© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 27-35,
2001
© 2001 Oxford University Press
Prognostic and Predictive Role of Proliferation Indices in Adjuvant Therapy of Breast Cancer
Affiliation of authors: Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Correspondence to: Maria Grazia Daidone, Ph.D., Department of Experimental Oncology, Unit 10, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1, 20133 Milan, Italy (e-mail: daidone{at}istitutotumori.mi.it).
 |
ABSTRACT |
|---|
 TopNotes Abstract BackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
In breast cancer, proliferative activity represents one of the biologic processes most thoroughly investigated for its association with tumor progression. In addition to the mitotic activity component of pathologic grading systems, several proliferation indices have provided independent information on prognosis and response to specific treatments in large retrospective studies. Recently, results from treatment protocols prospectively planned to test the clinical utility of proliferative activity have indicated that tumor cell proliferation markers identify two subsets among patients with lymph node-negative cancers: 1) those at a very low risk of relapse and 2) those who will benefit from regimens including antimetabolites. Future efforts should compare the prognostic accuracy of different proliferation markers, confirm preliminary evidence of a relationship between proliferation and response to specific systemic treatments, and standardize assay techniques to facilitate their transfer to general oncology practice.
|
BACKGROUND |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
Tumor-proliferative activity represents one of the cellular functions most thoroughly investigated in breast cancer for its association with neoplastic progression and metastatic potential. Several approaches, in addition to the measure of mitotic activity (volume/corrected mitotic index, mitotic activity index, and mitotic index) used by all pathologic grading systems (1), have been used by pathologists and cell biologists to determine and quantify the whole proliferative fraction or the discrete fractions of cells in specific cell cycle phases on consecutive series of clinical tumors (2,3). Initially, quantitative measurement of cells in the S phase of the cell cycle involved the evaluation of the fraction of tumor cells actively incorporating DNA precursors (labeled pyrimidine bases, such as [3H]thymidine, or halogenated analogues, such as bromodeoxyuridine or iododeoxyuridine) (4). Newer technologies include the evaluation by flow cytometry or image cytometry of cells with a DNA-synthesizing content (5) and the quantitation of the entire fraction of proliferating cells (i.e., the growth fraction) for the availability of antibodies raised against the nuclear antigen Ki-67 expressed by cycling cells (Ki-67/MIB-1, Ki-S2, and Ki-S5) (6,7). Such approaches, which are applied on different types of specimens (viable, frozen, or paraffin-embedded tissues), use different methods of evaluation (autoradiography, immunocytochemistry, or cytometry). Each of these methods has inherent advantages and disadvantages, including different feasibility rates, which for some indices ([3H]thymidine-labeling or bromodeoxyuridine-labeling indices [TLI or BrdULI, respectively]) appear to depend strictly on the availability of fresh tumor tissue, whereas for others (flow cytometric S-phase fraction [SPF]) depend on data analysis techniques and interpretation as well. Moreover, the different measures of proliferation do not always correlate well with one another in terms of biologic or clinical significance when analyzed on the same case series. In fact, a moderate or poor concordance has been observed not only between proliferation indices detecting cells in different cell cycle phases (i.e., SPF and Ki-67 or MIB-1) but also between indices evaluating the fraction of cells in the same cell cycle phase (i.e., SPF and TLI). In addition, proliferation markers showed slightly different sensitivity and specificity rates when related to clinical outcome (8–32) (Table 1
). However, at present, only one study (12) has specifically tested the prognostic capability of several different proliferation indices (BrdULI, MIB-1, and mitotic index) on the same series of lymph node-negative and lymph node-positive breast cancers. The results of this study, however, are not definitive, because a relatively small number of events limited the statistical power in subsets homogeneous for stage or clinical treatment.
|
|
PROGNOSTIC ROLE OF PROLIFERATION INDICES |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
A computerized literature search was performed using PubMed. "Breast cancer" and the name of each of the proliferation indices were selected as keywords. All available articles published as late as July 2000 were included. Original English articles were analyzed and selected for inclusion when they reported data on the relation between proliferation indices and clinical outcome, evaluated via univariate and/or multivariate analyses on independent case series of at least 100 patients with a minimum follow-up of 4 years. A total of 120 papers were identified in which results were reported from studies for which tumor specimens were available for determining proliferation indices without any a priori study design or prospective definition of specimen collection procedures at the time of therapeutic trial planning [studies providing level of evidence (LOE) III according to the Tumor Marker Grading Utility System proposed by Hayes et al. (33)]. About one third of those 120 papers dealt with studies carried out on patients with lymph node-negative breast cancers or with tumors at any stage, but for which only local–regional treatment was given. This group of studies analyzed the prognostic role of cell proliferation, i.e., its relation with disease-, event-, or relapse-free survival, in the absence of adjuvant systemic treatment. Regardless of the proliferative marker investigated and the criteria used to classify tumors as slowly or rapidly proliferating (mean, median, or continuous values), high proliferation indices were associated in univariate analyses with a high probability of relapse and death. This finding generally persisted in multivariate analyses in which features related to the patient (age and menopausal status), the disease (tumor size, regional lymph node status, and histologic/cytologic findings), or the biology of the tumor (markers associated with differentiation, hormone responsiveness, neoangiogenesis, and genomic alterations) were also considered (13–15,18,19,23,25,34–63) (Table 2
). In particular, proliferation indices such as TLI/BrdULI and SPF maintained their predictivity for disease-, event-, or relapse-free survival and for overall or cancer-specific survival, even in the presence of information provided by histologic or nuclear grade, despite the inclusion of mitotic index in all of the grading systems. Counts of mitotic figures were also independent predictors of relapse or death in the presence of histologic grade (18,52,58,60,61). Outcome studies had previously assessed the prognostic contribution of the different components of grading systems. The independent value of mitotic count clearly emerged in these studies (61,64), suggesting that it is useful to consider it separately, regardless of, or in addition to grade.
