Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP) plays a key role in the development and progression of many tumors. We found that in colorectal cancer (CRC) HCT116 cells, the binding of PTHrP to its receptor PTHR type 1 (PTHR1) activates events associated with an aggressive phenotype. In HCT116 cell xenografts, PTHrP modulates the expression of molecular markers linked to tumor progression. Empirical evidence suggests that the Met receptor is involved in the development and evolution of CRC. Based on these data, we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC cells. AIM: To elucidate the relationship among PTHR1, PTHrP, and Met in CRC models. METHODS: For in vitro assays, HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP (1-34) (10-8 M). Where indicated, cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide, the vehicle of the inhibitors. The protein levels were evaluated by Western blot technique. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the changes in gene expression. Wound healing assay and morphological monitoring were performed to evaluate cell migration and changes related to the epithelial-mesenchymal transition (EMT), respectively. The number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan (CPT-11), oxaliplatin (OXA), or doxorubicin (DOXO) with or without PTHrP. For in vivo tests, HCT116 cell xenografts on 6-wk-old male N:NIH (S)_nu mice received daily intratumoral injections of PTHrP (40 µg/kg) in 100 µL phosphate-buffered saline (PBS) or the vehicle (PBS) as a control during 20 d. Humanitarian slaughter was carried out and the tumors were removed, weighed, and fixed in a 4% formaldehyde solution for subsequent treatment by immunoassays. To evaluate the expression of molecular markers in human tumor samples, we studied 23 specimens obtained from CRC patients which were treated at the Hospital Interzonal de Graves y Agudos Dr. José Penna (Bahía Blanca, Buenos Aires, Argentina) and the Hospital Provincial de Neuquén (Neuquén, Neuquén, Argentina) from January 1990 to December 2007. Seven cases with normal colorectal tissues were assigned to the control group. Tumor tissue samples and clinical histories of patients were analyzed. Paraffin-embedded blocks from primary tumors were reviewed by hematoxylin-eosin staining technique; subsequently, representative histological samples were selected from each patient. From each paraffin block, tumor sections were stained for immunohistochemical detection. The statistical significance of differences was analyzed using proper statistical analysis. The results were considered statistically significant at P < 0.05. RESULTS: By Western blot analysis and using total Met antibody, we found that PTHrP regulated Met expression in HCT116 cells but not in Caco-2 cells. In HCT116 cells, Met protein levels increased at 30 min (P < 0.01) and at 20 h (P < 0.01) whereas the levels diminished at 3 min (P < 0.05), 10 min (P < 0.01), and 1 h to 5 h (P < 0.01) of PTHrP treatment. Using an active Met antibody, we found that where the protein levels of total Met decreased (3 min, 10 min, and 60 min of PTHrP exposure), the status of phosphorylated/activated Met increased (P < 0.01) at the same time, suggesting that Met undergoes proteasomal degradation after its phosphorylation/activation by PTHrP. The increment of its protein level after these decreases (at 30 min and 20 h) suggests a modulation of Met expression by PTHrP in order to improve Met levels and this idea is supported by our observation that the cytokine increased Met mRNA levels at least at 15 min in HCT116 cells as revealed by RT-qPCR analysis (P < 0.05). We then proceeded to evaluate the signaling pathways that mediate the phosphorylation/ activation of Met induced by PTHrP in HCT116 cells. By Western blot technique, we observed that PP1, a specific inhibitor of the activation of the proto-oncogene protein tyrosine kinase Src, blocked the effect of PTHrP on Met phosphorylation (P < 0.05). Furthermore, the selective inhibition of the ERK 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) using PD98059 and the p38 MAPK using SB203580 diminished the effect of PTHrP on Met phosphorylation/activation (P < 0.05). Using SU11274, the specific inhibitor of Met activation, and trypan blue dye exclusion test, Western blot, wound healing assay, and morphological analysis with a microscope, we observed the reversal of cell events induced by PTHrP such as cell proliferation (P < 0.05), migration (P < 0.05), and the EMT program (P < 0.01) in HCT116 cells. Also, PTHrP favored the chemoresistance to CPT-11 (P < 0.001), OXA (P < 0.01), and DOXO (P < 0.01) through the Met pathway. Taken together, these findings suggest that Met activated by PTHrP participates in events associated with the aggressive phenotype of CRC cells. By immunohistochemical analysis, we found that PTHrP in HCT116 cell xenografts enhanced the protein expression of Met (0.190 ± 0.014) compared to tumors from control mice (0.110 ± 0.012; P < 0.05) and of its own receptor (2.27 ± 0.20) compared to tumors from control mice (1.98 ± 0.14; P < 0.01). Finally, assuming that the changes in the expression of PTHrP and its receptor are directly correlated, we investigated the expression of both Met and PTHR1 in biopsies of CRC patients by immunohistochemical analysis. Comparing histologically differentiated tumors with respect to those less differentiated, we found that the labeling intensity for Met and PTHR1 increased and diminished in a gradual manner, respectively (P < 0.05). CONCLUSION: PTHrP acts through the Met pathway in CRC cells and regulates Met expression in a CRC animal model. More basic and clinical studies are needed to further evaluate the PTHrP/Met relationship.

