenopausal and perimenopausal women with advanced breast cancer. A meta-analysis of these trials containing more than 200 evaluable patients reported a median survival of 26.5 months, an overall response rate of 36% (44% in ER + patients), and a median duration of response of 44 weeks [33, 34], which were comparable to the outcomes historically obtained with oophorectomy in similar patient populations. A subsequent randomized trial comparing monthly goserelin to oophorectomy in premenopausal women with metastatic breast cancer again lacked statistical power but detected no significant difference in failure-free or overall survival rates between the two approaches [24]. Several randomized trials in the past two decades have compared tamoxifen to OA as first-line hormonal therapy for premenopausal women with metastatic breast cancer. While these trials were generally small, they suggested that tamoxifen and OA produced similar outcomes in the metastatic setting [1, 35, 36]. These trials are summarized in Table 1. A subsequent meta-analysis, performed in 1997, of more than 200 evaluable patients, found no significant difference in overall response rate, disease progression, or mortality between the two modalities [37]. The authors of that study did suggest that tamoxifen might be used first if sequential hormonal therapy was planned, both because response to tamoxifen was significantly predictive of response to OA and because there was a nonsignificant trend toward a higher response rate in second-line treatment when OA was used after tamoxifen [37]. In conclusion, we lack appropriately powered trials comparing tamoxifen to OA/OS; however, limited data indicate comparable results using either as monotherapy in premenopausal women with HR + metastatic breast cancer. Tamoxifen in Combination with OA/OS in the Metastatic Setting Three published randomized trials have compared combined hormonal therapy using tamoxifen and an LHRH analogue to endocrine monotherapy (the LHRH analogue in all but one of the trials) in premenopausal women with advanced breast cancer [25, 38, 39]. These trials are summarized in Table 2. A meta-analysis of these trials has been performed, and it suggests that the combination is superior to monotherapy for all end points, with significant benefits in mortality rate (22% relative reduction), rate of disease progression (30% relative reduction), rate of objective clinical response (39% versus 30%), and duration of response (19 months versus 11 months) [40]. Only one trial included in the meta-analysis, the international study, was designed to compare first-line combination endocrine therapy to sequential therapy, using goserelin with the addition of tamoxifen at the time of progression. Although half the participants initially assigned to goserelin monotherapy developed rapidly progressive disease and never received tamoxifen, the patients who did receive tamoxifen after progressing on goserelin had a similar outcome to women assigned combination therapy at the outset [38]. In summary, the combination of an LHRH analogue and tamoxifen may be superior to endocrine monotherapy Table 1. Randomized trials of ovarian ablation versus tamoxifen in locally advanced and metastatic breast cancer Study Patients n Treatment Outcome Ingle et al. (1986) [1] HR + or HR? 53 OA (surg) versus T No difference Buchanan et al. (1986) [35] Any HR 122 OA (surg) versus T No difference Sawka et al. (1997) [36] HR + or HR? 39 OA (XRT/surg) versus T No difference; closed due to poor accrual Abbreviations: HR? = hormone receptor status unknown; surg = oophorectomy; T = tamoxifen; XRT = ovarian irradiation.