|
The integration of proliferation indices with other clinical and pathobiologic factors has provided a better assessment of risk than the consideration of single variables. TLI was evaluated in a large, single-institution series of lymph node-negative breast cancer patients (38) in the presence of traditional prognostic factors (age, tumor size, estrogen receptor [ER], and progesterone receptor [PgR]). TLI, considered as a continuous variable and categorized by tree-structured regression analysis, was able to define subsets at different risk for local–regional relapse (in association with patient age) and distant metastasis (in association with tumor size and patient age). Cell proliferation alone was an independent prognostic discriminant for intermediate-size tumors (1–2 cm). Conversely, TLI was not predictive for the occurrence of contralateral cancers. Such findings, originally observed in 1800 cases with a median follow-up of 8 years (38), were recently updated at a follow-up of 10 years in 2250 cases. For local–regional relapse, a hazard ratio (HR) of 1.8 (95% confidence interval [CI] = 1.3 to 2.4) was found for patients aged less than or equal to 55 years with high TLI tumors versus those with low TLI tumors or who were aged more than 55 years (two-sided P value referred to Wald chi square = .0001). For distant metastasis, the HR was 1.9 (95% CI = 1.5 to 2.5; two-sided P value referred to Wald chi square = .0001) for patients with a tumor size greater than 2 cm and aged 46–65 years or with tumor size 1–2 cm and high TLI and 3.0 (95% CI = 2.3 to 4.0; two-sided P value referred to Wald chi square = .0001) for patients with a tumor size greater than 2 cm and aged less than or equal to 45 or 56–65 years when these subgroups were compared with patients at low risk (tumor size
1 cm or tumor size 1–2 cm and low TLI). Taken together, findings from phase I and II exploratory studies (65) indicate that proliferation indices are independent predictors of clinical outcome. However, similar to other pathobiologic markers such as tumor size and ER status, the predictive value of proliferation indices tends to decrease with longer follow-up in most series (66,67).
|
CONTRIBUTION OF PROLIFERATION INDICES TO THE IDENTIFICATION OF SUBSETS OF PATIENTS AT A VERY LOW RISK OF RELAPSE |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
Recently, the determination of proliferation indices, along with other biomarkers, has been prospectively planned as part of adjuvant and neoadjuvant treatment protocols. Although not all studies have been specifically designed to test the predictivity of tumor markers with adequate statistical power, it is likely that they will improve the quality and accuracy of available information. In addition, results are now becoming available from a few valuable prospective studies specifically designed to test marker utility. These studies will provide definitive evaluation of the clinical utility of proliferation indices.
The ability of cell proliferation to identify, in association with traditionally accepted prognostic factors, subgroups at different risk of local–regional or distant relapse has now been confirmed in an LOE II study performed in conjunction with the National Surgical Adjuvant Breast and Bowel Project Protocol B-14 study. Patients with lymph node-negative, ER-positive tumors were randomly assigned to receive adjuvant therapy with tamoxifen or placebo (66). SPF, in association with relatively few other prognostic factors (patient age, PgR status, and tumor size), identified a broad spectrum of risk categories in a subset of more than 800 women in this trial. In fact, the estimated 10-year disease-free survival probability was quite low (<30%) for patients younger than 35 years of age with large, PgR-negative tumors and a very high SPF. Conversely, patients 50 years of age or older with PgR-positive, 1-cm tumors and a negligible proliferative activity had a greater than 80% disease-free survival probability, and intermediate survival values were found for the other combinations of clinical and pathobiologic features. Such a score could provide an accurate assessment of individual patient prognosis and might suggest limiting aggressive adjuvant therapy to only selected women with lymph node-negative, ER-positive tumors.
To test the hypothesis that proliferation markers can discriminate among lymph node-negative patients at different levels of risk, the U.S. Intergroup performed a prospective, randomized clinical trial (LOE I) (68). From 1989 to 1993, 3899 patients with lymph node-negative breast cancer were randomly assigned as follows: Women whose tumors were too small for biochemical ER/PgR assay were classified at a very low risk and received only local–regional treatment. Those with tumors larger than 2 cm or with negative steroid hormone receptors were considered at a high risk, and systemic adjuvant treatment was administered. The "uncertain" risk subset, those patients with tumors less than or equal to 2 cm with positive steroid hormone receptors, had an S-phase fraction measured to discriminate between low and high risk. The 5-year clinical outcome of the subset initially at "uncertain" risk but later classified at low risk because of a low SPF score was superimposable to that of patients initially at low risk because of very small tumor size. The finding validated the utility of cell proliferation and has been independently confirmed in about 700 lymph node-negative tumors in a prospective investigation by Jones et al. (69), in which Ki-67/MIB-1 was considered in addition to SPF.
