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The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-1000
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ABSTRACT |
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 Top ABSTRACT IntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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3
activity [tamoxifen and other selective ER modulators (3)
], or potently down-regulate ER protein [fulvestrant (4)
]. Endocrine therapy is integral to the management of hormone-dependent breast cancers, and the expression of the ER and/or the PR by the tumor is a well-established predictor of response to endocrine therapy (5)
. In the setting of advanced breast cancer, patients with ER+/PR+ tumors have an 80% response rate, whereas those with ER+/PR- and ER-/PR+ tumors have response rates of 25–30% and 40–45%, respectively. The absence of HRs indicates a small (<10%) chance of benefit from endocrine therapy and argues against the use of hormonal manipulation. The ovary is the major site of estrogen production in the premenopausal woman. A smaller amount of estrogen is produced as a result of the aromatase-mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal tissues. In contrast, peripheral aromatization is the primary source of estrogen in postmenopausal women. This major difference in the means of estrogen production mandates distinct strategies for disrupting its production in premenopausal and postmenopausal women with breast cancer. Accordingly, ovarian ablation/suppression is the most effective means of decreasing estrogen production in premenopausal women, whereas aromatase inhibition is emerging as the backbone of hormonal therapy in postmenopausal women.
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Ovarian Ablation |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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; Ref. 7
). By indirect comparison, the efficacy of adjuvant ovarian ablation appears to be similar to that of adjuvant chemotherapy or tamoxifen in women less than 50 years of age (Table 2
; Refs. 7, 8, 9
). It is important to note that this analysis is likely to underestimate the benefit of ovarian ablation due to incomplete data on HR status.
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Strategies for Decreasing Ovarian Estrogen Production |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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Medical castration using LHRH analogues has emerged over the last 20 years as a treatment strategy generally felt to be as effective as surgical or radiation-induced ovarian ablation. These agents include LHRH agonists and antagonists, both of which decrease ovarian estradiol production indirectly by impinging on the hypothalamic-pituitary-ovarian axis (10 , 11) . Normally, the pulsatile release of LHRH by the hypothalamus causes the production of gonadotropins by the pituitary, which then stimulates the release of estradiol by the ovary. LHRH analogues bind to the pituitary LHRH receptors more avidly than LHRH itself. Thus, the chronic administration of LHRH analogues results in the down-regulation of pituitary LHRH receptors, effecting a dramatic suppression of gonadotropin secretion and consequent loss of ovarian steroid production. Although goserelin is the only LHRH agonist approved by the United States Food and Drug Administration for the treatment of metastatic breast cancer in pre- and perimenopausal women, others (leuprolide, triptorelin, and buserelin) are also sometimes used. LHRH antagonists (degarelix, abarelix, ganirelix, and cetrorelix) are investigational drugs that have been tested primarily in prostate cancer but hold promise for breast cancer as well. Whereas no LHRH analogue is currently approved for the adjuvant therapy of breast cancer, the efficacy of goserelin in premenopausal women with metastatic disease and the efficacy of adjuvant surgical ovarian ablation in premenopausal women support testing of their use in the adjuvant setting. The advantage of medical ovarian suppression is that it is a simple outpatient therapy that is completely reversible, thus preserving fertility in breast cancer survivors. Furthermore, emerging data suggest that LHRH agonists and antagonists may both have a direct antitumor effect (11) . The disadvantages are the hypothetical risk of stimulating latent tumor cells when estrogen production resumes at the time of drug withdrawal and the documented side effects of injection site reactions, tumor flare [a complication of LHRH agonists, not LHRH antagonists (11) ], and menopausal symptoms (15 , 16) . An additional disadvantage is the uncertainty of the optimal duration of treatment and the long-term complications of osteoporosis and hypercholesterolemia that develop in the estrogen-deficient state.
