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Browsing by Author "Sanchez, Cesar"

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Abstract PS6-37: Clinical stage is the only predictor of survival in breast cancer patients with a complete pathological response
(2021) Acevedo, Francisco; Walbaum, Benjamin; Merino, Tomas; Petric, Militza; Sanchez, Cesar
INTRODUCTION In breast cancer (BC) patients, achieving a complete pathological response (pCR) after neoadjuvant chemotherapy (NCT) is associated with better prognosis. Despite this, some of these patients will experience recurrences of the disease and will eventually die of BC. We identified clinical factors that can affect recurrence and survival in BC patients who achieve pCR.METHODSRetrospective analysis of a Chilean BC database including patients treated in public and private hospitals in Santiago, Chile from 2010 to 2019. pCR was defined as the absence of residual invasive disease in the breast and in the axillary lymph nodes (ypT0/is N0) at the completion of the NCT. Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS) and BC-specific survival (BCS) was measured from the time of diagnosis to the event or lost to follow-up. We performed Cox regression analysis to identify factors associated with prognosis.RESULTSFrom 855 patients who received NCT, 195 (22.8%) achieved pCR and were included in this study. Clinical characteristics are shown in table 1. 76 (37.9%) patients had hormone receptor positive (HR+) and 113 (57.4%) had Human epidermal growth factor 2 (HER2) positive tumors. 88.7% were treated with a regimen that included anthracyclines and taxanes. With a median follow-up of 36 months, three-year IDFS, DDFS and BCS and their 95% confidence intervals were 90.9% (84.7 - 94.6), 91.8% (86.0 - 95.3) and 93.8% (87.8 - 97.5); respectively. The stage at diagnosis was the only predictor associated with IDFS (Hazard ratio (HR) = 5.6; p = 0.02), DDFS (HR = 4.1, p = 0.07), and BCS (HR = 8.3, p = 0.04). Body mass index (BMI), age, hospital, HR or HER2 status, lymph node involvement, or the presence of an in-situ component, were not associated with prognosis in the multivariate analysis.CONCLUSIONThe clinical stage at diagnosis was the only predictor of survival in patients who achieved pCR after NCT. Short follow-up and few events may have affected these results. This data is consistent with previously published work. Table 1. Tumor and patient characteristicsMedian age49 (24 – 78)HospitalPublic57.4%Private43.6%BMIMedian27.2 (18.5 – 44.7)Overweight38.0%Obese31.9%Receptor StatusRH+/HER2-16.4%RH+/HER2+21.5%RH-/HER2+35.9%RH-/HER2-26.2%Clinical StageI2.1%II47.4%III50.5%Lymph Node +69.7%ypT0/N078.1%ChemotherapyAnthracycline5.1%Taxane6.2%Anthracycline-Taxane88.7% Citation Format: Francisco Acevedo, Benjamin Walbaum, Tomas Merino, Militza Petric, Cesar Sanchez. Clinical stage is the only predictor of survival in breast cancer patients with a complete pathological response [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-37.
An approximate dynamic programming approach to network-based scheduling of chemotherapy treatment sessions
(2024) Wenzel, Arturo; Saure, Antoine; Cataldo, Alejandro; Rey, Pablo A.; Sanchez, Cesar
A solution approach is proposed for the interday problem of assigning chemotherapy sessions at a network of treatment centres with the goal of increasing the cost-efficiency of system-wide capacity use. This network-based scheduling procedure is subject to the condition that both the first and last sessions of a patient's treatment protocol are administered at the same centre the patient is referred to by their oncologist. All intermediate sessions may be administered at other centres. It provides a systematic way of identifying effective multi-appointment scheduling policies that exploit the total capacity of a networked system, allowing patients to be treated at centres other than their home centre. The problem is modelled as a Markov decision process which is then solved approximately using techniques of approximate dynamic programming. The benefits of the approach are evaluated and compared through simulation with the existing manual scheduling procedures at two treatment centres in Santiago, Chile. The results suggest that the approach would obtain a 20% reduction in operating costs for the whole system and cut existing first-session waiting times by half. A key conclusion, however, is that a network-based scheduling procedure brings no real benefits if it is not implemented in conjunction with a proactive assignment policy like the one proposed in this paper.
