The Oncologist, Vol. 11, No. 10, 1081-1088, November 2006; doi:10.1634/theoncologist.11-10-1081
© 2006 AlphaMed Press
Neoadjuvant Use of Hormonal Therapy in Elderly Patients with Early or Locally Advanced Hormone Receptor–Positive Breast Cancer
E. Jane Macaskill,
Lorna Renshaw,
J. Michael Dixon
Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom
Key Words. Aromatase inhibitors • Tamoxifen • Letrozole • Anastrozole • Exemestane • Neoadjuvant • Breast cancer • Elderly
Correspondence:
J. Michael Dixon, Academic Office, Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. Telephone: 44-0-131-537-2907; Fax: 44-0-131-537-2653; e-mail: jmd{at}ed.ac.uk
Received October 24, 2005;
accepted for publication September 1, 2006.
 |
ABSTRACT
|
|---|
The management of the elderly patient with breast cancer is a challenge to the breast care team for a number of reasons. The higher rate of comorbidity in elderly patients increases the risk for complications and mortality following surgery and other adjuvant treatments such as chemotherapy and radiotherapy. The advent of using endocrine therapy in the neoadjuvant setting allows disease control and downstaging of tumors to allow less extensive surgery, with less morbidity compared with other available treatments. Tamoxifen has traditionally been the hormone therapy of choice for patients unable to undergo surgery, but development of resistance is a common feature. Newer third-generation aromatase inhibitors, in particular letrozole, are superior to tamoxifen in this setting with greater downstaging of tumor and disease control. The aromatase inhibitors are now the treatment of choice in elderly patients with estrogen receptor–positive breast cancer who are being considered for neoadjuvant therapy. These drugs are particularly suitable to the needs of an elderly population.
|
INTRODUCTION
|
|---|
When considering the issues surrounding management of the elderly patient with breast cancer, it is important to acknowledge that the "elderly" group varies widely in terms of individual health and related needs. It is therefore important to avoid an ageist attitude when devising patient management plans, but to recognize the practical aspects of caring for an increasing elderly population. Mobility, cognition, concurrent medications, and social factors all need to be taken into consideration. Comorbidity increases with age [1], and this comorbidity has implications when considering management strategies, particularly for patients who may be unfit either for major surgery or chemotherapy or even radiotherapy, but require control of their breast cancer. Concurrent medical problems need to be balanced against side effects of the drugs available for neoadjuvant hormonal therapy. Compliance with drug treatment is important when assessing the suitability of a patient for neoadjuvant hormonal therapy, as is the ability to attend appointments for review of response to treatment. Tamoxifen has traditionally been used in this situation as the neoadjuvant treatment of choice but is not always effective, and cancers do become resistant with time. Elderly patients with significant comorbidity and an advanced tumor at presentation pose a significant management problem. Third-generation aromatase inhibitors have recently been evaluated in this neoadjuvant setting in these challenging patients, with encouraging results.
|
CHEMOTHERAPY
|
|---|
Chemotherapy is rarely used in the treatment of elderly patients with breast cancer, particularly those with other medical problems, with only 3% of a recent study of 1,755 patients over age 70 treated for operable breast cancers receiving chemotherapy [2]. There are few randomized studies comparing chemotherapy and hormonal therapy in older women, almost certainly because of the choice of treatment between chemotherapy and hormonal therapy being based not only on tumor characteristics such as estrogen receptor (ER) positivity but also on the general health of these elderly patients. A small unpublished Russian study has suggested that there are similar clinical outcomes following either neoadjuvant hormonal therapy or chemotherapy [3]. In that study, 121 postmenopausal women with ER- and/or progesterone receptor–positive breast cancer stage T2N1–2, T3N0–1, T4N0–1 were randomized to receive either neoadjuvant doxorubicin and paclitaxel chemotherapy (every 3 weeks, four cycles; n = 62 patients) or neoadjuvant endocrine treatment with anastrozole (n = 30) or exemestane (n = 29) for 3 months prior to surgery. In the endocrine-treated group, 32% were >70 years of age, and 20% in the chemotherapy group were >70 years of age. Other baseline characteristics were similar for both groups. Clinical and mammographic objective response