1 S. C. Oncologia Medica, Azienda Ospedaliera, San Sisto 06132 Perugia, Italy; 2 Medical Oncology Clinic, 3 Translational Research Unit and 4 Department of Pathology, Jules Bordet Institute, Boulevard de Waterloo, 125, 1000 Brussels, Belgium
* Correspondence to: Dr M. Piccart, Jules Bordet Institute, Boulevard de Waterloo, 125, 1000 Brussels, Belgium. Tel: +32-2-541-32-06; Fax: +32-2-538-08-58; E-mail: martine.piccart{at}bordet.be
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Abstract |
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Key words: breast cancer, proliferative markers, prognostic markers, predictive markers
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Introduction |
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Tumor cell proliferation has been widely investigated in BC for its association with neoplastic growth, progression, and metastatic potential; the present article is a review of the knowledge gathered on tumor cell proliferative markers in the past decade, with a critical assessment of their prognostic and/or predictive value.
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Materials and methods |
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Selected for the present review were papers published in English in peer-reviewed journals before June 2004, which included at least 100 evaluable patients and in which the prognostic and predictive role of each marker was assessed through multivariate analyses. When more than one proliferative marker was evaluated, we referred to the most relevant one. The levels of evidence were provided according to the Tumor Marker Grading Utility System proposed by Hayes et al. [4] as shown in Table 1, and we arbitrarily decided to consider as large retrospective studies those including
200 patients. We cannot exclude the fact that some papers that did not find significant correlations for a certain proliferative markers, have never been published and, therefore, this could hamper our findings.
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Measurement of cells in the S phase |
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3H-thymidine labeling index |
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Prognostic role
Several papers, mostly retrospective and sometimes based on large series of BC patients, have reported a significant correlation between high TLI and poor clinical outcome in terms of relapse-free survival (RFS)/DFS, distant metastases-free survival (DMFS) and/or OS independently of N status, T size, histological grade, HR status and menopausal status [917
]. However, even if the results of these studies have consistently shown the feasibility and the high reproducibility of TLI as a measure of the tumor proliferative activity [18
, 19
] it has never been accepted as a standard prognostic marker for the reasons described above.
Predictive role
Three studies have evaluated the predictive role of TLI. In a retrospective study, 285 out of 403 women with more than three N-positive BC randomized to receive, as adjuvant chemotherapy, alternating or sequential courses of doxorubicin and CMF (cyclophosphamide, methotrexate, 5-fluorouracil) were analyzed [20]. The median values and ranges of TLI for the two arms were superimposable. Patients with high TLI had a significantly worse 12-year RFS, DMFS and OS and benefited significantly more from the sequential administration of doxorubicin and CMF. In two multicenter prospective phase III adjuvant trials, N-negative BC patients with high TLI, regardless of HR status, were randomized to receive chemotherapy (CT) or no further systemic therapy. In the first trial [21
], the adjuvant CT consisted of six courses of the classic CMF regimen. At a median follow-up of 81 months, a statistically significant increase in DFS was obtained with CT. Similar results were reported in the other trial utilizing an anthracycline-based regimen [cyclophosphamide, epirubicin and 5-fluorouracil (FEC)] for six courses [22
]. The analysis of relapse sites showed that CT reduced significantly all loco-regional relapses and led to a decrease in the number of distant metastases and contralateral tumors, although these differences were not significant. Despite the achievement of level 1 evidence by these two trials, TLI was not adopted in clinical practice given the technical problems reported above.
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Flow cytometry |
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Prognostic role
Since the first publication in 1987 [24], numerous papers have addressed the technological aspects of the method, the relationships of SPF with other standard prognostic factors and its association with clinical outcome. In 1992, the DNA Cytometry Consensus Conference supported by the National Cancer Institute concluded that the literature clearly showed a link between high SPF values and increased risk of recurrence and death for patients with primary BC, but the lack of a standardized procedure to prepare and to analyze tumor samples precluded recommending this method as a routine way to determine prognosis or to select treatment in the adjuvant or metastatic settings [25
]. Attempts to standardize the method have been made by several groups [23
, 26
30
], some of which have also prepared guidelines and recommendations and shown the possibility to increase interlaboratory reproducibility [31
]. Nonetheless, the Tumor Marker Panel of the American Society of Clinical Oncology recently did not include SPF among the standard markers to use for treatment decision-making in BC patients [2
]. Interestingly, high SPF has been associated with HR-negativity, larger T size, N-positivity and high grade in several reports, and has been found to be a significant independent prognostic factor for early BC patients in 41 out of 49 published papers enrolling a large number of patients (range 131709) [23
, 32
77
]. In the majority of the studies, high levels of SPF predicted worse DFS/RFS; in nine this was true only for OS [32
, 42
, 58
, 65
68
, 74
, 77
] and in 11 for both DFS and OS [23
, 33
, 37
, 40
, 51
, 59
, 61
, 69
]. However, only three studies were prospective [45
, 49
, 76
], and several weaknesses in the design, conduct, and interpretation of the results of these studies hamper the clinical utility of SPF for BC patients. First, the tumor tissue utilized differed across the studies, and while more often paraffin-embedded tissue blocks were processed (26 studies), in others fresh/frozen material was used. Secondly, the characteristics of patients enrolled in the different studies varied according to stage, menopausal status and treatment received. Thirdly, the median follow-up fluctuated from 26 months to 27 years. Fourthly, there was substantial variability in the assay methodology and in the selection of cut-off values. In fact, in some papers, one cut-off point was selected to separate high versus low SPF, while in others, two cut-off points were used in order to provide three categories as suggested by the DNA Cytometry Consensus Conference [25
].
