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Educational Supplement: Appendix
Traditional
and Newer Pathological Factors
Stuart
J. Schnitt, M.D.
During the last
two decades there has been an intensive effort by many investigators
to identify prognostic and predictive factors for patients with
breast cancer. Prognostic factors are defined as those capable of
providing information on clinical outcome at the time of diagnosis,
whereas predictive factors are defined as those capable of providing
information on the likelihood of response to a given therapeutic
modality (Gasparini, Pozza, Harris, 1993). Many recent studies have
focused on the potential prognostic and/or predictive role of newer
biological and molecular markers, such as growth factors and their
receptors, oncogenes and tumor suppressor genes and their products,
proteolytic enzymes, adhesion molecules, and markers of cellular
proliferation and angiogenesis, among others (Mansour, Ravdin, Dressler,
1994). However, studies of such factors have frequently yielded
conflicting results and clinical confusion (Loprinzi, Ravdin, de
Laurentiis, et al., 1994). Much of the confusion is due to the fact
that even studies evaluating the same prognostic marker often differ
in patient selection, treatment methods (including the use of systemic
therapy), methods for analyzing the marker, methods of statistical
analysis, length of patient followup, and prognostic markers to
which the new marker is being compared.
There is universal
agreement that the status of the axillary lymph nodes as determined
by routine pathologic evaluation remains the most important prognostic
factor for patients with breast cancer (Goldhirsch, Glick, Gelber,
et al., 1998). Although there is increasing interest in the use
of ancillary techniques, such as immunohistochemistry, to detect
occult tumor cells, the clinical significance of occult axillary
lymph node metastases detected exclusively by immunohistochemical
staining or any other ancillary technique is at present an unresolved
issue (Giuliano, Kelemen, 1998).
Among patients
with node-negative disease, the important prognostic factors are
generally considered to be tumor size, histologic and/or nuclear
grade, histologic type, and hormone receptor status (Goldhirsch,
Glick, Gelber, et al., 1998). Hormone receptor status is also the
most important predictive factor for response to systemic endocrine
therapy. At a recent consensus conference held under the auspices
of the College of American Pathologists (Fitzgibbons, Page, Weaver,
et al., 2000), a multidisciplinary group of pathologists, clinicians,
and statisticians reviewed prognostic and predictive factors in
breast cancer and categorized them based on the strength of published
evidence into the following groups:
Category
I: Factors proven to be of prognostic importance and useful
in clinical patient management. Included in this category are tumor
size, lymph node status, histologic grade, histologic type, mitotic
rate, and hormone receptor status.
Category
II: Factors that have been extensively studied biologically
and clinically, but whose import remains to be validated in statistically
robust studies. This category includes HER-2/neu, p53, lymphovascular
invasion, and proliferation markers.
Category
III: All other factors not sufficiently studied to demonstrate
their prognostic value. Included in this group are DNA ploidy, tumor
angiogenesis, epidermal growth factor receptor, transforming growth
factor-alpha, bcl-2, pS2, and cathepsin D.
In addition,
detailed recommendations for improvement of each factor were made,
based on the following goals: (1) to increase the uniformity and
completeness of pathologic evaluation; (2) to enhance the quality
of data collected about existing prognostic factors; and (3) to
improve patient care.
It is of interest
to recall that one of the four major issues discussed at the 1990
NIH consensus development conference on the treatment of early breast
cancer was the use of prognostic factors to manage patients with
node-negative disease. At that conference, a useful prognostic factor
was defined as one that had the following characteristics: (1) significant
and independent predictive value validated by clinical testing;
(2) identification that was feasible, reproducible, and widely available
with quality control; and (3) ease of interpretation by clinicians
and having therapeutic implications (NIH Consensus Conference, 1991).
Even at this time, 10 years later, few, if any, of the numerous
reported prognostic or predictive factors fulfill all three of these
criteria.
References
Fitzgibbons
PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic
factors in breast cancer. College of American Pathologists consensus
statement 1999. Arch Pathol Lab Med 2000;124:966-78. Abstract.
Gasparini G,
Pozza F, Harris A. Evaluating the potential usefulness of new prognostic
and predictive indicators in node-negative breast cancer patients.
J Natl Cancer Inst 1993;85:1206-18. Abstract.
Giuliano AE,
Kelemen PR. Sophisticated techniques detect obscure lymph node metastases
in carcinoma of the breast. Cancer 1998;83:391-3. Abstract.
Goldhirsch A,
Glick JH, Gelber RD, Senn HJ. Meeting highlights: International
consensus panel on the treatment of primary breast cancer. J Natl
Cancer Inst 1998;90:1601-8. Abstract.
Loprinzi CL,
Ravdin PM, de Laurentiis M, Novotny P. Do American oncologists know
how to use prognostic variables for patients with newly diagnosed
primary breast cancer? J Clin Oncol 1994;12:1422-6. Abstract.
Mansour EG,
Ravdin PM, Dressler L. Prognostic factors in early breast cancer.
Cancer 1994;74:381-400. Abstract.
NIH consensus
conference. Treatment of early-stage breast cancer. JAMA 1991;265:391-5.
No Abstract Available.
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