rates were similar for endocrine therapy and chemotherapy, and there was a trend for increasing rates of breast-conserving surgery in favor of endocrine therapy, with no significant differences in local recurrence rates at 34 months. Grade 3 or 4 toxicity for alopecia, neutropenia, cardiotoxicity, and neuropathy were experienced by significant numbers of women in the chemotherapy group. Neoadjuvant endocrine therapy was better tolerated, the most common adverse events reported being hot flushes, fatigue, vaginal bleeding, and arthralgia. Despite the small numbers in this study, these results do suggest that for patients with ER-positive tumors, neoadjuvant endocrine therapy is a reasonable alternative to chemotherapy, with similar response rates but less toxicity. This is particularly interesting in the light of results of a recent retrospective study of 1,731 patients who had primary chemotherapy [4]. The results showed better progression-free survival and overall survival for patients with hormone receptor–positive cancer who had had a pathologic complete response than those who had less than a complete response, with the same pattern for hormone receptor–negative tumors. A significantly lower rate of pathologic complete response to chemotherapy was achieved in patients with hormone receptor–positive tumors compared with those with hormone receptor–negative tumors (8% versus 24%; p < .0001). These data are consistent with the observation that patients with hormone receptor–positive disease are as likely to benefit from neoadjuvant hormonal therapy as they are to neoadjuvant chemotherapy.
|
TAMOXIFEN
|
|---|
Most studies that have used tamoxifen as a primary treatment have involved patients over the age of 70, and compared surgery with or without tamoxifen with the use of tamoxifen alone. There have been three large randomized trials of tamoxifen alone versus surgery alone [5–7]. While one trial found no difference between the two treatments at 6 years [5], the Nottingham study found a significantly higher local progression rate in the tamoxifen alone group [6]. This was confirmed in a multicenter European study [7] that also reported a shorter time to progression and shorter disease-free survival time, as well as poorer locoregional control, in the tamoxifen alone group. In these latter two studies, the median follow-up was 145 months and 120 months, respectively.
Three randomized trials have compared tamoxifen alone with surgery followed by tamoxifen [8–10]. In an Italian study, 474 patients were randomized to surgery followed by 5 years tamoxifen or 5 years tamoxifen alone; no difference was found in overall survival or breast cancer–specific survival at 80 months. There was a significantly higher local progression rate in the tamoxifen only arm (106 versus 27; p = .0001) [8]. In the two studies that reported follow-up of up to 12 years [9, 10], there was a significantly higher rate of local recurrence in the tamoxifen alone group and significantly lower overall death rates and breast cancer–related death rates in the tamoxifen only groups, although in one of the two studies the greater mortality was observed only after 3 years [9]. In none of the randomized trials were patients selected on the basis of ER status, and this will have influenced outcome, as ER-negative patients would have gained no benefit from tamoxifen. These studies were also not designed to assess the use of tamoxifen in the neoadjuvant setting, with surgery followed by tamoxifen. One conclusion from these studies is that using long-term tamoxifen treatment without surgery should be reserved for patients in whom life expectancy is short (2–3 years maximum) [9]. These studies did not clarify how long tamoxifen is effective when given as the sole therapy to women with hormone-sensitive cancer. One study has reported long-term follow-up data for 113 patients over the age of 70 who had been treated with tamoxifen as the sole therapy. The median time to local recurrence was 2.5–3 years, with more than half of the responders relapsing by 5 years [11]. In Edinburgh, a series of 100 women >70 years of age, with ER-positive tumors, were treated to investigate the time course of response with neoadjuvant tamoxifen [12]. Modified World Health Organization (WHO) criteria have been used to evaluate tumor response in the neoadjuvant setting as follows:
- Partial response (PR): reduction in tumor size
 50% from pretreatment size;
- Minor response (MR): reduction in tumor size 25% and <50% from pretreatment size;
- No change (NC): <25% decrease or <25% increase in tumor size from pretreatment size;
- Complete response (CR): no measurable tumor.
- Progressive disease (PD): 25% increase in tumor size from pretreatment size.