5 511 Role of Ovarian Ablation in Breast Cancer Table 2. Randomized trials of tamoxifen with or without OA/OS in locally advanced and metastatic breast cancer Study Patients n Treatment Outcome Boccardo et al. (1988) [25] HR + or HR? 48 OA (XRT/surg) versus No difference OA + T versus Z versus Z + T Jonat et al. (1995) [38] Any HR 318 Z + T versus T No difference in overall survival; PFS better with Z + T Klijn et al. (1988) [39] HR + or HR? 161 B versus T versus B + T PFS and overall survival better with B + T Abbreviations: B = buserelin; HR? = hormone receptor status unknown; PFS = progression-free survival; surg = oophorectomy; T = tamoxifen; XRT = ovarian irradiation; Z = goserelin. in premenopausal HR + women with advanced breast cancer and can be considered for first-line therapy. For women who receive either agent alone, crossover to the alternate therapy should be considered at the time of progression, before introduction of chemotherapy, except in women who have rapidly progressive or visceral disease [32]. EVIDENCE SUPPORTING THE ROLE OF OA IN PREMENOPAUSAL EARLY-STAGE BREAST CANCER PATIENTS Approximately 25% of breast cancer patients are premenopausal at the time of diagnosis [41]; of these, 60% have HR + tumors [42]. These women are regarded as potentially appropriate for hormonal manipulation. By far the most valuable assessment of the benefit of ovarian ablation in the adjuvant treatment of premenopausal breast cancer is the EBCTCG meta-analysis [10]. This overview of 12 randomized controlled trials enrolling a total of 2,102 patients reported that women under the age of 50 with early invasive breast cancer who underwent oophorectomy or ovarian irradiation, experienced approximately a 25% relative reduction in the risks of recurrence and mortality at 15 years of follow-up compared with those receiving no adjuvant therapy. This magnitude of benefit is similar to that achieved with adjuvant chemotherapy by indirect comparison and was seen regardless of nodal status [10]. Unfortunately, only four of the trials included in the EBCTCG meta-analysis, those in which chemotherapy was also used, collected data on ER status. There was a trend toward a greater benefit from ovarian ablation in the subset of women with ER + tumors, but this subgroup analysis is limited by the fact that receptor status information was unavailable for the majority of participants. Of note, ovarian ablation had a much smaller impact on outcome for women who also received chemotherapy, with nonstatistically significant lower relative risks for recurrence and mortality, of 10% and 8%, respectively. It was suggested that the smaller effect of ovarian ablation in patients receiving chemotherapy may be a consequence of chemotherapy-induced primary ovarian failure, although these data were neither specifically collected nor analyzed in the meta-analysis [10]. OA/OS IN ADJUVANT BREAST CANCER TREATMENT The EBCTCG overview reported that ovarian ablation confers a significant improvement in both disease-free and overall survival rates for women under the age of 50 with early-stage breast cancer. At 15 years of follow-up, the absolute benefit, both in terms of risk of recurrence and overall survival, was 6% ± 2% for ovarian ablation versus observation [10]. The fact that HR status was not routinely assessed when these trials were initiated suggests that the actual benefit of OA in HR + patients is likely to have been underestimated by the overview s results. However, in 2004, observation is seldom recommended to a premenopausal woman with early-stage HR + invasive breast cancer, and thus, the more germane question is: Is the benefit of OA in lieu of or in addition to that of chemotherapy and/or tamoxifen? OA/OS Versus Chemotherapy in the Adjuvant Setting The EBCTCG meta-analyses suggested, by indirect comparison, that OA and chemotherapy produce similar outcomes for premenopausal women with early-stage HR + breast cancer [10, 43]. The Oxford overview reported a 23.5% lower annual risk of recurrence and a 15.3% lower annual risk of death with use of polychemotherapy [43]. Anthracycline-containing regimens produce superior results, lowering annual risks of recurrence and death by 12% and 11%, respectively, relative to nonanthracycline-containing regimens [43]. By comparison, OA was reported to result in 25% lower risks of both recurrence and death at 15 years of follow-up [10]. As reviewed in further detail below, several randomized trials have subsequently compared the two approaches directly, using CMF versus various means of inducing ovarian failure in premenopausal women, and have generally failed to demonstrate any statistically significant differences in disease-free