Better overall survival in patients who achieve pathological complete response after neoadjuvant chemotherapy for breast cancer in a Chilean public hospital
(2021) Acevedo, Francisco; Petric, Militza; Walbaum, Benjamin; Robin, Julieta; Legorburu, Luisa; Murature, Geraldine; Guerra, Constanza; Navarro, Marisel; Canovas, María José; Sanchez, Cesar; Vargas, Lorena; Manzor, Manuel; Peña, José; Muñiz, Sabrina; Veglia, Paulina; Cartes, Raúl; Martinez, Raúl
Introduction: There is extensive evidence associating the response to neoadjuvant chemotherapy (NeoCT) with breast cancer (BC) survival. However, to the author’s knowledge, there is no published data in Chile. The objective of the study is to evaluate whether achieving pathological complete response (pCR) after NeoCT is associated with greater survival and lower risk of recurrence in a Chilean Public Health Service. Methods: Retrospective analysis of a database. Patients with a diagnosis of Stages I–III BC who received NeoCT between 2009 and 2019 were included. Clinical and pathological information were extracted from the clinical records. BC subtypes were defined using hormone receptor (HR) information (HR: oestrogen and/or progesterone) and epidermal growth factor type 2 (HER2), being divided into four groups: HR /HER2−, HR /HER2 , HR−/HER2 , HR-/HER2−. pCR was defined as the absence of invasive cancer in the breast and axilla (ypT0/is N0) after NeoCT. Results: Of 3,092 patients, 17.2% received NeoCT. Of these, 40.2% corresponded to HR /HER2−, 20.9% HR /HER2 , 18.2% HR−/HER2 and 20.7% HR−/HER2−. Overall, 24.8% achieved pCR, being the lowest for HR /HER2− (10.3%) and the highest for HR−/HER2 (53.2%). In the multivariable analysis, family history, HER2 and type of chemotherapy were associated with a greater probability of pCR. With a median follow-up of 40 months, the overall survival and metastasis-free survival (MFS) at 3 years were greater for the group with pCR compared to that which did not achieve it (90.5% versus 76.7%, p = 0.03 and 88.5% versus 71.4%, p = 0.003, respectively). The multivariable analysis confirmed this finding. Brain MFS was similar in both groups. Conclusion: NeoCT is associated with greater pCR in aggressive BC subtypes. In those, achieving pCR was associated with better survival in our study. To the author’s knowledge, this is the first study which evaluates the relation between pCR and BC subtypes in a Chilean public hospital.
Breast lesions with atypia in percutaneous biopsies, managed with surgery in the last 10 years
(2019) Carrillo, Mitzy; Maturana, Gregorio; Maiz, Cristobal; Romero, Diego; Dominguez, Francisco; Oddo, David; Villarroel, Alejandra; Razmilic, Dravna; Elena Navarro, Maria; Leon, Augusto; Sanchez, Cesar; Camus, Mauricio
Introduction: The optimal management of breast lesions with atypia (BLA), detected in percutaneous biopsies after screening mammograms, is a controversial issue. The aim of this paper is to compare histological diagnosis by percutaneous biopsy with the results of the surgical biopsy of these lesions and to analyse the changes to clinical approach this would imply.
Co-design of a Mobile App for Engaging Breast Cancer Patients in Reporting Health Experiences: Qualitative Case Study
(2023) Taramasco, Carla; Rimassa, Carla; Noel, Rene; Storm, Maria Loreto Bravo; Sanchez, Cesar
Background: The World Health Organization recommends incorporating patient-reported experience measures and patient-reported outcome measures to ensure care processes. New technologies, such as mobile apps, could help report and monitor patients' adverse effects and doubts during treatment. However, engaging patients in the daily use of mobile apps is a challenge that must be addressed in accordance with the needs of people.