Because amenorrhea often results from the administration of cytotoxic chemotherapy to premenopausal women with breast cancer, ovarian ablation is a potential indirect effect of adjuvant systemic chemotherapy. The risk of chemotherapy-induced amenorrhea is directly related to age and varies with the chemotherapy regimen used and the total duration of cytotoxic therapy (17 , 18) . The average rates of amenorrhea for classic oral CMF and standard AC [doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles] are 68% and 43%, respectively, but are clearly cycle and age dependent. CMF-induced ovarian failure occurs at rates of 10–33%, 33–81%, and 61–95% after 1, 6, and 12 cycles, respectively. In one study of 98 premenopausal women age 50 years or younger, chemotherapy-induced amenorrhea was observed in 0% (0 of 11) of women < 35 years old, 14% (2 of 14) of women 35–39 years old, 39% (7 of 18) of women 40–44 years old, and 100% (17 of 17) of women 45–50 years old (18) . The potential importance of chemotherapy-induced ovarian ablation is highlighted by a retrospective study of the IBCSG (19) . They found that patients less than 35 years old fared worse than patients 35 years or older, with DFS rates of 35% versus 47% and OS rates of 49% versus 62%, respectively. Furthermore, younger patients with ER+ breast cancers treated with chemotherapy alone had a significantly worse DFS than younger patients with ER- disease, but the DFS rates of older patients with ER+ and ER- disease were similar. This observation, together with the findings that this younger group of women has a low rate of chemotherapy-induced ovarian failure, underscores the potential importance of endocrine therapy for this patient subgroup.
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Comparison of Strategies for Abrogating Ovarian Estrogen Production |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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The Role of Ovarian Ablation |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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50 years). Five of the trials included the use of standard adjuvant chemotherapy, whereas the others did not. Tamoxifen was not used in any of the trials. Additionally, the ER status of the tumors was assessed in only 4 of the 12 trials, all of which included chemotherapy.
The 1995 EBCTCG analysis of ovarian ablation as the primary treatment of premenopausal women with breast cancer is shown in Table 1
. Surgical or radiation-induced oophorectomy as a sole treatment resulted in a 25 ± 7% reduction in the annual odds of recurrence and a 24 ± 7% reduction in the annual odds of death, regardless of nodal status. There was no impact on non-breast cancer mortality. Ovarian ablation tended to be more efficacious in women with ER+ tumors, although this subgroup analysis is limited by incomplete data as noted above. Interestingly, the impact of ovarian ablation was significantly less for women treated with ovarian ablation plus chemotherapy, with observed rates of reduction in the annual odds of recurrence and death of 10 ± 9% and 8 ± 10%, respectively. The lack of impact of ovarian ablation in women receiving chemotherapy is most likely related to the influence of chemotherapy-induced amenorrhea in these patients. These data are limited by the use of single-agent chemotherapy or chemotherapeutic agents with only modest activity compared with modern chemotherapy regimens. As discussed below, newer studies incorporating present-day combination chemotherapy regimens are reexamining these issues.
Preliminary results of the 2000 EBCTCG overview confirm trends observed in the 1995 overview, but the updated meta-analysis has not yet been published. These analyses definitively establish that adjuvant ovarian ablation as a single treatment modality significantly reduces recurrence and increases survival in women less than 50 years of age with early-stage breast cancer and support a greater benefit for this management strategy for women with ER+ tumors. Moreover, the magnitude of benefit appears to be similar to either adjuvant chemotherapy (8)
or tamoxifen (9)
alone (Table 2)
by indirect comparison. These data have stimulated renewed interest in further defining the role of ovarian ablation in the adjuvant therapy of breast cancer, and a number of issues are under active investigation. These include defining the relative contributions of ovarian ablation and chemotherapy in premenopausal women, evaluating the efficacy of combined ovarian ablation and chemotherapy, and evaluating the efficacy of combined endocrine therapy with ovarian ablation and tamoxifen (total estrogen blockade). Finally, the efficacy of therapy with LHRH agonists as a reversible means of ovarian ablation compared with the efficacy of therapy with tamoxifen alone or in sequence with chemotherapy is another unanswered question. A number of recent and ongoing clinical trials address these issues.
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Ovarian Ablation/Suppression Compared with Chemotherapy |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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.