After 3 months of tamoxifen, 72 patients had responded and one patient had progressive disease. The remaining 27 patients continued on tamoxifen for a further 3 months, during which time four responded and five progressed (Table 1 ). The observation drawn from these data is that it is unlikely that patients who do not have a response by 3 months will get a response with prolonged further treatment, and so if patients do not respond within this time period alternative treatments need to be considered.
|
LETROZOLE
|
|---|
A large, randomized trial known as PO24 compared 4 months of treatment with neoadjuvant letrozole or tamoxifen prior to surgery in 337 postmenopausal women with T2–4, N0–2, M0 breast cancers not eligible for breast-conserving surgery at the time of enrolment into the trial [13]. Objective response rates (ORRs) by palpation, mammography, and ultrasound were assessed, showing a significantly higher clinical response rate in letrozole-treated patients (55% versus 36%; p < .001), and significant results in favor of letrozole on ultrasound and mammograms. There was a significantly higher rate of breast-conserving surgery in the letrozole group than in the tamoxifen group, even in those patients with locally advanced cancer (Table 2). When these results were analyzed with respect to ER Allred scores, it was evident that not only were response rates to letrozole higher in the high ER score categories (6–8), but they were also higher in patients who had lower ER scores (3–5); responses were achieved only with letrozole. This has significant implications for the treatment of patients with tumors with low ER scores, who may still benefit from neoadjuvant letrozole treatment if required, whereas tamoxifen may not be as effective.
Superior biological efficacy with neoadjuvant letrozole compared with tamoxifen in ER-positive women was demonstrated in the PO24 study, which showed a significantly greater reduction in proliferation with letrozole; the reduction in the geometric mean Ki67 was 87% with letrozole compared with 75% with tamoxifen (p = .0009) [14].
In the Edinburgh Breast Unit, over 150 postmenopausal women have been treated with neoadjuvant letrozole for large operable or locally advanced breast cancer as part of an ongoing prospective audit assessing response [15]. Response was measured by palpation, ultrasound, and mammography at 0 and 3 months, and at 3-month intervals for those patients who continued on letrozole after 3-month review. The WHO criteria described above were used in the assessment of clinical response. Forty-two patients were continued on letrozole beyond 3 months because they were deemed unfit for surgery, declined surgery, or had a response but remained inoperable or still required mastectomy. Twenty-two of those patients were still taking letrozole at 12 months. Similar percentage reductions in tumor volume were apparent between 0 and 3 months, 3 and 6 months, and 6 and 12 months, with complete responses in 4/42 patients (9.5%) at 3 months, 12/42 patients (29%) at 6 months, and 8/22 patients (36%) at 12 months. One patient who had originally shown a response at 3 months developed disease progression at 12 months. These data show that neoadjuvant letrozole produces ongoing tumor shrinkage over 12 months. Patients in whom a response is seen at 3 months can expect a further reduction in tumor volume with continued treatment. The optimum duration of neoadjuvant letrozole was not identified in this study, but the data suggest that letrozole can be used safely in this context for up to 12 months.
|
ANASTROZOLE
|
|---|
A small study was performed in Edinburgh to assess the effects of neoadjuvant anastrozole on tumor volume [16]. Twenty-four postmenopausal women with newly diagnosed ER-rich tumors that were >3 cm were randomly allocated to receive either 1 mg (n = 12) or 10 mg (n = 12) of anastrozole for 12 weeks. Tumor volume reduction was assessed clinically and by ultrasound at 0, 4, 8, and 12 weeks, and by mammography at 0 and 12 weeks. A >50% reduction in tumor volume was seen in 18/24 patients, and no patients had disease progression. Although 17 of 24 patients would have required mastectomy prior to treatment, only two patients required this after neoadjuvant anastrozole.
Following these results in Edinburgh, anastrozole was compared with tamoxifen in the neoadjuvant setting in two large trials, known as the Pre-Operative Arimidex® Compared to Tamoxifen (PROACT) and Immediate Preoperative Arimidex®, Tamoxifen, or Combined with Tamoxifen (IMPACT) trials. In the IMPACT trial, 330 postmenopausal women with large operable (>2 cm) hormone receptor–positive breast cancers were randomized to receive either anastrozole or tamoxifen or the combination for 3 months prior to surgery [17]. The mean age was 73 (52–90) years in the anastrozole arm, and was similar in the tamoxifen and combination arms. Objective response was measured by calipers and ultrasound, and no significant difference was found among the three arms of the study (Table 3). There was a significantly higher conversion rate to breast-conserving surgery in the anastrozole group (45.7%) when compared with tamoxifen (22.2%; p = .03). All three treatments were well tolerated and significantly fewer patients developed vaginal discharge and thromboembolic events in the anastrozole group compared with tamoxifen.
