Evidence of circulating autoantibodies in cancer patient sera has created opportunities for exploiting them as biomarkers. We report the identification and the clinical validation of an autoantibody ...panel in newly diagnosed patients with early‐stage breast cancer. Proteomic approach and serological screening of a discovery set of sera (n = 80) were performed to identify tumor‐associated antigens (TAAs). Autoantibody levels were then measured in an independent validation set (n = 182) against a panel of five TAAs by enzyme‐linked immunosorbent assay. Sixty‐seven antigens that elicited a specific humoral response in breast cancer were identified and five antigens (GAL3, PAK2, PHB2, RACK1 and RUVBL1) were selected for validation. GAL3 and RACK1 showed significantly increased reactivity in early‐stage breast cancer. When combined, the five markers significantly discriminated early‐stage cancer from healthy individuals (AUC = 0.81; 95% CI 0.74–0.86). Interestingly, this value was high in both node‐negative early‐stage primary breast cancer (AUC = 0.81; 95% CI 0.72–0.88) and ductal carcinoma in situ (AUC = 0.85; 95% CI 0.76–0.95) populations. This autoantibody panel could be useful as a diagnostic tool in a screening strategy of early‐stage invasive breast cancer and preinvasive breast cancer. It could be particularly appropriate in complement to mammography for women with high breast density.
What's new?
This study shows the clinical relevance of a combination of five antigens as a blood‐screening test for early breast cancer detection. The antigens were identified using a proteomic approach and validated in an independent cohort of 182 samples by ELISA. Since the effectiveness of mammographic screening declines in cohorts of patients with dense breast tissue and small lesions, testing for the status of this biomarker panel may help improve the detection of early‐stage cancer in women.
To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial.
Pelvic irradiation delivered 45 Gy, ...followed by an 18-Gy boost. Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1, 4, and 7 during radiotherapy. Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45 Gy, followed by radical cystectomy in case of incomplete response. The European Organization for Research and Treatment of Cancer quality of life questionnaire QLQ-C30, specific items on bladder function, and the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) symptoms scale were used to evaluate quality of life before treatment and 6, 12, 24, and 36 months after treatment.
Median age was 68 years for 51 evaluable patients. Thirty-two percent of patients had T2a tumors, 46% T2b, 16% T3, and 6% T4. A visibly complete transurethral resection was possible in 66%. Median follow-up was 8 years. Bladder was preserved in 67% (95% confidence interval, 52-79%) of patients. Overall survival was 36% (95% confidence interval, 23-49%) at 8 years for all patients, and 45% (28-61%) for the 36 patients suitable for surgery. Satisfactory bladder function, according to LENT-SOMA, was reported for 100% of patients with preserved bladder and locally controlled disease 6-36 months after the beginning of treatment. Satisfactory bladder function was reported for 35% of patients before treatment and for 43%, 57%, and 29%, respectively, at 6, 18, and 36 months.
Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67% patients at 8 years. Quality of life and quality of bladder function were satisfactory for 67% of patients.
In patients with advanced colorectal cancer, leucovorin, fluorouracil, and irinotecan (FOLFIRI) is considered as one of the reference first-line treatments. However, only about half of treated ...patients respond to this regimen, and there is no clinically useful marker that predicts response. A major clinical challenge is to identify the subset of patients who could benefit from this chemotherapy. We aimed to identify a gene expression profile in primary colon cancer tissue that could predict chemotherapy response.
Tumor colon samples from 21 patients with advanced colorectal cancer were analyzed for gene expression profiling using Human Genome GeneChip arrays U133. At the end of the first-line treatment, the best observed response, according to WHO criteria, was used to define the responders and nonresponders. Discriminatory genes were first selected by the significance analysis of microarrays algorithm and the area under the receiver operating characteristic curve. A predictor classifier was then constructed using support vector machines. Finally, leave-one-out cross validation was used to estimate the performance and the accuracy of the output class prediction rule.
We determined a set of 14 predictor genes of response to FOLFIRI. Nine of nine responders (100% specificity) and 11 of 12 nonresponders (92% sensitivity) were classified correctly, for an overall accuracy of 95%.
After validation in an independent cohort of patients, our gene signature could be used as a decision tool to assist oncologists in selecting colorectal cancer patients who could benefit from FOLFIRI chemotherapy, both in the adjuvant and the first-line metastatic setting.
To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether ...pretreatment QoL predicts survival in patients with metastatic pancreatic cancer.
Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks.
Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin.
FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.
