Br. J. Surg. 1985, Vol. 72, January, 7-9

S. J. Nixon, R. J. C. Steele, A. R. Hawkins, J . McGregor and A. P. M. Forrest

Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK Correspondence to: Professor A. P. M. Forrest

Prediction of recurrence after mastectomy for operable breast cancer

A patient's risk of early recurrence after mastectomy for breast cancer has been estimated by using a combination of four prognostic factors. A computer program, designed to calculate the exact probability of recurrence within 2 years of mastectomy, was accurate when tested on 240 patients. A simple scoring system could identify patients at lower and greater risk than any single factor alone. Keywords: Mastectomy, breast cancer, recurrence

With the increasing use of adjuvant therapy in patients with breast cancer it has become important to predict rates of recurrence after mastectomy. At present the extent of axillary node involvement is regarded as the best indicator of prognosis but this requires a complete axillary dissection and pathological examination of up to 50 nodes. Next best is an indication of whether the axillary nodes are involved. This can be estimated with 90 per cent accuracy by sampling four lower axillary nodes'.

Other factors are known to influence the prognosis of operable breast cancer. These include tumour histo- logical grade5- ' and oestrogen receptor ~ t a t u s ~ , ~ , ~ .

We have examined the possibility of combining these three factors with axillary node status firstly by a computer program which calculated the exact probability of recurrence within 2 years of mastectomy and secondly by a simple scoring system.

Patients and methods Four published ~tudies"~. including 3 104 patients, were examined to obtain the reported rate of recurrence within 2 years of mastectomy related to tumour size, axillary and pectoral node involvement, oestrogen receptor status and histological grade. The resulting data base is shown in Table 1. In one of these series, 18 month (rather than 2 year) recurrence rates were reported and 2 year rates have been estimated on the assumption that recurrence rate is linear within this period.

From these data and using Bayes' probability theory, a computer program was designed to combine these four prognostic factors and to calculate the probability that a patient might have recurrence of disease within 2 years of mastectomy.

From this literature search it was apparent that four high risk factors (a) tumour size of 5cm or more, (b) axillary node involvement, (c) negative oestrogen receptor status and (d) poor histological differen- tiation were of approximately equal prognostic significance. A simple scoring system was devised giving one point for each of these four factors.

These two methods of prediction were applied to a series of 240 patients, all with invasive but operable breast cancer who were treated consecutively in our unit by simple mastectomy and pectoral node sampling during the period 1974-1977. All node positive patients received immediate postoperative radiotherapy. Node negative patients were randomly selected either to receive immediate radiotherapy or no further local treatment according to the protocol of the Edinburgh Breast Trial. Node positive patients were randomly selected for systemic therapy and received either 5-fluorouracil or no systemic treatment. Node negative patients received no systemic adjuvant therapy. These variations in treatment have been shown not to significantly affect prognosis.

All patients attended for regular follow-up at 3 monthly intervals during the first 2 years after mastectomy. The date of recurrence was defined as the date at which signs first occurred, regardlessof the interval between suspicion and confirmation of metastasis.

As half of the patients with negative nodes did not receive post- operative radiotherapy, recurrence in the non-irradiated operation field has not been regarded as a treatment failure but rather as an indication for delayed radiotherapy. Recurrence was therefore defined as any

systemic metastasis, regional disease or local recurrence in an irradiated area.

Tumour size was measured by calipers at the time of presentation and was known in 239 patients. Three groups were defined: 0-2 cm (TI); greater than 2 cm but less than 5 cm (T2); 5 cm or more (T3). There were 60 TI tumours, 125 T, tumours and 54 T, tumours.

Axillary node sampling was performed at mastectomy as described by uslO. Nodes were examined histologically at multiple levels and classified as being involved by tumour or free of involvement. Nodes had been identified in 201 patients. They contained tumour deposits in 97 patients and were negative in 104. In this early series no nodes were identified by surgeon or pathologist in 38 patients (a proportion we would now consider to be unsatisfactory). As the observed recurrence rates in these patients were the same for those with uninvolved nodes (8 versus 13 per cent 2 year recurrence) these two groups have been identified into a single 'node negative' group.

Oestrogen receptor concentration in the tumour was measured by saturation analysisg. Following incubation of tumour cytosol with varying concentration of H3-labelled and 'cold' oestradiol-l7B, bound and free oestradiol were separated by dextran-coated charcoal and the receptor concentration determined by Scatchard analysis using a five point assay. A level of 0.4 fmol/mg wet weight or less (equivalent to 10 fmol/mg protein) was considered as oestrogen receptor negative. Oestrogen receptor status was known in 208 patients and was positive in 130.

Histological sections of the primary tumour were reviewed by two of us. They were graded as being well, moderately or poorly differentiated by the criteria of Fisher'. Tumour grade was known in 224 patients; 19 were well differentiated, 67 moderately differentiated and 138 poorly differentiated.

