Hypersensitivity reactions to anticancer agents: Data mining of the public version of the FDA adverse event reporting system, AERS

Background

Cancer-testis antigens (CTAs) are suitable targets for cancer-specific immunotherapy. The aim of the study is to investigate the expression of CTAs in intrahepatic cholagiocarcinoma (IHCC) and evaluate their potential therapeutic values.

Methods

Eighty-nine IHCC patients were retrospectively assessed for their expression of CTAs and HLA Class I by immunohistochemistry using the following antibodies: MA454 recognizing MAGE-A1, 57B recognizing multiple MAGE-A (MAGE-A3/A4), E978 recognizing NY-ESO-1, and EMR8-5 recognizing HLA class I. The clinicopathological and prognostic significance of individual CTA markers and their combination were further evaluated.

Results

The expression rates of MAGE-A1, MAGE-A3/4 and NY-ESO-1 were 29.2%, 27.0% and 22.5%, respectively. The concomitant expression of CTAs and HLA class I antigen was observed in 33.7% of the IHCC tumors. We found that positive MAGE-3/4 expression correlated with larger tumor size (≥ 5 cm), tumor recurrence and poor prognosis. Moreover, we identified 52 cases (58.4%) of IHCC patients with at least one CTA marker expression, and this subgroup displayed a higher frequency of larger tumor size and a shorter survival than the other cases. Furthermore, expression of at least one CTA marker was also an independent prognostic factor in patients with IHCC.

Conclusion

Our data suggest that specific immunotherapy targeted CTAs might be a novel treatment option for IHCC patients.     

A phase I and pharmacokinetic study of capecitabine in combination with radiotherapy in patients with localised inoperable pancreatic cancer

Background

Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors, and small biopsies may thus not accurately reveal the EGFR expression. In addition, EGFR expression may also change during chemotherapy. The current study investigates the magnitude of these two issues.

Materials and methods

EGFR expression in diagnostic biopsies and resection specimen was compared in 53 NSCLC patients stage T1-4N0-1M0 treated with surgery without preceding chemotherapy (OP group), and 65 NSCLC patients stage T1-3N0-2M0 (NAC group) treated with preoperative carboplatin and paclitaxel in order to evaluate the discordance of EGFR expression between samples.

Results

Discordance between tumors dichotomized according to EGFR expression (high: H-score ≥200; low: H-score <200) in diagnostic biopsies and immediate resection specimens was 25 % in the OP group and 33 % in the NAC group (p = 0.628). Five (9 %) of primary tumors in the OP group and 4 (13 %) in the NAC group had increased EGFR expression in the resection specimens as compared to the diagnostic biopsies (p = 0.583). A decrease in EGFR expression was observed in 6 (11 %) in the OP group and 7 (23 %) in the NAC group (p = 0.148).

Conclusion

EGFR expression in 25 % of diagnostic biopsies may potentially not be accurate compared to the prevailing pattern in the whole tumor based on the larger resection specimens. This may potentially be an obstacle for proper use of antibodies targeting the EGFR in NSCLC. EGFR expression does, however, not change significantly during paclitaxel and carboplatin and rebiopsies in order to decide on anti-EGFR antibody therapy following chemotherapy do not seem warranted.     

Predictive and prognostic value of early response assessment using 18FDG-PET in advanced non-small cell lung cancer patients treated with erlotinib

Background

[18F]fluorodeoxyglucose (FDG)-PET is being evaluated as a tool for the early detection of response to various targeted agents in solid tumors. The aim of this study was to evaluate the predictive value of PET response after 2 days of erlotinib in unselected pretrated patients with stage IV NSCLC.

Patients and methods

FDG-PET/CT scans were conducted at baseline and after 2 days of erlotinib, with a CT evaluation performed at baseline and after 45–60 days of therapy. PET responses were evaluated by quantitative changes on SUVmax tumor/non-tumor ratio and classified according to EORTC criteria. PET responses were compared with RECIST responses and related to progression-free (PFS) and overall (OS) survival. Erlotinib effects on glucose uptake were also studied in a panel of NSCLC cell lines.

