Prognostic Value of Gene Signatures and Proliferation in Lymph-Node-Negative Breast Cancer

Abstract

IntroductionThe overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers.MethodsIllumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67.ResultsKaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n = 45), and 65% (n = 49, p = 0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n = 45) and 71% (n = 49, p = 0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n = 18), 79% (n = 42) and 68% (n = 34) for those in the low-, intermediate- and high-risk groups, respectively (p = 0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis.ConclusionThis pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.

Breast Cancer Prognostic Biomarker Using Attractor Metagenes and the FGD3–SUSD3 Metagene

“…Such imperfect comparisons, however, are still valuable. Many other publications, including some recently published ones (25,26), also use microarray values to compare breast cancer prognostic signatures.…”

Association Between Phosphorylated Histone H3 and Oncotype DX Recurrence Scores in Breast Cancer

“…Thus, the application of molecular testing such as Oncotype DX to predict who will most benefit from chemotherapy has become increasingly popular. However, there is increasing evidence that histologic evaluation of proliferation markers may provide similar prognostic and predictive information 9,10. We found that PhH3 has a strong correlation with Oncotype DX RS score, according to Dancey and Reidy’s23 categorization of correlation strength.…”

“…However, this may be the result of methodology because the IHC markers were assessed on TMAs taken from representative tumor areas rather than highest proliferation areas, whereas mitotic count was performed on whole slides in the region of highest proliferation. More recently, their group compared the prognostic ability of mitosis, PhH3, and Ki-67 as well as the gene profiles used in Oncotype DX and MammaPrint (Agendia Inc., Amsterdam) 10. PhH3 was again the strongest independent prognostic factor.…”

“…There are potential drawbacks with molecular testing, including the problem of tumor heterogeneity, “contamination” by nontumoral elements found in the stroma,8 and long turnaround times. Evidence also suggests that histologic and immunohistochemical features of breast carcinoma may provide similar recurrence information 9,10…”

“…However, because PhH3 does not exactly correlate with mitosis, variances between PhH3 and morphology-based mitotic counts can be expected 13,14. Whether or not these variances might provide meaningful insight into the predictive or prognostic value of PhH3 and other markers of proliferation has only recently been the focus of study, and results to date have been limited 10,15–19…”