As part of the IMPACT trial, proliferation was assessed by Ki67 after 2 weeks of treatment and at surgery (12 weeks after commencement of hormonal treatment). Initial results revealed that there was a significantly greater reduction in Ki67 in the anastrozole group than in the tamoxifen or combination groups at 2 weeks (p = .004) and 12 weeks (p < .001), but no significant relationship was found between Ki67 changes and clinical response. However, more recent data presented in San Antonio by the IMPACT trialists [18] confirmed a statistically significant correlation between Ki67 after 2 weeks of treatment and relapse-free survival after a median of 37 months of follow-up (hazard ratio [HR], 2.01; p = .002). Ki67 at baseline did not reach a significant correlation on multivariate analysis. The implication of these findings is that there is a predictive value in Ki67 at 2 weeks, which could be used as a prognostic tool for predicting response.
In the PROACT study, 451 postmenopausal women with large operable or potentially operable hormone receptor–positive breast cancers were randomized to anastrozole or tamoxifen for 3 months prior to surgery [19]. Patients who were receiving neoadjuvant chemotherapy were also included in this study; this was an exclusion criterion for the IMPACT trial, and about 30% in each arm received concomitant chemotherapy. The mean age of patients in this study was 67 years in both arms. In the overall population (including patients who received concomitant chemotherapy), there was no difference in overall response between anastrozole and tamoxifen as measured by calipers and ultrasound, but a nonsignificant trend in favor of anastrozole for the ORR was found in patients who had only hormonal therapy (n = 314) (Table 3 ). In this subgroup of patients with large or inoperable tumors, there was a significant improvement in actual surgery performed from that considered necessary at baseline in the anastrozole group, compared with tamoxifen (43% versus 30.8%; p = .04). Anastrozole was well tolerated in this trial, with 2% fatigue, 7% headache, and 8% hot flushes reported. Patients who received concomitant chemotherapy also reported alopecia, nausea, and vomiting.
|
EXEMESTANE
|
|---|
Twelve patients were treated with neoadjuvant exemestane in a small phase II trial in Edinburgh. Ten patients had a >50% reduction in tumor volume [20].
Two other phase II studies have reported results using neoadjuvant exemestane as a monotherapy. In Germany there was the German Neoadjuvant Aromasin® Initiative (GENARI) trial, in which postmenopausal women of a median age of 71 (range, 59–91) with hormone receptor–positive T2–4 tumors were treated with 25 mg of exemestane for 16 weeks prior to surgery. Of 27 patients, 10 had a partial response and 17 had stable disease. Fourteen of the 27 patients underwent breast-conserving surgery [21]. One patient had to discontinue treatment as a result of hospitalization with herpes zoster. Hot flushes were reported in 10 patients.
In a French study, 38 postmenopausal women with a median age of 66.7 years (range, 51.4–90.8) with ER-positive operable breast cancer were given 4–5 months of exemestane prior to surgery [22]. In that study, clinical response as measured on ultrasound confirmed a complete response in 5.9%, partial response in 64.7%, and stable disease in 23.5%. Breast-conserving surgery was achieved in 45.2% (31 patients). No grade 3 or 4 toxicities were observed.
In a Russian study, exemestane was compared with tamoxifen. One hundred fifty-one women with hormone receptor–positive breast cancer were randomized to receive either tamoxifen or exemestane for 3 months [23]. While the clinical ORR was greater for exemestane (76.3%) than for tamoxifen (40.0%; p = .05), similar outcomes were found in the two arms of the study for objective response on ultrasound and mammograms (Table 4). More patients in the exemestane group went on to have breast-conserving surgery than in the tamoxifen-treated group (36.8% versus 20.0%; p = .05). Both treatments were well tolerated.
|
BENEFITS AND RISKS OF USE OF NEOADJUVANT AROMATASE INHIBITORS
|
|---|
There are data available from the neoadjuvant setting to give insight into the potential long-term benefits and risks of hormonal therapy with aromatase inhibitors. In the adjuvant setting, there have been large randomized trials conducted comparing aromatase inhibitors with tamoxifen that have obtained data on the long-term effects. Patients treated with primary hormonal therapy should, when possible, undergo some form of surgical procedure, but for those patients for whom this is not possible, the effects of continued primary therapy over a long period of time are likely to be similar to those of adjuvant treatment.
