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Educational Supplement: Appendix
Prognostic
and Predictive Role of Proliferation Indices
Maria
Grazia Daidone, Ph.D.
Proliferative
cellular activity is one of the biological processes most thoroughly
investigated in breast cancer for its association with neoplastic
progression and metastatic potential. Several approaches, in addition
to the mitotic activity component of all pathologic grading systems,
have been used by pathologists and cell biologists to determine
and quantify the whole proliferative fraction or discrete fractions
of cells in specific cell cycle phases on consecutive series of
clinical tumors. Such approaches are based on different rationales,
including detection of proliferation-related antigens by way of
the Ki-67/MIB-1 labeling index and evaluation of the S-phase cell
fraction by quantifying nuclear DNA content or cells incorporating
DNA precursors (labeled pyrimidine bases, such as H-thymidine, or
halogenated analogs, such as bromo- or iododeoxyuridine). These
approaches employ different methods of evaluation (immunocytochemistry,
cytometry, or autoradiography), and each has advantages and disadvantages,
including different feasibility rates. Moreover, the different measures
of proliferation do not always prove to correlate with each other
in terms of biological or clinical significance when comparatively
analyzed on the same case series and may present slightly varying
sensitivity and specificity rates.
In general,
cell proliferation has proved to be associated with breast cancer
prognosis, even though its prognostic power tends to decline over
time, at least for the flow-cytometric S-phase cell fraction (FCM-S)
(Bryant, Fisher, Gunduz, et al., 1998). In patients with node-negative
breast cancer treated with local-regional therapy alone until relapse,
and in the presence of traditional prognostic factors (age, tumor
size, estrogen receptor [ER], and progesterone receptor [PgR]),
the S-phase fraction (evaluated as H-thymidine labeling index [TLI],
considered as a continuous variable and categorized by tree-structured
regression analysis) can be used to identify subsets at different
8-year risk of local-regional relapse (in association with patient
age) or distant metastasis (in association with tumor size and patient
age). Cell proliferation is the only prognostic discriminant for
intermediate-size (1-2 cm) tumors, whereas it is not predictive
for contralateral cancer (Silvestrini, Daidone, Luisi, et al., 1995).
In general, the prognostic information provided by FCM-S, TLI, or
the Ki-67/MIB-1 index is confirmed in multivariate analyses, including
DNA ploidy, p53 and bcl-2 expression, ER and PgR status, and histologic
or nuclear grade (Wenger, Clark, 1998; Scholzen, Gerdes, 2000).
This information helps to identify tumor phenotypes associated with
a high risk of relapse (high cell proliferation, alone and in association
with other unfavorable factors, such as young age, tumor size >2
cm, high pathologic grade, absence of ER or PgR, alterations in
oncogenes or in tumor suppressor genes) and with low risk of relapse
(low cell proliferation associated with older age, tumor size £2
cm, low pathologic grade, presence of ER or PgR, absence of genomic
alterations).
All of these
results, however, have been derived from investigations not specifically
planned to determine the clinical utility of the biomarker and,
in terms of quality of information, the outcomes of the studies
can be considered to be only hypothesis-generating, with the advantage
of long-term followup counterbalanced by marked heterogeneity in
technical and analytical procedures. The usefulness of prognostic
indicators in patient management can be tested in the context of
randomized treatment protocols in which evaluation of the utility
of biological information accounts for the primary or secondary
objective with an improved level of evidence (LOE) of results, as
in the following:
- Confirmatory studies to validate proliferative activity for
identifying subsets of patients at very low risk of relapse. Evidence
in favor of such a hypothesis is supported by the preliminary
outcome of a large LOE I study on node-negative breast cancers
(Hutchins, Green, Ravdin, et al., 1998) in which patients presenting
with ER-or PgR-positive, intermediate size tumors with a low FCM-S
exhibited an excellent prognosis without adjuvant treatment (5-year
disease-free survival [DFS], 88 percent), similar to patients
with tumors £1 cm in diameter. The result has been independently
confirmed on a substantial series of node-negative tumors in a
prospective investigation (Jones, et al., 1999), in which Ki-67/MIB-1
was considered in addition to FCM-S. It has also been confirmed
in a study derived from cases enrolled in a large randomized clinical
trial (NSABP B-14) that evaluated the effectiveness of adjuvant
tamoxifen in patients with ER-positive cancers (Bryant, Fisher,
Gunduz, et al., 1998). The latter study demonstrated the heterogeneous
clinical outcome of patients with tumors traditionally considered
at low risk and showed that FCM-S (as a continuous variable),
patient age, tumor size, and PgR better differentiated the risk
subsets, with the 10-year DFS rate ranging from 85 percent to
30 percent and overall survival rate from 95 percent to 40 percent.
On the basis of such a clinical and pathobiological classification,
it seems unlikely that the addition of adjuvant chemotherapy to
tamoxifen will improve clinical outcome in women at very low risk
of relapse.
For high-risk (ER-negative, node-negative) tumors, however, the
long-term results of a prospective randomized trial evaluating
the effectiveness of adjuvant CMF confirmed the efficacy of treatment
(Zambetti, Valagussa, Bonadonna, 1996). There was a benefit against
both slowly and rapidly proliferating tumors that was more evident
for the latter.
