Neoadjuvant tamoxifen for hormone-sensitive non-metastatic breast carcinomas in early postmenopausal women

L. Mauriac1,+, M. Debled1, M. Durand1, A. Floquet1, V. Boulanger1, C. Dagada1, N. Trufflandier1 and G. MacGrogan2

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.


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background

From 1984 to 1996, 1581 postmenopausal women aged 50–70 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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Neoadjuvant endocrine therapy was initially assessed in elderly patients with locally advanced breast carcinoma [1]. Many phase II studies [2], but only four randomised phase III studies [36] have been published. In the studies from Gazet et al. [4] and Robertson et al. [5], tamoxifen was given continuously up to a local or metastatic evolution of the disease and then compared with immediate surgery, either by lumpectomy or total mastectomy and without any adjuvant treatment. In the studies by Bates et al. [3] and Mustacchi et al. [6], tamoxifen given continuously was compared with surgery associated with adjuvant tamoxifen. The results show that immediate surgery obtains a better local control than tamoxifen, whereas patients treated with antiestrogen continuously have fewer metastatic relapses and equivalent survival (Table 1).


View this table:
[in this window]
[in a new window]
 
Table 1. Neoadjuvant hormonotherapy; randomised trials
 
Another therapeutical strategy would be to initiate endocrine therapy in order to prepare secondary local treatment, with an objective of conservation, as has been shown with neoadjuvant chemotherapy [711]. In all of these studies, tumours were not selected according to predictive factors of response to chemotherapy. On the contrary, it is recognised that steroid receptor positivity is predictive of a good response to hormonal manipulation, as much in an adjuvant [12] as in a palliative setting [13].

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Postmenopausal women with a breast tumour too large to be treated by immediate conserving surgery were proposed to receive a neoadjuvant treatment with tamoxifen if their tumour expressed steroid receptor positivity. In case of steroid receptor negativity, patients were treated by modified radical mastectomy or by neoadjuvant chemotherapy if they wanted a conserving treatment.

From 1985 to 1996, 199 women aged 50–70 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%).


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics
 
Tamoxifen was given for 4–6 months (median duration 5.34 months). Up to the end of 1995, 30 mg/day was given, and 20 mg/day after that, according to the posology usually applied at that time.

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 Kaplan–Meier method. Survival time, time to local recurrence and time to metastasis were computed from the start of tamoxifen date.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Clinical objective response was noted in 44% and 48% of T2/3 and T4 tumours, respectively. After neoadjuvant tamoxifen, locoregional treatment was carried out in 89 cases of T2/3 tumours (92%): 37 with modified radical mastectomy, 38 with conserving surgery and irradiation and 14 with exclusive irradiation. Conserving treatment rate after neoadjuvant tamoxifen was 53.6% for these operable tumours. Eight patients did not have local treatment after neoadjuvant tamoxifen. Two of them refused local treatment and continued with tamoxifen. The other six patients had a progression of their disease with tamoxifen and received chemotherapy; four of them could have locoregional treatment after completion of chemotherapy and the other two, with secondary metastatic disease, received a general treatment (Table 3).


View this table:
[in this window]
[in a new window]
 
Table 3. Local treatment after neoadjuvant tamoxifen
 
Locoregional treatment was carried out in 93 cases of T4 tumours (91%), either with modified radical mastectomy (37 cases) or with conserving surgery plus irradiation (19 cases). Twenty-four had exclusive irradiation after complete clinical regression. Thirteen patients who did not have regression of their tumour with tamoxifen received a subsequent irradiation; 11 of them did not have sufficient regression and mastectomy was finally carried out and the other two were able to have conserving surgery. So, conserving treatment was applied to 45 patients (44%). Of the nine remaining patients, two continued with tamoxifen: one patient refused local treatment and the other one could not have her tumour surgically removed. The other seven, who had a tumour progression with tamoxifen, received a second-line medical treatment: chemotherapy was prescribed to four patients because of a dramatic progression of the tumour, and a second-line hormonal treatment was given to the other three (Table 3).

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).



View larger version (8K):
[in this window]
[in a new window]
 
Figure 1. Actuarial curves of local recurrences after conserving treatment post-tamoxifen.

 


View larger version (15K):
[in this window]
[in a new window]
 
Figure 2. Metastasis-free survival.

 
Twenty-six (27%) and 37 (36%) deaths occurred in T2/3 and T4 tumours, respectively. Median survival is 102 months for T4 tumours, and it has not yet been reached after a 94 month follow-up for T2/3 (Figure 3).



View larger version (14K):
[in this window]
[in a new window]
 
Figure 3. Overall survival.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In elderly patients, several phase II trials have shown that first-line tamoxifen could obtain a good local control rate if selection of hormone-sensitive lesions is assessed. Four randomised phase III trials have been published so far. They compare, for locally advanced [4, 5, 15, 16] or operable breast tumours [4, 5], modified radical mastectomy to tamoxifen followed by salvage mastectomy in case of local progression. If local control is better in case of first-line surgery, overall survival is identical whatever the treatment arm.

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 51–60 years old and 36% for patients 61–70 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, 50–59 years, 60–69 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.


    Footnotes
 
+ Correspondence to: L. Mauriac, Department of Medical Oncology, Institut Bergonié, Regional Cancer Center, 229, cours de l’Argonne, 33076 Bordeaux cedex, France. Tel: +33-5-56-33-33-33; Fax: +33-5-56-33-33-85; E-mail: mauriac@bergonie.org Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1. Preece PE, Wood RA, Mackie CR, Cuschieri A. Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. BMJ 1982; 284: 869–870.