The Arimidex® or Tamoxifen Alone or in Combination (ATAC) trial randomized 9,366 postmenopausal women with invasive breast cancer (ER positive or unknown) to 5 years of adjuvant anastrozole, tamoxifen, or a combination of the two [24]. Anastrozole produced a small but significant disease-free survival benefit at 68 months, with an HR of 0.83 (0.73–0.94; p = .005) in the ER-positive group, compared with tamoxifen or the combination. There was a 53% lower rate of contralateral breast cancer intheanastrozole-treated group compared with tamoxifen or the combination (25%–71%; p = .001). The side-effect profiles of anastrozole and tamoxifen were shown to have differences in the ATAC study. Patients in the anastrozole arm were significantly less likely to experience hot flushes, vaginal bleeding or discharge, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic events, and deep venous thrombosis. There was no significant difference in ischemic cardiovascular disease between anastrozole and tamoxifen, despite a numerical trend in favor of tamoxifen. However, there were significantly more reports of arthralgia in patients taking anastrozole. Fractures of the hip or wrist, a source of considerable morbidity and mortality in the elderly, were not significantly more frequent with anastrozole, but there were significantly more fractures overall, and specifically fractures of the spine, in this group.
These differences in the toxicities of aromatase inhibitors compared with tamoxifen were also found in the Breast International Group (BIG) 1-98 study directly comparing letrozole with tamoxifen in 8,028 women. A median overall follow-up period of 35.5 months showed that patients receiving immediate treatment with letrozole rather than tamoxifen had superior disease-free survival (HR, 0.81; 0.70–0.93; p = .003), a better breast cancer relapse rate (absolute benefit, 3.4% at 5 years; p = .0002), and a significantly longer time to development of metastases (HR, 0.73), but no difference in overall survival [25]. Patients who took letrozole were significantly less likely to have a thromboembolic event, vaginal bleeding, and hot flushes, but had more fractures and arthralgia. There was a trend toward a higher cardiac event rate (4.1% versus 3.8%; p = .61) in the letrozole group, with significantly more cardiac failure (0.8% versus 0.4%). The number of patients with cardiac failure in total was small. In the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.17 trial of letrozole versus placebo for 5 years in patients who had already completed 5 years of tamoxifen, letrozole treatment did not result in a higher risk for hypercholesterolemia, cardiovascular events, clinical fractures, or osteoporosis [26]. Toxic effects were primarily of grade 1 or 2, and 4.5% of women in the letrozole group discontinued because of toxic effects, which overall was not significantly different from the 3.6% of women in the placebo group who withdrew for similar reasons (p = .11), and is therefore reassuring.
Exemestane has been examined in the adjuvant setting, with sequential use of exemestane therapy after 2–3 years of tamoxifen to complete 5 years of therapy, and was also recently shown to be significantly superior to 5 years of tamoxifen alone, with fewer events (HR, 0.73; 0.62–0.86) and an absolute disease-free survival benefit of 4.7% at 3 years [27]. Cardiovascular risk was highlighted in that study, with a small but nonsignificant higher number of myocardial infarcts in the exemestane group. The risk of anesthesia to an individual patient with cardiovascular risk factors must be weighed against the possible small increase in cardiovascular risk with the long-term use of aromatase inhibitors. Initial results from a study in healthy postmenopausal women have suggested that the aromatase inhibitors letrozole, anastrozole, and exemestane have slightly different effects on lipid profiles, and further investigation of this is warranted [28].
