Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with ~700,000 mortalities occurring due to CRC in 2012. The treatment options are effective in a small percentage of patients, and it is important to identify specific biomarkers in order to determine patients for whom the available therapies will be beneficial. It has been hypothesised that the PIK3CA gene mutation may affect the response to therapy of patients with metastatic CRC. In the present study, primary tumour specimens were collected from 156 patients with CRC who were treated in the Military Institute of Medicine in Warsaw (Warsaw, Poland). Codons 12 and 13 of exon 1 of KRAS, exons 11 and 15 of BRAF and exons 9 and 20 of PIK3CA were analysed for mutation using direct sequencing. The prognostic value of each mutation and the clinical and pathological variables of these tumours were estimated. The results revealed that PIK3CA mutations were present in 15 patients (9.6%), of whom seven (46.7%) possessed mutations in codon 9 and eight (53.3%) possessed mutations in codon 20. Mutation in the PIK3CA gene was detected in six patients with KRAS gene mutations, which accounted for 40% of PIK3CA-mutated tumours, and in one patient with BRAF mutations, which accounted for 6.6% of PIK3CA-mutated tumours. No significant differences were identified between the overall survival (OS) rates of patients with PIK3CA mutations (median OS, 56.7 months) and those with wild-type PIK3CA genes (median OS, 47.6 months) (P=0.1270). Univariate analysis identified that the following prognostic factors affected the OS rate in the current patient cohort: Gender, female patients survived for 57.5 months compared with 39.3 months for male patients (P=0.0111); and lymph node involvement grade, as survival of patients without lymph node metastases was 61.4 months compared with 45.4 months in patients presenting with metastases (P=0.0122). The findings of the present analysis indicate that PIK3CA mutation status is not a prognostic factor in CRC patients. In addition, no statistically significant association exists between tumours with PIK3CA mutations and clinical or pathological factors.

Mitomycin C and high-dose 5-fluorouracil with folinic acid as a therapeutic option for heavily pretreated patients with metastatic colorectal cancer: prospective phase II trial.

BACKGROUND: Standard treatment for patients with unresectable colorectal cancer metastases includes chemotherapy regimens based on irinotecan, oxaliplatin, fluoropyrimidines, anti-vascular endothelial growth factor therapy, and anti-EGFR. Additional therapeutic options are needed for patients with good performance status who have disease progression during or after standard therapies. METHODS: A nonrandomized phase II study was modeled as a two-stage Chen design. Eligible patients had a diagnosis of metastatic colorectal cancer (mCRC) with progression after prior cytotoxic regimens based on oxaliplatin and irinotecan. Treatment consisted of mitomycin C in combination with high-dose 5-fluorouracil (5-FU) and folinic acid (the MLF regimen; mitomycin C as an intravenous bolus of 6 mg/m² i.v. on days 1 and 22 every 7 weeks; folinic acid at 250 mg/m² in combination with 5-FU at 2,600 mg/m² as a continuous intravenous infusion (24 hours) weekly for 6 of every 7 weeks. RESULTS: The median age of the 74 eligible patients was 62 years (range: 47-79 years). In these heavily pretreated patients with mCRC, the MLF regimen was the fourth or fifth line in more than 60% of the patients. Two patients (3.2%) achieved a partial response, and 33 (53.2%) achieved a best response of stable disease, defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Median progression-free survival was 4.9 months. The median overall survival was 9.7 months. The most common nonhematologic side effects included mucositis (24.4% for all grades, and 9.5% with grade 3/4), diarrhea (15.0% for all grades, 13.6% with grade 3/4), fatigue (44.7% for all grades, 13.6% with grade 3/4), nausea (12.3% for all grades, 6.8% with grade 3/4), and peripheral neuropathy (17.6% for all grades, 2.7% with grade 3/4). Among the most frequent hematological toxicities were neutropenia (27.1% for all grades, 14.9% with grade 3/4), thrombocytopenia (18.9% for all grades, 8.1% with grade 3/4), and anemia (13.6% for all grades, 4.1% with grade 3/4). Dose reductions due to adverse events were necessary in 29 of 74 patients (37.6%), and discontinuation of therapy due to toxicity was necessary for 14 of 74 patients (18.2%). CONCLUSION: Our study shows the MLF regimen can be administered safely to patients with heavily pretreated mCRC. Median progression-free and overall survival compares favorably with other options used or approved in this setting. A randomized trial in this setting should be considered.

Resistance to first line platinum paclitaxel chemotherapy in serous epithelial ovarian cancer: the prediction value of ERCC1 and Tau expression.