Table 1 (literature derioed)

Data base for prediction of2 year recurrence u f e r mastectomy

PI P2

Size Less than lcm 1-1.9 cm 2-2.9 cm 3-3.9 cm 44 .9 cm 5-59 cm 6 cm or more

Node status Positive Negative

Positive Negative

Histology Grade 1 Grade 2 Grade 3

Receptor status

0.02 0.16 0-26 0.2 1 0.16 0.09 010

0.43 0.57

068 0-32

004 0.33 0.63

0.0 1 0.16 0.13 0.22 0.10 0.17 0.32

0.85 0.15

0.47 0.53

0.0 1 0.20 0.79

P1, probability of having sign in patients not recurring within 2 years P2, probability of having sign in patients recurring within 2 years

0007-1323/85/01000743$3.00 @ 1985 Buttenvorth & Co (Publishers) Ltd 7

Recurrence of breast cancer after mastectomy: S. J. Nixon et al.

Table 2 Two year recurrence related to single prognostic factors. The ‘expected’ nitmbers of recurrences are derived from the literature and the ‘ohserried’ from our series of 240 patients

Number recurring (%)

Total Expected Observed

Size T, (0-2cm) 60 T , (>2and <5cm) 125 T, (>5cm) 54

Negative 142 Positive 97

Positive 130 Negative 78

Grade 1 19 Grade 2 67 Grade 3 138

Total 240

Node status

Receptor status

Histology

6 21 21

10 35

21 24

1 9

36 51

Table 3 computer program, ’observed’ as seen in our 240 patients

Expected and ohseroed recurrence: ‘expected’ a s calculated by

Computer predicted Total Expected Observed recurrence rate (%) number recurrence recurrence

0-10 11-35 36-1 00 Total

120 5 11 (9%) 71 13 14 (18%)

240 44 51 (21%) 49 25 27 (55%)

Of the 240 patients in the study, all four prognostic factors were known in 204 patients, three factors in 22 patients and two factors in 14 patients. The data for each patient were entered into the computer program and the probability of 2 year recurrence calculated. In addition, each patient was given a score of 04 according to the presence of high risk factors.

All statistical analyses were performed using xz testing with Yates’ correction for small numbers where appropriate. When numbers were very small, Fisher’s exact test was used.

Results The pattern of recurrence in our patients is compared with that expected from the literature for each single prognostic factor in Tuble 2. There are no significant differences between the expected and observed recurrence rates.

The computer derived probability of recurrence within 2 years of mastectomy using all four factors in combination varied from 0-78 per cent in our patients. The mean, computer derived probability of recurrence was 18.3 per cent, i.e. 44 patients could be expected to have recurrence within 2 years. In fact, 51 did have recurrence, the difference between observed and expected being insignificant. The literature study indicated that there is overall a 21 per cent risk of recurrence within 2 years of mastectomy, identical to that observed in our patients and very similar to the computer derived prediction after combination of the risk factors. In Table 3 the patients are grouped into three categories of computer risk: (a) low risk with a calculated probability of 10 per cent or less; (b) medium risk between 11 and 35 per cent; (c) high risk of greater than 35 per cent. In each group the number of patients observed to suffer recurrence within 2 years is accurately predicted by thecomputer program. The underestimate of recurrence in the low risk group is not statistically significant.

The results of the scoring system are shown in Table 4. There was a progressive increase in the observed 2 year recurrence rate as the risk score increased from W. This was particularly

pronounced when three or four risk factors were present; 60 per cent of such patients have recurrence within 2 years of mastectomy. The difference in recurrence rates between patients with a risk score of 0-1,2 and 3 4 risk factors is highly significant ( P < 0.025).

Three statistically significant interrelations were found between the four prognostic factors. Poorly differentiated tumours were associated with involved axillary lymph nodes, negative oestrogen receptor status and were generally larger in size.

Discussion The identification of patients at high and low risk of recurrence after mastectomy is likely to have practical relevance in the decision for or against adjuvant therapy, particularly chemo- therapy or endocrine ablative surgery. Most clinicians reserve these treatments for patients at greatest risk of early recurrence and most controlled trials of adjuvant chemotherapy have limited its use to high risk patients. Axillary node involvement is the most commonly used indicator of poor prognosis although our literature study showed that oestrogen receptor status, histological differentiation and tumour size may have equal prognostic significance.

Improvement of the accuracy in predicting recurrence could be of value both in planning treatment for an individual patient and in trial design. Unless new prognostic factors are discovered any improvement can only be achieved by combining risk factors.

Previous authors3.’ have shown a definite additive value of nodal status and oestrogen receptor status in that node positive, receptor negative tumours have an extremely poor prognosis, whilst node negative, receptor positive patients have a very low recurrence rate”. Even when the results of all published studies are combined’ the association between nodal involvement and receptor status is weak, suggesting that they reflect different characteristics of tumour invasion. Although over 30 prognostic factors have been described, strong associations between many of them lessen their additive value. Based on previous work5 we therefore limited our study to the four best documented factors in the knowledge of definite although weak associations between

In our patients the progressive worsening of prognosis as the risk score increases clearly demonstrates that these four factors do have an additive value.