|
OPTIMIZING NEOADJUVANT TREATMENT OF BREAST CANCER IN ELDERLY PATIENTS
|
|---|
Elderly patients with newly diagnosed breast cancer need to be formally assessed for surgical risk, taking into consideration medical, social, and psychological factors. In patients for whom it is felt that a procedure such as mastectomy would be a significant risk because of other medical problems, hormonal therapy could be considered as the primary treatment provided that the tumor is ER rich. The treatment decision has to be made on an individual basis, with a number of issues to be addressed. In the case of a patient with significant cardiac problems, the risk of undergoing general anesthesia has to be weighed against the long-term effects of treatment with an aromatase inhibitor. In patients for whom there are medical problems that require investigation or management that may delay surgery for breast cancer, neoadjuvant therapy with letrozole can be used to control disease while the patient’s health is optimized, without compromising oncological outcomes. The downstaging of disease to allow less extensive surgery, such as breast-conserving surgery, is often possible. Even with low levels of ER, letrozole can be effective in the neoadjuvant setting for up to 4 months [13]. Few patients are unfit for definitive surgery, and even after a time of neoadjuvant treatment, with good response, local resection of tumors can be achieved under local anesthetic if required. While current evidence shows that patients are optimally treated with radiotherapy in combination with wide local excision of a breast cancer for comparable long-term disease control with that achieved by mastectomy, in patients with a shorter life expectancy local control of disease in the medium term can be acceptable when balanced by the surgical risk of undergoing a more extensive procedure requiring general anesthesia. The use of hormonal agents alone in a patient with a life expectancy of 2 years or more and operable breast cancer is not recommended, because patients often develop resistance that then requires further consideration of surgery and/or a change in therapy. Aromatase inhibitors have been used for up to 2 years in some patients with continued disease control, but the optimum or maximum time of use is unknown. The aim of neoadjuvant hormonal therapy should be to obtain maximum response and then consider surgery or other local treatments such as radiotherapy.
Patients undergoing neoadjuvant treatment require regular monitoring to assess clinical response. The frequency of monitoring needs to be tailored to meet the patient’s individual requirement for transport and their mobility and cooperation. Monitoring of patients during primary hormonal therapy should be performed regularly using a number of modalities to ensure accurate assessment. In trials from Edinburgh, monitoring of these patients has been done every 3 months initially, combining clinical, ultrasound, and mammographic assessments, or photography when appropriate. Thereafter, assessments need to be flexible, but should be initially every 6 months and thereafter once yearly. After surgery, treatment with aromatase inhibitors should continue if there has been a response, because these drugs have been shown to be superior when given as adjuvant therapy to postmenopausal women with ER-positive cancer.
|
CONCLUSIONS
|
|---|
The management of the elderly patient with locally advanced or early breast cancer should be tailored to meet the individual needs of the patient and those caring for them. Aromatase inhibitors, particularly letrozole, have been shown in randomized trials to be more effective than tamoxifen, the agent traditionally used in this setting, even in patients with ER-poor (Allred score, 3–5) tumors. In comparison with tamoxifen, there is a higher incidence of osteoporosis and fractures with long-term treatment with aromatase inhibitors and preventative therapies may be necessary, particularly in less mobile patients. The optimum duration of neoadjuvant treatment has yet to be identified, but current evidence points to 3 months of treatment initially, with a review of clinical response at that stage. This time scale allows optimization of patient health prior to anesthesia, and potentially allows downstaging of disease from inoperable to operable, or from mastectomy to breast-conserving surgery, thus allowing less extensive surgery, or surgery under local anesthesia. Patients who continue on treatment require regular monitoring of response, as resistance can develop and the tumor can increase in size.
|
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
|
|---|
The authors indicate no potential conflicts of interest.
|
REFERENCES
|
|---|
- Yancik R, Wesley MN, Ries LAG et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001;285:885–892.[Abstract/Free Full Text]
- Pierga JY, Girre V, Laurence V et al. Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age. Breast 2004;13:369–375.[CrossRef][Medline]
- Semiglazov VF, Semiglazov V, Ivanov V etal. The relative efficacy of neoadjuvant endocrine therapy vs chemotherapy in postmenopausal women with ER positive breast cancer. Proc Am Soc Clin Oncol 2004;22:519.
