Jinneth Acosta

Novel predictive biomarkers for cervical cancer prognosis

High hypoxic, glycolytic and acidosis metabolisms characterize cervical cancer tumors and have been described to be involved in chemoradioresistance mechanisms. Based on these observations, the present study assessed four selected novel biomarkers on the prognosis of locally advanced cervical carcinoma. A total of 66 patients with stage IIB/IIIB cervical cancer were retrospectively included. The protein expression levels of glucose transporter 1 (GLUT1), carbonic anhydrase 9 (CAIX) and hexokinase 1 (HKII) were investigated by immunohistochemistry on tumor biopsies, hemoglobin was measured and the disease outcome was monitored. A total of 53 patients (80.3%) presented a complete response. For these patients, the protein expression levels of GLUT1, CAIX and HKII were overexpressed. A significant difference was observed (P=0.0127) for hemoglobin levels (≤11 g/dl) in responsive compared with non-responsive patients. The expression of GLUT1 is associated with a lower rate of both overall and disease-free survival, with a trend of decreased risk of 1.1x and 1.5x, respectively. Co-expression of GLUT1 and HKII is associated with a decreased trend risk of 1.6x for overall survival. Patients with hemoglobin levels ≤11 g/dl had a 4.3-fold risk (P=0.02) in decreasing both to the rate of overall and disease-free survival. The presence of anemic hypoxia (hemoglobin ≤11 g/dl) and the expression of GLUT1 and/or HKII influence treatment response and are associated with a lower overall and disease-free survival. The present results demonstrated that these biomarkers may be used as predictive markers and suggested that these metabolic pathways can be used as potential novel therapeutic targets.

Abstract C39: GLUT1 and hemoglobin levels: Hypoxic markers of treatment response in patients with locally advanced cervical cancer.

Background: The increased expression of GLUT1 and HKII CAIX in cervical cancer is associated with progression, metastasis, and poor survival rates. The aim of this study was to evaluate the predictive utility of GLUT1, CAIX, and HKII and hemoglobin levels versus tumor response to exclusive radiotherapy and concomitant chemoradiotherapy in patients with cervical carcinoma located. Methods: Sixty-six patients (FIGO IIB, IIIB) were included retrospectively for the period 2001-2007. Twenty-two of them received exclusive radiotherapy, and 44 received concurrent radiochemotherapy. The expression of GLUT1, CAIX, and HKII was studied by immunohistochemistry in paraffin-embedded biopsies taken before treatment. The expression levels of the proteins were correlated with clinical factors pathological, response to treatments (responders and non-responders), overall survival, and disease-free survival. Results: Of the 66 patients, 53 (80.3%) showed a complete response to treatment, of whom 16 received exclusive radiotherapy and 37 received concurrent radiochemotherapy. Protein expression levels of GLUT1, CAIX, and HKII were increased in cancer patients and as a particular feature of staining were observed that GLUT1 inmunostaining was frequently localized together to the blood vessels. Hemoglobin levels ≤ 11g/dl were statistically significant compared to the response to treatment (p=0.0127), with a trend of 4.3-fold risk of treatment failure in the group of nonresponders. We found that when expressed GLUT1, both the rate of overall survival and disease-free survival showed a trend risk of decrease of 1.1 times and 1.5 times respectively; when co-expressed GLUT1 and HKII was observed a trend risk of decrease of 1.6 times in the rate overall survival. Patients with hemoglobin levels ≤ 11g/dl had a risk 4.3-fold (p=0.02) decrease in both the overall survival rate as the rate of disease-free survival. Conclusion: The presence of anemic hypoxia (Hbg ≤ 11g/dl), expression of GLUT1, co-expression of GLUT1 and HKII, may influence the response to treatment, and therefore in overall and disease-free survival. The study and detection of these markers could contribute to infer the metabolic and hypoxic state of tumors, so that the therapeutic management may be optimized by considering such markers as predictive markers and/or as molecular targets. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C39. Citation Format: Pablo Moreno-Acosta, Alfredo Romero-Rojas, Schyrly Carrillo, Oscar Gamboa, Jinneth Acosta, Josep Balart-Serra, Nicolas Magne. GLUT1 and hemoglobin levels: Hypoxic markers of treatment response in patients with locally advanced cervical cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C39.

Abstract 435: Prognostic biomarkers as molecular targets for individualized neoadjuvant treatment for cervical cancer