The prognostic refinement of the intermediate-risk subset by proliferation markers was also studied by our group at the Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. We investigated whether TLI provides an additive contribution to breast cancer-scoring systems already validated and/or accepted for routine use, based on different clinical and morphopathobiologic features of proven prognostic utility. In lymph node-negative breast cancer, in particular, we tested TLI within risk categories defined according to criteria (based on patient age, tumor size, histologic grade, and ER and PgR status) proposed in the 1998 St. Gallen's International Consensus Conference on the Treatment of Primary Breast Cancer (70). Our study was carried out on a series of 549 women who had primary, resectable invasive breast cancer. All of them were histologically lymph node negative with no radiologic or clinical evidence of distant metastasis, synchronous bilateral tumor, or concomitant second primary neoplasm and underwent surgery at the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan during the period from January 1991 to December 1994 (median follow-up, 5 years). The case series (Table 3) was consecutive with respect to TLI determined at the time of diagnosis (71) but independent of the series we previously published on TLI (8,36,38). Patients were subjected to mastectomy (132 [24%] cases) or quadrantectomy plus radiotherapy (417 [76%] cases), and all of them underwent axillary lymph node dissection (median number of examined lymph nodes = 18). None of the women received systemic postoperative therapy until new disease manifestation was documented, and all of them underwent follow-up examination at the outpatient clinic of the Istituto Nazionale per lo Studio e la Cura dei Tumori, as previously described (38). Primary treatment failure was defined as the first documented evidence of local recurrence or regional axillary relapse (six events), distant metastasis (53 events), contralateral breast cancer (18 events), or a combination of these events. Steroid receptors were evaluated by the dextran-coated charcoal technique (38), and histologic grade was determined according to the procedures of Elston and Ellis (72).
|
Patient age, tumor size, histologic grade, and TLI (divided into three classes on the basis of its frequency distribution in relapsed cases), but not ER or PgR, provided prognostic information for 5-year relapse (Table 4
) and, with the exception of histologic grade, retained their independent relevance even in multivariate analysis. When age, size, histologic grade, ER, and PgR were combined according to the St. Gallen criteria (70), several risk categories of prognostic importance were defined (Fig. 1). No relapses occurred in the minimal-low-risk subset (ER-positive and/or PgR-positive, grade 1 tumors 1 cm in patients older than 35 years [2.7% of the cases]). Relapse rates of 29% and 14%, respectively, were observed for the subsets at high risk (patients <35 years old or with tumors >2 cm, or ER-negative and/or PgR-negative, or grade 3 [60.1% of the cases]) or at intermediate risk (patients not included in the two previous categories, i.e., those with tumors 1–2 cm in size, ER-positive and/or PgR-positive, and of histologic grade 1 or 2 [37.2% of the cases]). A statistically significant association (chi square test; two-sided P = .014) was observed between the St. Gallen categories and TLI. The fraction of slowly proliferating tumors decreased from the minimal-low-risk to the high-risk subset (from 60% to 40% of the cases), with a parallel increase in the fraction of rapidly proliferating tumors (from 13% to 30% of the cases). The overall concordance among the three St. Gallen or TLI classes was limited to only about one third of the cases. TLI provided no prognostic additive information within the high-risk subset (5-year relapse probability for high versus low–intermediate TLI, 29% and 28%, respectively), in which at least one of five unfavorable factors was already present. Conversely, in the intermediate-risk group, TLI was able to separate further the patients into two subsets with different relapse probabilities (5-year relapse for the high [30%] versus the low-intermediate [9%] TLI subsets; HR = 3.4, 95% CI = 1.4 to 8.3; two-sided P value referred to Wald chi square = .0076) (Fig. 2). The results, in keeping with those previously reported for SPF (68), support the use of cell proliferation for better prognostic resolution within intermediate-risk categories, even in the presence of information provided by grading.
|
|
35 years old; 15 cases); dotted line: intermediate-risk subset (including ER-positive and/or PgR-positive, grade 1–2, 1- to 2-cm tumors from patients
|
|
CLINICAL UTILITY OF PROLIFERATION INDICES IN IDENTIFYING HIGH-RISK LYMPH NODE-NEGATIVE PATIENTS WHO NEED AGGRESSIVE TREATMENT |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
In the last decade, an additional aim of prospective studies using cell kinetic features was to investigate whether lymph node-negative breast cancer patients defined as high risk on the basis of tumor cell proliferation could benefit from adjuvant polychemotherapy. Three phase III randomized trials using TLI (73,74) or the mitotic activity index (75) have been activated in Europe. Patients were randomly assigned to receive adjuvant chemotherapy (e.g., cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] or 5-fluorouracil, doxorubicin, and cyclophosphamide) versus no systemic therapy. These studies measured tumor cell proliferation and instituted quality-control programs for analytical and preanalytical phases of cell kinetic determinations (71,76–79).
