Significance of ERCC1 and Hormonal Receptor Expression in Ovarian Cancer.

Background & Objectives : Ovarian carcinoma usually has a relatively poor prognosis. A rational approach to identify patients, who are likely to benefit from therapy, is urgently needed. Excision repair cross-complementation group 1 enzyme (ERCC1) has been proposed as a molecular predictor of clinical resistance to platinum-based chemotherapy. Steroid hormone receptors are important determinants of prognosis and predictive behavior in tumor tissues of several origins. The present study aimed to investigate the expression profile of ERCC1, ER & AR in patients with Ovarian carcinoma and their association with patient outcome. Methods : This is a prospective study which included 77 patients with ovarian carcinoma who were treated with platinum based chemotherapy at the National Cancer Institute (NCI) in Egypt during the period 7/2016- 7/2018. We evaluated the expression of ER, AR, and Excision repair cross-complementation group 1 enzyme (ERCC1) by immunohistochemistry. Expression profiles were compared to clinical, histologic and prognostic factors, the clinical outcome and survival. All patients received platinum containing chemotherapy regimen. Result : Of the 77 patients with ovarian cancer, 66.2 % (51/77) were ERCC1-positive, 49.4 % (38/77) were AR positive & 75.3 % (58/77) were ER positive. Platinum resistance was found in eight of the tumors with positive ERCC1 protein expression compared with two among the patients with negative tumor staining for ERCC1 (P = 0.643). There was significant association between ER & AR expression and pathological subtypes (p = 0.004, 0.007) respectively. There were no significant association between ER, AR& ERCC1 expression and PFS (P = 0.447,P = 0.162, P = 0.508 respectively) or OS (P = 0.781, P = 0.569, P = 0.381 respectively). Based on Cox proportional hazards regression analysis ERCC1, ER &AR were not independent factors affecting the prognosis of patients with ovarian carcinoma. Conclusion : These results demonstrate that positive ERCC1 expression is not associated with clinical resistance to platinum-based chemotherapy, ERCC1, AR& ER expression are not independent factors affecting the prognosis of patients with epithelial ovarian tumors and not associated with survival benefits. J. Med. Invest. 67 : 391-398, August, 2020.

Diagnostic and Prognostic Potential of Biomarkers CYFRA 21.1, ERCC1, p53, FGFR3 and TATI in Bladder Cancers.

The high occurrence of bladder cancer and its tendency to recur in combination with a lifelong surveillance make the treatment of superficial bladder cancer one of the most expensive and time-consuming. Moreover, carcinoma in situ often leads to muscle invasion with an unfavorable prognosis. Currently, invasive methods including cystoscopy and cytology remain a gold standard. The aim of this study was to explore urine-based biomarkers to find the one with the best specificity and sensitivity, which would allow optimizing the treatment plan. In this review, we sum up the current knowledge about Cytokeratin fragments (CYFRA 21.1), Excision Repair Cross-Complementation 1 (ERCC1), Tumour Protein p53 (Tp53), Fibroblast Growth Factor Receptor 3 (FGFR3), Tumor-Associated Trypsin Inhibitor (TATI) and their potential applications in clinical practice.

ERCC1 expression in advanced colorectal cancer and matched liver metastases.

BACKGROUND: Platinum-based chemotherapy is part of the standard treatment for patients with colorectal cancer. ERCC1 is a potential predictive biomarker for platinum-based chemotherapy. The aim of this study was to examine interobserver agreement on ERCC1 protein expression in primary colorectal cancer as well as corresponding liver metastasis. Furthermore, comparison of ERCC1-expression in primary tumor and the corresponding liver metastasis was performed. METHODS: Forty patients with primary colorectal cancers and corresponding liver metastases were included. One slide was stained with the anti-ERCC1 antibody, 4F9 clone (DAKO) and evaluated by two gastrointestinal pathology consultants and a pathology registrar separately. Interobserver agreement was evaluated for primary tumors and liver metastases using kappa (κ) statistics. Discordant scorings were reviewed, and consensus was obtained. The expression in primary tumor was compared with the corresponding liver metastases. RESULTS: For the primary tumors agreement was found in 85% of the tumors corresponding to an unweighted kappa value of 0,79 (95% CI 0,64-0,94). For the liver metastases agreement was found in 76% corresponding to an unweighted kappa value of 0,64 (95% CI 0,49-0,79). When comparing primary tumors to the corresponding metastases, no concordance in ERCC1-expression was observed. CONCLUSION: Interobserver agreement of ERCC1 expression was good for both primary tumors and liver metastases, which is crucial for a potential predictive biomarker. As no concordance between primary tumor and liver metastases was found it seems to be of high importance to use tissue from actual tumor burden for evaluation of ERCC1 expression. Further studies and correlation to clinical outcome are warranted.