Survival effect of probiotics in a rat model of colorectal cancer treated with capecitabine.

BACKGROUND: Probiotics are used to manage a number of gastrointestinal disorders due to their beneficial properties. Clinical reports showed that probiotics also improve the life quality of patients with colorectal cancer (CRC) subjected to oncologic treatment. In a CRC animal model, probiotics supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy, enhancing the antitumor effect of 5-fluorouracil (5-FU) chemotherapy. Based on these data, we hypothesize that the administration of probiotics impact positively in the overall survival and life quality of rats with CRC under the treatment of capecitabine, which is the pro drug of 5-FU. AIM: To evaluate the probiotics effects in a rat CRC model treated with capecitabine and followed until the end of life. METHODS: 1,2-Dimethylhidrazine dihydrochloride (1,2-DMH) was employed as carcinogen inductor of CRC. Fifty male Wistar-Lewis rats were randomly assigned to one of five following groups: Control (n = 5), Control + probiotics (Control-P group, n = 5), 1,2-DMH alone (DMH group, n = 10), 1,2-DMH + capecitabine (DMH-C group, n = 10), 1,2-DMH + probiotics (DMH-P group, n = 10) and 1,2-DMH + capecitabine + probiotics (DMH-C-P group, n = 10). All parametric data were expressed as the mean ± SD. The statistical significance of differences was analyzed using one-way ANOVA. Data were analyzed with InfoStat software. The results were considered statistically significant at P < 0.05. Overall survival was evaluated with the Kaplan-Meier estimator with the log-rank test. RESULTS: The data of mean overall survival for DMH, DMH-P, DMH-C, DMH-C-P, Control and Control-P groups were 250 d [95% confidence interval (CI): 242.5-253.1], 268 d (95%CI: 246.3-271.4), 380 d (95%CI: 337.8-421.9), 480 d (95%CI: 436.9-530.7), 588 d (95%CI: 565.8-609.3) and 590 d (95%CI: 564.3-612.9), respectively, with a significant difference between DMH-C and DMH-C-P groups (P = 0.001). Comparing all groups by Kaplan-Meier estimator, we found a significantly different in the overall survival of DMH and DMH-P groups respect to DMH-C (P = 0.001) and DMH-C-P (P = 0.001) groups; interestingly, there were no meaningful differences between Control, Control-P and DMH-C-P groups (P = 0.012). The tendency of change in body weight gain of the rats at 90 d of finishing DMH administration was similar in Control group compared with DMH-C and DMH-C-P groups; however, and of relevance, DMH-C-P group has experienced a higher body weight gain at the end of animal's life than DMH-C group (P = 0.001). In DMH-C-P group we found a positive effect of probiotics in clinical manifestations since diarrhea, constipation and blood stool were absenting. Also, the tumor burden was lower in DMH-C-P than DMH-C, DMH-P or DMH groups (1.25 vs 1.81 vs 3.9 vs 4.8 cm2, respectively). DMH-C and DMH-C-P groups showed only mucinous carcinoma type while in other DMH groups the tumor types were variable. However, mucinous carcinoma from DMH-C-P group showed invasion until muscularis propria layer. Interestingly, metastatic lymph node was observed in DMH, DMH-C and DMH-P groups but not in DMH-C-P. All animals in Control group died from natural causes without objective injuries. All animals of DMH and DMH-P groups died from tumor complications (i.e., obstruction or intestinal perforation); however, this cause was seen only in 44.5% of DMH-C and DMH-C-P groups. CONCLUSION: Probiotics administration improves life quality of rats with CRC under capecitabine treatment and also has a positive effect in the overall survival of these animals treated with this drug.

The prognostic significance of metastatic pattern in stage IV male breast cancer at initial diagnosis: a population-based study.

PURPOSE: Metastatic pattern (MP) is a prognostic factor in women with breast cancer. However, the prognostic significance of MP in male breast cancer patients remains unknown. METHODS: Using the SEER database, we gathered demographic information and disease characteristics for men diagnosed with de novo metastatic breast cancer from 2010 to 2017. Metastases to bone, brain, liver, and lung were used to define MP (bone-only, visceral, bone and visceral [BV], or other). Statistical analyses were performed to identify associations between overall survival (OS) and MP, as well as other patient and tumor features. We used multivariate logistic regression to evaluate factors associated with sites of metastases. RESULTS: We included 250 patients. MP distribution was bone = 38.8%, visceral = 14.8%, BV = 33.2%, and other = 13.2%. Median OS for each was bone = 33 months, visceral = 23 months, BV = 20 months, and other = 46 months (p = 0.046). Patients with brain metastases had significantly shorter OS compared with no brain metastases (median OS = 9 months vs. 30 months; p < 0.001). Compared with other subtypes, triple negative had the shortest OS (median 9 months, p < 0.001). Logistic regression modeling revealed that compared with HR+/HER2- breast cancers, HR-/HER2+ had higher odds of liver metastases and triple negative had higher odds of brain metastases. Patients younger than 50 years had a significantly greater risk of developing brain metastases. CONCLUSIONS: MP and tumor subtype can predict OS outcomes in men with metastatic breast cancer at diagnosis. Brain metastases confer very poor prognosis.