Results

Fifty-three patients were enrolled. At 2 days of erlotinib, 20 (38 %) patients showed partial metabolic response (PMR), 25 (47 %) had stable metabolic disease (SMD) and 8 (15 %) had progressive metabolic disease (PMD). All patients with PMD had confirmed RECIST progression at 45–60 days. Patients with early PMR and SMD had significantly longer PFS (p < 0.001 and p = 0.001, respectively) and OS (p = 0.001 for both) than PMD patients.

Conclusions

FDG-PET assessment after 2 days of erlotinib could be useful to identify early resistent patients and to predict survival in unselected NSCLC pretreated population.     

Serum integrin-linked kinase (sILK) concentration and survival in non-small cell lung cancer: a pilot study

Background

Integrin-linked kinase (ILK) is an intracellular signaling protein critically involved in cellular growth and motility. In non-small cell lung cancer (NSCLC), increased ILK expression has been associated with decreased recurrence-free and overall survival. Recently, ILK has also been detected in the serum of NSCLC patients.

Objective

To assess the prognostic impact of preoperative serum ILK (sILK) concentration on overall survival in surgically amenable NSCLC.

Patients and methods

Preoperative sILK was quantified by ELISA in 50 newly diagnosed NSCLC patients. After surgery, patients were followed-up for a median interval of 2.5 years.

Results

Serum ILK concentrations ranged from 0 to 2.44 ng/ml. Mean sILK was around 2.3 times higher in the 16 patients who died as compared to the 34 patients who survived (1.04 vs. 0.45 ng/ml, p = 0.001). In univariate time-to-event analysis, increased sILK was associated with adverse survival [Hazard ratio (HR): 4.03, 95 % CI: 2.00–8.13, p < 0.001]. This association prevailed after multivariable adjustment for several clinical, demographic, and laboratory parameters (HR: 3.85, 95 % CI: 1.53–9.72, p = 0.004).

Conclusions

Serum ILK shows potential as a novel strong and independent prognostic marker for postoperative survival in surgically amenable NSCLC.     

Influence of DNA repair RAD51 gene variants in overall survival of non-small cell lung cancer patients treated with first line chemotherapy

Purpose

Lung cancer continues to be the most frequent cancer with approximately one million people worldwide dying of this disease each year. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. The RAD51 protein is the key protein for homologous recombination, an evolutionarily conserved mechanism for DNA damage repair and the generation of genetic diversity. We conducted this study in order to investigate the effect of the RAD51 G135C polymorphism in treatment response to combined platinum taxanes/gemcitabine first line chemotherapy in NSCLC patients.

Methods

We analysed RAD51 G135C polymorphism in 243 NSCLC patients using PCR–RFLP methodology.

Results

There were no statistically significant differences between the groups of NSCLC patients with the different genotypes regarding tumour stage (p = 0.232). Our results indicate that the mean survival rates were statistically different according to the patient’s genotypes. The group of patients carrying the C allele presented a higher mean survival rate than the other patients (56.0 months vs. 41.7 months; p = 0.024). Moreover, regarding smoking history, our results demonstrate that overall survival time differed significantly according to the patient’s genotypes in smoker and ex-smoker individuals (p = 0.034). No statistically significant differences were found in the genotype frequencies and overall survival rate among non-smoker NSCLC patients (p = 0.413).

Conclusions

This is the first study evaluating the effect of the RAD51 G135C polymorphism in NSCLC patient survival. Our results suggest that RAD51 genotypes could be useful molecular markers for predicting the clinical outcome of NSCLC patients.     

Differing effects of adjuvant chemotherapy according to BRCA1 nuclear expression in gastric cancer

Background

We aimed to investigate the role of BRCA1 nuclear expression in sporadic gastric cancer; currently, the role remains unknown.

Methods

Patients with gastric cancer who received curative operation with D2 dissection were enrolled in this study. Adjuvant chemotherapy was administered at the discretion of the physician. According to BRCA1 nuclear expression analysis by immunohistochemistry (IHC) on tissue microarrays using anti-BRCA1 antibody MS110, BRCA1 expression was classified as negative, low expression, and high expression.

