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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A026
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.
------> 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
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
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.