Multidisciplinary approach to COVID-19 and cancer: consensus from scientific societies in Argentina.

INTRODUCTION: The world is living through an outbreak of an acute respiratory syndrome caused by a new betacoronavirus known as coronavirus 2 (SARS CoV-2), which has been declared an international public health emergency by the World Health Organisation. Cancer patients are a very special population in this setting since they are more susceptible to viral infections than the general population. Several recommendations have been made on this issue, most of them based on expert opinion and institutional experience. It is essential to gather the evidence available for decision making. OBJECTIVE: To review the evidence available in order to create a multi-institutional position from the perspective of scientific societies in Argentina involved in the management of cancer patients. METHODOLOGY: The review included two phases: 1) search and systematic revision of the medical literature; 2) consensus and revision of the document drafted by national scientific societies involved in the management and care of cancer patients using the modified Delphi method. The final results were presented at a videoconference with all the participants. Also, additional comment and recommendations were discussed. The final document was revised and approved for publication by the members of the panel. RESULTS: The consensus panel included 18 representatives from scientific societies from Argentina who assessed the evidence and then made recommendations for the management of cancer patients in our country. International guidelines (CDC; ASCO, NCCN and ESMO) were considered as a background for analysis, as well as institutional guidelines and an open ad hoc survey administered to 114 healthcare professionals from the scientific societies involved in this study.The recommendations are grouped as follows: 1) general care interventions-training of the personnel, cleaning and disinfection of the hospital premises and patient scheduling; 2) treatment decisions-patient care, surgeries, immunosuppressive therapy, radiotherapy and screening; 3) ethical considerations-optimisation of resources, end-of-life care for critically-ill patients; 4) management of hospitalised patients; and 5) wellbeing of the healthcare team.The general recommendation arising from the study is that the management of cancer patients must adapt to the exceptional pandemic status quo without disregarding treatment or cure options. Moreover, healthcare professional accompaniment of all patients should not be neglected. All healthcare professionals must make a significant joint effort to create multidisciplinary teams to discuss the most appropriate measures for each particular situation. CONCLUSIONS: The scientific evidence available on this topic worldwide is in progress. This together with the epidemiologically shifting scenario poses unprecedented challenges in the management of cancer amidst this global pandemic. Furthermore, the key role of the healthcare structural organisation appears evident, such as the drafting of clear guidelines for all the stakeholders, adaptability to constant change and an interdisciplinary shared vision through consensus to provide adequate care to our cancer patients in the light of uncertainty and fast-paced change.

Prognostic Significance of Tumor Subtypes in Women With Breast Cancer According to Stage: A Population-based Study.

OBJECTIVES: The contribution of tumor subtypes (TS) in each stage of breast cancer with the use of contemporary therapies is unclear. The aim of this study was to analyze differences in overall survival (OS) by TS according to stage compared with other factors. MATERIALS AND METHODS: We evaluated women with breast cancer diagnosed between 2010 and 2013 with known estrogen receptor and progesterone receptor (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Patient characteristics were compared between TS. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Breast cancer-specific survival was a secondary endpoint. RESULTS: We included 166,054 patients. TS distribution was: 72.5% HR-positive/HER2-negative, 10.8% HR-positive/HER2-positive, 4.8% HR-negative/HER2-positive, and 12% triple-negative (TN). Patients with HR-positive/HER2-negative tumors were older, had a lower grade and presented with the earlier stage (all P<0.0001). OS was significantly different according to TS in each stage (Pinteraction<0.0001). HR-positive/HER2-negative had the best OS in stage I (3-year OS, 97.2%). In contrast, HR-positive/HER2-positive had the best 3-year OS in stage II (94.5%), stage III (87.8%), and stage IV (54.8%). There was a 40.1% difference in OS at 3 years in stage IV between TN and HR-positive/HER2-positive. Multivariate analysis adjusted for age, race, grade, histology, and marital status confirmed these results. CONCLUSIONS: Although HR-positive/HER2-negative tumors had better clinicopathologic features, the HR-positive/HER2-positive group had the best OS in most stages. OS was significantly different by TS in each of the 4 stages and these results remained significant in the multivariate model.

