Calpain-2 expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer

Ovarian cancer is routinely treated with surgery and platinum-based chemotherapy. Resistance is a major obstacle in the efficacy of this chemotherapyregimen and the ability to identify those patients at risk of developing resistance is of considerable clinical importance. The expression ofcalpain-1, calpain-2 and calpastatin were determined using standard immunohistochemistry on a tissue microarray of 154 primary ovarian carcinomasfrom patients subsequently treated with platinum-based adjuvant chemotherapy. High levels of calpain-2 expression was significantly associatedwith platinum resistant tumours (P = 0.031). Furthermore, high expression of calpain-2 was significantly associated with progression-free(P = 0.049) and overall survival (P = 0.006) in this cohort. The association between calpain-2 expression and overall survival remained significantin multivariate analysis accounting for tumour grade, stage, optimal debulking and platinum sensitivity (hazard ratio = 2.174; 95% confidenceinterval = 1.144–4.130; P = 0.018). The results suggest that determining calpain-2 expression in ovarian carcinomas may allow prognostic stratificationof patients treated with surgery and platinum-based chemotherapy. The findings of this study warrant validation in a larger clinical cohort

Calpain-1 expression is associated with relapse-free survival in breast cancer patients treated with trastuzumab following adjuvant chemotherapy

The calpain family, and their endogenous inhibitor calpastatin, has been implicated in cancer progression, and recent in vitro data have indicated a role in trastuzumab resistance. The aims of our study were to examine expression levels of calpastatin, calpain‐1 and calpain‐2 in breast tumours from patients treated with trastuzumab following adjuvant chemotherapy to determine their potential as biomarkers to predict therapeutic response. The expression of calpastatin, calpain‐1 and calpain‐2 was determined, using immunohistochemistry (IHC), in tumours from a series of 93 patients with primary breast cancer treated with surgery and adjuvant chemotherapy with or without trastuzumab followed by trastuzumab to complete 1 year of therapy. IHC was performed using tissue microarrays constructed from cores taken from intratumour and peripheral tumour areas. Expression was correlated with clinicopathologic variables and patient outcome. Calpastatin expression was correlated with Nottingham prognostic index (p = 0.003) and lymph node status (p = 0.007). Trastuzumab resistance was defined as disease relapse during therapy. Calpain‐1 expression is associated with relapse‐free survival (p = 0.001) and remained significant in multivariate analysis accounting for confounding pathological and treatment variables (hazard ratio 4.60, 95% confidence interval 1.05–20.25; p = 0.043). Calpain‐1 may be a useful biomarker to predict relapse‐free survival in breast cancer patients treated with adjuvant trastuzumab and chemotherapy. A larger verification study is warranted

The prognostic and predictive power of redox rotein expression for anthracycline-based chemotherapy response in locally advanced breast cancer

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P¼0.05) and catalase (P¼0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P¼0.017) and thioredoxin reductase (P¼0.022) were independent prognostic factors for distant metastasis free survival and TxNIP for overall survival (P¼0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P¼0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments

Expression of thioredoxin system and related peroxiredoxin proteins is associated with clinical outcome in radiotherapy treated early stage breast cancer

Background and purposeDeregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Expression of the thioredoxin system proteins (thioredoxin, thioredoxin reductase and thioredoxin interacting protein) and downstream peroxiredoxins (I–VI), was examined in tumor specimens from early stage breast cancer patients, subsequently treated by breast conserving surgery and locoregional radiotherapy, to determine if redox protein expression is associated with clinical outcome.Material and methodsNuclear and cytoplasmic expression was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors.ResultsHigh expression of cytoplasmic peroxiredoxin-I correlated with a greater risk of local recurrence ( p = 0.009). When nuclear and cytoplasmic expression patterns were combined, patients with low nuclear but high cytoplasmic expression of peroxiredoxin-I increased significance ( p = 0.005). Both were independent factors ( p = 0.006 and 0.003) from multivariate analysis. Associations were obtained between tumor grade and nuclear thioredoxin interacting protein ( p = 0.01) and with cytoplasmic expression of peroxiredoxin-V ( p = 0.007) but not with peroxiredoxin-I suggesting that the latter may exert influence via regulation of oxidative stress rather than via altering the tumor phenotype.ConclusionsResults highlight the potential of using redox protein expression, namely peroxiredoxin-I, to predict clinical outcome and support further studies to validate its usefulness as an independent prognostic, and potentially predictive, marker

