Br. J. Surg. 1992, Vol. 79, December, 1314-1 316

S. C . Low, A. R . Dixon. J. Bell*, 1. 0. Ellis*, C. W. Elston*, J. F. R. Robertson and R . W. Blarney Professorial Unit of Surgery and *Department of Pathology, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK Correspondence to: Mr S . C. Low

Tumour oestrogen receptor content allows selection of elderly patients w i t h breast cancer for conservative tamoxifen treatment Immunocytochemical analysis was used to determine tumour oestrogen receptor (E R ) content in elderly patients with primary operable breast cancer. Only those E R positive were selected for conservative treatment with tamoxifen alone. Initial response was compared with that of historical controls not selected according to E R status. Early progressive disease was markedly reduced at 6 months, from 30 per cent in the unselected control group to 2 per cent in the study group ( P < 0.001). Immunocytochemical analysis is useful for the initial selection of elderly patients with breast cancer who may be treated with tamoxifen alone.

Tamoxifen can be used as an alternative to surgery for the treatment of primary operable breast cancer in the elderly’-4. Two randomized prospective trials comparing surgery with tamoxifen have shown no difference in overall survival in the two treatment groups5s6. The latter trial6 examined only tumours < 5 cm in diameter. Although there was no difference in survival between the two groups, surgery gave significantly better ultimate control of primary disease than did tamoxifen treatment, largely because of a high rate (30 per cent) of initial disease progression on tamoxifen. Disease in a further 14 per cent of patients progressed after an initially favourable response. Mastectomy should therefore be considered the optimal initial approach. However, in one-third of patients long-term local control was achieved with tamoxifen for up to 5 years, suggesting that this drug might benefit selected patients. Oestrogen receptor immunocytochemical analysis (ERICA) of fine-needleaspirates of breast cancer is a good predictor of response to hormonal treatment’-’. In these studies, patients received the same treatment regardless of the ER-ICA result. In the present trial of surgery uersus tamoxifen, the ER-ICA result has been used to select elderly patients with primary operable breast cancer for treatment with tamoxifen alone.

represents 100 per cent of tumour cells stained strongly. A minimum of 100 cells per sample was considered necessary for a satisfactory assay. Repeat fine-needle aspiration was carried out if specimens were inadequate. For the purposes of the trial, H scores c 100 were considered ER negative and those 100,positive. Patients who were ER positive were randomized to a trial of surgery uersus tamoxifen alone (20 mg twice daily). All patients with ER-negative tumours were excluded from the trial and treated surgically. Response to treatment with tamoxifen was assessed clinically by measuring tumour size at intervals of 3 months. Patients were assigned to one of four categories of response (progression, disease static, partial regression and complete regression) using Union Internacional Contra la Cancrum criteria12. Response was determined at 3 and 6 months, and on subsequent follow-up, unless there was earlier disease progression. The ‘best assessment’ of response to tamoxifen represents patients with disease that was static at 6 months, going on to partial or complete regression, and those with partial regression at 6 months going on to complete regression (i.e. it is the best response of each patient to date). Tamoxifen treatment was continued as long as there was no evidence of progression, at which point mastectomy was recommended.

Results Patients and methods

This formula produces an H score between 0 and 300, where 300

To date, a total of 139 patients have been studied, of whom 23 (17 per cent) had inadequate specimens for ER-ICA requiring repeat fine-needle aspiration. ER-ICA scores were 2 100 in 98 patients, and these were randomized to a trial of surgery ( n = 44) versus tamoxifen ( n = 54). A total of 41 patients had ER-ICA scores < 100 and were excluded from the trial. This report examines the group of 54 ER-positive patients treated with tamoxifen alone, of whom 50 could be assessed for initial response. The mean age in this group was 78 (range 70-87) years with a median follow-up of 13 (range 3-31) months. The median tumour size was 3 (range 1-5) cm. Response to tamoxifen is shown in Table 1. Objective regression (partial or complete) was achieved in 43 patients on best assessment. Almost all of these showed at least partial regression at 6 months: only one patient (with an ER-ICA score of 200) showed initial progression of disease, at 3 months. In Table 2 these results are compared with those of historical controls: 57 patients from a previous trial6 who were similarly treated and assessed but who were not selected with regard to ER status. At 6 months there is a marked reduction in the number of those with early progression, from 30 per cent in the unselected control group to 2 per cent in the present study group (1’ = 13.8, 1 d.f., P < 0.001). The distribution of individual ER-ICA scores in patients with a favourable initial response is shown in Figure 1. There