Overall Survival of Men and Women With Breast Cancer According to Tumor Subtype: A Population-based Study.

OBJECTIVES: To analyze differences in overall survival (OS) between male breast cancer (MBC) and female breast cancer (FBC) according to tumor subtype compared with other factors. MATERIALS AND METHODS: We evaluated men and women with breast cancer between 2010 and 2013 with known hormone receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Patient characteristics were compared between groups. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Breast cancer-specific survival was a secondary endpoint. RESULTS: We included 1187 MBC and 166,054 FBC. Median follow-up was 21 months (range, 1 to 48) for both groups. OS at 3 years for MBC and FBC was 85.6% and 90.4%, respectively (P=0.0002). MBC were more ductal, had higher grade, presented with more advanced stage and were often HR+/HER2- (each P<0.0001). MBC had worse OS than FBC in HR+/HER2- (Hazard ratio [HaR], 1.5; P=0.0005), HR+/HER2+ (HaR, 2.8; P<0.0001) and triple negative (HaR, 4.3; P<0.0001) (Pinteraction<0.02). MBC had significantly worse OS than FBC in stages I and II, but similar OS in stages III and IV (Pinteraction<0.01). In multivariate analysis, HR+/HER2+ was the only subtype with significant differences in OS between MBC and FBC (HaR, 2.0; P=0.002). CONCLUSIONS: OS was significantly different in both groups. Men had worse OS in early stages while similar OS in stages III and IV. There were significant differences in OS according to tumor subtype; compared with women, men with HR+/HER2+ tumors had twice the risk of death.

Potential therapeutic targets for growth arrest of colorectal cancer cells exposed to PTHrP.

Although PTHrP is implicated in several cancers, its role in chemoresistance is not fully elucidated. We found that in CRC cells, PTHrP exerts proliferative and protective effects and induces cell migration. The aim of this work was to further study the effects of PTHrP in CRC cells. Herein we evidenced, for the first time, that PTHrP induces resistance to CPT-11 in Caco-2 and HCT116 cells; although both cell lines responded to the drug through different molecular mechanisms, the chemoresistance by PTHrP in these models is mediated through ERK, which in turn is activated by PCK, Src and Akt. Moreover, continue administration of PTHrP in nude mice xenografts increased the protein levels of this MAPK and of other markers related to tumorigenic events. The understanding of the molecular mechanisms leading to ERK 1/2 activation and the study of ERK targets may facilitate the development of new therapeutic strategies for CRC treatment.

Chilean Gastric Cancer Task Force: A study protocol to obtain a clinical and molecular classification of a cohort of gastric cancer patients.

Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000 deaths/y. Clinical outcomes and response to "one size fits all" therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response.The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein-Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up.The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03158571, Registered on May 18, 2017.

Prognostic factors and survival according to tumour subtype in women presenting with breast cancer brain metastases at initial diagnosis.

BACKGROUND: The presence of brain metastases at the time of initial breast cancer diagnosis (BMIBCD) is uncommon. Hence, the prognostic assessment and management of these patients is very challenging. The aim of this study was to analyse the influence of tumour subtype compared with other prognostic factors in the survival of patients with BMIBCD. METHODS: We evaluated women with BMIBCD, reported to Surveillance, Epidemiology and End Results program from 2010 to 2013. Patients with other primary malignancy were excluded. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS). RESULTS: We included 740 patients. Median OS for the whole population was 10 months, and 20.7% of patients were alive at 36 months. Tumour subtype distribution was: 46.6% hormone receptor (HR)+/HER2-, 17% HR+/HER2+, 14.1% HR-/HER2+ and 22.3% triple-negative. Univariate analysis showed that the presence of liver metastases, lung metastases and triple-negative patients (median OS 6 months) had worse prognosis. The HR+/HER2+ subtype had the longest OS with a median of 22 months. In multivariate analysis, older age (hazard ratio 1.8), lobular histology (hazard ratio 2.08), triple-negative subtype (hazard ratio 2.25), liver metastases (hazard ratio 1.6) and unmarried patients (hazard ratio 1.39) had significantly shorter OS. CONCLUSIONS: Although the prognosis of patients with BMIBCD is generally poor, 20.7% were still alive 3 years after the diagnosis. There were substantial differences in OS according to tumour subtype. In addition to tumour subtype, other independent predictors of OS are age at diagnosis, marital status, histology and liver metastases.

Locoregional treatment and overall survival of men with T1a,b,cN0M0 breast cancer: A population-based study.

