Background: Loss of expression of the cyclin-dependent kinase (cdk) inhibitor p27 has been associated with decreased survival among patients receiving adjuvant chemotherapy. The I-SPY Trial is a multicenter study of locally advanced breast cancer in which pretreatment tumor biopsies were obtained prior to the administration of anthracycline and taxane-based neoadjuvant therapy, and serial MRIs were performed to assess response to treatment. The aim of this study was to determine if loss of tumor p27 expression was associated with response to cytotoxic therapy.
Methods: Eligible patients had biopsy-confirmed primary breast cancer measuring at least 3 cm. Immunohistochemistry for p27 was performed centrally on pretreatment core samples using rabbit anti-p27 (Upstate Cell Signaling #06–445). Nuclear p27 was classified as absent (no staining), low (1–50% staining) or normal (>50% staining). Following completion of chemotherapy, post-surgical excision/mastectomy cases were reviewed centrally to determine response to therapy including residual cancer burden (RCB) and pathologic complete response (pCR) rate. Exact Chi2 was used to compare proportions.
Results:Pretreatment samples from 164 of 237 enrolled patients demonstrated that p27 expression was absent in 55 (33%), low in 96 (58%) and normal in 14 (8%). P27 loss was not associated with patient age. Compared to normal p27 expression, absent p27 was significantly associated with ER negativity (48% vs. 14%; p=0.03), PR negativity (59% vs. 21%; p=0.03), Her2 overexpression (28% vs. 14%; p=0.017) and basal molecular subtype (29% vs. 13%). The proportion of patients with p27 loss (absent or low) was higher for those with high Ki-67 expression compared to low/mod expression (98% compare to 88%) and lower for grade 1 (72% vs 92%) compared to grade 2/3 tumors (p=0.071 and p=0.090, respectively). Low or absent p27 was not associated with response to therapy as measured by pCR, RCB or change in tumor diameter by MRI.
Conclusions: p27 loss in this neoadjuvant patient population was associated with aggressive tumor features, but not predictive of response to cytotoxic therapy. These findings suggest that the poor prognosis associated with loss of p27 is not due to relative chemotherapy resistance.