In oncology, a rational approach to identify patients who are likely to benefit from therapy, already before initiation of treatment, is urgently required. Excision repair cross-complementation group 1 enzyme (ERCC1) has been proposed as a molecular predictor of clinical resistance to platinum-based chemotherapy. Other data suggest Tau protein expression as a predictor of clinical outcome in cancer patients treated with paclitaxel-based chemotherapy as low tau expression may render microtubules more vulnerable to paclitaxel. Therefore, the combination of ERCC1 and Tau may be a valuable predictor of sensitivity to platinum/paclitaxel treatment. The primary aim of the study was to investigate whether ERCC1 and Tau protein expression correlates with patient outcome in newly diagnosed epithelial ovarian cancer (EOC) patients. Formalin-fixed, paraffin-embedded tissue sections from 227 newly diagnosed EOC patients were used for immunohistochemical staining for ERCC1 and Tau proteins. All patients received standard first-line combination platinum and paclitaxel chemotherapy. The patients were divided in a training set of 84 patients and an independent validation cohort of 143 patients. Neither ERCC1 nor Tau expression was associated with clinical response or platinum resistance in both the training and validation sets. Patients with ERCC1-positive tumors had significantly shortened progression-free and overall survival compared to patients with ERCC1-negative tumors, p<0.00001 and p=0.0006. In multivariate analysis ERCC1 also proved as an independent predictor of PFS and OS with HR of 3.86 and 1.98, respectively but the data could not be confirmed in the validation set. Tau expression was not associated with PFS or OS in this study. ERCC1 and Tau might serve as biomarkers of DNA repair and for paclitaxel sensitivity but the present study could not validate ERCC1 or Tau protein expression in tumors as pre-treatment tools to predict sensitivity to first-line platinum/paclitaxel chemotherapy.

Wnt/ß-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer.

BACKGROUND: ß-catenin is the key protein in the WNT signalling pathway and it forms adherent junctions together with E-cadherin. In ovarian carcinoma, abnormal expression of ß-catenin, E-cadherin and WNT-1 was observed, but their prognostic and predictive role is unclear. The aim of this study was to clarify the prognostic and predictive role of E-cadherin, ß-catenin and WNT-1 in advanced epithelial ovarian carcinoma (AEOC). METHODS: The expression of E-cadherin, ß-catenin and WNT-1 was determined by immunohistochemistry in AEOC. The correlation between expression of these proteins and progression-free survival (PFS) and overall survival (OS) was evaluated. Statistical analyses included Kaplan-Meier estimation, log-rank test, Spearman correlation and Cox proportional-hazards model. RESULTS: In ovarian cancer, intense expression of E-cadherin, ß-catenin and WNT-1 was found. In multivariate analysis, strong membrane ß-catenin expression was an independent unfavourable predictor for PFS (HR 2.19, 95% CI 1.09-4.39; p = 0.028), while in univariate analysis, strong membrane ß-catenin expression was a prognostic factor for OS in patients with AOC (p = 0.039). In multivariate analysis, only resistance to first-line chemotherapy was an adverse independent prognostic factor for OS (HR 16.84; 95% CI 5.07-55.98; p < 0.0001). Additionally, strong membranous ß-catenin expression was associated with resistance to platinum-based chemotherapy (p = 0.027). CONCLUSIONS: These findings support that WNT/ß-catenin pathway and E-cadherin are important factors in advanced epithelial ovarian cancer.

Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system.

BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) is found in many types of neoplasms. The aim of the study was to evaluate EGFR expression in colorectal cancer (CRC) specimens and to determine whether EGFR expression correlates with clinicopathological data and overall survival. PATIENTS AND METHODS: Tissue specimens from 181 consecutive CRC patients treated at the Military Institute of Medicine in 2006-2010 were collected and examined for EGFR expression, by immunohistochemistry staining. The staining intensity and percentage of cells with membranous EGFR expression were scored and then grouped according to the parameters of the Allred Scoring system. Cutoff values were subjected to further statistical analysis. Univariate tests and a multivariate Cox proportional hazards model were used in data analysis. RESULTS: EGFR was overexpressed in 96 of 181 CRC specimens (53%). EGFR expression was not correlated with other clinicopathological variables. On univariate analysis, overexpression of EGFR, determined by PS (percentage score) (>3) and total score (sum of PS and intensity score) (>4), was associated with poor overall survival. On multivariate analysis, EGFR overexpression (PS > 3) was an independent adverse prognostic factor (hazard ratio [HR] 1.62; 95% confidence interval [CI]: 1.03-2.53). Elevated carcinoembryonic antigen (CEA) serum concentration before treatment, performance status (Word Health Organization [WHO]-2), and tumor localized in colon and liver metastases were also independent unfavorable prognostic factors. CONCLUSION: EGFR overexpression (PS > 3) in a CRC patient population was an independent adverse prognostic factor. Implementation of the Allred Scoring system criteria into clinical practice might facilitate treatment decisions in CRC patients.

Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy.

BACKGROUND: The aim of the study was to evaluate predictive and prognostic significance of microtubule-associated protein Tau in epithelial ovarian cancer (EOC) patients treated with paclitaxel and platinum-based chemotherapy. METHODS: 74 patients with EOC (stage I-IV) who underwent cytoreductive surgery followed by standard paclitaxel/platinum chemotherapy were included in the retrospective analysis. Their formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for Tau protein, using semi-quantitative DAKO test. Tau expression was acknowledged as negative (0 and 1+) or positive (2+ and 3+). The correlation between Tau expression, progression free survival (PFS) and overall survival (OS) was evaluated. Statistical analysis included Kaplan-Meyer estimator, long rank test, Mann Whitney test and Cox proportional hazards model. RESULTS: 25.7% (19/74) and 74.3% (55/74) of the patients were classified as Tau-negative and Tau-positive, respectively. Median PFS was 28.7 months for Tau-negative group and 15.9 months for Tau-positive group (p = 0.0355). In the univariate analysis 3-year OS in Tau-negative and Tau-positive groups was 80.2% and 52.4%, respectively (p = 0.0198). Low expression of protein Tau was associated with better OS, whereas an advanced stage at diagnosis, suboptimal surgery, serous histological type and resistance to first line chemotherapy were each correlated with worse OS (p <0,05). In multivariate analysis only resistance to first line chemotherapy remained significant (HR 22.59; 95% CI, 8.71-58.55; p <0.0001). CONCLUSIONS: Negative tau protein seems to be both good prognostic factor and a predictor of response to paclitaxel/platinum-based chemotherapy in EOC patients.

K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy.

BACKGROUND: CRC caused more than 600,000 estimated deaths in 2008. Dysregulated signaling through the RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway due to mutations in K-Ras and B-Raf are common events in CRC. METHODS: Incidence of mutations in codons 12 and 13 of K-Ras and exons 11 and 15 of B-Raf were analyzed in amplified PCR products from primary tumors of 273 patients with CRC, and their prognostic and predictive significance was assessed. The prognostic role of clinical and pathological factors was also examined. RESULTS: K-Ras mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13. B-Raf gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15. Multivariate analysis revealed a predictive significance for K-Ras mutations with respect to time to progression in patients treated with irinotecan and oxaliplatin as first-line chemotherapy. There was no predictive significance for B-Raf gene mutation status in these patients. The following risk factors were found to affect overall survival (OS) rates: primary tumor location, lymph node involvement grade, carcinoembryonic antigen (CEA) level before treatment, and performance status according to WHO criteria. CONCLUSIONS: Based on the results of this study, K-Ras mutation status may be a suitable indicator of patient eligibility and a prognostic indicator for responsiveness to anti-EGFR therapy alone, or in combination with chemotherapy. Also, K-Ras mutation status may predict time to progression in patients treated with irinotecan and oxaliplatin.

The role of Tau protein in resistance to paclitaxel.

Resistance to taxanes, related to limited efficacy of systemic therapy in cancer patients, is multifactorial. Among mechanisms of resistance to taxanes, those related to microtubule-associated proteins (MAP), including protein Tau, are of great importance. Protein Tau (50-64 kD) binds to beta-tubulin in the same place as paclitaxel. In preclinical studies, low expression of Tau in cancer cells was associated with increased sensitivity to paclitaxel. High expression of Tau protein in ER-positive breast cancers indicates resistance to taxane-containing chemotherapy and sensitivity to hormonal treatment. This article reviews current knowledge on predictive value of protein Tau in response to taxanes. Better understanding of its role may facilitate patients selection to this sort of treatment and lead to treatment optimization.

Metastatic colorectal cancer in the elderly: An overview of the systemic treatment modalities (Review).