BACKGROUND: Male breast cancer (MaBC) is an understudied disease; information about locoregional treatment and outcomes in patients with early stage is unknown. We aimed to analyse patient characteristics, locoregional treatment and overall survival (OS) of T1a,b,cN0M0 male breast cancer. METHODS: We evaluated men with T1a,b,cN0M0 breast cancer reported to Surveillance, Epidemiology, and End Results program from 1988 to 2012. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. RESULTS: We included 1263 patients. Median age was 66 years (range 27-103). Median follow-up was 62 months (range 1-294). OS at 5 and 10 years were 85.1% and 66.5%, respectively. Distribution according to tumour sub-stage was: T1a 6.5%, T1b 20.7% and T1c 72.8%. Mastectomy was performed in >74% of patients of each tumour size group and overall 44.1% had >5 lymph nodes examined (LNE). Univariate analysis showed that patients with T1c, no surgery and 0 LNE had worse prognosis. In multivariate analysis, older age (hazard ratio [HR] 11.09), grade 3/4 tumours (HR 1.7), no surgery (HR 3.3), 0 LNE (HR 5.1) and unmarried patients (HR 1.7) had significantly shorter OS. There were no differences in OS between breast conservation versus mastectomy and 1-5 LNE versus > 5 LNE. CONCLUSION: Men with early breast cancer have a favourable OS. However, older age, higher grade, no breast surgery, no LNE and unmarried status emerged as poor prognostic characteristics. Efforts to decrease the high rates of mastectomy and extensive LNE should be taken given similar OS observed with breast conservation and 1-5 LNE, respectively.

Role of difucosylated Lewis Y antigen in outcome of locally advanced cervical squamous cell carcinoma treated with cisplatin regimen.

BACKGROUND: Several mechanisms are involved in the development of resistance to therapy in locally advanced cervical squamous cell carcinoma (LACSCC). Studies have shown that CD44 and Lewis Y antigen (LeY) form a complex that is associated with chemoresistance, tumor invasion and metastasis. We assessed the role of CD44 and LeY in the outcome of LACSCC patients treated with different chemotherapy regimens. METHODS: 126 LACSCC patients at FIGO stages IIB-IVA were selected from the GOCS database: 74 patients included in 3 different prospective phase II trials in the neoadjuvant setting (vinorelbine, docetaxel, ifosfamide-vinorelbine-cisplatin) and 52 patients treated with standard radiochemotherapy based on cisplatin (RCBC). Clinical data at baseline, disease-free survival (DFS) and overall survival (OS) were recorded. Univariate and multivariate Cox models were employed. RESULTS: Median age was 45.6 years (range: 24.9-80.5). Sixty-three and 47 tumors were CD44+ and LeY+, respectively. Tumors with expansive growth showed higher grade (p = 0.0024), mitotic index (p = 0.0505), tumor necrosis (p = 0.0191), LeY+ (p = 0.0034) and CD44+/LeY+ coexpression (p = 0.0334). CD44+ cells were present in 91.3% of patients with local recurrence (p = 0.0317). Advanced stage was associated with LeY+ tumors. Patients treated with RCBC had worse DFS and OS when their tumors expressed LeY (p = 0.0083 and p = 0.0137, respectively). Pre-treatment hemoglobin level, FIGO stage and tumor response remained the most significant prognostic factors in Cox regression. CONCLUSIONS: In our cohort of LACSCC patients, the coexpression of CD44 and LeY was not associated with worse outcome. However, in the subgroup of patients receiving RCBC, LeY expression was correlated with shorter DFS and OS.

Prognostic factors in male breast cancer: a population-based study.

Prognostic factors in male breast cancer (MaBC) are controversial. The objective of this study was to analyze patient characteristics and prognostic factors in MaBC over the last decade. Using the Surveillance, Epidemiology, and End Results program, we extracted MaBC patients diagnosed between 2003 and 2012. Patient characteristics were compared between tumor grades. We conducted univariate and multivariate analyses to determine the effects of each prognostic variable on overall survival (OS). The study included 2992 patients. The majority had ductal (85 %), ER-positive (95.1 %), and PR-positive (86 %) breast cancer; however, only 12.4 % had grade I tumors. Stage I and II disease represented 73 % of cases. There was a significant association between grade III/IV tumors with ductal histology, ER and PR negativity, advanced stage, receipt of mastectomy and radiotherapy, and breast cancer death (all P < 0.05). ER-positive patients had better OS (hazard ratio 0.69, P = 0.03); however, after 7.5 years, OS rates by ER status were similar. In multivariate analysis, older age, grade III/IV tumors, stage IV disease, no surgery, no radiotherapy, ER-negative tumors, and unmarried patients had significantly shorter OS (all P < 0.05). Over the past decade, MaBC has been diagnosed most frequently with early stages of disease and high rates of ER positivity; however, grade I is uncommon. ER positivity is associated with better prognosis, mainly during the first 5 years after diagnosis. Age at diagnosis, tumor grade, stage, surgery, radiotherapy, ER, and marital status have clear impact on OS in MaBC.

From Molecular Biology to Clinical Trials: Toward Personalized Colorectal Cancer Therapy.

