Which cyclin E prevails as prognostic marker for breast cancer? Results from a retrospective study involving 635 lymph node-negative breast cancer patients.
OBJECTIVE
To evaluate the prognostic value of cyclin E with a quantitative method for lymph node-negative primary breast cancer patients.


METHODS
mRNA transcripts of full-length and splice variants of cyclin E1 (CCNE1) and cyclin E2 (CCNE2) were measured by real-time PCR in frozen tumor samples from 635 lymph node-negative breast cancer patients who had not received neoadjuvant or adjuvant systemic therapy.


RESULTS
None of the PCR assays designed for the specific splice variants of the cyclins gave additional prognosis-related information compared with the common assays able to detect all variants. In Cox multivariate analysis, corrected for the traditional prognostic factors, high levels of cyclin E were independently associated with a short distant metastasis-free survival [hazard ratio (HR), 3.40; P < 0.001 for CCNE1 and HR, 1.76; P < 0.001 for CCNE2, respectively]. After dichotomizing the tumors at the median level of 70% tumor cells, the multivariate analysis showed particularly strong results for CCNE1 in the group of 433 patients with stroma-enriched primary tumors (HR, 5.12; P < 0.001). In these tumors, the worst prognosis was found for patients with estrogen receptor-negative tumors expressing high CCNE1 (HR, 9.89; P < 0.001) and for patients with small (T1) tumors expressing high CCNE1 (HR, 8.47; P < 0.001).


CONCLUSIONS
Our study shows that both CCNE1 and CCNE2 qualify as independent prognostic markers for lymph node-negative breast cancer patients, and that CCNE1 may provide additional information for specific subgroups of patients.
Sieuwerts
Anieta M
AM
Department of Medical Oncology, Erasmus MC, Rotterdam, The Netherlands. a.sieuwerts@erasmusmc.nl
Look
Maxime P
MP
Meijer-van Gelder
Marion E
ME
Timmermans
Mieke
M
Trapman
Anita M A C
AM
Garcia
Roberto Rodriguez
RR
Arnold
Miranda
M
Goedheer
Anneke J W
AJ
de Weerd
Vanja
V
Portengen
Henk
H
Klijn
Jan G M
JG
Foekens
John A
JA
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics*; D016213:Cyclins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D015513:Oncogene Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; C503688:CCNE2 protein, human; D019927:Cyclin E; D016213:Cyclins; D015513:Oncogene Proteins; D012333:RNA, Messenger