6 Prowell, Davidson 512 Table 3. Randomized trials of adjuvant chemotherapy versus OA/OS Study Patients n Treatment Outcome Jonat et al. (2002) [23] N + 1,640 CMF 6 versus Z 2 years No difference in HR + ; CMF better in HR Scottish Cancer Trial N CMF 6-8 versus OA (XRT/surg) No difference Breast Group (1993) [44] Schmid et al. (2001) [45] N +, HR CMF 6 versus leuprorelin No difference acetate 2 years Ejlertsen et al. (1999) [46] Stage II, HR CMF 9 versus OA (XRT) No difference Abbreviations: surg = oophorectomy; XRT = ovarian irradiation; Z = goserelin. survival (DFS) or overall survival rates. Unfortunately, extrapolation of this conclusion to current practice is limited by the fact that none of the trials used regimens containing anthracyclines or taxanes, which currently represent the standard of care. These four trials are summarized in Table 3 [23, 44-46]. The Scottish trial randomized 332 women with nodepositive (N + ) breast cancer, irrespective of receptor status, to OA (oophorectomy or ovarian irradiation) versus six to eight cycles of CMF chemotherapy. At a median follow-up of 6 years, there was no difference in event-free or overall survival rates; however, a subgroup analysis noted that ER + women had a trend toward longer survival with OA, while ER women had a trend toward a better outcome with chemotherapy [44]. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial randomized 1,640 women with N + breast cancer, of any receptor status, to ovarian suppression (2 years of goserelin) versus six cycles of CMF. In ER + patients (approximately 75% of participants), there was no significant difference in DFS or overall survival rate at a median follow-up of 6 years; however, in the subset of women who were ER, chemotherapy was superior in terms of both DFS and overall survival. Of note, while both treatments were associated with amenorrhea and loss of bone density, patients randomized to receive goserelin were less likely to remain amenorrheic after 3 years (approximately 35% versus 80%) and had more recovery of bone density than patients who had received chemotherapy [23]. Taken in aggregate, these trials in unselected premenopausal women with early-stage breast cancer fail to demonstrate the superiority of either chemotherapy or OA/OS; however, all these trials used chemotherapy regimens that would be considered suboptimal by current standards. In light of this and the fact that subset analyses nonetheless consistently favor chemotherapy in ER patients, ovarian ablation should not be regarded as a standard treatment option for women with ER tumors. Similarly, given that goserelin appears to produce comparable, and potentially superior, results in ER + women relative to chemotherapy, ovarian suppression may be the preferred approach for women with ER + disease for whom preservation of fertility is a priority [20]. OA/OS Combined with Chemotherapy in the Adjuvant Setting Breast cancer that develops in young women is more likely to be poorly differentiated, with a higher proliferation index, and as such would be expected to carry a worse prognosis, a finding that has been confirmed in many population-based studies and cancer registries [47-52]. Although chemotherapy significantly improves both DFS and overall survival rates among premenopausal patients [43], young patients continue to have inferior outcomes when compared with postmenopausal patients. Five randomized trials designed to assess the benefit of combining OA/OS with chemotherapy have been reported to date. They failed to demonstrate a definite benefit in terms of either DFS or overall survival rate with the routine addition of OA/OS to chemotherapy. The trials were not necessarily restricted to women with ER + disease, and retrospective subset analyses suggest that younger ER + women, particularly those who fail to develop chemotherapy-related amenorrhea, may benefit from the addition of goserelin. Table 4 contains a summary of these trials, three of which are discussed in greater detail below [49, 53-59]. The Eastern Cooperative Oncology Group intergroup trial INT0101 randomized 1,504 women with HR +, N + breast cancer to six cycles of cyclophosphamide/doxorubicin/5-fluorouracil (CAF) chemotherapy, CAF followed by 5 years of goserelin (CAFZ), or CAF followed by 5 years of goserelin and tamoxifen (CAFZT). There was no significant difference in overall survival, although the women who received tamoxifen in addition to CAFZ had a significantly higher DFS rate. Unfortunately, a CAFT arm was not included in this trial because tamoxifen was not a standard therapy for premenopausal, HR + women at the

7 513 Role of Ovarian Ablation in Breast Cancer Table 4. Randomized trials of adjuvant chemotherapy with or without OA/OS Study Patients n Treatment Outcome IBCSG (2001) [56] N +, HR OA + T versus OA + T + AC/EC No difference Arriagada et al. (2003) [57] Stage I/II 926 Chemotherapy (any) versus No difference Chemotherapy (any) + OA (XRT/medical) Davidson et al. (2003) [58] N +, HR + 1,504 CAF 6 versus CAF 6, No difference in overall survival; Z 5 years versus DFS better with T added CAF 6, Z + T 5 years Castiglione-Gertsch et al. Stage I/II, N 1,063 CMF 6 versus Z 2 years No difference in ER + ; CMF + Z (2003) [59] versus CMF 6, Z 1.5 years better in ER Abbreviations: EC = epirubicin/cyclophosphamide; T = tamoxifen; XRT = ovarian irradiation; Z = goserelin. time of trial initiation. Of note, a