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0007-I 323/Y2/12131 4 0 3

Since February 1989, 139 patients over 70 years of age with primary operable breast cancer (Tli2NO,,M a ) and fit for surgery have been studied prospectively. Fine-needle aspirates were obtained for diagnosis and ER measurement by ER-ICA. Specimens were smeared on to glass slides (three slides for ER-ICA: two for the assay, one in reserve) and air-dried. Specimens for ER-ICA were fixed within 30min of sampling in 10 per cent neutral buffered formalin for lOmin, followed by 100 per cent methanol at - 10 to -20°C for 3 min, then acetone at - 10 to -20°C for 2 min. Slides were then washed in Tris-buffered saline (pH 7.5-7.6) and kept in a buffered glycerol-sucrose storage medium at -20°C. ER-ICA was performed weekly using a kit (Abbott Laboratories, North Chicago, Illinois, USA) with monoclonal antibody H-222, and a subsequent staining procedure as has been previously described’ O. Quantification of ER-ICA results was performed by assessment of the intensity of nuclear staining (no staining, 0; staining weak but above background level, 1; moderate staining, 2; strong or intense staining, 3) and the percentage of cells at each level of intensity. A histochemical score (H score’’ )was derived from these two parameters: ER-ICA H score = (percentage of cells stained at intensity category 1) 2 x (percentage of cells stained at intensity category 2) 3 x (percentage of cells stained at intensity category 3 )

+ +

1992 Butterworth-Heinemann Ltd

Treatment of breast cancer in t h e elderly: S. C. Low et a\.

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Table 1 Initial response to tamoxifen

?5 Time of assessment

c Q

m

L

Complete regression Partial regression Disease static Progression of disease Total

3 months

6 months

Best assessment

14 22 13 1 50

21 19 6 1 47*

26 17 6 1 50

*In three patients follow-up was < 6 months; at 3 months regression was partial in two patients and disease static in one

-m 4 0

12

24 36 48 60 72 Duration of response (months)

84

No. at risk

Table 2 Comparison of present results with historical controls Response at 6 months

Oestrogen receptorpositive group

Unselected control group*

Complete regression Partial regression Disease static Progression of disease Total

21 19 6 1 47

22 9 9 17 57

t

Figure 2

41 16 9

22 8 4

15 6 1

11 3 1

7 2

-

6 1

-

Duration of response according to type: complete regression regression and disease static ( 0 ) .Patients with static disease have poorer local control than complete responders (xz = 8.9, I d f . , P c 0 4 1 ) and partial responders (xz = 4.2, 1 d f . , P < 0.05) by log rank test

(o), partial

(e),

was a trend towards a larger proportion of high scores ( > 150) from static disease to complete regression. To date, five patients with a favourable initial response have suffered local relapse (Table 3). Figure 2 shows the actuarial local relapse-free survival rate according to the type of initial response (excluding initial progressors) in patients from past and present trials treated with tamoxifen alone. (The previous study6 has been updated for best assessment of response' and these data then combined with those of the present study. 1

*From Robertson et aL6

250

Complete 53 28 Partial Static 16

e e

Discussion This randomized trial attempts to identify a group of elderly patients who will benefit from tamoxifen treatment alone and retests the hypothesis that some patients with operable breast cancer can be spared surgery. Tamoxifen does not compromise overall survival, but has questionable efficacy in controlling locoregional disease. The solution to this problem may lie in good patient selection, two aspects of which need to be addressed. Disease static ( n = 6)

Pa rt ia I regression ( n = 17)

Complete regression ( n = 26)

Response to tamoxifen

Figure 1 Oestrogen receptor immunocytochemical analysis ( ER-1CA ) score according to type of response. r, = 0.05

Table 3 Secondary progression of disease in .five patients treated with tamoxifen alone Duration of response (months)

Patient no.

