Decreased immunoreactivity for p27 protein in patients with early‐stage breast carcinoma is correlated with HER‐2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status

Abstract

BACKGROUNDThe objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin‐dependent kinase inhibitor p27(Kip1) in patients with early‐stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers.METHODSImmunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow‐up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group.RESULTSIn the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER‐2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki‐67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10‐year DFS: low p27 expression, 53% ± 5%; high p27 expression, 55% ± 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% ± 4%; high p27 expression, 32% ± 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5‐fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction).CONCLUSIONSThis analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early‐stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER‐2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy. Cancer 2003;97:1591–600. © 2003 American Cancer Society.DOI 10.1002/cncr.11224

Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2–positive breast cancer cells in a synergistic manner

“…We observed decreased p27 nuclear immunoreactivity in association with HER-2 overexpression, which has previously been shown for lymph node -negative breast cancer (40). Cytoplasmic p27 was detected in SKBR-3 cells, whereas significant levels of nuclear p27 were observed in MCF-7 and MDA-MB-453 cells, although the majority of p27 was cytoplasmic in the latter.…”

Low p27 Expression Predicts Early Relapse and Death in Postmenopausal Hormone Receptor–Positive Breast Cancer Patients Receiving Adjuvant Tamoxifen Therapy

“…An unfavorable outcome was observed in patients with low p27 expression regardless of the adjuvant systemic treatment. In the International Breast Cancer Study Group Ludwig Trial V, p27 protein expression was assessed in lymph node-negative and lymph node-positive breast cancer patients, but it did not show any significant prognostic value with regard to disease-free and overall survival (47). However, in the lymph node-negative population, the benefit from one course of perioperative chemotherapy (CMF i.v.)…”

“…However, in previous studies, different cutoff points, depending on the percentage of positive tumor cells ranging from 10% to 50% (32,43,(47)(48)(49) or different scores consisting of staining intensity and percentage of positive tumor cells (18,32,33,41,44,50), have been applied. In the present study, we explored two different cutoff points (50% and 70%) and obtained similar results.…”

The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis

“…Akt is activated in HER2-amplified breast cancers (reviewed above) and activated Akt phosphorylates p27 inhibiting its function by excluding it from the nucleus (Liang et al, 2002;Shin et al, 2002;Viglietto et al, 2002). Several clinical studies have also established that HER2-overexpressing breast cancers have reduced p27 expression compared with other types of breast cancers (Newman et al, 2001;Loden et al, 2003;Spataro et al, 2003). HER2 mediates p27 degradation likely through mechanisms that involve MAPK (Yang et al, 2000;Donovan et al, 2001;Lenferink et al, 2001).…”