subgroup analysis suggested that the youngest women (under age 40) had a trend toward a greater benefit from the addition of goserelin to CAF. The investigators hypothesize that this may be because the youngest patients are less likely to experience chemotherapy-related amenorrhea, a feature that has been correlated with better outcomes in some prior retrospective analyses [22, 58]. The International Breast Cancer Study Group (IBCSG) VIII trial enrolled 1,063 women with N, mostly ER + breast cancer and randomized them to receive six cycles of oral CMF chemotherapy followed by goserelin for 1.5 years, CMF alone, or goserelin alone for 2 years. There was no difference between CMF and goserelin for HR + women. Among HR women, there were significantly fewer first events with the combined chemohormonal therapy [59]. Interpretation of these results is difficult due to the original 2 2 design, which included a no treatment arm, and the fact that the subgroup analysis by HR status was done retrospectively. The Zoladex in Premenopausal Patients (ZIPP) trial enrolled a heterogeneous group of 2,648 women with stage I or II breast cancer, 56% of whom were ER +, 42% of whom were N +, and 43% of whom received adjuvant chemotherapy. They were randomized in a 2 2 factorial design comparing 2 years each of tamoxifen, goserelin, the combination, or no hormonal manipulation. There was no significant difference in overall survival at a median follow-up of 4 years, although there was a significant 25% greater DFS rate in the women receiving goserelin. In subgroup analysis, this benefit was greatest in ER + women. Women also receiving tamoxifen or chemotherapy had a slightly better DFS rate with the addition of goserelin [55]. Taken in aggregate, the combination of OA/OS with adjuvant chemotherapy does not appear to improve overall survival over chemotherapy alone for premenopausal women with early-stage breast cancer. Women with HR tumors appear to derive little benefit from OA/OS in the adjuvant setting. Subgroup analyses suggest that younger women with HR + disease, particularly those who fail to develop chemotherapy-related amenorrhea, may have a greater DFS rate with the addition of goserelin following standard adjuvant chemotherapy. Appropriately powered randomized prospective trials are needed to clarify what role, if any, ovarian suppression should play in this subset of patients. OA/OS Combined with Tamoxifen in the Adjuvant Setting Results of the EBCTCG overview published in 1998 revealed a significant improvement in outcome for women under the age of 50 with HR + breast cancer who were treated with tamoxifen, with a 45% relative reduction in recurrence and a 32% relative reduction in mortality [60]. This benefit was seen regardless of use of adjuvant chemotherapy and confirmed tamoxifen s role in the adjuvant treatment of HR + premenopausal breast cancer. Because this is a relatively recent change in practice, few trials have compared tamoxifen to goserelin as monotherapy or assessed their efficacy as combination therapy. To date, only two trials have examined OA/OS with or without tamoxifen in the absence of chemotherapy. The Southeast Asian trial enrolled 709 women with early-stage breast cancer of any receptor status and randomized them at mastectomy to receive either immediate oophorectomy plus tamoxifen or observation until time of relapse. Among the ER + patients, there was a statistically significant higher 5-year DFS rate, 75% versus 58%, as well as a trend toward a higher overall survival rate with the active therapy arm relative to observation alone [61]. This trial strongly supports the use of endocrine therapy in premenopausal women with early-stage HR + breast cancer. The INT 0142 trial enrolled 350 women with N, <3 cm HR + breast cancer to receive either tamoxifen for 5 years or tamoxifen with any form of OA/OS. Unfortunately the trial was closed prematurely because of poor accrual and lacks statistical

8 Prowell, Davidson 514 power. At the 5-year follow-up, there was no difference in DFS or overall survival rates between groups [62]. A number of trials have evaluated combination endocrine therapy (tamoxifen plus OA/OS) versus chemotherapy in HR + premenopausal women. These include the Gruppo di Ricerca in Oncologia Clinica e Terapie Associate (GROCTA) trial, the French Adjuvant Study Group (FASG) 06 trial, and another French trial [63-65]. Although all were relatively small trials, none detected a significant difference between the treatment strategies in terms of either DFS or overall survival. In contrast, the larger Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial, which randomized 1,045 premenopausal women with stage I-II HR + breast cancer to receive either six cycles of intravenous CMF chemotherapy or 5 years of tamoxifen plus 3 years of goserelin reported a significantly greater DFS rate, but not overall survival rate, favoring the combined endocrine therapy [26]. Unfortunately, none of these trials included tamoxifen in the chemotherapy arms, as currently represents the standard