Departments of 1Medical Oncology and 2Pathology, Institut Bergonié, Regional Cancer Center, Bordeaux, France
Received 25 April 2001; revised 3 August 2001; accepted 27 August 2001.
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Abstract |
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From 1984 to 1996, 1581 postmenopausal women aged 5070 years old were treated at Institut Bergonié for an infiltrative non-metastatic breast carcinoma with a positive estrogen and/or progesterone receptor determination.
Patients and methods
Among them, 199 were treated with first line tamoxifen. Ninety-seven had operable disease (T2 >30 mm, T3, N0/1) and 102 had T4 tumours.
Results
After a mean treatment duration of 5.3 months, 89 T2 and T3 (92%) and 93 T4 (91%) were treated by surgery (conservative or not) with or without irradiation, or by irradiation alone. Conserving treatment levels were 53.6% and 44%, respectively. The other women were treated with either second-line chemotherapy or another hormonotherapy; the remaining patients continued regularly with tamoxifen. Overall survival is analysed with a 83 month median follow-up.
Conclusions
A comparison between neoadjuvant endocrine therapy and surgery seems feasible to assess the concept of neoadjuvant hormonotherapy.
Key words: locally advanced breast cancer, neoadjuvant endocrine therapy, operable breast cancer, postmenopausal women
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Introduction |
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So, it seemed possible to propose a neoadjuvant hormonal treatment to women with a tumour that was too large to be treated by conserving surgery and who met the criterion of response to hormonal treatment. This approach, which is currently used in elderly patients, seems to be applicable in younger women.
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Materials and methods |
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From 1985 to 1996, 199 women aged 5070 years old were treated at Institut Bergonié according to this strategy. All of them had a core biopsy to assess diagnosis of infiltrative breast carcinoma and to verify hormone-sensitivity of the tumour. Measurement of the receptors included the determination of cytosolic and nuclear sites and was performed by the single point dextran charcoal method [14]. The limits of positivity established for estrogen and progesterone receptors (ER and PgR) were 10 and 15 fM/mg protein, respectively. None of the patients had metastatic disease as determined by chest X-ray, bone scan and liver ultrasound.
Patient characteristics with clinical, pathological (tumour types) and hormonal (steroid receptors by dextran charcoal micromethod) features are described in Table 2. Pathological grading was not assessed because reliability is not asserted on small tumour samples from core biopsy [14]. Ninety-seven women had T2 or T3 tumour not available for immediate conserving surgery and 102 had a T4 tumour. Forty-eight tumours of the T2 or T3 subgroup were positive (49%) for both receptors ER+ PgR+; 41 were ER+ PgR (42%) and eight were ER PgR+ (8%). Sixty-one tumours of the T4 subgroup were positive (60%) for both receptors; 38 were ER+ PgR (37%) and three were ER PgR+ (3%).
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Clinical examination was carried out after 2 months of treatment, and at 4 and 6 months. Breast tumour and axillary node assessments were performed by clinical examination and measures were reported on a diagram with bi-dimensional measurement. At completion of neoadjuvant treatment, multidisciplinary clinical and mammographic control was carried out in order to assess the residual tumour and to propose a locoregional treatment.
If tumour regression was sufficient to allow conservation of the breast, exclusive irradiation or conserving surgery plus irradiation was carried out.
After completion of locoregional treatment, tamoxifen was continued for 2 years. No adjuvant chemotherapy was delivered, even if nodal involvement was noted after axillary clearance.
Statistical methods
Statistical analyses were carried out using Medlog and Statistical Analysis System (SAS) procedures. Survival, recurrence-free and metastasis-free curves were generated using the KaplanMeier method. Survival time, time to local recurrence and time to metastasis were computed from the start of tamoxifen date.
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Results |
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Tumour regression was analysed according to steroid receptor status. Conserving treatment rates were as good for tumours with both positive receptors as for tumours with only one positive receptor.
After a median follow-up of 83 months, we have observed six and nine isolated local recurrences in T2/3 and T4 tumours, respectively, treated with breast conservation. The local recurrence rate has been equivalent during the follow-up between the two tumour groups (Figure 1). Metastatic relapses occurred in 29 and 42 cases in T2/3 and T4 tumours respectively. Median metastasis-free survival is 88 months for T4, whereas it has not been reached after an 81 month follow-up for T2/3 (Figure 2).