Colorectal cancer (CRC) is one of the most frequently occurring types of cancer. Worldwide, more than 800,000 new cases of CRC are diagnosed each year. The median ages at CRC diagnosis and death are 71 and 75 years, respectively. The majority ot patients (50-60%) with colorectal cancer are diagnosed at stage IV disease. Patients aged 65 or older are characterized by a higher incidence of significant co-morbidities, decreased regenerative capacity of bone marrow and worse general performance. Anti-neoplastic therapies used for the treatment of colorectal cancer include irinotecan, oxaliplatin, 5-fluorouracil, leucovorin, capecitabine and monoclonal antibodies. Analysis of the efficacy of the presented chemotherapeutic and chemoimmunotherapeutic regimens in the treatment of metastatic CRC in patients older than 65 and 70 years compared to 'younger' patients, generally demonstrated comparable efficacy, time to disease progression and overall survival. Age criterion should not be considered when assessing the eligibility of patients with metastatic CRC for treatment of the above-mentioned chemotherapeutic and chemoimmunotherapeutic regimens. Treatment should be individualized based on the potential risks and benefits anticipated for each patient.

Cystatin C as a parameter of glomerular filtration rate in patients with ovarian cancer.

AIMS: To evaluate the potential role of serum cystatin C as a marker of renal function in patients with ovarian cancer. METHODS: Treatment of consecutive ovarian cancer patients who were eligible for chemotherapy with paclitaxel (135 mg/m²/24 h) and cisplatin (75 mg/m²) every 3 weeks in 6 cycles. Glomerular filtration rate (GFR) markers, i.e. serum levels of creatinine and cystatin C, estimated by the Cockcroft-Gault and Modification of Diet in Renal Disease formulas, were recorded before each cycle and 3 weeks after the 6th course. RESULTS: The median age of 34 patients was 54 years. In the initial stage of treatment, we did not observe any correlation between cystatin C and other GFR markers. We noted a significant association between cystatin C and tumor extent on spiral CT scans (diameter: >1 cm) performed at baseline (p = 0.004), and after the 1st (p = 0.03) and 2nd cycle (p = 0.026). We observed a correlation between cystatin C and CA-125 level before chemotherapy (R = 0.4; p = 0.02) and after the 1st cycle (R = 0.43; p = 0.04). CONCLUSION: The results of our study suggest that cystatin C is not a reliable marker of the GFR in ovarian cancer patients, probably due to its nature as a cysteine protease inhibitor.

Salvage therapy with topotecan in heavily pretreated ovarian cancer patients.

BACKGROUND: We showed feasibility and efficacy of topotecan in third or a higher line of chemotherapy in heavily pretreated ovarian cancer (HPOC) patients. METHODS: Between January 2004 and June 2007, 25 cases of HPOC were treated with topotecan as 30-min infusion at the dose of 1.5 mg/m2 through 5 consecutive days every 21 days. We assessed toxicity profile using NCI CTC and the response was measured according to RECIST and CA-125 criteria described by Rustin. RESULTS: Heavily pretreated ovarian cancer received at least two cycles of topotecan (median 6, range 2-6) with prior chemotherapy lines (median 3, range 3-7). In 20 HPOC who met RECIST criteria results were as follows: PR, 6/20 (30%); NC, 7/20 (35%); PD, 7/20 (35%). Biochemical response was noted in 20 patients having ?15% (3/20) of 75% and 20% (4/20) of 50% decline of CA-125. Time to progression was median 6 months (95% CI: 4.06-6.18) and overall survival was median 9 months (95% CI: 8.69-16.27). In multivariate analysis, primary optimal debulking and response to primary chemotherapy (HR = 0.24, 95% CI: 0.08-0.69, P = 0.0084; HR = 0.38, 95% CI: 0.14-0.98, P = 0.0448, respectively) were independent prognostic factors when assessed in relation to salvage therapy with topotecan. We did not observe difference in side effects after topotecan treatment among patients in relation to the higher number of previously used chemotherapy line (3 vs. >3). CONCLUSIONS: We state that topotecan is able to offer a control of ovarian cancer, despite previous treatment, but reliable management is needed to alleviate hematologic toxicity.

[Long-term remission after erlotinib therapy in an elderly patient with advanced non-small-cell lung cancer. Case report and conclusions for clinical practice]. / Dlugotrwala remisja po leczeniu erlotynibem u chorej na zaawansowanego niedrobnokomórkowego raka pluca w podeszlym wieku. Opis przypadku i wnioski dla praktyki klinicznej.

Small molecule tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) - gefitinib and erlotinib - have recently been used as a therapeutic option in advanced non-small cell lung cancer (NSCLC) patients relapsing after first- or second-line chemotherapy. We report here a case of long-term remission in an elderly, non-smoking woman with advanced NSCLC after chemotherapy failure, who was selected for erlotinib therapy using demographic and clinical criteria. Based on this example and on the literature data we discuss the need for careful patient selection for this new therapeutic method.