Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy

Abstract

Introduction. Prediction of response to preoperative breast cancer chemotherapy may offer a substantial optimization of medical management of this disease. The most efficient prediction would be done a priori, before the start of chemotherapy and based on the biological features of patient and tumor. Numerous markers have been proposed but none of them has been applied as a routine. The role of MKI67 and HSP90 expression has been recently suggested to predict treatment sensitivity in HER2-positive breast cancer. The aim of this study was to validate the utility of proliferation based markers (MKI67 and CDK1) and heat shock proteins (namely HSP90) to predict response to chemotherapy in cohort of breast cancer patients treated preoperatively. Material and methods. Ninety-three patients with breast cancer, all females, mean age 42.2 years, among them 32% T1-T2 patients, 49% T3 patients and 13% with T4 tumor stage, 27% N0, 42% N1, 16% N2, 15% N3 were subjected to initial chemotherapy. The majority of patients (86%) received anthracycline and taxane chemotherapy. Among the patients there were 9 individuals with metastatic disease (M1) at initial presentation, and 11 patients were not treated surgically after initial chemotherapy (no sufficient disease response). From 82 patients operated on, 20 patients (24%) showed pathological complete response (pCR), while in 62 patients there was Results. There were no statistically significant differences in MKI67 and CDK1 expression between pCR and no pCR groups (p = 0.099 and 0.35, respectively), although the median expression of both genes was slightly higher in pCR group. In contrast, both HSP90AA1 and HSP90AB1 transcripts showed decreased expression in pCR group (medians 0.77 and 0.55) when compared to no pCR group (median 0.86 and 0.73), statistically significant for HSP90AA1 (p = 0.031) and of borderline significance for HSP90AB1 (p = 0.054). The most significant predictor of pCR was the ratio of CDK1 transcript to HSP90AA transcript. This ratio was significantly higher in CR group (median 0.99) than in no CR group (median 0.68, p = 0.0023), and showed a potential diagnostic utility (area under receiver operating characteristic [ROC] curve 0.72). Conclusions. HSP90AA1 and AB1 genes exhibit low expression in breast cancers highly sensitive to chemotherapy and may indicate the patients with higher probability of pathological complete response. The ratio of HSP90AA1 to proliferation-related markers (CDK1 or MKI67) may be even better predictor of pCR chance, with higher expression of proliferation genes and lower stress response in patients sensitive to chemotherapy.

Association of breast cancer grade with response to neoadjuvant chemotherapy assessed postoperatively

“…The importance of proper selection increases with the growing number of treatment options for patients with breast cancer. The growing role of genomic approaches by complex or simpler predictors [24] is to be appreciated, but until they become more widespread in clinical practice, both tumour grade and surrogate St Gallen subtypes should be considered important features predicting the probability of pCR.…”

Heat Shock Protein 90 Family Isoforms as Prognostic Biomarkers and Their Correlations with Immune Infiltration in Breast Cancer

“…A research illuminated that HSP90AA1 was overexpressed in BRAC and was correlated with shorter OS and aggressive clinicopathological features, including high clinical stage, large tumors, and lymph node involvement [ 37 ]. Jarzab et al found that low expression of HSP90AA1 and HSP90AB1 might indicate higher sensitivity to chemotherapy and higher probability of pathological complete response in BRAC patients [ 18 ]. Cheng et al found that high expression of HSP90AA1 and HSP90AB1 might be independent factors predicting poor prognosis of TNBC and ER+/HER2− patients, respectively, which was quite inconsistent with our findings [ 16 ].…”

“…The diagnostic, prognostic, or predictive potentials of HSP90s genes had been partly reported previously [ 3 , 14 – 18 ]. However, the role of each HSP90s family member in the development and progression of every certain subtype of BRAC remains unknown.…”

<p>Predictors of Neoadjuvant Chemotherapy Response in Breast Cancer: A Review</p>

“…80 Moreover, the ratio of CDK1 transcript to HSP90AA transcript was significant in the predictor of pCR for patients receiving NAC. 81 Besides, quinone oxidoreductase 1 (NQO1) was observed to rise in terms of the residual breast tumor tissues after NAC. 82…”