2. Howell A, Robertson JFR. The primary use of endocrine therapy. In Dowsett M, Howell A (eds): Primary Medical Therapy for Breast Cancer: Clinical and Biological Aspects. ESO Scientific Updates, Vol. 4. Amsterdam: Elsevier 1999; 23–37.

3. Bates T, Riley DL, Houghton J et al. Breast cancer in elderly women: a Cancer Research Campaign trial comparing treatment with tamoxifen and optimal surgery with tamoxifen alone. The Elderly Breast Cancer Working Party. Br J Surg 1991; 78: 591–594.

4. Gazet JC, Ford HT, Bland JM et al. Prospective randomised trial of tamoxifen versus surgery in elderly patients with breast cancer. Eur J Surg Oncol 1994; 20: 207–214.[Medline]

5. Robertson JFR, Ellis IO, Elston CW, Blamey RW. Mastectomy of tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 1992; 28A: 908–910.

6. Mustacchi G, Milani S, Pluchinotta A et al. Tamoxifen or surgery plus tamoxifen as primary treatment for elderly patients with operable breast cancer: The G.R.E.T.A. Trial. Group for Research on Endocrine Therapy in the Elderly. Anticancer Res 1994; 14: 2197–2200.[ISI][Medline]

7. Fisher B, Brown A, Mamounas E et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997; 15: 2483–2493.[Abstract]

8. Makris A, Powled TJ, Ashley SE et al. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 1998; 9: 1179–1184.[Abstract]

9. Mauriac L, Durand M, Avril A, Dilhuydy JM. Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Ann Oncol 1991; 2: 347–354.[Abstract]

10. Scholl SM, Fourquet A, Asselain B et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumors considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer 1994; 30A: 645–652.

11. Semiglazov VF, Topuzov EE, Bavli JL et al. Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol 1994; 5: 591–595.[Abstract]

12. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–1467.[ISI][Medline]

13. Osborne CK. Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 1998; 51: 227–238.[ISI][Medline]

14. Mauriac L, Wafflart J, Durand M et al. Apport de la drill-biopsie dans le bilan préthérapeutique des adénocarcinomes mammaires. Bull Cancer 1981; 68: 417–421.[ISI][Medline]

15. Williams MR, Gilson D, Marsh L et al. The early results from a randomised study of radiotherapy versus Nolvadex (tamoxifen) as initial treatment for stage III breast cancer. Eur J Surg Oncol 1988; 14: 235–240.[ISI][Medline]

16. Willsher PC, Robertson JFR, Chan SY et al. Locally advanced breast cancer: early results of a randomised trial of multimodal therapy versus initial hormone therapy. Eur J Cancer 1997; 33: 45–49.[Medline]

17. Furr BJA, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 1984; 25: 127–205.[ISI][Medline]

18. Henderson IC. Principles in the management of metastatic disease: Endocrine therapy of metastatic breast cancer. In Harris JR, Hellman S, Henderson IC, Kinne DW (eds): Breast Diseases, 2nd edition. Philadelphia, PA: J.B. Lippincott Company 1991; 559–603.

19. Elledge RM, Green S, Pugh R et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 2000; 89: 111–117.[ISI][Medline]

20. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1–15.[ISI][Medline]

21. Soubeyran I, Quénel N, Coindre JM et al. pS2 protein: a marker improving prediction of response to neoadjuvant tamoxifen in post-menopausal breast cancer patients. Br J Cancer 1996; 74: 1120–1125.[ISI][Medline]

22. Eiermann W, Mauriac L, Semiglazov V. Neoadjuvant treatment of postmenopausal breast cancer patients and impact on breast-conserving surgery: a double blind randomized study comparing letrozole to tamoxifen—The Letrozole Neoadjuvant Breast Cancer Study Group. 25th ESMO Congress, Hamburg, 13–17 October 2000. Ann Oncol 2000; 11 (Suppl 4): 16 (Abstr 610).

23. Dezou S. Hormonothérapie première par tamoxifène de cancers du sein non métastatiques. A propos de 100 cas. Thesis, Université Victor Segalen Bordeaux 2. Thèse Bordeaux 1989, no. 3031.

24. Miller WR, Anderson TJ, Hawkins RA et al. Neoadjuvant endocrine treatment: the Edinburgh experience. In Dowsett M, Howell A (eds): Primary Medical Therapy for Breast Cancer: Clinical and Biological Aspects. ESO Scientific Updates, Vol. 4. Amsterdam: Elsevier 1999; 89–99.

25. Fisher B, Bryant J, Wolmark N et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998; 16: 2672–2685.[Abstract]

26. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942.[ISI][Medline]

27. Gelber RD, Cole BF, Goldhirsch A et al. Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival. Lancet 1996; 347: 1066–1071.[ISI][Medline]

28. Mauriac L, Blanc-Vincent MP, Luporsi E et al. Standards, options et recommandations: hormonothérapie dans les cancers du sein non métastatiques. Bull Cancer 2000; 87: 469–490.[ISI][Medline]

29. Mauriac L, MacGrogan G, Avril A et al. Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonié Bordeaux Groupe Sein (IBBGS). Ann Oncol 1999; 10: 47–52.[Abstract]

30. Broet P, Scholl SM, de la Rochefordière A et al. Short and long-term effects on survival in breast cancer patients treated by primary chemotherapy: an updated analysis of a randomized trial. Breast Cancer Res Treat 1999; 58: 151–156.[ISI][Medline]