Results

Among 318 cases, 155 cases (48.7 %) were identified as BRCA1-negative by IHC and 96 cases (30.2 %) revealed BRCA1 low expression, 67 cases (21.0 %) showed BRCA1 high expression. The negative or reduced expression of BRCA1 was more frequent in more advanced-stage disease (p < 0.001) and was associated with perineural invasion (p = 0.032). Disease-free survival (DFS) was significantly decreased with reduced BRCA1 expression (p = 0.027). This tendency was also observed in overall survival (OS), although the difference was not significant. The poorer prognosis of BRCA1-negative tumors was overcome through adjuvant chemotherapy. The benefit of adjuvant chemotherapy for DFS and OS in stage III was enhanced only in BRCA1-negative tumors (p < 0.001, p < 0.001, respectively), but not in BRCA1-positive tumors (p = 0.236, p = 0.148, respectively).

Conclusion

The reduction of BRCA1 nuclear expression is associated with advanced stage and perineural invasion. Moreover, negative BRCA1 nuclear expression is a predictive marker regarding the benefit of adjuvant chemotherapy in sporadic gastric cancer; these novel findings are of great importance, and further, larger studies are warranted.     

Longitudinal assessment of TUBB3 expression in non-small cell lung cancer patients

Introduction

Class-III-beta-tubulin (TUBB3) expression may be a potential predictive factor for treatment with microtubule interfering cytotoxic drugs in non-small cell lung cancer (NSCLC). Potential changes in TUBB3 expression during chemotherapy may be of interest if future choice of chemotherapy is to be based on TUBB3 expression. If the biomarker expression changes during chemotherapy, biopsies before initiation of chemotherapy beyond first line may be needed if treatment decision is to be based on TUBB3 expression. Thus, the aim was to explore TUBB3 expression heterogeneity and changes during chemotherapy.

Materials and methods

TUBB3 expression was investigated by immunohistochemistry performed on diagnostic biopsies and on available subsequent resection specimens in 65 NSCLC patients stage T1-3N0-2 who received neoadjuvant carboplatin and paclitaxel (NAC-group). Another group of 53 NSCLC patients stage T1-4N0-1 was treated with surgery alone without preceding chemotherapy (OP-group). Paired repeated samples were compared in order to evaluate for changes in TUBB3 expression.

Results

No statistically significant change in TUBB3 expression was observed between initial diagnostic biopsies and subsequent surgical resections of primary tumors in either the OP-group (p = 0.124) or the NAC-group (p = 0.414). When dichotomized into high and low TUBB3 expression, discordance between diagnostic biopsies and resection specimens of the primary tumors occurred in 22?% and 40 % in the OP-group and NAC-group, respectively (p = 0.169). Significantly more patients having low TUBB3 expression experienced down-staging during neoadjuvant chemotherapy compared to patients having high TUBB3 expression (p = 0.022).

Conclusion

A high degree of discordance of TUBB3 expression between paired repeated tumor samples was observed, which likely reflects intratumoral heterogeneity. This emphasizes a need for optimal tumor tissue samples in order to stratify patients based on TUBB3 expression. No significant changes in TUBB3 expression after neoadjuvant carboplatin and paclitaxel chemotherapy occurred, suggesting no need for rebiopsy in case second-line chemotherapy with microtubule interfering cytotoxic treatments is necessary.     

Clinical potential of the anticancer drug sensitivity test for patients with synchronous stage IV colorectal cancer

Purpose

We retrospectively evaluated the clinical efficacy and feasibility of a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) to guide therapy for patients with stage IV colorectal cancer (CRC).

Methods

We investigated 38 patients with stage IV CRC. All patients were younger than 85 years and had untreated evaluable metastatic lesions. The primary tumors were surgically resected, and the tissue samples were investigated by CD-DST. Patients treated with in vitro sensitive drugs were defined as Group A (n = 14), while those treated with in vitro non-sensitive drugs were defined as Group B (n = 24). We evaluated response rate (RR), progression-free survival (PFS), and overall survival (OS).

Results

RR was 85.71 % in Group A and 41.67 % in Group B (p = 0.0079). The median PFS was 696.5 days in Group A and 297.5 days in Group B (p = 0.0326). The median OS was 1,023.4 days in Group A and 518.5 days in Group B (p = 0.0061).