ER-ICA score

Initial response

1

120 100 190 130 210

Complete regression Partial regression Partial regression Disease static Disease static

2 3 4 5

22 15 11 10

9

~~

ER-ICA, oestrogen receptor immunocytochemical analysis

Br. J. Surg.. Vol. 79, No. 12,

December 1992

Initial response A proportion (up to 35 per cent) of tumours will continue to progress in patients receiving tamoxifen. Gaskell et aL8 found that it was possible to predict early progression of tumours (40 per cent locally advanced) using ER-ICA: when more than 25 per cent of cells were immunostained there was no incidence of early progression, but below this level 86 per cent of tumours progressed. Using the same cut-off value, Davies et a[.' studied a similar group of patients and reported a 93 per cent rate of initial progression in those with ER-ICA-negative tumours against 9 per cent in those with ER-ICA-positive tumours. The present study confirms the effectiveness of ER-ICA in selecting out the patients likely to have early progression from those likely to have a favourable initial response to tamoxifen. Duration of response Patients with a favourable initial response to tamoxifen show a definite risk of subsequent local relapse. Horobin et aL4 followed 113 patients over 5 years with primary breast cancer treated with tamoxifen only and found that disease control eventually failed in 62 per cent. They observed that tamoxifen, in effect, only delayed more definitive therapy. While ER-ICA appears to be effective in selecting those whose disease will

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Treatment of breast cancer in the elderly:

S.C. Low et

al.

progress early, it is less useful in predicting the duration of response. Reports from Horobin et Falk et a1.I4, and the present data indicate that the duration of response may be related to the type of response. It may be possible to select patients for long-term treatment with tamoxifen in two stages. ER-ICA should be used initially to select out those tumours likely to progress early and which should be treated with surgery. The remaining patients should be treated with tamoxifen and a second selection carried out at 6 months. Those with static disease are at high risk of local relapse and should be considered for surgery.

Acknowledgements This study was supported by a grant from the Cancer Research Campaign.

References 1. 2. 3. 4. 5.

Preece PE, Wood RAB, Mackie CR, Cuschieri A. Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. BMJ 1982; 284: 869-70. Bradbeer JW, Kyngdon J . Primary treatment of breast cancer in elderly women with tamoxifen. CIin Oncol 1983; 9: 31-4. Margolese RG, Foster RS Jr. Tamoxifen as an alternative to surgical resection for selected geriatric patients with primary breast cancer. Arch Surg 1989; 124: 548-51. Horobin JM, Preece PE, Dewar JA, Wood RAB, Cuschieri A. Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifenonly.BrJSurg 1991;78:213-17. Gazet JC, Ford HT, Bland JM, Markopoulos CH, Coombes RC, Dixon RC. Prospective randomised trial of tamoxifen uersus

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surgery in elderly patients with breast cancer. Lancet 1988; i: 679-81. 6. Robertson JFR, Todd JH, Ellis 10, Elston CW, Blamey RW. Comparison of mastectomy with tamoxifen for treating elderly patients with operable breast cancer. BMJ 1988; 297: 511-14. 7. Coombes RC, Powles TJ, Berger U et al. Prediction of endocrine response in breast cancer by immunocytochemical detection of oestrogen receptor in fine-needle aspirates. Lancet 1987; ii: 701-3. 8. Gaskell DJ, Sangsterl K, Hawkins RA, Chetty U, Forrest APM. Relation between immunocytochemical estimation of oestrogen receptor in elderly patients with primary breast cancer and response to tamoxifen. Lancet 1989; i: 1044-6. 9. Davies N, Moir G , Carpenter R et al. ERICA predicts response to tamoxifen in elderly women with breast cancer. Ann R Coll Surg Engl 1991; 73: 361-3. 10. Walker KJ, Bouzubar N, Robertson J et al. Immunocytochemical localization of estrogen receptor in human breast tissue. Cancer Res 1988; 48: 6517-22. 11. McCarthy KS Jr, Miller LS, Cox EB, Konrath J, McCarthy KS Sr. Estrogen receptor analyses: correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985; 109: 716-21. 12. Hayward JL, Carbone PP, Heuson JC, Kumoaka S, Segaloff A, Reubens RD. Assessment of response to therapy in advanced breast cancer. Br J Cancer 1977; 35: 292-8. 13. Robertson JFR, Ellis 1 0 , Elston CW, Blarney RW. Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 1992; 28A: 908-10. 14. Falk GL, Gwynne-Jones D, Gray JC. Efficacy of tamoxifen as the primary treatment of operable breast cancer in the high risk patient. Aust N Z J Surg 1989; 59: 543-5. Paper accepted 9 May 1992

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