During the past years, molecular studies through high-throughput technologies have led to the confirmation of critical alterations in colorectal cancer (CRC) and the discovery of some new ones, including mutations, DNA methylations, and structural chromosomal changes. These genomic alterations might act in concert to dysregulate specific signaling pathways that normally exert their functions on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Targeted therapy against key components of altered signaling pathways has allowed an improvement in CRC treatment. However, a significant percentage of patients with CRC and metastatic CRC will not benefit from these targeted therapies and will be restricted to systemic chemotherapy. Mechanisms of resistance have been associated with specific gene alterations. To fully understand the nature and significance of the genetic and epigenetic defects in CRC that might favor a tumor evading a given therapy, much work remains. Therefore, a dynamic link between basic molecular research and preclinical studies, which ultimately constitute the prelude to standardized therapies, is very important to provide better and more effective treatments against CRC. We present an updated revision of the main molecular features of CRC and their associated therapies currently under study in clinical trials. Moreover, we performed an unsupervised classification of CRC clinical trials with the aim of obtaining an overview of the future perspectives of preclinical studies.

Prognostic significance of tumor subtypes in male breast cancer: a population-based study.

Substantial controversy exists about the prognostic role of tumor subtypes in male breast cancer (MaBC). The aim of this study was to analyze the characteristics of each tumor subtype in MaBC and its association with prognosis compared with other factors. We evaluated MaBC patients between 2010 and 2012 with known estrogen receptor, progesterone receptor [together hormone receptor (HR)] status, and human epidermal growth factor receptor 2 (HER2) status reported to the Surveillance, Epidemiology, and End Results program. Patients were classified as: HR-positive/HER2-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, and triple-negative (TN). Univariate and multivariate analyses determined the effect of each variable on overall survival (OS). We included 960 patients. Patient distribution was 84.9 % HR-positive/HER2-negative, 11.6 % HR-positive/HER2-positive, 0.6 % HR-negative/HER2-positive, and 2.9 % TN. TN patients were younger, had higher grade, presented with more advanced stage, were more likely to have mastectomy, and to die of breast cancer (all P < 0.05). Univariate analysis showed that HER2 positivity was associated with shorter OS (hazard ratio 1.90, P = 0.031) and TN patients had worse prognosis (hazard ratio 5.10, P = 0.0004). In multivariate analysis, older patients (hazard ratio 3.10, P = 0.032), those with stage IV (hazard ratio 16.27, P < 0.001) and those with TN tumors (hazard ratio 4.61, P = 0.002) had significantly worse OS. We observed significant differences in patient characteristics according to tumor subtype. HER2-positive and TN represented a small proportion of cases. In addition to age and stage, tumor subtype has clear influence on OS in MaBC.

Expression of ERCC1 and TUBB3 in locally advanced cervical squamous cell cancer and its correlation with different therapeutic regimens.

BACKGROUND: Several studies in solid tumors have shown that expression of excision repair cross-complementation group 1 (ERCC1) and class III ß-tubulin (TUBB3) can predict response to chemoradiotherapy and might be prognostic factors. We assessed the role of ERCC1 and TUBB3 expressions as predictive and prognostic factors in locally advanced cervical squamous cell carcinoma (LACSCC) patients treated with different neoadjuvant regimens. METHODS: ERCC1 and TUBB3 were detected in 88 patients with LACSCC by immunohistochemical analysis. Sixty-two patients were included in 3 different prospective trials and grouped as follows: vinorelbine or docetaxel (group A, n = 44) and ifosfamide-vinorelbine-cisplatin (group B, n = 18). Both groups were compared with standard cisplatin chemoradiotherapy (group C, n = 26). Clinical data at baseline, disease-free survival (DFS) and overall survival (OS) were also collected. Univariate and multivariate Cox models were used to analyze the risk factors. RESULTS: Thirty-five patients (39.8%) and 18 (20.5%) had high ERCC1 and TUBB3 expression, respectively. Both proteins were overexpressed in tumors with unfavorable characteristics. High ERCC1 was associated with advanced FIGO stage (p = 0.034) and progressive disease (49% vs. 28%). Poor DFS (p = 0.021) and OS (p = 0.005) were observed in group C patients with high ERCC1 expression. Multivariate analysis showed that ERCC1 expression, FIGO stage and pretreatment hemoglobin level were significant prognostic factors (p = 0.002, p = 0.008 and p = 0.005, respectively). CONCLUSIONS: ERCC1 expression could be a predictive and prognostic factor in LACSCC patients who receive cisplatin monotherapy. Conversely, TUBB3 had no impact on survival in patients treated with antimicrotubule agents.

