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The Role of Redox-Regulating Enzymes in Inoperable Breast Cancers Treated with Neoadjuvant Chemotherapy.

ABSTRACT: Although validated predictive factors for breast cancer chemoresistance are scarce, there is emerging evidence that the induction of certain redox-regulating enzymes may contribute to a poor chemotherapy effect. We investigated the possible association between chemoresistance and cellular redox state regulation in patients undergoing neoadjuvant chemotherapy (NACT) for breast cancer. In total, 53 women with primarily inoperable or inflammatory breast cancer who were treated with NACT were included in the study. Pre-NACT core needle biopsies and postoperative tumor samples were immunohistochemically stained for nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), thioredoxin (Trx), and peroxiredoxin I (Prx I). The expression of all studied markers increased during NACT. Higher pre-NACT nuclear Prx I expression predicted smaller size of a resected tumor (p = 0.00052; r = -0.550), and higher pre-NACT cytoplasmic Prx I expression predicted a lower amount of evacuated nodal metastasis (p = 0.0024; r = -0.472). Pre-NACT nuclear Trx expression and pre-NACT nuclear Keap1 expression had only a minor prognostic significance as separate factors, but when they were combined, low expression for both antibodies before NACT predicted dismal disease-free survival (log-rank p = 0.0030). Our results suggest that redox-regulating enzymes may serve as potential prognostic factors in primarily inoperable breast cancer patients.

SUBMITTER: Roininen N

PROVIDER: S-EPMC5733970 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Role of Redox-Regulating Enzymes in Inoperable Breast Cancers Treated with Neoadjuvant Chemotherapy.

Roininen Nelli N Haapasaari Kirsi-Maria KM Karihtala Peeter P

Oxidative medicine and cellular longevity 20171119

Although validated predictive factors for breast cancer chemoresistance are scarce, there is emerging evidence that the induction of certain redox-regulating enzymes may contribute to a poor chemotherapy effect. We investigated the possible association between chemoresistance and cellular redox state regulation in patients undergoing neoadjuvant chemotherapy (NACT) for breast cancer. In total, 53 women with primarily inoperable or inflammatory breast cancer who were treated with NACT were includ ...[more]

PMID: 29348788

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Project description:BackgroundHigh expression of Stathmin 1 (STMN1) protein is related to a poor prognosis in various tumors, including breast cancer. In our previous study, a phospho-STMN1 signature was conducted to predict outcomes in adjuvantly treated breast cancer patients. This study aimed to explore the relationship of STMN1 expression with our phospho-STMN1 signature and the prognosis of patients treated with neoadjuvant chemotherapy (NACT).MethodsA retrospective analysis of 116 patients who received NACT in The First Affiliated Hospital of Sun Yat-sen University between December 2008 and March 2016 was conducted. Patients were followed up through telephone once a year until 2022. The levels of STMN1, Ser16, Ser25, Ser38, and Ser63 phosphorylation and GRP78 expression in pre-NACT biopsy specimens from the patients were detected by immunohistochemistry. The recurrence risk score for each patient was calculated using the p-STMN1/GRP78 model. Clinical and pathological parameters, pathological complete response and objective response rates, and survival data were analyzed.ResultsIn patients with NACT-treated breast cancer, high levels of STMN1, Ser25 phosphorylation, Ser38 phosphorylation, and GRP78 were related to worse disease-free survival (DFS), as was a high p-STMN1/GRP78 model risk score. In contrast, high Ser16 and Ser63 phosphorylation levels were related to better DFS [p-STMN1/GRP78 model: P=0.002, HR =0.180 (0.061-0.534); STMN1: P=0.001, HR =0.290 (0.147-0.572); Ser16: P=0.036, HR =2.019 (1.049-3.886); Ser25: P=0.013, HR =0.392 (0.188-0.819); Ser38: P=0.001, HR =0.293 (0.153-0.559); Ser63: P=0.006, HR =3.346 (1.407-7.961); GRP78: P=0.010, HR =0.417 (0.214-0.815)]. However, no significant statistical difference was found in the multivariate regression. The relationship between these markers and the therapeutic effect of NACT (pathological complete response and objective response) showed the same tendency with survival. The area under the receiver operating characteristic curve for the p-STMN1/GRP78 model was 0.790 (P=0.001) with sensitivity of 70% and specificity of 74%.ConclusionsThe expression and serine phosphorylation status of STMN1 may be beneficial as biomarkers for predicting the prognosis of breast cancer patients treated with NACT. Our p-STMN1/GRP78 model could become a widely applied signature for assessing the metastatic risk of breast cancer patients, potentially facilitating their individualized management before NACT.

Project description:Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called 'triple negative paradox'. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9-10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3-8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC.

Dataset Information

The Role of Redox-Regulating Enzymes in Inoperable Breast Cancers Treated with Neoadjuvant Chemotherapy.

Publications

The Role of Redox-Regulating Enzymes in Inoperable Breast Cancers Treated with Neoadjuvant Chemotherapy.

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