From the different methods available to assess proliferative activity in breast cancer, the MAI meets the criteria of well-established prospective prognostic value, stable thresholds, good repro-ducibility and practicality. It can therefore be used to stratify patients for adjuvant therapy. The Ki67 labeling index assessed with the MIB1 antibody is a good runner-up, and may become clinically applicable after further methodological

<10 situ carcinoma,1

especially in high-grade

12 24 36 48 60 72 Survival time (months)

Figure 3.2 Survival of lymph node-negative breast cancer patients with low and high mitotic activity index (MAI) prospective results from the Dutch MMCP study.85

fine-tuning. The other methods are of biological rather than practical value.

Prognostic value of cell cycle-regulating genes

The prognostic value of expression patterns of cell cycle-regulating genes has been less well studied than, for example, MAI and MIB1. Some interesting data regarding cell cycle regulators have, however, been described which help us to understand changes in rate of proliferation in tumors, and some changes in expression seem to have some clinical value.

Cyclin A is expressed in the late phases of the cell cycle, and may thereby function as a marker of proliferating cells. The cyclin A labeling index (not influenced by amplification152) is indeed positively correlated with proliferation.59 In a few breast cancer studies, a high cyclin A labeling index was associated with poor


Cyclin B is also expressed in the late phases of the cell cycle, and has been found to increase in frequency from normal breast tissue to atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and invasive carcinoma.154 In one study, high cyclin B levels predicted poor prognosis.155

Cyclin D1, mainly expressed in the G1 phase, seems to play a role in breast carcinogenesis, since mRNA and protein overexpression is quite often found in ductal hyperplasia and in

DCIS, which recur more frequently than low-grade ones.158 159 Overexpression of cyclin D1 protein or mRNA occurs in the vast majority of invasive lobular carcinomas, but not in lobular carcinoma in situ.160

Overexpression of cyclin D1 in invasive breast cancers occurs in 40-50% of all cases,91,161,162 about half of which is due to amplification of the cyclin D1 gene (CCND1) on chromosome 11q13. This amplification, and corresponding overexpression, is associated with a more aggressive tumor phenotype and/or worse progno-sis.152,163-164 In contrast, overexpression of the cyclin D1 protein was negatively correlated with proliferation, and by itself was not indicative of prognosis in large series of patients with stage I/II breast cancer,91'162'167-169 whereas mRNA studies gave contradictory results.170,171

This apparent contradiction between the clinical impact of gene amplification and protein overexpression may be explained by the finding that approximately only half of the cases with overexpression of the cyclin D1 protein have amplification of the CCND1 gene. Since overexpression of the cyclin D1 protein is significantly linked with estrogen receptor (ER) positivity,91'162'167'172 and since cyclin D1 is turned on by activated ER, the other half of the cases with overexpression of the cyclin D1 protein in breast cancer may be due to 'normal' stimulation by estradiol. The strong association between cyclin D1 and ER may explain why cyclin D1-positive patients respond better to adjuvant therapy.173 The ability of cyclin D1 to upregulate p21WAF1 may explain the negative correlation between cyclin D1 and proliferation.174

For cyclin E, also mainly expressed in the G1 phase, overexpression is correlated with a more aggressive phenotype, including high proliferation175,176 and reduced survival.177-182

Overexpression of p21WAF1 (also known as p21CIF1), a cyclin-dependent kinase (CDK) inhibitor, was correlated with reduced disease-

free survival in several studies,105,106,183-185 but not in all.168 In the study of Domagala et al,186 no direct association was found between p21WAF1 expression and overall survival. However, a significantly poorer survival was noted for

p21WAF1-negative/p53-positive patients treated with adjuvant chemotherapy. Similar results were obtained by Caffo et al183 and Thor et al.185 These data indicate that the p21WAF1/p53 phenotype may predict therapeutic response to chemo- and hormonal therapy. This may relate to underlying mutations in p53 resulting in failure to induce p21WAF1 and apoptosis. Also, the subcellular localization of p21WAF1 may be important. Although p21WAF1 should have its major function in the nucleus, p21WAF1 cytoplasmic staining is often found, and seems to be associated with high p53 levels and poor prognosis.155 These results are rather confusing, since p21WAF1 is basically a cell cycle inhibitor.

Lack or loss of p27Kip1, another CDK inhibitor, is usually associated with higher proliferation, and indicates poor prognosis in breast cancer in most studies,54,176,178-180,187 especially when p27Kip1 is lost in combination with overexpression of cyclin E.180 Not all studies have confirmed the adverse prognostic effect of loss of p27Kip1,54,168 and in one study188 high p27Kip1 expression interestingly was an indicator of poor prognosis in node-negative cases. Loss of p16INK4A (CDKN2A) seems to have no impact in breast cancer: varying frequencies of p16INK4A loss have been described,189,190 without prognostic impact.191 Retinoblastoma protein (pRb) expression does not seem to be of prognostic significance either.191-193

There have been very many studies of p53 in breast cancer, as described in Chapter 12.

Although there are many conflicting results,194,195

the majority of studies show that p53 accumula-

tion,185,196,197 or mutation,164 is correlated with increased proliferation,198 and is associated with poor prognosis38,49 and poor clinical response to primary chemotherapy.199 CDK4 protein overexpression, as well as CDK4 gene amplification, have also been found in invasive breast carcinomas, but do not correlate with prognosis.169 Although the catalytic form of telomerase (hTERT) is not strictly a cell cycle-regulating protein, hTERT levels are correlated with proliferative activity of breast cancer.200-203 However, evaluation of its prognostic significance has yielded conflicting results.200-202,204,205

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