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20 fmol/mg protein). Conversely, 6 months of oral CMF was associated with improved survival in women whose tumors had low levels of ER (<20 fmol/mg protein). A Scandinavian trial compared radiation-induced ovarian failure with nine cycles of i.v. CMF in 732 women with stage II HR+ breast cancer (23) . The 5-year DFS and OS rates were 67% and 78% for ovarian ablation and 66% and 82% for CMF; these differences were not statistically significant. It is important to note that 68% of patients treated on the CMF arm became amenorrheic as a result of therapy.
The ZEBRA trial is the largest study to directly compare ovarian suppression and chemotherapy, randomizing 1640 premenopausal women with lymph node-positive breast cancer to treatment with either six cycles of oral CMF or 2 years of monthly goserelin (24) . For those women with ER+ tumors (80% of the total enrollment), the two treatments resulted in equivalent DFS and OS at a median follow-up of 6 years. Subset analysis suggested that women who developed CMF-related ovarian failure had longer DFS than those who did not. The importance of using tumor HR status to select appropriate patients was demonstrated by the superior DFS and OS for CMF compared with goserelin in women with ER- tumors. Importantly, whereas 80% of women treated with CMF remained amenorrheic at 3 years, about 65% of patients treated on the goserelin arm regained menstrual function by 1 year after completing therapy. Moreover, the substantial bone loss that occurred with both therapies improved after completion of goserelin, but not after CMF. These data thus support the use of goserelin as a reasonable treatment option for women with lymph node-positive, ER+ breast cancer, particularly those wishing to preserve fertility.
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Ovarian Suppression Integrated with Adjuvant Chemotherapy |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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The ZIPP trial used a 2-by-2 factorial design to compare tamoxifen for 2 years, goserelin for 2 years, tamoxifen and goserelin for 2 years, and no hormonal therapy in 2648 premenopausal women with early-stage breast cancer (28 , 29) . Enrolled patients were somewhat heterogeneous, with 42% having lymph node-positive disease, and 56% having ER+ disease. Moreover, 43% received elective adjuvant chemotherapy. At a median follow-up of about 4 years, there was a statistically significant 23% decrease in first events in women treated with goserelin (P = 0.001), although the benefit was less pronounced in women receiving concurrent tamoxifen or chemotherapy. The clinical benefit was greatest in patients with ER+ tumors. There is no statistically significant difference in OS (P = 0.12), although data continue to mature.
IBCSG Trial 11-93 enrolled 174 patients (median age, 45 years) with lymph node-positive, HR+, early-stage breast cancer and compared the efficacy of ovarian ablation/suppression, tamoxifen, and four cycles of anthracycline-based chemotherapy with the efficacy of ovarian ablation/suppression plus tamoxifen alone (30) . Of the enrolled patients, 26% underwent surgical oophorectomy, 11% had ovarian ablation by radiation, and 63% were treated with a LHRH agonist to suppress ovarian function. At a median follow-up of 4.4 years, the 4-year DFS rates for hormonal therapy alone and hormone therapy plus chemotherapy were 88 ± 4% and 87 ± 4% (P = 0.63), respectively; corresponding OS rates were 96 ± 2% and 92 ± 3% (P = 0.36). Because it was closed prematurely due to low accrual rates, the power of this study is limited by the small patient numbers.
The fourth trial, IBCSG VIII, compared classic oral CMF followed by 1.5 years of goserelin to either six cycles of classic oral CMF alone or 2 years of goserelin alone in pre- and perimenopausal women with lymph node-negative breast cancer; a fourth observational arm closed after 46 patients had been accrued (31)
. Of the 1063 enrolled patients, 19% were less than 40 years of age, 62% had tumors of 2 cm or less, and 70% had ER+ tumors; the majority of tumors classified as ER- actually expressed low levels of ER. At a median follow-up of 5.7 years, multivariate analysis revealed a statistically significant decrease in first events with the addition of chemotherapy to goserelin in women with ER- disease only (P = 0.01). Overall, 2 years of goserelin therapy was equivalent to six cycles of oral CMF across all age groups.