Colorectal cancer (CRC) is one of the most common causes of cancer death throughout the world. In this work our aim was to study the role of the phosphoserine aminotransferase PSAT1 in colorectal ...cancer development.
We first observed that PSAT1 is overexpressed in colon tumors. In addition, we showed that after drug treatment, PSAT1 expression level in hepatic metastases increased in non responder and decreased in responder patients. In experiments using human cell lines, we showed that ectopic PSAT1 overexpression in colon carcinoma SW480 cell line resulted in an increase in its growth rate and survival. In addition, SW480-PSAT1 cells presented a higher tumorigenic potential than SW480 control cells in xenografted mice. Moreover, the SW480-PSAT1 cell line was more resistant to oxaliplatin treatment than the non-transfected SW480 cell line. This resistance resulted from a decrease in the apoptotic response and in the mitotic catastrophes induced by the drug treatment.
These results show that an enzyme playing a role in the L-serine biosynthesis could be implicated in colon cancer progression and chemoresistance and indicate that PSAT1 represents a new interesting target for CRC therapy.
Purpose Longitudinal analysis of health-related quality of life (HRQoL) remains unstandardized and compromises comparison of results between trials. In oncology, despite available statistical ...approaches, results are poorly used to change standards of care, mainly due to lack of standardization and the ability to propose clinical meaningful results. In this context, the time to deterioration (TTD) has been proposed as a modality of longitudinal HRQoL analysis for cancer patients. As for tumor response and progression, we propose to develop RECIST criteria for HRQoL. Methods Several definitions of TTD are investigated in this paper. We applied this approach in early breast cancer and metastatic pancreatic cancer with a 5-point minimal clinically important difference. In breast cancer, TTD was defined as compared to the baseline score or to the best previous score. In pancreatic cancer (arm 1: gemcitabine with FOLFIRI.3, arm 2: gemcitabine alone), the time until definitive deterioration (TUDD) was investigated with or without death as event. Results In the breast cancer study, 381 women were included. The median TTD was influenced by the choice of the reference score. In pancreatic cancer study, 98 patients were enrolled. Patients in Arm 1 presented longer TUDD than those in Arm 2 for most of HRQoL scores. Results of TUDD were slightly different according to the definition of deterioration applied. Conclusion Currently, the international ARCAD group supports the idea of developing RECIST for HRQoL in pancreatic and colorectal cancer with liver metastasis, with a view to using HRQoL as a co-primary endpoint along with a tumor parameter.
Conventional-dose chemotherapy (CDCT) and high-dose chemotherapy (HDCT) may both be successfully used as salvage treatment for patients with metastatic germ cell tumors (GCTs) who experience ...progression with first-line treatment.
Data on 1,984 patients with GCTs who experienced progression after at least three cisplatin-based cycles and were treated with either cisplatin-based CDCT or carboplatin-based HDCT chemotherapy were collected from 38 centers or groups worldwide. Of 1,984 patients, 1,594 (80%) were eligible, and among the eligible patients, 1,435 (90%) could reliably be classified into one of the following five prognostic categories based on prior prognostic classification: very low (n = 76), low (n = 257), intermediate (n = 646), high (n = 351), and very high risk (n = 105). Within each of the five categories, the progression-free survival (PFS) and overall survival (OS) after CDCT and HDCT were compared using the Cox model adjusted for significant distributional differences between important variables.
Overall, 773 patients received CDCT, and 821 patients received HDCT. Both treatment modalities were used with similar frequencies within each prognostic category. The hazard ratio for PFS was 0.44 (95% CI, 0.39 to 0.51) stratified on prognostic category, and the hazard ratio for OS was 0.65 (95% CI, 0.56 to 0.75), favoring HDCT. These results were consistent within each prognostic category except among low-risk patients, for whom similar OS was observed between the two treatment groups.
This retrospective analysis suggests a benefit from HDCT given as intensification of first salvage treatment in male patients with GCTs and emphasizes the need for another prospective randomized trial comparing CDCT to HDCT in this patient population.
Purpose
Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to ...study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials.
Methods
The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software.
Results
We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate.
Conclusion
These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL.
Health-related quality of life has become increasingly important in clinical trials over the past two decades. The R package QoLR is a recently developed package for the longitudinal analysis of ...health-related quality of life in oncology. This package contains the scoring of most of the European Organisation for Research and Treatment of Cancer quality of life questionnaires and some programs to analyze the time to a health-related quality of life score deterioration as a modality of longitudinal analysis in oncology.
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