Results are available from the multicenter Italian study by Amadori et al. (73). Patients were eligible for the study if they were younger than 70 years of age, underwent radical or conservative resection plus radiotherapy, had lymph node-negative tumors histologically assessed, and had TLI and ER determinations available. A total of 278 patients with high (>3%) TLI were accrued and randomly assigned to receive CMF or no further treatment. Disease-free survival probability curves showed a 5-year benefit in CMF-treated patients versus untreated patients (83% versus 72%), with a reduction in local–regional (6.4% versus 2.9%) and distant relapses (21.3% versus 12.4%) and in the annual risk of relapse (approximately 40%), even when adjusted for age, tumor size, type of surgery, and PgR content. The benefit of CMF treatment was mostly evident for cases at very high risk, i.e., with TLI values greater than 6.8% (corresponding to the third tertile of TLI frequency distribution).
The results support the use of cell proliferation to select patients with lymph node-negative tumors at a high risk of recurrence. The finding of a greater benefit from antimetabolite-based regimens in tumors with the highest proliferation is in keeping with the evidence from studies measuring cell proliferation as part of prospective randomized clinical trials comparing systemic treatment with observation or radiotherapy in either lymph node-positive or high-risk, lymph node-negative patients (80–82).
|
PROLIFERATION INDICES AND RESPONSE TO SYSTEMIC ADJUVANT TREATMENTS |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
There has been a renewed emphasis in the search for biologic predictive factors, i.e., markers able to identify patients who are more or less likely to benefit from specific therapies. Compared with prognostic factors, however, this field of research is more difficult to investigate, since the ideal study should include the prospective evaluation of the marker within the context of a randomized clinical study designed to compare systemic therapies with local–regional therapies. Proliferative activity represents a biomarker that may be both prognostic and predictive. As for most putative biologic predictors, present data mainly acquired from LOE III studies are insufficient to draw firm conclusions regarding the predictive role of proliferation indices in choosing either endocrine therapy or chemotherapy and are only suggestive of relations that should be further investigated and analyzed.
As regards predictors of response to chemotherapy, emerging evidence from adjuvant and neoadjuvant studies (83,84) generally indicates a benefit of polychemotherapy including S-phase-specific drugs for patients with rapidly proliferating tumors, even though such a finding is not unequivocal. In fact, in companion studies of prospective, randomized clinical trials comparing systemic treatment with observation or radiotherapy, an advantage from CMF on long-term outcome was present only in rapidly proliferating tumors (80) or in rapidly and in slowly proliferating tumors (85), but the benefit was greater in the former (81,82).
Up to now, few studies have investigated whether cell kinetics provides information on the efficacy of different treatment schedules. In an ancillary study analyzing 70% of the cases entered in a randomized treatment protocol aimed at comparing alternating and sequential regimens of doxorubicin and CMF in breast cancer patients who had 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 (86). The data could be explained by a partial synchronization of cells in the G2–M phase of the cell cycle following the initial administration of doxorubicin at a high dose intensity and by a subsequent presentation during the CMF cycles of a large number of cells sensitive to S-phase-specific drugs.
As regards prediction of response to endocrine therapy, evidence from adjuvant and neoadjuvant studies generally indicates a greater benefit for patients with slowly proliferating tumors, either within ER-positive subsets or in the presence of information provided by PgR (87,88), although contrasting results are present in the literature (89). All of the data have been obtained from retrospective clinical analyses, and prospective studies are needed.
|
CONCLUSIONS |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
Proliferation indices can be markers of clinical utility. In fact, in lymph node-negative breast cancers, the usefulness of cell proliferation in identifying subsets at a very low risk of relapse has been assessed in large retrospective studies and validated in prospective studies (68,69), and the benefit from chemotherapy regimens including antimetabolites in treating rapidly proliferating tumors has been assessed in a phase III prospective study (73). Further effort should be made to define the relative prognostic accuracy of the different proliferation markers within prospective clinical trials and to confirm the preliminary evidence of a relationship between proliferation and response to specific systemic treatments.
In addition to clinicobiologic effectiveness and usefulness, laboratory quality-control programs should be considered to promote the transferability of these measurements from the research laboratories to general practice (90). Effort should be devoted to standardize methodologies and interpretation criteria to improve reliability, accuracy, and reproducibility of assay results within and among the different laboratories. Moreover, links should be created among the different quality-control programs so as to share common methodologies so that clinical trial results can be extrapolated to routine practice.
|
NOTES |
|---|
Supported in part by grants from the Italian Health Ministry and the Italian Research Council (CNR).
|
REFERENCES |
|---|
|
TopNotesAbstractBackgroundPrognostic Role of Proliferation...Contribution of Proliferation...Clinical Utility of...Proliferation Indices and...ConclusionsReferences |
|---|
1 van Diest PJ, Brugal G, Baak JP. Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol 1998;51:716–24.[ISI][Medline]
2 Barnes DM, Gillett CE. Determination of cell proliferation. J Clin Pathol Mol Pathol 1995;48:M2–M5.
3 Silvestrini R. Cell kinetics: prognostic and therapeutic implications in human tumors. Cell Prolif 1994;27:561–9.
4 Meyer JS, Connor RE. In vitro labeling of solid tissues with tritiated thymidine for autoradiographic detection of S-phase nuclei. Stain Technol 1977;52:185–95.[ISI][Medline]
5 Hedley DW. Flow cytometry using paraffin-embedded tissue: five years on. Cytometry 1989;10:229–41.[CrossRef][ISI][Medline]
6 Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol 2000;182:311–22.[CrossRef][ISI][Medline]
7 Rudolph P, Alm P, Heidebrecht HJ, Bolte H, Ratjen V, Baldetorp B, et al. Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer. J Natl Cancer Inst 1999;91:271–8.