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

PurposeEarly-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response.Methods and MaterialsThe nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-θ, -π, and -α) was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors.ResultsA high cytoplasmic expression of glutathione S-transferase-θ significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-θ also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade.ConclusionsOur results support the use of redox protein expression, namely glutathione S-transferase-θ and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy

Calpain-2 expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer

Abstract Ovarian cancer is routinely treated with surgery and platinum-based chemotherapy. Resistance is a major obstacle in the efficacy of this chemotherapy regimen and the ability to identify those patients at risk of developing resistance is of considerable clinical importance. The expression of calpain-1, calpain-2 and calpastatin were determined using standard immunohistochemistry on a tissue microarray of 154 primary ovarian carcinomas from patients subsequently treated with platinum-based adjuvant chemotherapy. High levels of calpain-2 expression was significantly associated with platinum resistant tumours (P = 0.031). Furthermore, high expression of calpain-2 was significantly associated with progression-free (P = 0.049) and overall survival (P = 0.006) in this cohort. The association between calpain-2 expression and overall survival remained significant in multivariate analysis accounting for tumour grade, stage, optimal debulking and platinum sensitivity (hazard ratio = 2.174; 95% confidence interval = 1.144-4.130; P = 0.018). The results suggest that determining calpain-2 expression in ovarian carcinomas may allow prognostic stratification of patients treated with surgery and platinum-based chemotherapy. The findings of this study warrant validation in a larger clinical cohort

Thioredoxin interacting protein and its association with clinical outcome in gastro-oesophageal adenocarcinoma

AbstractThe overall prognosis for operable gastro-oesophageal adenocarcinoma remains poor and therefore neoadjuvant chemotherapy has become the standard of care, in addition to radical surgery. Certain anticancer agents (e.g. anthracyclines and cisplatin) generate damaging reactive oxygen species as by-products of their mechanism of action. Drug effectiveness can therefore depend upon the presence of cellular redox buffering systems that are often deregulated in cancer. The expression of the redox protein, thioredoxin interacting protein, was assessed in gastro-oesophageal adenocarcinomas. Thioredoxin interacting protein expression was assessed using conventional immunohistochemistry on a tissue microarray of 140 adenocarcinoma patients treated by primary surgery alone and 88 operable cases treated with neoadjuvant chemotherapy. In the primary surgery cases, high thioredoxin interacting protein expression associated with a lack of lymph node involvement (p=0.005), no perineural invasion (p=0.030) and well/moderate tumour differentiation (p=0.033). In the neoadjuvant tumours, high thioredoxin interacting protein expression was an independent marker for improved disease specific survival (p=0.002) especially in cases with anthracycline-based regimes (p=0.008). This study highlights the potential of thioredoxin interacting protein as a biomarker for response in neoadjuvant treated gastro-oesophageal adenocarcinoma and may represent a useful therapeutic target due to its association with tumour progression

The prognostic and predictive power of redox protein expression for anthracycline-based chemotherapy response in locally advanced breast cancer. Modern pathology : an official journal of the United States and Canadian Academy of Pathology

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre-treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase, thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P ¼ 0.05) and catalase (P ¼ 0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P ¼ 0.017) and thioredoxin reductase (P ¼ 0.022) were independent prognostic factors for distant metastasisfree survival and TxNIP for overall survival (P ¼ 0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P ¼ 0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments