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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].


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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 cases with a median follow-up of 8 years 38 , were recently updated at a follow-up of 10 years in cases.

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For local—regional relapse, a hazard ratio HR of 1. For distant metastasis, the HR was 1. 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, 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 study.

Patients with lymph node-negative, ER-positive tumors were randomly assigned to receive adjuvant therapy with tamoxifen or placebo 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 women in this trial.

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. Intergroup performed a prospective, randomized clinical trial LOE I 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 finding validated the utility of cell proliferation and has been independently confirmed in about lymph node-negative tumors in a prospective investigation by Jones et al. 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.

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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 St. Our study was carried out on a series of 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 to December 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, 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 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 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.

Gallen criteria 70 , several risk categories of prognostic importance were defined Fig. Gallen categories and TLI. The overall concordance among the three St. Gallen or TLI classes was limited to only about one third of the cases. 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.

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. Patients were randomly assigned to receive adjuvant chemotherapy e.

These studies measured tumor cell proliferation and instituted quality-control programs for analytical and preanalytical phases of cell kinetic determinations 71, 76— Results are available from the multicenter Italian study by Amadori et al. 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. The benefit of CMF treatment was mostly evident for cases at very high risk, i.

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— There has been a renewed emphasis in the search for biologic predictive factors, i.

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, Up to now, few studies have investigated whether cell kinetics provides information on the efficacy of different treatment schedules.

The data could be explained by a partial synchronization of cells in the G 2 —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 All of the data have been obtained from retrospective clinical analyses, and prospective studies are needed.

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 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 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. Relapse-free survival curves for patients with resectable breast cancer by risk categories according to the St.

Relapse-free survival was analyzed as a function of tumor [ 3 H]thymidine-labeling index TLI. Solid line: low TLI 0. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. B ackground. P rognostic R ole of P roliferation I ndices. C onclusions. R eferences.

Correspondence to: Maria Grazia Daidone, Ph. Oxford Academic. Google Scholar.

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Rosella Silvestrini. Cite Citation. Permissions Icon Permissions.

Abstract In breast cancer, proliferative activity represents one of the biologic processes most thoroughly investigated for its association with tumor progression. Table 1. Silvestrini et al. Open in new tab. Table 2. Table 3. Table 4. Open in new tab Download slide. Proliferation markers in tumours: interpretation and clinical value.

J Clin Pathol. Determination of cell proliferation. J Clin Pathol Mol Pathol. Silvestrini R. Cell kinetics: prognostic and therapeutic implications in human tumors. Cell Prolif.

In vitro labeling of solid tissues with tritiated thymidine for autoradiographic detection of S-phase nuclei. Stain Technol.

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Hedley DW. Flow cytometry using paraffin-embedded tissue: five years on. Scholzen T, Gerdes J. The Ki protein: from the known and the unknown. J Cell Physiol. Immunologic proliferation marker Ki-S2 as prognostic indicator for lymph node-negative breast cancer. J Natl Cancer Inst. Prognostic significance of proliferative activity and ploidy in node-negative breast cancers.

Ann Oncol. Biotech Histochem. Thymidine labeling index and Ki growth fraction in breast cancer: comparison and correlation with prognosis. Breast Cancer Res Treat. Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki antibodies: its prognostic value on short-term recurrences. Eur J Cancer.