8
Silvestrini R, Daidone MG, Del Bino G, Mastore M, Luisi A, Di Fronzo G, et al. Prognostic significance of proliferative activity and ploidy in node-negative breast cancers. Ann Oncol 1993;4:213–9.
9 He W, Meyer JS, Scrivner DL, Koehm S, Hughes J. Assessment of proliferating cell nuclear antigen (PCNA) in breast cancer using anti-PCNA PC10 and 19A2: correlation with 5-bromo-2'–deoxyuridine or tritiated thymidine labeling and flow cytometric analysis. Biotech Histochem 1994;69:203–12.[ISI][Medline]
10 Rudas M, Gnant MF, Mittlbock M, Neumayer R, Kummer A, Jakesz R, et al. Thymidine labeling index and Ki-67 growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat 1994;32:165–75.[CrossRef][ISI][Medline]
11 Gaglia P, Bernardi A, Venesio T, Caldarola B, Lauro D, Cappa AP, et al. Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki-67 antibodies: its prognostic value on short-term recurrences. Eur J Cancer 1993;29A:1509–13.[CrossRef]
12
Thor AD, Liu S, Moore DH 2nd, Edgerton SM. Comparison of mitotic index, in vitro bromodeoxyuridine labeling, and MIB-1 assays to quantitate proliferation in breast cancer. J Clin Oncol 1999;17:470–7.
13 Meyer JS, Province MA. S-phase fraction and nuclear size in long term prognosis of patients with breast cancer. Cancer 1994;74:2287–99.[CrossRef][ISI][Medline]
14 Peiro G, Lerma E, Climent MA, Segui MA, Alonso MC, Prat J. Prognostic value of S-phase fraction in lymph-node-negative breast cancer by image and flow cytometric analysis. Mod Pathol 1997;10:216–22.[ISI][Medline]
15 Winchester DJ, Duda RB, August CZ, Goldschmidt RA, Wruck DM, Rademaker AW, et al. The importance of DNA flow cytometry in node-negative breast cancer. Arch Surg 1990;125:886–9.[Abstract]
16
Simpson JF, Gray R, Dressler LG, Cobau CD, Falkson CI, Gilchrist KW, et al. Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189. J Clin Oncol 2000;18:2059–69.
17 Hatschek T, Grontoft O, Fagerberg G, Stal O, Sullivan S, Carstensen J, et al. Cytometric and histopathologic features of tumors detected in a randomized mammography screening program: correlation and relative prognostic influence. Breast Cancer Res Treat 1990;15:149–60.[CrossRef][ISI][Medline]
18 Eskelinen M, Lipponen P, Papinaho S, Aaltomaa S, Kosma VM, Klemi P, et al. DNA flow cytometry, nuclear morphometry, mitotic indices and steroid receptors as independent prognostic factors in female breast cancer. Int J Cancer 1992;51:555–61.[ISI][Medline]
19 Lipponen P, Papinaho S, Eskelinen M, Klemi PJ, Aaltomaa S, Kosma VM, et al. DNA ploidy, S-phase fraction and mitotic indices as prognostic predictors of female breast cancer. Anticancer Res 1992;12:1533–8.[ISI][Medline]
20 Joensuu H, Toikkanen S, Klemi PJ. DNA index and S-phase fraction and their combination as prognostic factors in operable ductal breast carcinoma. Cancer 1990;66:331–40.[CrossRef][ISI][Medline]
21 Keshgegian AA, Cnaan A. Proliferation markers in breast carcinoma: mitotic figure count, S-phase fraction, proliferation cell nuclear antigen, Ki-67 and MIB-1. Am J Clin Pathol 1995;104:42–9.[ISI][Medline]
22 Dettmar P, Harbeck N, Thomssen C, Pache L, Ziffer P, Fizi K, et al. Prognostic impact of proliferation-associated factors MIB1 (Ki-67) and S-phase in node-negative breast cancer. Br J Cancer 1997;75:1525–33.[ISI][Medline]
23 Harbeck N, Dettmar P, Thomssen C, Henselmann B, Kuhn W, Ulm K, et al. Prognostic impact of tumor biological factors on survival in node-negative breast cancer. Anticancer Res 1998;18:2187–97.[ISI][Medline]
24 Railo M, Lundin J, Haglund C, von Smitten K, von Boguslawsky K, Nordling S. Ki-67, p53, Er-receptors, ploidy and S-phase as prognostic factors in T1 node negative breast cancer. Acta Oncol 1997;36:369–74.[ISI][Medline]
25 Brown RW, Allred CD, Clark GM, Osborne CK, Hilsenbeck SG. Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer. Clin Cancer Res 1996;2:585–92.[Abstract]
26 Wiesener B, Hauser-Kronberger CE, Zipperer E, Dietze O, Menzel C, Hacker GW. p34cdc2 in invasive breast cancer: relationship to DNA content, Ki67 index and c-erbB-2 expression. Histopathology 1998;33:522–30.[CrossRef][ISI][Medline]
27 Gasparini G, Boracchi P, Verderio P, Bevilacqua P. Cell kinetics in human breast cancer: comparison between the prognostic value of the cytofluorimetric S-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry. Int J Cancer 1994;57:822–9.[ISI][Medline]