In summary, these trials do not establish a definitive benefit for combined medical ovarian suppression and chemotherapy. However, it has been suggested that the subgroup of premenopausal patients with HR+ tumors who do not become amenorrheic with chemotherapy may benefit from the addition of ovarian ablation. Additional studies are required to clarify this issue.
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Ovarian Ablation Combined with Tamoxifen |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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Two trials have assessed ovarian ablation with or without tamoxifen in the absence of chemotherapy. The first is an Intergroup trial that enrolled 350 premenopausal women with lymph node-negative, HR+ breast cancers less than 3 cm in size. Patients were randomized to 5 years of tamoxifen or 5 years of tamoxifen plus any form of ovarian ablation. This trial closed early due to poor accrual; first analysis is planned for late 2002. The second trial was conducted in Southeast Asia and accrued 709 premenopausal women with early-stage breast cancer, randomizing them to oophorectomy plus tamoxifen either at the time of definitive surgery or at relapse (32) . At a mean follow-up of 3.6 years, 5-year DFS rates were 75% and 58% (P = 0.0075, adjusted) for the therapy and observation arms, respectively; corresponding OS rates were 78% and 70% (P = 0.41, unadjusted). Not surprisingly, the benefit was limited to women with HR+ tumors. Interestingly, the cost efficacy analysis resulted in a cost estimate of $351 per year of life gained (compared with chemotherapy for lymph node-negative and lymph node-positive patients, where the cost estimates per year of life gained are $11,300 and $5,000, respectively). These data thus provide strong evidence for the cost-effective clinical benefit of adjuvant treatment with surgical oophorectomy and tamoxifen in Asian women with operable HR+ breast cancer.
Other trials have compared combined endocrine therapy with chemotherapy. The GROCTA trial enrolled 244 premenopausal women with lymph node-positive, HR+ breast cancer in a study comparing six cycles of oral CMF with ovarian ablation (by surgery, radiation, or 2 years of goserelin) plus 5 years of tamoxifen (33) . At a median follow-up of 76 months, there was no difference in DFS or OS. The FASG 06 trial compared total estrogen blockade with 3 years of tamoxifen and the LHRH agonist triptoreline to six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide in 333 premenopausal women with lymph node-positive, HR+ breast cancer (34) . At a median follow-up of 54 months, there was no statistically significant difference between the two treatment approaches, with DFS and OS rates of 92% and 97% for endocrine therapy and 81% and 93% for chemotherapy. Another small French trial compared 5-fluorouracil, doxorubicin, and cyclophosphamide with ovarian ablation (oophorectomy or radiotherapy) and tamoxifen in 162 premenopausal women with lymph node-positive, HR+ disease (35) . This trial was stopped early due to poor accrual and is thus underpowered, but it revealed no differences in DFS or OS. A larger trial conducted by the ABCSG similarly compared combined endocrine therapy with 3 years of goserelin plus 5 years of tamoxifen to six cycles of i.v. CMF in 1045 premenopausal women with stage I or II HR+ breast cancer (36) . At a median follow-up of 42 months, combination endocrine therapy was associated with a statistically significant improvement in DFS compared with CMF (P = 0.02), with no difference in OS. Of note, women in the CMF group who developed amenorrhea had significantly longer DFS and OS than those who retained ovarian function. These trials are difficult to compare because of the absence of tamoxifen in the chemotherapy arms and the use of different CMF regimens that have a variable propensity to cause ovarian failure.
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Conclusions and Future Directions |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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In the aggregate, the data suggest that the clinical benefit of chemotherapy followed by 5 years of tamoxifen appears to be similar to the clinical benefit of ovarian ablation/suppression plus 5 years of tamoxifen in premenopausal women with HR+ early-stage breast cancer, although this has not been definitively established in a randomized clinical trial (40 , 41) . The choice between these approaches will depend largely on the local clinical practice pattern and the comorbid conditions and psychosocial milieu of the patient. There are two points to consider in choosing therapy. First, the studies used CMF chemotherapy rather than anthracycline-based chemotherapy, and it is clear that anthracyclines have a modestly superior efficacy. Thus, for women with higher risk tumors (lower HR expression, high-grade or lymph node-positive disease), anthracycline-containing chemotherapy regimens may be the preferred therapy. Second, it is clear that the role of ovarian ablation/suppression in patients who remain premenopausal after chemotherapy remains a pivotal area for further research.