of care for premenopausal, HR + patients. Furthermore, as discussed elsewhere, the chemotherapy regimens used would be considered suboptimal treatment by current standards, as none contained taxanes and several did not contain anthracyclines [43]. As a result, the trials are difficult to translate into present clinical practice. These trials are summarized in Table 5. In summary, virtually all premenopausal women with early-stage HR + breast cancer should receive adjuvant endocrine therapy. Combined endocrine therapy appears to be at least as effective as adjuvant CMF chemotherapy in this population. Further prospective trials are needed comparing combined endocrine therapy with tamoxifen monotherapy and with the combination of tamoxifen plus chemotherapy. Recommendations for Adjuvant Endocrine Therapy from Consensus Meetings Two recent conferences released consensus statements on the role of adjuvant endocrine therapy in premenopausal women. The 2000 U.S. NIH Consensus Development Conference on the Adjuvant Therapy for Breast Cancer concluded that standard adjuvant chemotherapy should be recommended for the majority of premenopausal women with early-stage breast cancer. Women with HR + disease should also be given adjuvant hormonal therapy in the form of tamoxifen for 5 years, with consideration of ovarian suppression as an alternative to tamoxifen for selected women. The consensus panel determined that there was insufficient evidence at the time to support addition of ovarian suppression to standard adjuvant chemotherapy followed by 5 years of tamoxifen [66]. In contrast, the 2003 International Conference on the Adjuvant Therapy of Primary Breast Cancer in St. Gallen, Switzerland, emphasized the primary role of endocrine therapy and concluded that combination endocrine therapy with ovarian suppression and tamoxifen is an acceptable alternative to standard adjuvant chemotherapy followed by tamoxifen in premenopausal women with HR + breast cancer [67]. CONCLUSIONS Ovarian ablation has been used for over a century and is most often achieved by oophorectomy. Ovarian suppression with the LHRH analogues has increasingly become a popular choice in the U.S. because of their ease of administration, tolerability, and potential reversibility, which is of particular concern for young premenopausal women with early-stage breast cancer. In the metastatic setting, OA/OS and tamoxifen appear to have similar efficacies as first-line monotherapy for premenopausal women with HR + breast cancer and may be more effective when used in combination. In the adjuvant setting, OA/OS monotherapy results in superior DFS and overall survival rates compared to observation in women with HR + breast cancer, regardless of nodal status. Combined endocrine therapy with OA/OS and tamoxifen yields outcomes comparable to those obtained with adjuvant CMF chemotherapy for premenopausal women with HR + breast cancer. Some subset analyses suggest that young women who fail to develop chemotherapy-related amenorrhea benefit most from the addition of OA/OS. Table 5. Randomized trials of adjuvant chemotherapy versus combined endocrine therapy Study Patients n Treatment Outcome Boccardo et al. (2000) [63] N +, HR CMF 6 versus Z + T 5 years No difference Roche et al. (2000) [64] N +, HR FEC 6 versus triptorelin + T 3 years No difference Roche et al. (1996) [65] N +, HR FAC 6 versus OA (surg/xrt) + T 2 years No difference Jakesz et al. (2002) [26] Stage I/II, HR + 1,045 CMF 6 versus Z 3 years + T 5 years DFS better with Z + T Abbreviations: FEC = fluorouracil/epirubicin/cyclophosphamide; surg = oophorectomy; T = tamoxifen; XRT = ovarian irradiation; Z = goserelin.

9 515 Role of Ovarian Ablation in Breast Cancer Several important issues regarding the role of OA/OS in the treatment of breast cancer remain unresolved. Areas of investigation in ongoing or planned clinical trials include: the value of combining adjuvant chemotherapy, tamoxifen, and LHRH analogues; the appropriate duration of therapy with LHRH analogues in the adjuvant setting; the long-term sequelae of OA/OS among young breast cancer survivors; further refinement of the population most likely to benefit from ovarian ablation or suppression; and the use of LHRH analogues to translate advances with aromatase inhibitors into the treatment of premenopausal breast cancer patients. ACKNOWLEDGMENTS Dr. Prowell is the recipient of an American Society of Clinical Oncology Young Investigator Award and a Pearl M. Stetler Foundation Award. Dr. Davidson is partially funded by an NIH Specialized Program in Research Excellence (SPORE) grant, CA 88843, and the Breast Cancer Research Foundation. REFERENCES 1 Ingle JN, Krook JE, Green SJ et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol 1986;4: Veronesi U, Pizzocaro G, Rossi A. Oophorectomy for advanced carcinoma of the breast. Surg Gynecol Obstet 1975;141: Conte CC, Nemoto T, Rosner D et al. Therapeutic oophorectomy in metastatic breast cancer. Cancer 1989;64: Oriana S, Bohm S, Baeli A et al. Clinical response and survival according to estrogen receptor levels after bilateral ovariectomy in advanced breast cancer. Eur J Surg Oncol 1989;15: Beatson GW. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;2: , Lett H. An analysis of 99 cases of inoperable carcinoma of the breast treated by oophorectomy. Lancet 1905;i: Davidson NE. Ovarian ablation as treatment for young women with breast cancer. J Natl Cancer Inst Monogr 1994;16: Goodwin PJ, Ennis M, Pritchard KI et al. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17: Clarke MJ. Ovarian ablation in breast cancer, 1896 to 1998: milestones along hierarchy of evidence from case report to Cochrane review. BMJ 1998;317: Early Breast Cancer Trialists Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996;348: Lees AW, Giuffre C, Burns PE et al. Oophorectomy versus radiation ablation of ovarian function in patients with metastatic carcinoma of the breast. Surg Gynecol Obstet 1980;151: Nissen-Meyer R. Ovarian suppression and its supplement by additive hormonal treatment. INSERM 1975;55: Leung SF, Tsao SY, Teo PM et al. Ovarian ablation failures by radiation: a comparison of two dose schedules. Br J Radiol 1991;64: Dees EC, Davidson NE. Ovarian ablation as adjuvant therapy for breast cancer. Semin Oncol 2001;28: Limonta P, Montagnani Marelli M, Moretti RM. LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action. Expert Opin Investig Drugs 2001;10: Harvey HA, Lipton A, Max DT et al. Medical castration produced by the GnRH analogue leuprolide to treat metastatic breast cancer. J Clin Oncol 1985;3: Donegal WL. Breast cancer and pregnancy. Obstet Gynecol 1977;50: Reichman BS, Green KB. Breast cancer in young women: effect of chemotherapy on ovarian function, fertility, and birth defects. J Natl Cancer Inst Monogr 1994;16: Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 1996;14: Emens LA, Davidson NE. Adjuvant hormonal therapy for premenopausal women with breast cancer. Clin Cancer Res 2003;9:486S-494S. 21 Ball J. Age-associated incidence of chemotherapy-related amenorrhea (CRA) following adjuvant doxorubicin, cyclophosphamide, and paclitaxel (AC/TAXOL) in early-stage breast cancer. Proc Am Soc Clin Oncol 2001:1810a. 22 Collichio F, Pandya K. Amenorrhea following chemotherapy for breast cancer: effect on disease-free survival. Oncology (Huntingt) 1994;8: Jonat W, Kaufmann M, Sauerbrei W et al. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002;20: Taylor CW, Green S, Dalton WS et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998;16: Boccardo F, Rubagotti A, Perrotta A et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: results of a multicentric Italian study. Ann Oncol 1994;5: Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide,

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11 517 Role of Ovarian Ablation in Breast Cancer 56 International Breast Cancer Study Group. Randomized controlled trial of ovarian function suppression plus tamoxifen versus the same endocrine therapy plus chemotherapy: is chemotherapy necessary for premenopausal women with nodepositive, endocrine-responsive breast cancer? First results of International Breast Cancer Study Group Trial Breast 2001;10: Arriagada R, Le MG, Spielmann M et al. Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Proc Am Soc Clin Oncol 2003;22:14a. 58 Davidson N, O Neill A, Vukov A et al. Chemohormonal therapy in premenopausal node-positive, receptor-positive breast cancer: An Eastern Cooperative Oncology Group phase III intergroup trial (E5188, INT-0101). Proc Am Soc Clin Oncol 2003;22:15a. 59 Castiglione-Gertsch M, O Neill A, Price KN et al. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003;95: Early Breast Cancer Trialists Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351: Love RR, Duc NB, Allred DC et al. Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 2002;20: The Oncologist s editorial office has moved to: AlphaMed Press 318 Blackwell Street, Suite 260 Durham, North Carolina USA Phone: (Eastern time) Fax: Robert N, Wang M, Wood W et al. Phase III comparison of tamoxifen with ovarian ablation in premenopausal women with axillary node negative receptor positive breast cancer <3 cm. Proc Am Soc Clin Oncol 2003;22:16a. 63 Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 2000;18: Roche H, Kerbrat P, Bonneterre J et al. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients with positive hormone-receptor (HR + ) and 1-3 node-positive (N + ) tumor, results of the FASG 06 trial. Proc Am Soc Clin Oncol 2000;19:72a. 65 Roche H, Mihura J, de Lafontan B et al. Castration and tamoxifen versus chemotherapy (FAC) for premenopausal, node and receptor positive breast cancer patients: a randomized trial with a 7 years median follow-up. Proc Am Soc Clin Oncol 1996;15: National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1-3, J Natl Cancer Inst Monogr 2001;30: Goldhirsch A, Wood WC, Gelber RD et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003;21: Please direct all correspondence, including changes of subscriber address, to the Journal s new office effective immediately. Thank you.