First-line endocrine therapy for advanced breast cancer. A real-world study at a Latin American university health institution
(TAYLOR & FRANCIS LTD, 2020) Walbaum, Benjamin; Acevedo, Francisco; Medina, Lidia; Bravo, M. Loreto; Merino, Tomas; Camus, Mauricio; Dominguez, Francisco; Mondaca, Sebastian; Galindo, Hector; Nervi, Bruno; Ibanez, Carolina; Madrid, Jorge; Pena, Jose; Koch, Erica; Garrido, Marcelo; Pinto, Mauricio P.; Sanchez, Cesar
Objective: Clinical guidelines recommend the use of endocrine therapy (ET) in advanced hormone receptor positive (HR+) human epidermal growth factor receptor type 2 negative (HER2-) breast cancer (BC) patients in the absence of visceral disease or ET resistance. Furthermore, studies indicate similar response and survival rates using ET or cytotoxic chemotherapy (CT). Methods: Herein, we assessed clinical characteristics, type of systemic therapy and survival rates of advanced HR + HER2-BC patients in our database. Results: A total of 172 advanced HR + HER2-BC patients were treated at our institution between 1997 and 2019. Sixty percent received first-line ET (4% received combined ET). Median age of this subset was 55 years (range: 30-86). Similarly, the median age of patients that received CT was 54 years (range: 21-83). Over time, 30% of patients received ET in the 2000-2005 period; this increased to 70% in the 2016-2019 period (p = .045). Overall survival (OS) was 97 months and 51 months for patients treated with ET or CT, respectively (p = .002). Conclusions: To the best of our knowledge this is the first study assessing the use of ET in Chilean advanced HR + HER2-BC patients. Several patients in our institution receive CT without indication. The increase in ET usage over time can be attributed to better and faster immunohistochemical detection methods for Estrogen Receptor (ER), changes in educational and government policies, and a wider variety of ET options. Finally, clinical trials have failed to demonstrate a substantial benefit of CT over ET in this setting.
Machine learning analysis of a Chilean breast cancer registry
(2021) Acevedo, Francisco; Causa, Leonardo; Bravo, Sebastián; García, Pablo; Cuevas, Ricardo; Bravo, Maria Loreto; Avellaira, Carla; Muñiz, Sabrina; Petric, Militza; Martinez, Raúl; Guerra, Constanza; Navarro, Marisel; Taramasco, Carla; Sanchez, Cesar
In recent years, artificial intelligence (AI) and machine learning (a form of AI) have offered valuable tools for medicine by applying and training algorithms in order to make predictions. Herein, we applied a machine learning algorithm to analyze data from a >20 year breast cancer (BC) registry elaborated in two Chilean health institutions (a public hospital and a private center) that includes a total of 4838 patients and their basic clinicalpathological characteristics. Preliminary results suggest that this cohort of patients can be subdivided into five clusters according to key variables that also correlate with overall survival and disease-free survival rates. To our knowledge this is the first Latin American report of its kind. Our laboratory is currently expanding these analyses.
Multi-stage process for chemotherapy scheduling and effective capacity determination
(2023) Cataldo, Alejandro; Sufan, Sebastian; Lorca, Alvaro; Andresen, Max; Sanchez, Cesar; Saure, Antoine
A novel solution approach is developed for the scheduling of chemotherapy sessions at cancer treatment centers. The problem is divided into two subproblems determining the day (interday scheduling) and the time slots (intraday scheduling), respectively. The interday subproblem is solved by a model that allows for effective treatment center capacity choices while the intraday subproblem is addressed using two optimization models. New patient arrivals and treatment protocols specifying the latest starting date and session spacing are sources of uncertainty. Unlike other existing approaches, the proposed method incorporates the concept of effective treatment capacity which facilitates the interaction between the interday and intraday subproblems allowing them to be solved sequentially and iteratively to thus achieve much more resource-efficient solutions. A case study using real data from a Chilean cancer center to conduct comparative simulations of its manual scheduling methods and the proposed methodology found that the latter almost always performed better, often significantly so, on makespan, resource utilization, overtime, and patient diversion metrics.
Needs and satisfaction levels of breast cancer patients
(2024) Ramis, Sylvia; Acevedo, Francisco; Bravo, M. Loreto; Pena, Jose; Bravo, Paulina; Medina, Lidia; Muniz, Sabrina; Ibanez, Carolina; Walbaum, Benjamin; Merino, Tomas; Marin-Olivo, Erick; Pinto, Mauricio P.; Sanchez, Cesar
Introduction. Knowing and satisfying the needs of breast cancer (BC) patients (P) and their caregivers (CG) during treatment can help to improve their quality of life. This study assessed the needs of BC-P, their CG and health professionals (HP) and their perception before and after an intervention aiming to improve healthcare. Methods. The study included an academic center (AC) and a public hospital (PH). Data were obtained from interviews, focus groups and self-completed surveys. A content analysis was performed using Nvivo software. Due to COVID19 restrictions, educational videos were delivered to HPs describing the identified needs. Finally, satisfaction surveys were applied to P and CG, before and after this intervention. Results. A total of 22 participants were interviewed (7P, 5CG and 10HP). Three main needs were identified: 1) Healthcare related needs, 2) Financial issues and 3) Social support. Subsequently, a satisfaction survey was applied to users (stage I; n=93) and the identified needs were used to design an intervention that consisted of educational videos directed towards HP. Following the intervention a second survey was applied (stage II; n=71). Both surveys revealed high levels of satisfaction among users. Following the second survey, we noticed the emergence of other needs, mainly related to nutrition and the improvement of facilities. Conclusions. This is the first study in Chile assessing BC-P needs from the perspective of P, their CG and HP. All participants indicated that information and social/financial support were the most relevant needs.