- Clinical utility of proliferative activity for treatment decision-making
in high-risk node-negative breast cancer patients. To test the
improvement in clinical outcome following adjuvant chemotherapy
in high-risk cases defined on the basis of tumor proliferative
activity, a prospective multicentric trial was conducted between
1989 and 1993 (Amadori, Nanni, Marangolo, et al., 2000). In that
trial, patients with high-TLI tumors were randomized to receive
either CMF or no further treatment following surgery ±
radiotherapy. At a median followup of 80 months, relapses had
occurred in 28 of the 137 patients who received CMF and in 47
of the 141 patients treated with local-regional therapy alone.
A reduction in the annual relapse risk of about 40 percent with
chemotherapy treatment was associated with an 11 percent absolute
benefit for 5- year DFS (83 percent [95 percent CI, 77-89] for
CMF-treated patients versus 72 percent [95 percent CI, 65-79]
for untreated patients, p=0.028). Also shown was a reduction of
both local-regional (from 6.4 percent to 2.9 percent) and distant
relapses (from 21.3 percent to 12.4 percent). The benefit of CMF
treatment was most evident in cases at high riskthat is,
with TLI values in the second (DFS: 88 percent versus 78 percent,
p=0.037) and third tertile (DFS: 78 percent versus 58 percent,
p=0.024).
In summary,
the results support the use of cell proliferation to select high-risk
patients with node-negative tumors. The finding of a higher benefit
from antimetabolite-based regimens in tumors with the highest proliferation
is in keeping with the evidence from retrospective studies (to be
prospectively validated) that proliferation indices may be used
to help predict treatment response in adjuvant and neoadjuvant settings
(Wenger, Clark, 1998).
In addition,
cell proliferation can provide information regarding the efficacy
of different treatment schedules. In an ancillary study analyzing
70 percent of the cases entered in a randomized treatment protocol
designed to compare alternating versus sequential regimens of doxorubicin
and CMF in breast cancer patients with more than three positive
axillary lymph nodes, the benefit of sequential administration was
mainly evident in patients with tumors with low to intermediate
proliferation rates (Silvestrini, Luisi, Zambetti, et al., 2000).
Methodologically,
proliferation indices in part fulfill common requirements for clinical
use in terms of technical-biological effectiveness. They have been
proven to describe the specific biological phenomenon, as well as
to provide results that are informative and rapidly obtainable at
a reasonable cost when needed for clinical decisionmaking.
However, further
effort should be devoted to standardizing methodologies and interpretation
criteria (mainly for FCM-S results) to improve the reliability,
accuracy, and reproducibility of assay results within and among
different laboratories by promoting and maintaining quality control
programs (found in several countries for FCM-S and TLI), and to
establishing guidelines for classifying tumors according to proliferative
activity. There should also be guidelines for reporting and comparing
results. All of these factors, in addition to the inherent heterogeneity
of case series, could account for the variability seen in results.
In terms of
clinical effectiveness, proliferation indices need to be further
validated in the context of randomized trials to assess their utility
to identify low-risk patients (both in the presence of traditional
prognostic factors, including pathological grade, and in cases diagnosed
in recent years that are possibly epidemiologically and biologically
different from those diagnosed in prior decades) and to make decisions
about whether to use specific adjuvant therapies.
References
Amadori D, Nanni
O, Marangolo M, Pacini P, Ravaioli A, Rossi A, et al. Disease-free
survival advantage of adjuvant cyclophosphamide, methotrexate, and
fluorouracile in patients with node-negative rapidly proliferating
breast cancer; a randomised multicenter study. J Clin Oncol 2000;18:3125-34.
Abstract.
Bryant J, Fisher
B, Gunduz N, Costantino JP, Emir B. S-phase fraction combined with
other patient and tumor characteristics for the prognosis of node-negative,
estrogen-receptor-positive breast cancer. Breast Cancer Res Treat
1998;51:239-53. Abstract.
Hutchins L,
Green S, Ravdin P, et al. CMF versus CAF with and without tamoxifen
in high-risk node-negative breast cancer patients and a natural
history follow-up study in low-risk node-negative patients: first
results of intergroup trial INT 0102. [abstract]. Proc Am Soc Clin
Oncol 1998;17:1a. Jones, et al. [Abstract]. Proc Am Soc Clin Oncol
1999. Abstract.
Scholzen T,
Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell
Physiol 2000;182:311-22. Abstract.
Silvestrini
R, Daidone MG, Luisi A, Boracchi P, Mezzetti M, Di Fronzo G, et
al. Biologic and clinicopathologic factors as indicators of specific
relapse types in node-negative breast cancer. J Clin Oncol 1995;13:697-704.
Abstract.
Silvestrini
R, Luisi A, Zambetti M, Cipriani S, Valagussa P, Bonadonna G, et
al. Cell proliferation and outcome following doxorubicin plus CMF
regimens in node-positive breast cancer. Int J Cancer 2000;87:405-11.
Abstract.
Wenger CR, Clark
GM. S-phase fraction and breast cancera decade of experience.
Breast Cancer Res Treat 1998;51:255-65. Abstract.
Zambetti M,
Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate
and fluorouracil in node-negative and estrogen receptor-negative
breast cancer. Updated results. Ann Oncol 1996;7:481-5. Abstract.
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