Predictive role
We found only one retrospective study evaluating the predictive role of SPF for adjuvant tamoxifen therapy in stage IIII BC patients with progesterone receptor (PgR)-positive tumors [78]. While with univariate analysis, tamoxifen improved the clinical outcome of patients with high SPF more than in those with low SPF, this effect disappeared with multivariate analysis.
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Tymidine kinase |
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Prognostic role
We found only one prospective study [82] of 290 N-negative and N-positive BC patients in whom high TK activity was significantly correlated with high grade and PgR-negativity and predicted a worse RFS in the pre/peri-menopausal subset and worse OS in the postmenopausal subgroup.
Predictive role
The predictive value of TK was retrospectively evaluated in two studies [81, 84
], of which one analyzed 1692 BC patients [84
]. In both studies, high levels were correlated with large T size and HR-negativity [84
] or PgR-negativity [81
]. In the first, all N-positive patients received CT with a regimen containing fluorouracil [CMF or CAF (cyclophosphamide, doxorubicin and 5-fluorouracil)] and no endocrine therapy [81
]. High levels of TK were predictive of worse RFS and OS independently of the treatment, as though the overexpression of this enzyme could allow tumor cells to escape the effects of fluorouracil and methotrexate. In the second study, high TK was predictive of better disease specific survival (DSS) and distant relapse-free interval in N-negative patients treated with anthracycline-based CT (FAC or FEC) in comparison with those untreated [84
].
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Proliferation associated antigens (Ki-67, MIB 1) |
---|
Prognostic role
In the last decade, a large number of papers have been published and, even after taking into consideration the inevitable publication bias in favor of positive trials, it is now clear that the Ki-67/MIB 1 protein has a prognostic value for many types of malignant tumors. In BC, all the selected studies [89103
] have shown a statistically significant correlation with clinical outcome (DFS and/or OS) as reported in Table 2, but all except one [104
] are retrospective. The number of patients included ranged from 127 to 707, and the populations were heterogeneous, except in three studies [91
, 96
, 102
], which analyzed only N-negative patients. The median follow-up length ranged from 31 months [90
, 92
] to 13.5 years [103
], and other relevant differences among these studies were related to the type of antibody utilized, the cut-off value selected to define high versus low proliferative activity, and the number of cells counted. Although, the Ki-67/MIB 1 protein expressed as Ki-67 index (percentage of cells staining positive) is widely used in the routine assessment of prognostic markers, it is not considered a standard one [1
, 105
] due to the lack of an international standardization method for antigen retrieval, staining procedures and scoring methods (semi quantitative and quantitative).
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Cyclins E |
---|
Prognostic role
The prognostic role of cyclin E (E1) has been retrospectively evaluated in several studies [120, 124
132
] shown in Table 4. The majority of these studies included patients with early stage BC, but in two of them [120
, 124
], stage IV patients were also entered. Few studies analyzed only N-negative patients [126
128
] and in two of them the same patient population was evaluated with just 59 tamoxifen-treated patients added [126
]. In some studies no systemic adjuvant treatment was administered, while in others, all patients or only a subgroup of them received CT and/or endocrine therapy. IHC was the most common evaluation method even if the antibodies utilized and the cut-off values were different. Western blotting analysis was performed in two studies [120
, 124
], while RT-PCR was chosen in another one [132
]. Cyclin E was prognostic in seven out of 10 studies [120
, 125
130
]. Keiomarsi et al. found that the overexpression of cyclin E was accompanied by the appearance of low molecular weight (LMW) isoforms, and both were a reliable prognostic marker in stage IIII BC patients [120
]. In fact, the hazard ratio for death due to BC in patients with high levels of cyclin E was higher than the hazard ratio associated with any other biological marker examined (seven times higher than the hazard ratio associated with N metastases). All N-negative patients with high levels of cyclin E (12 out of 114) died of BC. In some studies a correlation between cyclin E and high histological grade [126
129
, 131
] or ER negativity [124
, 126
129
, 131
, 132
] has been reported, while an inverse correlation with p27 was observed in a study where both factors were prognostic [133
]. No definitive conclusion about the prognostic role of cyclin E can be derived from these studies. In fact, a standardization of evaluation methods and scoring systems and large prospective studies are required. No data on the potential prognostic role of cyclin E2 in BC have been published.