Conclusions

The CD-DST can define chemoresistant and chemosensitive tumors. The use of CD-DST might be one of the tools to supplement informed consent prior to initiation of therapy.     

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors

Background

Inhibitor of growth 4 (ING4) has deserved attention as a tumor suppressor gene in many malignant tumors. In our study, we investigated ING4 immunoexpression in gastrointestinal stromal tumors (GISTs) and its prognostic value.

Method

The expression of ING4 and Ki67 was investigated in 41 samples of various risk gastrointestinal stromal tumors by immunohistochemical technique. The associations of ING4 expression and clinicopathological parameters, and prognosis of the patients, were analyzed by multivariate Cox regression analysis.

Results

ING4 expression showed a decreased trend from lower-risk to high-risk gastrointestinal stromal tumors, and an opposite trend for Ki67 expression. In lower-risk tumors, it was found the expression level of ING4 was 78.95 % ± 27.90 % and that of Ki67 was 4.42 % ± 3.75 %. However, in high-risk tumors, the expression level of ING4 was 9.23 % ± 7.66 % and that of Ki67 was 18.50 % ± 9.09 %. There was a strongly negative correlation between the expression levels of ING4 and Ki67. A significant difference was observed in the expression of ING4 between invasion and non-invasion (p < 0.001). The expression of ING4 was markedly correlated with tumor size (p < 0.001), mitotic index (p < 0.001), tumor necrosis (p = 0.021), invasion (p < 0.001), recurrence and metastasis (p = 0.021), and mortality (p < 0.001).

Conclusion

The low expression level of ING4 protein was correlated with high-risk GISTs. ING4 might be involved in the progression of GISTs and inhibit its invasion. ING4 might be one of the prognostic indicators in GISTs.     

MET Gene Amplification and Overexpression in Chinese Non–Small-Cell Lung Cancer Patients Without EGFR Mutations

Background

The prevalence and clinical pathologic characteristics of MET amplification and overexpression in Chinese patients with non–small-cell lung cancer (NSCLC) remain unknown. In this multicenter study, we sought to reveal the frequency and clinical pathologic characteristics of MET amplification and to explore the predictive value of MET amplification and overexpression status in relation to survival in Chinese NSCLC patients.

MCAM expression is associated with poor prognosis in non-small cell lung cancer

Background

MCAM has been recently identified as a biomarker for epithelial–mesenchymal transition (EMT) and is potentially involved in metastasis of cancer. The current study aimed at investigating the expression of MCAM in non-small-cell lung cancer (NSCLC) and its clinico-pathological significance.

Methods

A follow-up analysis was performed on 118 patients with NSCLC resected by lobectomy or pneumectomy with systematic lymph node dissection. All patients were followed for 6–60 months. Immunostaining of tissue sections from primary tumors and their lymph node metastasis was performed and evaluated using monoclonal antibody against MCAM, E-cadherin, and vimentin. Correlations were investigated between MCAM immunostaining in primary tumors and E-cadherin, vimentin immunostaining, lymph node metastasis, and survival.

Results

MCAM protein expression was found in 46.61 % of squamous cell carcinomas and 37.47 % of adenocarcinomas; MCAM expression positively correlated with vimentin, but inversely with E-cadherin (both P values <0.05). There were significant correlations between the MCAM immunostaining score in primary tumors and in their lymph node metastasis (P = 0.03). According to the Kaplan–Meier survival estimate, the level of MCAM expression in primary tumors was a statistically significant prognostic factor (P < 0.05).

Conclusions

MCAM expression in surgically treated NSCLC is clearly associated with lymph node metastasis and poor prognosis.     

A novel approach to simultaneously scan genes at fragile sites

Background

Previous studies indicate that alterations in Human Leukocyte Antigen (HLA) class I expression are frequent in colorectal tumors. This would suggest serious limitations for immunotherapy-based strategies involving T-cell recognition. Distinct patterns of HLA surface expression might conceal different immune escape mechanisms employed by the tumors and are worth further study.

