6th ESACP Congress, Heidelberg, April 7-11, 1999

A026
------> Abstract too long for 6thESACP abstract reprint in ACP. Authors have been asked to submit shortened abstract version <---------
SELECTION OF LYMPH NODE NEGATIVE UNFAVOURABLE PREMENOPAUSAL BREAST CANCER PATIENTS FOR ADJUVANT SYSTEMIC THERAPY CAN BE DONE BEST BY THE MAI
Baak JPA and other MMMCP collaborators

Department of Pathology, Free University of Amsterdam, Netherlands

Breast cancer is an increasingly important health care problem. Prognosis can be improved by means of adjuvant therapy. For example, adjuvant chemotherapy (ACT) can improve the prognosis in lymph node (LN)+ premenopausal patients, and the result is better in those women with smaller metastatic deposits in their axillary nodes. Thus, premenopausal women, which are LN-negative probably may benefit most from ACT, but the side effects can be serious and only a small percentage of all LN-negative patients die from metastatic disease. As a result, the over-aggressive advice to treat all LN-negative patients with ACT is not well accepted. Accurate prognostic factors should be used to identify LN-negative, yet high risk breast cancer patients for systemic adjuvant treatment.
Classical factors as tumour diameter, histological grade and type, tumour border and angio- invasion are considered to have (some) prognostic value. Of these, histological grade is probably the most accurate one, but interobserver reproducibility is not optimal. Since 1975, a large number of other potential prognosticators has been analysed, like oestrogen and progesterone receptor (OR, PR), DNA ploidy, p53, neu, p21, apoptosis, neovascularisation, Rb, PAI-1, cathepsin-D and many others.
It is important to note, however, that Good Laboratory Practice (GLP) sets certain conditions to a prognostic laboratory test, before it can be used routinely in clinical practice. Some essential conditions are that the test should be 1) highly accurate and reproducible, 2) well established in different independent patient groups (without change of the decision threshold used), 3) widely available or applicable. Furthermore, 4) a Quality Control/Assurance protocol should be clearly established and tested. 5) The price/performance ratio should be good and 6) it is preferable that the feature used is biologically understandable. Clearly, only very few prognostic factors that ever have been proposed, fulfill all these criteria.
It has been shown by many investigators that features associated with proliferation (e.g, Thymidin Labelling Index, %S phase cells, %Ki-67, Mitotic Activity Index = MAI) are strong independent prognostic factors, also in LN-negative patients. This is especially true for the Mitotic Activity Index (MAI) for which the historic, biologic and methodologic prognostic proof is very strong. The reproducibility and prognostic accuracy of the MAI has been confirmed in the Dutch prospective Multicenter Morphometric Mammary Carcinoma Project (MMMCP) in which nearly 3,500 patients have been enrolled in 1988 an 1989. Of these, nearly 600 patients were LN-negative and premenopausal. Follow up of all patients is at least 8 years. As in many previous independent retrospective and prospective studies, all yearly interim analyses of the MMMCP material have shown that the MAI is by far the strongest predictor of outcome. The 8 year survival of LN-negative MAI >=10 patients is the same as patients with 1 or 2 positive lymph nodes. If MAI >=10, 8 year death rate is 34%, contrasting 5% if MAI <10. Multiple regression also showed that the MAI is the strongest prognostic factor. Thus, MAI <10 versus >=10 "explains" all the prognostic information contained in other prognostic features (like tumour diameter, grade, type, OR). Further analysis of patient subgroups, e.g. with different tumour diameters (<1, 1-2, 2-3, 3-5, >5), or different grades, reveals that in all subgroups MAI =10 is the prognostic determinator of each feature studied.
Interobserver reproducibility of the MAI in the MMMCP is very high (Kappa >0.90 for all centers), contrasting the low reproducibility of grade (Kappa <0.50). Moreover, MAI can be performed without special equipment, apart from a good quality standard microscope, and mitoses counts is a standard procedure in all pathology laboratories in the Netherlands.
Thus, at the moment the MAI is the only adequately validated, highly accurate, well reproducible and widely available prognostic factor in LN-negative breast cancer in the Netherlands.
Calculation for the Netherlands indicates that the annual gain in lives saved as a result of ACT is mainly, if not only in the group of patients with MAI >=10. The use of this selection criterion for ACT could prevent unnecessary over-treatment in approximately 825 women per year with a MAI <10 of the in total 1500 premenopausal breast cancer. By treating the 675 patients per year with a MAI >=10, 51-58 lives can be saved. If all 1500 premenopausal LN-negative patients would be treated by ACT, only 0-5 additional patients maybe rescued. Evaluation of other potential selection criteria (e.g. tumour diameter >2, or >3, OR-, or combinations like the one proposed at the St. Gallen consensus meeting) reveals that the theoretical gain in life-saving is much lower in comparison of that with MAI >=10, while over-treatment being much higher.
The same holds for LN-negative postmenopausal patients <70 years.
Interestingly, 45% of all LN-negative patients have a MAI >=10 - a slightly higher percentage than patients with a tumour diameter >2 centimetres (which form 38% of all LN-negative breast cancer women).
It therefore is proposed to select patients with a MAI >=10 for adjuvant systemic therapy. The subsequent choice of type of systemic treatment may be determined by OR positivity or negativity.