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Cyclin D1 |
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Prognostic role
As shown in Table 5, seven retrospective studies have analyzed the prognostic role of cyclin D1 in 1509 patients. In two of these studies stage IIV BC patients were included [137, 138
]; the median follow-up ranged from 75 months to 16.7 years. The most common evaluation method was IHC, with different antibodies and cut-off values utilized. Gene amplification and IHC were both assessed in two studies [139
, 140
]. A strong correlation between overexpression of cyclin D1 and HR-positivity has been reported in the majority of trials, but cyclin D1 does not appear to be a strong prognostic marker. In fact, its overexpression has been associated with better RFS in only one study [140
] and with better RFS and OS in another one [137
].
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Cdk inhibitors |
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Prognostic role
In some adjuvant studies, the prognostic role of p27 in BC patients has been retrospectively evaluated by IHC utilizing different monoclonal antibodies [133, 146
156
]. Cells were considered positive only when nuclear staining was identified, and the percentage of immunoreactive cells was scored in the majority of studies as low or high using a cut-off value of 50%. The number of patients analyzed ranged from 102 to 830, and they received no adjuvant systemic treatment, CT alone, hormone therapy alone, or both. Low levels of p27 were associated with worse clinical outcome in eight out of 12 studies, but no impact on prognosis was reported in four of them including the two with the largest number of patients [152
, 153
, 155
, 156
] (Table 6). An inverse relationship was found between p27 levels and histological grade, and a positive one with ER status, in the majority of studies. Furthermore, an inverse correlation with cyclin E levels [121
, 133
] was observed, whereas higher concentrations of p27 were associated with increased concentrations of cyclin D1 and low tumor grade [151
, 152
, 157
] or cyclin D expression and bcl-2 positivity [154
]. A statistically significant correlation between low p27 protein expression and HER2 overexpression (158160) could validate the hypothesis that one pathway for HER2 oncogenic activity seems to rely on down regulation of the cell-cycle regulator p27 [161
]. Interestingly, a decrease in the p27 levels has been reported in a trastuzumab-resistant HER2-positive cell line, and the resistance could be reverted by proteasome inhibitors such as MG 132, which induced p27 expression [162
]. An inverse correlation with p53 was shown in three out of five studies where it was analyzed [147
, 154
, 163
]. In addition, in 202 Askenazi Jewish BC patients [149
], BRCA 1/2 mutations were associated with low levels of p27, and both were identified as independent prognostic factors. The failure of some studies to find a prognostic value for p27 might reflect differences in tumor fixation, methods of staining and scoring, and also the prolonged storage time of the archival tumor blocks utilized in several studies [145
]. Therefore, it is crucial to define a uniform methodology for tumor processing, staining and scoring and to evaluate p 27 in large prospective trials.
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p21WAF1/CIP1 |
---|
Prognostic role
The prognostic role of p21WAF1 has been retrospectively analyzed in several adjuvant studies [169178
], with a number of patients ranging from 104 to 798, and a wide range of median follow-up times (Table 8). IHC was the evaluation method for p21WAF1 in all trials, and only tumor cells with detectable nuclear staining were considered positive. However, different monoclonal antibodies and scoring systems were adopted. When p21WAF1 was correlated with standard prognostic factors and other biological markers, contradictory results were obtained. Since p21WAF1 is a downstream effector in the p53-specific pathway of growth control, p53 was analyzed in all trials, although in the majority of them no association was found. Low expression of p21WAF1 was correlated with high histologic grade in three studies [171
, 172
, 178
], while in one study the opposite was observed [170
]. A positive association with proliferative activity was reported in three studies in which MIB-1 [175
], Ki-67 [174
] or cell nuclear antigen (PCNA) were measured; in contrast [177
], an inverse association was seen with HR status in two [172
, 175
] and with N status in three studies [170
172
]. Low levels of p21WAF1 were an independent prognostic factor for DFS only or for DFS and OS in three studies [171
, 172
, 178
], even if in one of them it depended on the cut-off value chosen [178
]. Moreover, low expression of p21WAF1 was prognostic only in combination with increased expression of p53 in three studies [170
, 174
, 178
]. The combination of low levels of p21WAF1 and low SPF or low levels of cyclin A were associated with good prognosis on multivariate analysis in a study conducted in a relatively small number of patients [169
]. The heterogeneity of the results reported in these studies calls for the necessity to standardize the evaluation method and scoring system for p21WAF1 determination.
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Topoisomerase II![]() |
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Prognostic role
Only three retrospective adjuvant studies evaluating overexpression of topoII by IHC were selected through the criteria chosen (Table 9) [192
, 193
, 196
]. A positive association with HER2 overexpression or amplification was observed in all of them, as well as with tumor size or stage, and in two studies also with high Ki-67 or MIB 1 [192
, 193
]. Overexpression of topo II
predicted a shorter DFS, specific survival (SS) and/or OS in multivariate analysis only in two studies [193
, 196
]. Large prospective studies using standardized methods are needed to better define the potential clinical relevance of topo II
as a prognostic factor.
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Conclusions |
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Received for publication January 18, 2005. Revision received April 11, 2005. Accepted for publication April 12, 2005.
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