Method

We applied four-color multiparameter flow cytometry (FCM), using a large panel of alloantigen-specific anti-HLA-A and -B monoclonal antibodies, to study membranous expression of individual HLA alleles in freshly isolated colorectal cancer cell suspensions from 21 patients.

Results

Alterations in HLA class I phenotype were observed in 8 (38%) of the 21 tumors and comprised loss of a single A or B alleles in 4 cases, and loss of all four A and B alleles in the other 4 cases. Seven of these 8 tumors were located on the right side of the colon, and those showing loss of both HLA-A and -B membranous expression were all of the MSI-H phenotype.

Conclusion

FCM allows the discrimination of complex phenotypes related to the expression of HLA class I. The different patterns of HLA class I expression might underlie different tumor behavior and influence the success rate of immunotherapy.     

Predictive value of APE1, BRCA1, ERCC1 and TUBB3 expression in patients with advanced non-small cell lung cancer (NSCLC) receiving first-line platinum–paclitaxel chemotherapy

Purpose

Drug resistance is not only one of the major obstacles to treatment but also a poor prognosis in advanced non-small cell lung cancer (NSCLC) patients. The aim of this study was to evaluate the predictive value of APE1, BRCA1, ERCC1 and TUBB3 in advanced NSCLC patients who received platinum–paclitaxel treatment.

Methods

One hundred and thirty-six advanced NSCLC patients, who were treated with first-line platinum–paclitaxel chemotherapy, were enrolled in this study. The protein expression levels of APE1, BRCA1, ERCC1 and TUBB3 were assessed by immunohistochemistry and analyzed for the association with response to chemotherapy and progression-free survival (PFS) and overall survival (OS).

Results

Patients with negative expression of APE1, ERCC1 or TUBB3 benefited from platinum plus paclitaxel regimen chemotherapy. ERCC1-negative patients had better PFS (P = 0.016) and OS (P = 0.030) compared with positive patients. Similarly, the APE1-negative patients showed better PFS (P = 0.004) and longer OS though statistically insignificant. Multivariate analysis showed that APE1 and ERCC1 were independent predictor for PFS (HR 2.07; P = 0.004 and HR 1.66; P = 0.016) and OS (HR 1.99; P = 0.008 and HR 1.64; P = 0.040). Moreover, patients with both APE1- and ERCC1-negative or both APE1- and TUBB3-negative tumors had significantly higher response rate, longer median PFS and OS following treatment with platinum and paclitaxel (P < 0.05).

Conclusion

The data indicate that APE1, ERCC1 and TUBB3 could be a useful biomarker to predict clinical outcome in patients with advanced NSCLC receiving first-line platinum–paclitaxel chemotherapy.     

Concurrent radiotherapy plus epidermal growth factor receptor inhibitors in patients with human papillomavirus-related head and neck cancer

Purpose

Concurrent radio-chemotherapy (RT-CT) is the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), but RT plus epidermal growth factor receptor (EGFR) inhibitors is an effective option when CT is not appropriate. Human papillomavirus (HPV) is associated with an improved prognosis in LA-HNSCC; however, it has not been fully studied as a prognostic factor after RT + EGFR inhibitors.

Experimental design

Immunohistochemical expression of p16INK4A and PCR of HPV16 DNA were retrospectively analyzed in tumor blocks from 52 stage III/IV LA-HNSCC patients treated with RT + EGFR inhibitors. Disease-free survival (DFS) and overall survival (OS) were analyzed by the Kaplan–Meier method.

Results

DNA of HPV16 was found in six of 52 tumors (12 %) and p16 positivity in eight tumors (15 %). After a median follow-up time of 45 months (6–110), p16-positive patients treated with RT + EGFR inhibitors showed an improved DFS (2-year DFS 75 vs. 44 %, HR 0.25, 95 % CI 0.06–0.99, p = 0.047) compared with p16-negative patients. These differences were outperformed when compared by HPV16 status (2-year OS rates of 83 vs. 58 %, HR 0.17, 95 % CI 0.02–0.99, p = 0.049 and 2-year DFS rates of 83 vs. 45 %, HR 0.17, 95 % CI 0.02–0.99, p = 0.049). In the Cox regression analysis with OS as the end point, ECOG 0–1 was the only prognostic factor independently associated with a good prognosis in the multivariable analysis.