A number of important questions have been raised by analyses of the available clinical trials studying ovarian ablation/suppression and by emerging data on the efficacy of newer endocrine therapies (aromatase inhibitors and fulvestrant) compared with tamoxifen. First, the optimal duration of therapy with LHRH analogues, which induce ovarian failure that is typically reversible, remains an open question. Second, the value of sequential chemotherapy and ovarian ablation/suppression, particularly in those women not rendered physiologically postmenopausal by adjuvant chemotherapy, remains to be determined. Third, the utility of combined endocrine therapy with ovarian ablation and tamoxifen or aromatase inhibitors has shown promise in the treatment of premenopausal women with metastatic disease and may have an important role in the adjuvant setting. Several active or planned trials address these issues (Table 4
; Ref. 42
). Importantly, carefully designed clinical trials should also include cause-specific morbidity and mortality end points to evaluate the long-term side effects of ovarian ablation and total estrogen blockade. The availability of newer selective endocrine agents and a better understanding of the patients likely to benefit from hormonal therapy should facilitate the design of highly informative clinical trials that more clearly define the role of endocrine manipulation in the management of early-stage premenopausal breast cancer.
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Open Discussion |
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TopABSTRACTIntroductionOvarian AblationStrategies for Decreasing...Comparison of Strategies for...The Role of Ovarian...Ovarian Ablation/Suppression...Ovarian Suppression Integrated...Ovarian Ablation Combined with...Conclusions and Future...Open DiscussionREFERENCES |
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Dr. Nancy E. Davidson: I get about three of those calls a week. Half of the people who call want to use Zoladex, and half don’t.
Dr. Kathleen Pritchard: Randomize the calls into the trial.
Dr. Buzdar: But how do you do it?
Dr. Davidson: I tell patients that there is this controversy; we’re not sure what to do. Some of them actually do opt for the LHRH agonist, and then we get into this difficult question of when we’re going to stop. For the few I have who are on it, I say we’re going to do it for 2 years, then we’ll reassess. I’d be curious to know what the others around the table are doing.
Dr. Buzdar: I talk about all the data with the patients, but I have not utilized LHRH agonists. I just give tamoxifen in premenopausal patients.
Dr. Pritchard: I’m doing much what you’re doing. I’m increasingly discussing it with patients and you do get patients coming and calls coming. I don’t do it routinely, and I more often discuss permanent ovarian ablation as opposed to an LHRH agonist. But we’re keen on doing the SOFT trial, and I think we’ll find that very easy to do in our setting because it’s an open question.
Dr. Davidson: I know that our IBCSG colleagues are very interested in the other two trials, the PERCHE and the TEXT. So would the people in North America do those trials?
Dr. Pritchard: I’m surveying Canadian National Cancer Institute participants to see if people will do TEXT or not, and my guess is they won’t. I think it’s a worthwhile question, but I don’t think North American investigators are going to do it.
Dr. James Ingle: If you’re using evidence-based medicine, SOFT is the correct study to do.
Dr. Pritchard: I think SOFT is easier. It’s more in line with what we’re doing.
Dr. Eric Winer: I think it’s more attractive because we’re not convinced of what we’re doing.
Dr. Davidson: I like the SOFT trial because it addresses my questions: if the patient is still premenopausal after I give my chemotherapy, what do I do, or if I didn’t want to give chemotherapy, what’s the best hormone therapy?
Dr. Pritchard: Will Americans put patients in the TEXT trial?
Dr. Davidson: I probably wouldn’t activate it at my institution. It’s not that I’m uninterested, it’s just that I don’t consider ovarian suppression standard.