Multivariate analysis is a powerful technique for the construction of predictive indices, It calculates a relative weighting of prognostic factors, indicates which factors in combination give the best predictive index and which factors make no additional significant contribution. The method had been applied to predicting recurrence5 and death after mastec- tomy’ I . In the latter study, the correlation between poor histological grade and negative receptor content reduced the value of receptor status as a contributing factor. However, we have recently been able to show that the prognostic value of oestrogen receptor can be greatly enhanced by critical choice of the ‘cut-off level between receptor positive and negative” and also by correction for tumour cellularity.

The value of a simple scoring system such as we originally reportedI4 has subsequently been confirmed’ to identify high

Table 4 point scoring system

The observed 2 year recurrence according t o a simple four-

Risk score Total Recurrence (%)

0 41 1 (2%) 1 74 8 (11%) 2 71 13 (18%) 3 41 24 iW3 4 7 5 (71%) Total 240 51

8 Br. J. Surg.. Vol. 72, No. 1, January1985

Recurrence of breast cancer after mastectomy: S. J. Nixon et al.

and low risk patient groups with a greater sensitivity than is achieved by any single factor alone. Its ease of use makes it more widely available and acceptable than complex formulae or computer derived calculations.

Bayes' probability theory presumes that there are no inter- relations between factors under test. It has been used in the field of computer assisted diagnosis. If associations between our factors were strong then the computer program would be expected to underestimate risk in low risk patients and to overestimate risk in high risk patients. We found a slight (but statistically insignificant) tendency to underestimate risk in low risk patients but the predicted risk in high risk patients was very accurate and justifies the use of this mathematical approach.

It may be possible to develop further our prognostic index either by inclusion of new factors or by a more detailed analysis of the four factors we have used. In the present study we have classified nodes as involved by tumour or free of tumour without reference to the extent, number or position of involved nodes. Each of these parameters has been shown to enhance the prognostic value of axillary nodal status and may improve the accuracy of prediction if included in our model. However, to obtain this information a formal axillary clearance operation and tedious examination of a large number of lymph nodes is required.

A comparison between the published prognostic indices and our own would be appropriate. However, the two previous studies have required knowledge of the number5 or site" of involved axillary nodes. As our patients had axillary sampling only we are not able to test these published indices on our patients but hope to do so on a more recent series of patients treated by mastectomy with axillary clearance.

In conclusion, we have shown that a simple score of four well- established prognostic factors can identify patient groups at high and low risk of recurrence after mastectomy. An accurate quantitation of risk can be obtained using Bayes' probability theory without the need for more elaborate mathematical models.

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Forrest APM, Stewart HJ, Roberts MM, Steele RJC. Simple mastectomy and axillary node sampling (pectoral node biopsy) in the management of primary breast cancer. Ann Surg 1982; 1%:

Fisher B, Slack NH, Bross IDJ. Cancer of the breast: size of neoplasm and prognosis. Cancer 1969; 24: 1071-80. Knight WA, Livingston RB, Gregory El, McGuire WL. Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer. Canc Res 1977; 37: 4669-71. Maynard PV. Prognostic factors in breast cancer: the formation of a prognostic index. Clin Oncol 1979; 5: 227-36. Breast Cancer Study Group. Identification of breast cancer patients with high risk of early recurrence after radical mastec- tomy. Cancer 1978; 42: 2809-26. Bloom HJG, Richardson WW. Histological grading and prognosis in breast cancer. Br J Canc 1957; 11: 359-77. Fisher ER, Redmond C, Fisher B. Histological grading of breast cancer. Pathol Ann 1980; 239-51. Bishop HM, Blamey RW, Elston CW, Haybittle JL, Nicholson RI, Grif€iths K. Relationship of oestrogen receptor status to survival in breast cancer. Lancet 1979; ii: 283-4. Hawkins RA, Roberts MM, Forrest APM. Oestrogen receptors and breast cancer: current status. Br J Surg 1980; 67: 15349. Forrest APM. Total mastectomy and pectoral node biopsy. In: Rob C, Smith R, eds. Atlas of General Surgery. London: Butterworths, 1981: 123-9. Haybittle JL, Blamey RW, Elston CW, Johnson J, Doyle PJ, Campbell FC, Nicholson RI, Griffiths K. A prognostic index in primary breast cancer. Br J Canc 1982; 45: 3614. Steele RJC, Forrest APM, Hawkins RA. Oestrogen receptors and survival in early breast cancer. Br Med J 1982; 284: 1190. Nixon SJ, Steele RJC, Hawkins AR, Forrest APM. Prognostic value of oestrogen receptorsignificance of the 'cut-off level. Lungenbecks Arch Chir 1982; 357: 209-10. Nixon SJ, Steele RJC, MacGregor J, Hawkins RA, Forrest APM. The prediction of early recurrence after mastectomy for breast cancer. Br J Surg 1981; 68: 802.

371-7.

Paper accepted 11 July 1984

Br. J. Surg., Vol. 72, No. 1, January 1985 9