28 Jansen RL, Hupperets PS, Arends JW, Joosten-Achjanie SR, Volovics A, Schouten HC, et al. MIB-1 labelling index is an independent prognostic marker in primary breast cancer. Br J Cancer 1998;78:460–5.[ISI][Medline]
29 Leong AC, Hanby AM, Potts HW, Tan DS, Skilton D, Ryder K, et al. Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast. Int J Cancer 2000;89:26–31.[CrossRef][ISI][Medline]
30 Clahsen PC, van de Velde CJ, Duval C, Pallud C, Mandard AM, Delobelle-Deroide A, et al. The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer. Eur J Surg Oncol 1999;25:356–63.[CrossRef][ISI][Medline]
31 Jacquemier JD, Penault-Llorca FM, Bertucci F, Sun ZZ, Houvenaeghel GF, Geneix JA, et al. Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: a multiparametric and immunohistochemical analysis. J Pathol 1998;184:130–5.[CrossRef][ISI][Medline]
32 Pietilainen T, Lipponen P, Aaltomaa S, Eskelinen M, Kosma VM, Syrjanen K. The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer. J Cancer Res Clin Oncol 1996;122:687–92.[CrossRef][ISI][Medline]
33 Hayes DF, Trock B, Harris AL. Assessing the clinical impact of prognostic factors: when is "statistically significant" clinically useful? Breast Cancer Res Treat 1998;52:305–19.[CrossRef][ISI][Medline]
34 Medri L, Nanni O, Volpi A, Scarpi E, Dubini A, Riccobon A, et al. Tumor microvessel density and prognosis in node-negative breast cancer. Int J Cancer 2000;89:74–80.[CrossRef][ISI][Medline]
35 Paradiso A, Mangia A, Barletta A, Fusilli S, Marzullo F, Schittulli F, et al. Heterogeneity of intratumour proliferative activity in primary breast cancer: biological and clinical aspects. Eur J Cancer 1995;31A:911–6.[CrossRef]
36 Silvestrini R, Daidone MG, Di Fronzo G, Morabito A, Valagussa P, Bonadonna G. Prognostic implication of labelling index versus estrogen receptors and tumor size in node-negative breast cancer. Breast Cancer Res Treat 1986;7:161–9.[CrossRef][ISI][Medline]
37 Courdi A, Hery M, Dahan E, Gioanni J, Abbes M, Monticelli J, et al. Factors affecting relapse in node-negative breast cancer. A multivariate analysis including the labeling index. Eur J Cancer Clin Oncol 1989;25:351–6.[CrossRef][ISI][Medline]
38
Silvestrini R, Daidone MG, Luisi A, Boracchi P, Mezzetti M, Di Fronzo G, et al. Biologic and clinico-pathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 1995;13:697– 704.
39 Cooke TG, Stanton PD, Winstanley J, Murray GD, Croton R, Holt S, et al. Long-term prognostic significance of thymidine labelling index in primary breast cancer. Eur J Cancer 1992;28:424–6.
40 Tubiana M, Pejovic MH, Koscielny S, Chavaudra N, Malaise E. Growth rate, kinetics of tumor cell proliferation and long-term outcome in human breast cancer. Int J Cancer 1989;44:17–22.[ISI][Medline]
41 Aubele M, Auer G, Falkmer U, Voss A, Rodenacker K, Jutting U, et al. Identification of a low-risk group of stage I breast cancer patients by cytometrically assessed DNA and nuclear texture parameters. J Pathol 1995;177:377–84.[CrossRef][ISI][Medline]
42 Sigurdsson H, Baldetorp B, Borg A, Dalberg M, Ferno M, Killander D, et al. Indicators of prognosis in node-negative breast cancer. N Engl J Med 1990;322:1045–53.[Abstract]
43 O'Reilly SM, Camplejohn RS, Barnes DM, Millis RR, Rubens RD, Richards MA. Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry. J Clin Oncol 1990;8:2040–6.[Abstract]
44 Harbeck N, Dettmar P, Thomssen C, Berger U, Ulm K, Kates R, et al. Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: 6-year median follow-up. Br J Cancer 1999;80:419–26.[CrossRef][ISI][Medline]
45 Merkel DE, Winchester DJ, Goldschmidt RA, August CZ, Wruck DM, Rademaker AW. DNA flow cytometry and pathologic grading as prognostic guides in axillary lymph node-negative breast cancer. Cancer 1993;72:1926–32.[CrossRef][ISI][Medline]
46 Balslev I, Christensen IJ, Rasmussen BB, Larsen JK, Lykkesfeldt AE, Thorpe SM, et al. Flow cytometric DNA ploidy defines patients with poor prognosis in node-negative breast cancer. Int J Cancer 1994;56:16–25.[ISI][Medline]
47
Stal O, Dufmats M, Hatschek T, Carstensen J, Klintenberg C, Rutqvist LE, et al. S-phase fraction is a prognostic factor in stage I breast carcinoma. J Clin Oncol 1993;11:1717–22.