Características clínicas y patológicas del cáncer de mama triple negativo y su comparación con los otros subtipos en pacientes del Hospital Provincial Neuquén / Clinical and pathological feautures of triple-negative breast cancer. Comparison with other subtypes in patients in the Hospital Provincial Neuquén

Introducción: El cáncer de mama está constituido por un grupo heterogéneo de tumores. La ausencia de los receptores de estrógeno, progesterona y de HER-2 , es decir, tumores triple negativo (TN), está asociada a carcinomas de gran tamaño, elevado grado histológico y mayor recurrencia, que los demás subtipos tumorales. Objetivo: Describir las características clínico-patológicas de las pacientes con cáncer de mama invasivo TN y compararlas con aquellas que presentaron tumores que expresan al menos un receptor positivo (+1RP).Materiales y métodos: Se analizaron retrospectivamente 185 pacientes con cáncer de mama invasivo que concurrieron al Hospital Provincial Neuquén entre enero de 2006 y diciembre de 2010. Las pacientes fueron agrupadas en aquéllas con tumores TN y con +1RP. Resultados: El 19,5% (36/185) de las pacientes presentó tumores TN y el 80,5% (149/185) +1RP. El seguimiento medio fue 2,5 años (DE±1,5; rango 0-6 años) y la edad al diagnóstico fue 54,9±2,1 años en TN versus 55,4±1 años en +1RP. El grado histológico 3 fue estadísticamente más frecuente en los tumores TN que en los +1RP (73,5% vs. 41,8%; p=0,0008). Asimismo, los tumores TN fueron de mayor tamañoy estadio más avanzado que aquéllas con +1RP. La recurrencia fue estadísticamente más elevada en los TN (22,6% vs. 7,5%, p=0,0132). No se hallaron diferencias significativas tanto en la sobrevida global como en el tiempo libre de progresión en ambos grupos. Conclusión: Las pacientes con cáncer de mama triple negativo se presentaron con tumores de mayor tamaño, alto grado histológico y estadio más avanzado, que en el resto de las pacientes al momento del diagnóstico.

Características clínicas y patológicas del cáncer de mama triple negativo y su comparación con los otros subtipos en pacientes del Hospital Provincial Neuquén / Clinical and pathological feautures of triple-negative breast cancer. Comparison with other subtypes in patients in the Hospital Provincial Neuquén

Introducción: El cáncer de mama está constituido por un grupo heterogéneo de tumores. La ausencia de los receptores de estrógeno, progesterona y de HER-2 , es decir, tumores triple negativo (TN), está asociada a carcinomas de gran tamaño, elevado grado histológico y mayor recurrencia, que los demás subtipos tumorales. Objetivo: Describir las características clínico-patológicas de las pacientes con cáncer de mama invasivo TN y compararlas con aquellas que presentaron tumores que expresan al menos un receptor positivo (+1RP).Materiales y métodos: Se analizaron retrospectivamente 185 pacientes con cáncer de mama invasivo que concurrieron al Hospital Provincial Neuquén entre enero de 2006 y diciembre de 2010. Las pacientes fueron agrupadas en aquéllas con tumores TN y con +1RP. Resultados: El 19,5% (36/185) de las pacientes presentó tumores TN y el 80,5% (149/185) +1RP. El seguimiento medio fue 2,5 años (DE±1,5; rango 0-6 años) y la edad al diagnóstico fue 54,9±2,1 años en TN versus 55,4±1 años en +1RP. El grado histológico 3 fue estadísticamente más frecuente en los tumores TN que en los +1RP (73,5% vs. 41,8%; p=0,0008). Asimismo, los tumores TN fueron de mayor tamañoy estadio más avanzado que aquéllas con +1RP. La recurrencia fue estadísticamente más elevada en los TN (22,6% vs. 7,5%, p=0,0132). No se hallaron diferencias significativas tanto en la sobrevida global como en el tiempo libre de progresión en ambos grupos. Conclusión: Las pacientes con cáncer de mama triple negativo se presentaron con tumores de mayor tamaño, alto grado histológico y estadio más avanzado, que en el resto de las pacientes al momento del diagnóstico.(AU)

High expression of sLex associated with poor survival in Argentinian colorectal cancer patients.

AIM: Colorectal cancer (CRC) is one of the most prevalent malignancies in Argentina with 11,043 new cases and 6,596 deaths estimated to have occurred in 2008. The present study was developed to clarify the differential expression of MUC1, MUC2, sLex, and sLea in colorectal cancer patients and their relationship with survival and clinical and histological features. METHODS: Ninety primary tumor samples and 43 metastatic lymph nodes from CRC patients were studied; follow-up was documented. Twenty-six adenoma and 68 histological normal mucosa specimens were analyzed. An immunohistochemical approach was applied and statistical analysis was performed. RESULTS: In tumor samples, MUC1, sLea, and sLex were highly expressed (94%, 67%, and 91%, respectively); also, we found a significantly increased expression of the 3 antigens in primary tumors and metastatic lymph nodes compared with normal mucosa and adenomas. MUC2 was expressed in 52% of both normal mucosa and CRC samples; this reactivity significantly decreased in metastatic lymph nodes (p<0.05). A multiple comparison analysis showed that MUC1 and sLex discriminated among 3 groups: normal, adenoma, and CRC tissues. The increase of sLex expression showed an association with recurrence, and survival analysis showed that a high sLex staining was significantly associated with a poor survival. By multivariate analysis MUC1 inmunoreactivity correlated positively and significantly with tumor size, while MUC2 expression showed the opposite correlation. CONCLUSIONS: The correlation of sLex overexpression in primary tumors and metastatic lymph nodes, the discrimination among the normal, adenoma, and CRC groups based on sLex expression, as well as its association with recurrence and survival, all suggest a prognostic role of sLex in Argentinian CRC patients.