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Discussion |
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Neoadjuvant endocrine therapy has not been used so far for postmenopausal patients with operable or locally advanced breast carcinoma. This approach is supported by results from endocrine treatment carried out for patients of identical age in a palliative [17] or adjuvant setting [12]. Objective response rates are 31% for patients 5160 years old and 36% for patients 6170 years old; for elderly patients (>70 years), objective response rates are 45% [17]. In an adjuvant setting, tamoxifen reduces the risk of recurrence and of death in the same proportion whatever the age, 5059 years, 6069 years or older patients [12].
Selection of patients with the criterion of response to hormonal manipulation is currently assessed by the determination of hormonal status either with biological analysis [18] or by immunohistochemistry [19]. This has been shown in a metastatic [13] and in an adjuvant setting [20]. In a neoadjuvant setting, we have shown such a correlation between receptor status and response to tamoxifen [21]. Patients >70 years old had identical response rates to those of younger postmenopausal patients. Furthermore, in this study prediction of hormonal sensitivity of the tumours can be improved by the analysis of pS2 protein, allowing the definition of three subgroups of patients: pS2 and ER+ tumours, pS2 or ER+ tumours and pS2 and ER tumours, with response rates to neoadjuvant tamoxifen of 60%, 45% and 8%, respectively [21].
Improvement of neoadjuvant hormonal treatment efficacy could be improved by using other hormonal compounds. A double-blind randomised trial comparing tamoxifen with letrozole shows a better objective response rate and a better conserving treatment rate for patients receiving the aromatase inhibitor [22].
The optimal duration of neoadjuvant tamoxifen treatment has been demonstrated empirically [23]: a 3 month minimum seems necessary and, due to a risk of progression after a treatment of 6 months, locoregional treatment has to be delivered before this time [24].
Complete response rates after neoadjuvant endocrine therapy have only been assessed in one clinical trial comparing neoadjuvant tamoxifen to letrozole [22]. This rate is low (2%) (data not shown), very different from that obtained by neoadjuvant chemotherapy. Pathological complete response after neoadjuvant chemotherapy is associated with a better outcome [25], but no study has been performed to show that after neoadjuvant endocrine therapy pathological complete response is a predictive factor of better survival.
If neoadjuvant endocrine therapy does not reduce tumour bulking it is possible to continue local treatment by surgery (mastectomy) or by neoadjuvant chemotherapy if breast conservation is important to the patient. On the contrary, if neoadjuvant endocrine therapy significantly reduces tumour size, it will allow the surgeon to conserve the breast; a further evaluation of prognostic factors will be done with axillary clearance in order to set the indication of an adjuvant chemotherapy. Such a strategy was not applied when this study was initiated, a long time before publication of meta-analysis of adjuvant treatment [26]. From this study, which involves several large randomised trials, we can conclude that adjunction of adjuvant chemotherapy to tamoxifen improves disease-free survival significantly. In the meta-analysis of 2000 (not yet published), overall survival is improved by chemotherapy, but although the benefit in terms of overall survival is significant for women >50 years old, it is less than that observed in younger patients. Furthermore, it is not certain, despite these definite results, that the statistically significant benefit is a reality for each individual patient. The meta-analysis performed by Gelber et al. shows that in terms of disease-free and overall survival this benefit is small (5, 4 and 2 months for disease-free and overall survival) if we take into account quality of life (Q-TWIST) [27]. Adjuvant chemotherapy after neoadjuvant tamoxifen could be proposed to postmenopausal patients who have a very high risk of recurrence [28].
At the moment, there has been no clinical trial that compares survival of patients with large tumours or locally advanced lesions treated with first-line mastectomy with patients treated with neoadjuvant endocrine therapy, as has been done for neoadjuvant chemotherapy [811, 25, 29, 30]. The results of our present study support such a trial being conducted, without jeopardizing patient outcome. In the neoadjuvant endocrine treatment group, locoregional treatment would be followed by adjuvant chemotherapy in case of poor prognostic factors evaluated on pathological axillary analysis.
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Footnotes |
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References |
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