48
Isola J, Visakorpi T, Holli K, Kallioniemi OP. Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients. J Natl Cancer Inst 1992;84:1109–14.
49 Bosari S, Lee AK, Tahan SR, Figoni MA, Wiley BD, Heatley GJ, et al. DNA flow cytometric analysis and prognosis of axillary lymph node-negative breast carcinoma. Cancer 1992;70:1943–50.[CrossRef][ISI][Medline]
50 Johnson H Jr, Masood S, Belluco C, Abou-Azama AM, Dee S, Kahn L, et al. Prognostic factors in node-negative breast cancer. Arch Surg 1992;127:1386–91.[Abstract]
51 Witzig TE, Ingle JN, Cha SS, Schaid DJ, Tabery RL, Wold LE, et al. DNA ploidy and the percentage of cells in S-phase as prognostic factors for women with lymph node negative breast cancer. Cancer 1994;74:1752–61.[CrossRef][ISI][Medline]
52 Joensuu H, Toikkanen S. Identification of subgroups with favorable prognosis in breast cancer. Acta Oncol 1992;31:293–301.[ISI][Medline]
53 Klintenberg C, Stal O, Nordenskjold B, Wallgren A, Arvidsson S, Skoog L. Proliferative index, cytosol estrogen receptor and axillary node status as prognostic predictors in human mammary carcinoma. Breast Cancer Res Treat 1986;7 Suppl:S99–106.
54 Arnerlov C, Emdin SO, Lundgren B, Roos G, Soderstrom J, Bjersing L, et al. Mammographic growth rate, DNA ploidy, and S-phase fraction analysis in breast carcinoma. A prognostic evaluation in a screened population. Cancer 1992;70:1935–42.[CrossRef][ISI][Medline]
55 Stanton PD, Cooke TG, Oakes SJ, Winstanley J, Holt S, George WD, et al. Lack of prognostic significance of DNA ploidy and S phase fraction in breast cancer. Br J Cancer 1992;66:925–9.[ISI][Medline]
56 Fisher B, Gunduz N, Costantino J, Fisher ER, Redmond C, Mamounas EP, et al. DNA flow cytometric analysis of primary operable breast cancer. Relation of ploidy and S-phase fraction to outcome of patients in NSABP B-04. Cancer 1991;68:1465–75.[CrossRef][ISI][Medline]
57 Toikkanen S, Joensuu H, Klemi P. The prognostic significance of nuclear DNA content in invasive breast cancer—a study with long-term follow-up. Br J Cancer 1989;60:693–700.[ISI][Medline]
58 Ladekarl M, Jensen V. Quantitative histopathology in lymph node-negative breast cancer. Prognostic significance of mitotic counts. Virchows Arch 1995;427:265–70.[ISI][Medline]
59 Kato T, Kimura T, Miyakawa R, Fujii A, Yamamoto K, Kameoka S, et al. Clinicopathologic study associated with long-term survival in Japanese patients with node-negative breast cancer. Br J Cancer 2000;82:404–11.[CrossRef][ISI][Medline]
60 Aaltomaa S, Lipponen P, Eskelinen M, KosmaVM, Marin S, Alhava E, et al. Prognostic scores combining clinical, histological and morphometric variables in assessment of the disease outcome in female breast cancer. Int J Cancer 1991;49:886–92.[ISI][Medline]
61 Clayton F. Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal breast carcinomas. Mitotic count is the best single predictor. Cancer 1991;68:1309–17.[CrossRef][ISI][Medline]
62 Iacopetta B, Grieu F, Powell B, Soong R, McCaul K, Seshadri R. Analysis of p53 gene mutation by polymerase chain reaction-single strand conformation polymorphism provides independent prognostic information in node-negative breast cancer. Clin Cancer Res 1998;4:1597–602.[Abstract]
63 Pinder SE, Wencyk P, Sibbering DM, Bell JA, Elston CW, Nicholson R, et al. Assessment of the new proliferation marker MIB1 in breast carcinoma using image analysis: associations with other prognostic factors and survival. Br J Cancer 1995;71:146–9.[ISI][Medline]
64 Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer 1993;71:1258–65.[CrossRef][ISI][Medline]
65 Altman DG, Lyman GH. Methodological challenges in the evaluation of prognostic factors in breast cancer. Breast Cancer Res Treat 1998;52:289–303.[CrossRef][ISI][Medline]
66 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.[CrossRef][ISI][Medline]
67 Hilsenbeck SG, Ravdin PM, de Moor CA, Chamness GC, Osborne CK, Clark GM. Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 1998;52:227–37.[CrossRef][ISI][Medline]
68 Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M. 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]. Proceedings of the 34th Annual Meeting of the American Society of Clinical Oncology; 1998 May 16–19; Los Angeles, CA. Proc ASCO 1998;17:abstract 2.
69 Jones S, Clark G, Koleszar S, Ethington G, Mennel R, Paulson E, et al. Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome without adjuvant chemotherapy [abstract]. Proceedings of the 35th Annual Meeting of the American Society of Clinical Oncology; 1999 May 15–18; Atlanta, GA. Proc ASCO 1999;18:abstract 262.