Dr. Pritchard: My sense as well is that we’ll survey people, and we won’t get a lot of enthusiasm.
Dr. Winer: I think the PERCHE is also an important study. It is also one that would have a very hard time accruing in the United States.
Dr. Dowsett: There are already 40,000 women coming into these trials, and there’s going to be another 10,000 or 20,000 as well. At the end, we’re not going to have data on long-term use of aromatase inhibitors. We’ve learned that the aromatase inhibitors are more effective than tamoxifen in just about every circumstance. There are issues that may make them questionable in certain circumstances, but we’ve actually made a step forward in our endocrine therapy. Only, it’s going to take another 10 years to work out how we use them if we stick to current study design algorithms. Somehow we don’t seem to move forward in delivering these advances more rapidly.
Dr. Osborne: These trials accrue very quickly, but then you wait for the cancers to recur. That’s the main problem.
Dr. Ingle: Prevention studies are going to be even more of a problem. We’re going to have to identify surrogate end points so that we can do the studies quickly and it’s not just our patients’ children that get the benefit of the new knowledge.
Dr. Mitch Dowsett: It’s really depressing that it’s going to take another 8 years to work out whether we should give an aromatase inhibitor before tamoxifen or vice versa.
Dr. Pritchard: Yes, but it’s the right thing to do.
Dr. Brian Long: But what happens when the recurrences occur? In the data from the letrozole versus tamoxifen metastatic trial, the slide you presented showed the survival lines merging for both letrozole and tamoxifen. This suggested to me that tamoxifen wasn’t working second line. Are the doctors here actually giving tamoxifen second line to women who relapse after aromatase inhibitors?
Dr. Davidson: Is that information being captured in arimidex, tamoxifen, alone or in combination, what therapy the patients receive upon relapse?
Dr. Buzdar: Even though no specific therapy is being dictated, that information will be captured at 10-year follow-up.
Dr. Pritchard: So patients who relapse following anastrozole, you would have some record of what they get next and whether they respond?
Dr. Buzdar: Response is not being collected, but all the event rates will be captured up to 10 years—that’s in the protocol—at yearly intervals.
Dr. Steven Come: In every advanced disease trial when they’ve tried to collect information on therapies after relapse, it’s been useless because the choice so depends on the patient’s situation and the doctor’s bias.
Dr. Johnston: Out in the community people are saying "Tamoxifen is a good drug I’ve used for many years; I’ll use that." We’ve got our reasons that we think it might not work second line, which is why I think the crossover data from the letrozole/tamoxifen first line study is crucially important to help answer that question.
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FOOTNOTES |
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2 Nancy E. Davidson has previously received an unrestricted gift to support her research from AstraZeneca [Wilmington, DE (maker of tamoxifen and goserelin)], and she has served as a paid consultant for AstraZeneca and Eli Lilly (Indianapolis, IN). To whom correspondence should be addressed, at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 409, Baltimore, MD 21231-1000. Phone: (410) 955-8489; Fax: (410) 614-4073; E-mail: davidna{at}jhmi.edu
3 The abbreviations used are: ER, estrogen receptor; PR, progesterone receptor; HR, hormone receptor; LHRH, luteinizing hormone-releasing hormone; EBCTCG, Early Breast Cancer Trialists’ Collaborative Group; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; CAF, cyclophosphamide, doxorubicin, and fluorouracil; CAFZ, CAF followed by 5 years of goserelin; CAFZT, CAF followed by 5 years of goserelin and tamoxifen; DFS, disease-free survival; OS, overall survival; ZEBRA, Zoladex Early Breast Cancer Research Association; IBCSG, International Breast Cancer Study Group; ABCSG, Austrian Breast Cancer Study Group; ZIPP, Zoladex in Premenopausal Patients; GROCTA, Italian Breast Cancer Adjuvant Study Group; FASG, French Adjuvant Study Group; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial; PERCHE, Premenopausal ER+ Chemotherapy Trial.
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REFERENCES |
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50 years of age (7)