Prognostic markers in node‐negative breast cancer: A prospective study

Abstract

Background: Despite years of research, it is still unclear which women with node-negative (N-) breast cancer will need adjuvant chemotherapy and which women are being treated unnecessarily. Our goal was to determine which factors best predicted disease free survival (DFS) or cancer-specific overall survival (OS) and, therefore, select the correct patients for treatment. A total of 11 parameters were measured: estrogen receptor (ER), progesterone receptor (PR), age, race, ploidy status, %G0/G1 (% non-DNA synthesis), %S (% S-phase), cathepsin D status, size, stage, and histologic grade.Results: In this prospective study, we followed 556 N-patients diagnosed between 1991 and 1996. The tumors were 56% ER؉, 51% PR؉, 30% diploid, with a mean %S of 8.9%. The level of cathepsin D ranged from 0.50 to 155 pmol/mg of protein with a mean of 42.9 pmol/mg of protein. There were 87 recurrences (16%) and 72 cancer deaths (13%), with a median follow-up of 7.8 years. Ploidy status (p ‫؍‬ 0.01), S-phase activity (p ‫؍‬ 0.003), G1 phase activity (p ‫؍‬ 0.02) and age (p ‫؍‬ 0.01) were able to significantly predict DFS in a univariate manner. All of the measurable factors were significant or borderline significant in predicting OS in a univariate manner except for age, race, and ER status. In multivariate analysis with S-phase included, it was the only remaining factor in DFS and OS; with S-phase excluded, age and ploidy status remained as factors for DFS in stepwise regression, while PR, size, and cathepsin D were the remaining factors that predicted cancer-specific OS. The effect of adjuvant treatment on prognosis was also analyzed.Conclusions: Both biochemical and clinical parameters have the potential to predict prognosis for Nbreast cancer. In this large prospective clinical trial, with a median follow-up of 7.8 years, no individual marker adequately predicted the prognosis for an individual patient. %S activity was the best independent marker, but only 77% of the tumors provided this value. Subset analysis provided improved prognostication, but there were limits to its utility. These data represents a definitive study starting in 1991 and ending in 2002.

Prognostic relevance of DNA flow cytometry in breast cancer revisited: The 25-year experience of the Portuguese Institute of Oncology of Lisbon

“…However, in the long-term follow-up study (11), DNA ploidy retained an independent prognostic value for DFS in the subset of patients with axillary node-negative breast cancer, a subset for whom it is difficult to identify significant prognostic indicators for. This finding has been corroborated by others (33,34). Therefore, it is important that DNA ploidy can aid in the prediction of recurrence risk of patients with axillary node-negative breast cancer.…”

“…Similarly to numerous studies (10,19,33,34,37,46), results from the Portuguese Institute of Oncology of Lisbon have consistently identified a strong association between the grade of tumour differentiation and DNA ploidy in breast cancer (11,32). This result is explained by the similar biological significance of these characteristics, reflecting the extent, type and complexity of genomic abnormalities of the tumour (38,47).…”

“…Contradictory findings may result from differences in study design and technical, analytical and interpretative methods (15,(17)(18)(19)(20). Despite these limitations, the prognostic significance of DNA ploidy and SPF in breast cancer is relatively consensual, at least in univariate models (3,10,33). However, an important question remains in relation to the clinical utility and predictive value of DNA ploidy and SPF in the selection of adjuvant therapies.…”

Novel molecular prognostic markers in breast cancer

“…However, measurements have not been standardized and their prognostic ability not confirmed on a larger scale. Technical problems with accurately calculating the expression of p53 protein products or identifying gene mutations have plagued the utility of this marker as well [19,20]. More promising markers include plasminogen activator inhibitor (PAI-1) and urokinase plasminogen activator (uPA).…”

Problem Poser—How to Interpret Divergent Prognostic Evidence of Simultaneously Measured Tumor Markers?

“…Their usefulness is tested by relating the relapses to the expression of these markers. Whereas estrogen-and progesterone-receptor expressions are assumed to be favourable for the patient [3,4] because they reflect a more differentiated (and hence less aggressive) tumour, the proto-oncogene p53 [5,6] and human epidermal growth factor receptor (HER2) [7] are associated with accelerated malignant growth. Additionally, the nuclear Y-box (YB) protein-1 staining pattern in breast cancer cells and surrounding tissue has been shown to be predictive for drug resistance, indicating a poorer long-term outcome [8].…”