Sixteen years follow-up results of a randomized phase II trial of neoadjuvant fluorouracil, doxorubicin, and cyclophosphamide (FAC) compared with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in stage III breast cancer: GOCS experience.

Neoadjuvant chemotherapy (NAC) allows direct evaluation of the tumor's sensitivity to therapy, eradication of micrometastatic disease and the possibility of performing breast conserving surgery. The aim of this study was to describe long-term results of NAC in stage III breast cancer patients. We evaluated 126 patients that participated in a phase II randomized trial of neoadjuvant FAC compared with CMF. Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Median follow-up was 4.5 years (range 0.2-16.4). Objective response rate (OR) was similar in both groups (61 % for FAC, 66 % for CMF, P = NS). There were no differences in median disease free survival (DFS) or overall survival (OS) (5.1 vs 3.3 years and 6.7 vs 6.3 years for FAC and CMF, respectively). After 16 years of follow-up, 53 patients are still alive. Multivariate analysis showed that the number of pathologically involved lymph nodes (pLN) was the only factor associated with both, DFS and OS (P = 0.0003 and P = 0.0005, respectively). Both regimens were well tolerated, CMF had higher incidence of grade 3-4 leukopenia, thrombocytopenia, and stomatitis, whereas alopecia was more common in FAC. To the best of our knowledge, this is the first study to report long-term outcomes of FAC and CMF in the neoadjuvant setting. Within the sensitivity of our study, both regimens showed similar OR, long-term toxicity, DFS, and OS rate at 16 years. After 5 years, the hazard of death seems to decline. The prolonged follow-up of this study provides a unique opportunity to evaluate factors that predict long-term outcomes. After 16 years of follow-up, the number of pLN remains the most powerful predictor of survival.

Treatment of early breast cancer, a long-term follow-up study: the GOCS experience.

Most cases of breast cancer are diagnosed at early stage of disease; therefore, treatment is oriented to increase the disease-free interval (DFI) and overall survival (OS). The prognosis, in comparison with other malignancies, has improved in the last decades as a result of mammographic screening. The aim of the study was to report the incidence of local and distant recurrence, DFI and OS in patients (pts) with stage I and stage II breast cancer over a period of 26 years divided into three groups. From January 1978 to December 2004, 927 women with early breast cancer (EBC) were included, 350 were stage I and 577 Stage II (AJCC 2002). Patients were divided according to the year of diagnosis into three periods of 10 years: Group A (1978-1987) 135 pts, Group B (1988-1997) 412 pts, and Group C (1998-2004) 380 pts. DFI was analyzed from the date of initial diagnosis to the date of local or distant recurrence. OS was estimated from the date of initial diagnosis to the last follow-up or date of death. Median age was 51 years (28-92). Conservative surgery was performed in 69% of pts, adjuvant radiation therapy in 78%, adjuvant chemotherapy in 29%, and adjuvant hormone therapy in 18%. The median follow-up was 8.4 years (0.3-30). The mean tumor size in Group A was 2.7 cm, in Group B 2.2 cm, and in Group C 1.94 cm (p = 0.0001). The percentage of pts with stage I increased from 13% in Group A to 38% in Group B and to 47% in Group C (p = 0.0001). Local recurrence was documented in 5% of all pts, whereas 28% developed metastatic disease. The DFI and OS showed a statistically significant difference among the three groups (p = 0.005). DFI rate at 5, 10, 15, 20, and 25 years was 71%, 67%, 65%, 65%, and 64%, respectively. OS at 5, 10, 15, 20, and 25 years was 82%, 62%, 49%, 39%, and 28%, respectively. Factors that had an effect in OS demonstrated by the multivariate regression analysis were: Tumor size, ER status, and nodal involvement (p < 0.001). Clinical outcomes in EBC in our experience are similar to those reported in international literature. The DFI and OS showed a statistically significant difference among the three groups. This group of pts continues to have a good prognosis as shown by the OS rate at 5, 10, 15, 20, and 25 years, although a high percentage of pts still to have recurrence and die from breast cancer after 5, 10, 15, 20, and 25 years of follow-up.