Conclusion

In this study, p16/HPV16-positive patients with LA-HNSCC treated with RT + EGFR inhibitors showed a better survival, not confirmed in multivariate analysis.     

Reduced-dose docetaxel for castration-resistant prostate cancer has no inferior impact on overall survival in Japanese patients

Background

In clinical practice, an adapted regimen with dose reduction is applied to castration-resistant prostate cancer (CRPC) treated with docetaxel because of its toxicity. However, there are few reports on the impact of dose reduction on survival.

Methods

Fifty-seven patients with CRPC treated with first-line docetaxel in a single institution from 2005 to 2008 were evaluated retrospectively.

Results

The median follow-up period was 20.5 months. Twenty-eight patients (49 %) received a standard 60 mg/m² regimen (SR), and 29 patients (51 %) received an adapted regimen (AR) with dose reduction. There was no difference in their baseline characteristics. The prostate-specific antigen response rates were not significantly different between the SR and AR groups (50 vs. 62 %, p = 0.36). Progression-free survival (PFS) and overall survival (OS) were also not significantly different between the groups (PFS 5.3 vs. 7.3 months, p = 0.39; OS 26.4 vs. 27.1 months, p = 0.53, respectively). No significant difference in the incidence of grade 3 or 4 adverse events was noted between the groups (89 vs. 83 %, p = 0.70). In multivariate analysis, hemoglobin and alkaline phosphatase were significant predictive factors for OS (hazard ratios 2.81 and 2.39, p = 0.012 and 0.024, respectively).

Conclusions

A reduced-dose regimen of docetaxel has no inferior impact on OS. Further studies on the optimal dose of docetaxel for Japanese patients are required.     

Polymorphisms in HIF-1alpha affect presence of lymph node metastasis and can influence tumor size in squamous-cell carcinoma of the glottic larynx

Background

HIF-1alpha plays a key role in the development and progression of cancer. Its polymorphic variants C1772T and G1790A have been associated with greater susceptibility to cancer and increased tumor progression.

Methods

We determined the distribution of these polymorphisms among 121 patients with glottic cancer and 154 healthy volunteers by PCR–RFLP. We also analyzed the relationship between the presence of these polymorphisms and various clinicopathologic variables.

Results

Advanced tumors (T3–T4) were associated with the TT variant (p = 0.036), which was present in 75 % of T4 tumors (p = 0.008). Among patients with nodal metastasis (N+), 41.7 and 22 % were carrying the TT and GA variants, respectively, compared with 9.4 and 2 % of the patients with no metastasis (N0), (p = 0.006 and p = 0.032).

Conclusions

The presence of the TT and GA variants were associated with lymph node metastasis, while the presence of the TT variant can be associated with larger tumor size.     

Oropharyngeal cancer related to Human Papilloma Virus: incidence and prognosis in Madrid,Spain

Purpose

To report the incidence of HPV-related oropharyngeal cancer (OC) in our region, and determine the influence of HPV status on survival among patients treated with chemoradiation (CRT).

Methods

A total of 102 patients with stage II–IV OC treated by CRT at four hospitals in Madrid, Spain were retrospectively reviewed. Immunohistochemistry analysis was performed to evaluate p16 expression in pretreatment tumor block samples obtained from these patients. HPV-positive and HPV-negative patients were compared to assess differences in overall survival (OS), loco-regional control and disease-free survival.

Results

Of the tumor samples evaluated, 26.7 % were p16 positive. HPV-positive patients were younger (median age, 56 vs 59 years; p = 0.052). No significant differences were observed in terms of tumor stage, gender, or smoking habit between HPV+ and HPV? patients. HPV+ patients showed a trend towards better OS (67.4, vs 49.7 %; hazard ratio, 0.55; p = 0.095).

Conclusions

Incidence of HPV-related OC in our region is similar to that reported in other regions in Europe, yet lower than in North America. We observed a trend for improved OS in patients with HPV+ oropharyngeal cancer.