Neutrophil/lymphocyte ratio in complete blood count as a mortality predictor in breast cancer
(SOC MEDICA SANTIAGO, 2016) Mimica, Ximena; Acevedo, Francisco; Oddo, David; Ibanez, Carolina; Medina, Lidia; Kalergis, Alexis; Camus, Mauricio; Sanchez, Cesar
Background: The white blood cell count is one of the most sensitive markers associated with inflammation. The neutrophil/lymphocyte count ratio may be an independent factor for breast cancer mortality. Aim: To assess the predictive value of the neutrophil/lymphocyte ratio for mortality in breast cancer. Material and Methods: Review of the database of a cancer center of a University hospital. Patients with infiltrating breast cancer treated between 1997 and 2012 were selected. The pathology type and lymph node involvement were obtained from the pathology report. The expression of estrogen, progesterone and Human Epidermal Growth Factor Receptor 2 (HER2) was determined by immunohistochemistry or in situ fluorescent hybridization (FISH). The absolute peripheral neutrophil and lymphocyte counts were obtained from a complete blood count obtained at least three months before treatment. Patients were followed for a median of 61 months (range 1-171). Results: From 323 eligible patients, after excluding those in stage IV and those without an available complete blood count, 131 patients were analyzed (81 with negative receptors and 117 HER2 enriched). The neutrophil/lymphocyte ratio was similar in both types of tumors (2.1 and 1.91 respectively). Twenty two patients died during follow-up. Surviving patients with HER2 enriched tumors had a lower neutrophil/lymphocyte ratio than those who died (1.79 and 3.21 respectively, p < 0.01). In a multivariate analysis, including age, tumor stage and lymph node involvement as confounding factors, the neutrophil/lymphocyte ratio was still significantly associated with a risk of death with a hazard ratio of 2.56. Conclusions: A high neutrophil/lymphocyte ratio in the complete blood count can be a predictor of death in breast cancer.
Oncological resection, myasthenia gravis and staging as prognostic factors in thymic tumours: a Chilean case series
(2021) Salas, Patricio; Solovera, Maria Eliana; Bannura, Felipe; Muñoz-Medel, Matias; Cordova-Delgado, Miguel; Sanchez, Cesar; Ibañez, Carolina; Garrido, Marcelo; Koch, Erica; Acevedo, Francisco; Mondaca, Sebastian; Nervi, Bruno; Madrid, Jorge; Peña, Jose; Pinto, Mauricio P.; Valbuena, José; Galindo, Hector
Background: Thymic epithelial tumours are rare and highly heterogeneous. Reports from the United States suggest an overall incidence of 0.15 per 100,000/year. In contrast, the incidence of these tumours in Latin America is largely unknown and reports are scarce, somewhat limited to case reports. Methods: Herein, we report a series of 38 thymic tumours from a single institution, retrospectively incorporated into this study. Patient characteristics and outcomes including age, sex, stage, paraneoplastic syndromes, treatment regimens and the date of decease were obtained from medical records. Results: Most cases in our series were females and young age (<50 years old) and early stage by Masaoka-Koga or the Moran staging systems. Also, a 34% of patients had myasthenia gravis (MG). Next, we analysed overall survival rates in our series and found that the quality of surgery (R0, R1 or R2), MG status and staging (Masaoka-Koga, Moran or TNM) were prognostic factors. Finally, we compared our data to larger thymic tumour series. Conclusions: Overall, our study confirms complete surgical resection as the standard, most effective treatment for thymic epithelial tumours. Also, the Masaoka-Koga staging system remains as a reliable prognostic factor but also the Moran staging system should be considered for thymomas.
Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study1
(2023) Gelderblom, Hans; Jones, Robin L.; Blay, Jean-Yves; George, Suzanne; von Mehren, Margaret; Zalcberg, John R.; Kang, Yoon-Koo; Razak, Albiruni Abdul; Trent, Jonathan; Attia, Steven; Le Cesne, Axel; Siontis, Brittany L.; Goldstein, David; Boye, Kjetil; Sanchez, Cesar; Steeghs, Neeltje; Rutkowski, Piotr; Druta, Mihaela; Serrano, Cesar; Somaiah, Neeta; Chi, Ping; Harrow, Brooke; Becker, Claus; Reichmann, William; Sherman, Matthew L.; Ruiz-Soto, Rodrigo; Heinrich, Michael C.
Purpose: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL).Patients and methods: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade & GE;3 treatment-emergent adverse events per patient over 1 year of follow-up.Results: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days).Conclusion: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.& COPY; 2023 Deciphera Pharmaceuticals LLC. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial
(2024) Heinrich, Michael C.; Jones, Robin L.; George, Suzanne; Gelderblom, Hans; Schoeffski, Patrick; von Mehren, Margaret; Zalcberg, John R.; Kang, Yoon-Koo; Razak, Albiruni Abdul; Trent, Jonathan; Attia, Steven; Le Cesne, Axel; Siontis, Brittany L.; Goldstein, David; Boye, Kjetil; Sanchez, Cesar; Steeghs, Neeltje; Rutkowski, Piotr; Druta, Mihaela; Serrano, Cesar; Somaiah, Neeta; Chi, Ping; Reichmann, William; Sprott, Kam; Achour, Haroun; Sherman, Matthew L.; Ruiz-Soto, Rodrigo; Blay, Jean-Yves; Bauer, Sebastian
INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.
Surgical treatment in oligometastatic breast cancer
(2019) Vargas, Catalina; Maiz, Cristobal; Elena Navarro, Maria; Oddo, David; Sanchez, Cesar; Bustos, Marisa; Camus, Mauricio
Metastatic breast cancer (MBC) management is based on systemic treatment (ST), while the local therapy role remains controversial. We present the case of a 36-year-old woman with a diagnosis of hormone receptor-positive and human epidermal growth factor receptor type 2-positive breast cancer and isolated sternal metastasis, who received neoadjuvant ST with complete remission and later primary tumour surgery. Oligometastatic patients are a subgroup of MBC that can benefit from aggressive local therapies, even with curative intent.
Survival rates of advanced estrogen-receptor positive breast cancer. Analysis of 211 cases
(2020) Sanchez, Cesar; Dominguez, Francisco; Galindo, Hector; Camus, Mauricio; Oddo, David; Villarroel, Alejandra; Razmilic, Dravna; Pena, Jose; Elena Navarro, Maria; Medina, Lidia; Merino, Tomas; Briones, Juan; Acevedo, Francisco
Background: About 80% of breast cancer (BC) cases express estrogen receptor (ER), which has been correlated with good prognosis and response to estrogen deprivation Aim: To characterize ER positive advanced BC (ABC) patients treated at our institution assessing the impact of clinical presentation (stage IV, de novo disease at diagnosis versus systemic recurrence) and BC subtype on survival rates. Material and Methods: We evaluated 211 ER+ advanced BC (ABC) patients, treated between 1997 and 2017. Results: The median overall survival (OS) was 37 months. Median OS for the period 1997/2006 and 2007/2017 were 33 and 42 months, respectively (p = 0.47). Luminal A, ABC stage IV disease at diagnosis displayed better OS rates than Luminal B stage IV tumors (100 and 32 months respectively, p < 0.01). Conclusions: Clinical presentation (stage IV vs. systemic recurrence) and tumor subtype are key determinants of OS in ABC.
Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
(2013) Zhong, Hua; Sanchez, Cesar; Spitrzer, Dirk; Plambeck-Suess, Stacy; Gibbs, Jesse; Hawkins, Williams G.; Denardo, David; Gao, Feng; Pufahl, Robert A.; Lockhart, Albert C.; Xu, Mai; Linehan, David; Weber, Jason; Wang-Gillam, Andrea
Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

Browsing by Author "Sanchez, Cesar"

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