70
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.
71 Silvestrini R. Feasibility and reproducibility of the [3H]-thymidine labelling index in breast cancer. The SICCAB Group for Quality Control of Cell Kinetic Determination. Cell Prolif 1991;24:437–45.[ISI][Medline]
72 Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991;19:403–10.[ISI][Medline]
73
Amadori D, Nanni O, Marangolo M, Pacini P, Ravaioli A, Rossi A, et al. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative rapidly proliferating breast cancer: a randomized multicenter study. J Clin Oncol 2000;18:3125–34.
74 Paradiso A, Schittulli F, Mangia A, Marzullo F, De Lena M. Randomized clinical trial of adjuvant FEC polychemotherapy for rapidly proliferating node-negative breast cancer. Int J Biol Markers 2000;15:270.
75 Baak JP, van Diest PJ, Benraadt T, Matze-Cok E, Brugghe J, Schuurmans LT, et al. The Multi-Center Morphometric Mammary Carcinoma Project (MMMCP) in The Netherlands: value of morphometrically assessed proliferation and differentiation. J Cell Biochem Suppl 1993;17G:220–5.
76 van Diest PJ, Baak JP, Matze-Cok P, Wisse-Brekelmans EC, van Galen CM, Kurver PH, et al. Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol 1992;23:603–7.[CrossRef][ISI][Medline]
77 Collan YU, Kuopio T, Baak JP, Becker R, Bogomoletz WV, Deverell M, et al. Standardized mitotic counts in breast cancer. Evaluation of the method. Pathol Res Pract 1996;192:931–41.[ISI][Medline]
78 Baldetorp B, Bendahl PO, Ferno M, Alanen K, Delle U, Falkmer U, et al. Reproducibility in DNA flow cytometric analysis of breast cancer: comparison of 12 laboratories' results for 67 sample homogenates. Cytometry 1995;22:115–27.[CrossRef][ISI][Medline]
79 D'hautcourt JL, Spyratos F, Chassevent A. Quality control study by the French Cytometry Association on flow cytometric DNA content and S-phase fraction (S%). The Association Francaise de Cytometrie. Cytometry 1996;26:32–9.[CrossRef][ISI][Medline]
80 Stal O, Skoog L, Rutqvist LE, Carstensen JM, Wingren S, Sullivan S, et al. S-phase fraction and survival benefit from adjuvant chemotherapy or radiotherapy of breast cancer. Br J Cancer 1994;70:1258–62.[ISI][Medline]
81 O'Reilly SM, Camplejohn RS, Millis RR, Rubens RD, Richards MA. Proliferative activity, histological grade and benefit from adjuvant chemotherapy in node positive breast cancer. Eur J Cancer 1990;26:1035–8.
82
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.
83 Wenger CR, Clark GM. S-phase fraction and breast cancer—a decade of experience. Breast Cancer Res Treat 1998;51:255–65.[CrossRef][ISI][Medline]
84 Daidone MG, Veneroni S, Benini E, Tomasic G, Coradini D, Brambilla C, et al. Biological markers and changes induced in their profiles following primary chemotherapy: relevance for short- and long-term clinical outcome. In: Howell A, Dowsett M, editors. ESO scientific updated. Vol. 4. Amsterdam (The Netherlands): Elsevier; 1999. p. 53–72.
85 Dressler LG, Eudey L, Gray R, Tormey DC, McGuire WL, Gilchrist KW, et al. Prognostic potential of DNA flow cytometry measurements in node-negative breast cancer patients: preliminary analysis of an intergroup study (INT 0076). J Natl Cancer Inst Monogr 1992;11:167–72.
86 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.[CrossRef][ISI][Medline]
87
Silvestrini R, Daidone MG, Mastore M, Di Fronzo G, Coradini D, Boracchi P, et al. Cell kinetics as a predictive factor in node-positive breast cancer treated with adjuvant hormone therapy. J Clin Oncol 1993;11:1150–5.
88 Daidone MG, Luisi A, Martelli G, Benini E, Veneroni S, Tomasic G, et al. Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers from elderly women. Br J Cancer 2000;82:270–7.[CrossRef][ISI][Medline]
89 Ferno M, Stal O, Baldetorp B, Hatschek T, Kallstrom AC, Malmstrom P, et al. Results of two or five years of adjuvant tamoxifen correlated to steroid receptor and S-phase levels. South Sweden Breast Cancer Group, and South-East Sweden Breast Cancer Group. Breast Cancer Res Treat 2000;59:69–76.[CrossRef][ISI][Medline]
90 Gion M, Boracchi P, Biganzoli E, Daidone MG. A guide for reviewing submitted manuscripts (and indications for the design of translational research studies on biomarkers). Int J Biol Markers 1999;14:123–33.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. J. Kim, S. Nakayama, Y. Miyoshi, T. Taguchi, Y. Tamaki, T. Matsushima, Y. Torikoshi, S. Tanaka, T. Yoshida, H. Ishihara, et al. Determination of the specific activity of CDK1 and CDK2 as a novel prognostic indicator for early breast cancer Ann. Onc., January 1, 2008; 19(1): 68 - 72. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||