1.
Bagwell, C B, et al.
(författare)
Optimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimens
2001
Ingår i: Cytometry. - : Wiley. - 0196-4763 .- 1097-0320. ; 46:3, s. 121-135
Tidskriftsartikel (refereegranskat) abstract
Developing a reliable and quantitative assessment of the potential virulence of a malignancy has been a long-standing goal in clinical cytometry. DNA histogram analysis provides valuable information on the cycling activity of a tumor population through S-phase estimates; it also identifies nondiploid populations, a possible indicator of genetic instability and subsequent predisposition to metastasis. Because of conflicting studies in the literature, the clinical relevance of both of these potential prognostic markers has been questioned for the management of breast cancer patients. The purposes of this study are to present a set of 10 adjustments derived from a single large study that optimizes the prognostic strength of both DNA ploidy and S-phase and to test the validity of this approach on two other large multicenter studies. Ten adjustments to both DNA ploidy and S-phase were developed from a single node-negative breast cancer database from Baylor College (n = 961 cases). Seven of the adjustments were used to reclassify histograms into low-risk and high-risk ploidy patterns based on aneuploid fraction and DNA index optimum thresholds resulting in prognostic P values changing from little (P < 0.02) or no significance to P < 0.000005. Other databases from Sweden (n = 210 cases) and France (n = 220 cases) demonstrated similar improvement of DNA ploidy prognostic significance, P < 0.02 to P < 0.0009 and P < 0.12 to P < 0.002, respectively. Three other adjustments were applied to diploid and aneuploid S-phases. These adjustments eliminated a spurious correlation between DNA ploidy and S-phase and enabled them to combine independently into a powerful prognostic model capable of stratifying patients into low, intermediate, and high-risk groups (P < 0.000005). When the Baylor prognostic model was applied to the Sweden and French databases, similar significant patient stratifications were observed (P < 0.0003 and P < 0.00001, respectively). The successful transference of the Baylor prognostic model to other studies suggests that the proposed adjustments may play an important role in standardizing this test and provide valuable prognostic information to those involved in the management of breast cancer patients.
2.
Baldetorp, Bo, et al.
(författare)
DNA and cell cycle analysis as prognostic indicators in breast tumors revisited
2001
Ingår i: Clinics in Laboratory Medicine. - 0272-2712 .- 1557-9832. ; 21:4, s. 875-
Tidskriftsartikel (refereegranskat) abstract
Both DNA ploidy and S-phase ploidy are promising prognostic factors for node-negative breast cancer patients. Based largely on the analysis of one large study, much of the reported problems with these factors have been caused by some unappreciated complexities in categorizing DNA ploidy into low- and high-risk groups and the lack of some necessary adjustments to eliminate unwanted correlations between DNA S-phase and ploidy. When both DNA ploidy and S-phase are compensated properly, they become independent prognostic markers, forming a powerful prognostic model.
3.
Rennstam, Karin, et al.
(författare)
Chromosomal rearrangements and oncogene amplification precede aneuploidization in the genetic evolution of breast cancer
2001
Ingår i: Cancer Research. - 1538-7445. ; 61:3, s. 1214-1219
Tidskriftsartikel (refereegranskat) abstract
Breast carcinoma is thought to arise because of multiple successive changes in the genome of the normal epithelial cells. However, little is known of the order of appearance of different types of genetic aberrations We studied the ERBB2 (Her-2/neu) and CCND1 (cyclin D1) oncogene amplification in flow cytometrically sorted diploid and nondiploid tumor cell populations by fluorescence in situ hybridization (FISH). The purity of the cell sorting was confirmed by static DNA image cytometry. Spectral karyotyping was used to define differences in a genome-wide manner between two distinctly different aneuploid cell clones found in each of two breast cancer cell lines. FISH indicated the presence of gene amplification both in diploid and nondiploid cell clones in 17 of the 21 amplification-containing tumors analyzed. The oncogene copy numbers remained unchanged throughout aneuploidization in 11 of 17 tumors. The remaining six tumors showed an increase in oncogene copy number as well as the number of chromosome 11 or 17 centromeres (the original location of CCNDI and ERBB2, respectively). Breast carcinoma cell lines MDA-157 and MDA-436 showed a significant number of chromosomal rearrangements in the near-diploid clones, which were present in duplicate in the corresponding aneuploid (polyploid) clones. These results indicate that ploidy shift, ie., aneuploidization, in breast cancer is a late genetic event which is preceded by both oncogene amplifications as well as many chromosomal rearrangements.
4.
Rudolph, Pierre, et al.
(författare)
Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer
2001
Ingår i: Human Pathology. - : Elsevier BV. - 1532-8392 .- 0046-8177. ; 32:3, s. 311-319
Tidskriftsartikel (refereegranskat) abstract
Simultaneous overexpression of c-erbB-2 and p53 has been reported to be prognostically unfavorable in breast cancer. Herein, we show that concurrent overexpression of these 2 proteins is associated with a marked reduction in the relative fraction of cells in G(1) phase of the cell cycle, indicating an accelerated cell cycle progression. Using an immunohistochemical approach, we examined 261 cases of node-negative infiltrating ductal carcinomas of the breast with respect to c-erbB-2 and p53 expression and to the proliferative activity measured by the Ki-67 index. By means of a novel monoclonal antibody, Ki-S2, which exclusively recognizes proliferating cells in the S, G(2), and M phases of the reproductive cycle, we were further able to calculate the relative fraction of the cells having passed the restriction point at the G(1)/S boundary, thus defining a cycling ratio (CR). The results were correlated with clinical outcome; median follow-up time was 96 months. Tumors that simultaneously overexpressed c-erbB-2 and p53 had a high median CR and followed an unfavorable course. However, increased CRs were also observed independently of c-erbB-2 and p53 overexpression, suggesting that other molecular mechanisms may contribute to acceleration of cell cycle progression. In a multivariate analysis that included patient age, tumor size, hormone receptor status, c-erbB-2 and p53 expression, and the Ki-67 index, CR emerged as the most significant independent predictor of overall and disease-free survival (P <.0001). It is concluded that the CR is a gauge of cell cycle deregulation and therefore may be a powerful indicator of the biologic behavior of cancers.