- Guarneri V, Broglio K, Kau SW et al. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 2006;24:1037–1044.[Abstract/Free Full Text]
- Gazet JC, Ford HT, Coombes RC et al. Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. Eur J Surg Oncol 1994;20:207–214.[Medline]
- Kenny FS, Robertson JF, Ellis IO et al. Long-term follow-up of elderly patients randomised to primary tamoxifen or wedge mastectomy as initial therapy for operable breast cancer. Breast 1998;7:335–339.[CrossRef]
- Fentiman IS, Christiaens MR, Paridaens R et al. Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy. Eur J Cancer 2003;39:309–316.[CrossRef][Medline]
- Mustacchi G, Ceccherini R, Milani S et al. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 2003;14:414–420.[Abstract/Free Full Text]
- Fennessy M, Bates T, MacRae K et al. Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer. Br J Surg 2004;91:699–704.[CrossRef][Medline]
- Bates T, Fennessy M, Riley DL et al. Breast cancer in the elderly: surgery improves survival. The results of a Cancer Research Campaign trial. Eur J Cancer 2001;37(suppl 5):7.
- Horobin JM, Preece PE, Dewar JA et al. Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifen only. Br J Surg 1991;78:213–217.[Medline]
- Dixon JM. Neoadjuvant therapy: surgical perspectives. In: Miller WR, Ingle JN, eds. Endocrine Therapy in Breast Cancer. New York: Marcel Dekker, 2002:197–212.
- Eiermann W, Paepke S, Appfelstaedt J et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12:1527–1532.[Abstract/Free Full Text]
- Ellis MJ, Coop A, Singh B et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 2003;63:6253–6231.
- Renshaw L, Murray J, Young O et al. Is there an optimal duration of neoadjuvant letrozole therapy? Breast Cancer Res Treat 2004;88(suppl 1):S36.
- Dixon JM, Renshaw L, Bellamy C et al. The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study. Clin Cancer Res 2000;6:2229–2235.[Abstract/Free Full Text]
- Smith I, Dowsett M, on behalf of IMPACT Trialists. Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in post-menopausal women: the IMPACT trial. Breast Cancer Res Treat 2003;82 (suppl 1):S6.
- Dowsett M, A’Hern R, Smith I et al. Ki67 after 2 weeks’ endocrine treatment predicts relapse-free survival (RFS) in the IMPACT trial. Breast Cancer Res Treat 2005;94(suppl 1):Abstract.
- Cataliotti L, Buzdar A, Noguchi S et al. Efficacy of preoperative anastrozole compared with tamoxifen in postmenopausal women with hormone receptor positive breast cancer. Presented at the 4th European Breast Cancer Conference, Hamburg, Germany, March 17, 2004.
- Miller WR, Dixon JM. Endocrine and clinical endpoints of exemestane as neoadjuvant therapy. Cancer Control 2002;9(suppl 2):9–15.[Medline]
- Krainick U, Astner A, Jonat W et al. Phase II study to define safety and efficacy of exemestane as preoperative therapy for postmenopausal patients with primary breast cancer - final results of the German Neoadjuvant Aromasin Initiative (GENARI). Breast Cancer Res Treat 2003;82 (suppl 1):S55.
- Tubiana-Hulin M, Spyratos F, Becette V et al. Phase II study of neoadjuvant exemestane in postmenopausal patients with operable breast cancer. Breast Cancer Res Treat 2003;82(suppl 1):S106.
- Semiglazov VF, Semiglazov VV, Ivanov VG et al. Neoadjuvant endocrine therapy: exemestane vs tamoxifen in postmenopausal ER+ breast cancer patients (T1-4, N1-2, M0). Proc Am Soc Clin Oncol 2005;23:11s. Abstract 530.
- Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60–62.[CrossRef][Medline]
- Thurlimann BJ, Keshaviah A, Mouridsen H et al. BIG 1-98: randomized, double-blind phase III study to evaluate letrozole vs tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol 2005;23:6s. Abstract 511.
- Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in post-menopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–1802.[Abstract/Free Full Text]
- Coombes RC, Hall E, Snowdon CF et al. The Intergroup Exemestane Study: a randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen—updated survival analysis. Breast Cancer Res Treat 2004;88(suppl 1):S7.
- McCloskey E, Eastell R, Lakner G et al. Initial results from the LEAP study: the first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women. Breast Cancer Res Treat 2005;94(suppl 1):s101. Abstract 2052.
|
Top
Abstract
Introduction