Cervical cancer is one of the most prevalent malignancy and of higher mortality in the world, and is considered a marker of underdevelopment. Conventional radiotherapy is one of the treatments used for this type of cancer. 30 to 40% of patients with similar prognosis factors not respond equally to a comparable standard treatment. The poor response to radiotherapy leads to the development of innovative and effective therapies for cervical cancer locally advanced, metastatic and refractory. A comparative analysis of cervical cancer in the context of other cancers may reveal that it is relatively smaller number of targeted molecular agents that have been tested. Accordingly, a number of biological agents are currently in clinical development for the purpose of, inhibiting angiogenesis, molecularly address EGFR and IGF-1R, modulation of cell cycle, of histone deacetylases, COX-2, mTOR and tumor microenvironment (hypoxia and glycolysis). Within work that we have been developing, reported that gene expression of IGF1R is a strong predictive marker for lack of response to radiotherapy, patients have 28.6 times higher risk of failure treatment; Objective: To determine whether expression of IGF-IR, GAPDH, HIF-1 alpha, Survivin, GLUT1, CAIX, HKII and clinicopathological parameters can be used as prognostic biomarkers to treatment outcome and as possible molecular targets. Patients & Methods: This prospective cohort study included 149 patients with squamous cell carcinomas of the uterine cervix in FIGO stages IIB and IIIB between 2008 and 2011. The mean age was 46 years. Of the 149 patients, 61 were treated with radiotherapy and 88 with concurrent radiochemotherapy. Expression of the proteins CAIX, GLUT-1, HIF1α, HKII, IGF-IRα, IGF-IRβ and Survivin was determined by immunohistochemistry in biopsies taken before treatment. Results: The highest increase was found in expression of GAPDH (100%), Survivin (87%), followed of, IGF-IRα (76.5%), IGF-IRβ (74.5%), IGF-IRα and IGF-IRβ concordance in the expression(73%), HIF1α (74.1%); strong expression was observed with low frequency for GLUT-1 (31.1%), CAIX (16.2%), HKII (10.6%). We found that patients who do not express IGF-1Rs, GLUT1 and having hemoglobin levels > 11g/dl have improved overall survival compared to those that express IGF-1Rs, GLUT1 and having hemoglobin ≤ 11g/dl (P = 0.0158). Conclusions: Using the expression of GLUT1, IGF-1Rs and Hb levels (≤ 11g/dl) as therapeutic molecular targets could contribute to an appropriate therapeutic management as individualized neoadjuvant treatment for cervical cancer Citation Format: Pablo Moreno-Acosta, Oscar Gamboa, Diana Mayorga, Alfredo Romero, Jinneth Acosta, Maria Carolina Sanabria, Martha Cotes Mestre, Nicolas Magne. Prognostic biomarkers as molecular targets for individualized neoadjuvant treatment for cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 435.

Abstract B10: Predictive and prognostic biomarkers at personalized treatment of locally advanced cervical cancer

Introduction: Cervical cancer is one of the most prevalent malignancy and of higher mortality in the world, and is considered a marker of underdevelopment. Conventional radiotherapy is one of the treatments used for this type of cancer. 30 to 40% of patients with similar prognosis factors not respond equally to a comparable standard treatment. The poor response to radiotherapy leads to the development of innovative and effective therapies for cervical cancer locally advanced, metastatic and refractory. A comparative analysis of cervical cancer in the context of other cancers may reveal that it is relatively smaller number of targeted molecular agents that have been tested. Accordingly, a number of biological agents are currently in clinical development for the purpose of, inhibiting angiogenesis, molecularly address EGFR and IGF-1R, modulation of cell cycle, of histone deacetylases, COX-2, mTOR and tumor microenvironment (hypoxia and glycolysis). Within work that we have been developing, reported that gene expression of IGF1R is a strong predictive marker for lack of response to radiotherapy, patients have 28.6 times higher risk of failure treatment; Patients & Methods: This prospective cohort study included 149 patients with squamous cell carcinomas of the uterine cervix in FIGO stages IIB and IIIB between 2008 and 2011. The mean age was 46 years. Of the 149 patients, 61 were treated with radiotherapy and 88 with concurrent radiochemotherapy. Expression of the proteins CAIX, GLUT-1, HIF1α, HKII, IGF-IRα, IGF-IRβ and Survivin was determined by immunohistochemistry and P53 Arg72Pro polymorphism by allele specific PCR in biopsies taken before treatment. Results: The highest increase was found in expression of GAPDH (100%), Survivin (87%), followed of, IGF-IRα (76.5%), IGF-IRβ (74.5%), IGF-IRα and IGF-IRβ concordance in the expression(73%), HIF1α (74.1%); strong expression was observed with low frequency for GLUT-1 (31.1%), CAIX (16.2%), HKII (10.6%). For polymorphism Arg72Pro of P53 was found that genotype Arg/Arg is the most frequently (59.8) in patients with cervical locally advanced cancer and that compared to the control group (non-tumor tissue of the cervix with histopathologic diagnosis of cervicitis without evidence of squamous intraepithelial lesion or malignancy) (P = 0.000), and published reports, his presence confirms their possible participation in the development of this cancer, however we found no association with the outcome and response to treatment. Patients who received chemoradiotherapy compared to those who received radiotherapy showed higher survival times, both for overall survival and disease-free. Patients with hemoglobin levels ≤ 11g/dl had a risk 2.53-fold (p = 0.01) decrease in both the overall survival rate as the rate of disease-free survival. Conclusions: We found that the expression of IGF-IRβ detected by immunohistochemistry is a prognostic marker that affects overall survival and disease-free survival; the detection and study before treatment of the expression of HIF1α, CAIX, GLUT 1 and HKII, considered as biological factors pre-existing, contributes to infer the metabolic and hypoxic state, as also at the rational use of new modalities in radiotherapy, radiochemotherapy and gene therapy in the regulation of hypoxia. Citation Format: Pablo Moreno-Acosta, Oscar Gamboa, Alfredo Romero-Rojas, Jinneth Acosta, Martha Cotes Mestre, Diana Mayorga, Magda Pacheco, Gladys Aguilera, Nicolas Magne. Predictive and prognostic biomarkers at personalized treatment of locally advanced cervical cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B10.

369 Diagnosis and molecular targeting for individualized treatment of patients with pre-neoplastic lesions and locally advanced cervical cancer

Background: The natural history of HPV infection and development of cervical intraepithelial neoplasia indicate that most lesions disappear without treatment in contrast to a significant proportion of high-grade lesions that progress to invasive cancer if not treated. Persistent infection with high-risk HPV may be necessary for the development of cervical cancer. The purpose of the study was make a retrospective molecular diagnosis that include detection of HPV16 variants, polymorphism Arg72Pro of P53, expression of anti-apoptotic markers such as IGF-1R and Survivin, and hypoxic markers and glycolytic as GLUT1 and CAIX and markers of progression as hTERT in samples invasive cancer and preneoplastic lesions taken in 2002 and 1986; the results may be useful to propose an appropriate therapeutic management.