Predictive Value of ERCC1, ERCC2, and XRCC Expression for Patients with Locally Advanced or Metastatic Gastric Cancer Treated with Neoadjuvant mFOLFOX-4 Chemotherapy.

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant mFOLFOX-4 chemotherapy were enrolled between January 2009 and January 2018. We analyzed clinicopathological features and ERCC1, ERCC2, and XRCC1 expression to identify potential predictors of clinical response. Among the 58 patients, 16 (27.6%) were categorized into the response group (partial response) and 42 into the nonresponse group (stable disease in 24 patients and progressive disease in 18 patients). A multivariate analysis showed that ERCC1 overexpression (P = 0.003), ERCC2 overexpression (P = 0.049), and either ERCC1 or ERCC2 overexpression (P = 0.002) were independent predictors of response following mFOLFOX-4 neoadjuvant chemotherapy. Additionally, ERCC1 and ERCC2 overexpression did not only predict the response but also progression-free survival (both P < 0.05) and overall survival (both P < 0.05). ERCC1 and ERCC2 overexpression are promising predictive biomarkers for patients with locally advanced or metastatic GC receiving neoadjuvant mFOLFOX-4 chemotherapy and the potential clinical implication is mandatory for further investigation.

The thioredoxin-mediated recycling of Arabidopsis thaliana GRXS16 relies on a conserved C-terminal cysteine.

BACKGROUND: Glutaredoxins (GRXs) are oxidoreductases involved in diverse cellular processes through their capacity to reduce glutathionylated proteins and/or to coordinate iron­sulfur (Fe-S) clusters. Among class II GRXs, the plant-specific GRXS16 is a bimodular protein formed by an N-terminal endonuclease domain fused to a GRX domain containing a 158CGFS signature. METHODS: The biochemical properties (redox activity, sensitivity to oxidation, pKa of cysteine residues, midpoint redox potential) of Arabidopsis thaliana GRXS16 were investigated by coupling oxidative treatments to alkylation shift assays, activity measurements and mass spectrometry analyses. RESULTS: Activity measurements using redox-sensitive GFP2 (roGFP2) as target protein did not reveal any significant glutathione-dependent reductase activity of A. thaliana GRXS16 whereas it was able to catalyze the oxidation of roGFP2 in the presence of glutathione disulfide. Accordingly, Arabidopsis GRXS16 reacted efficiently with oxidized forms of glutathione, leading to the formation of an intramolecular disulfide between Cys158 and the semi-conserved Cys215, which has a midpoint redox potential of - 298 mV at pH 7.0 and is reduced by plastidial thioredoxins (TRXs) but not GSH. By promoting the formation of this disulfide, Cys215 modulates GRXS16 oxidoreductase activity. CONCLUSION: The reduction of AtGRXS16, which is mandatory for its oxidoreductase activity and the binding of Fe-S clusters, depends on light through the plastidial FTR/TRX system. Hence, disulfide formation may constitute a redox switch mechanism controlling GRXS16 function in response to day/night transition or oxidizing conditions. GENERAL SIGNIFICANCE: From the in vitro data obtained with roGFP2, one can postulate that GRXS16 would mediate protein glutathionylation/oxidation in plastids but not their deglutathionylation.

Predictive value of excision repair cross- complementation group 1 expression in locoregionally advanced nasopharyngeal carcinoma receiving cisplatin-based concurrent chemoradiotherapy.

BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is recommended for nasopharyngeal carcinoma (NPC) at advanced stages. Excision repair cross-complementation group 1 (ERCC1) plays an important function in the repair of DNA damage that is a critical process of chemo- and radiotherapy. OBJECTIVE: This study aimed to investigate the clinical significance of ERCC1 expression in NPC treated with cisplatin-based concurrent chemoradiotherapy in locoregionally advanced NPC. METHODS: The expression level of ERCC1 and its association with clinicopathological characteristics in 205 locoregionally advanced NPC patients receiving cisplatin-based concurrent chemoradiotherapy were analyzed retrospectively. RESULTS: The correlation analysis revealed that the treatment-sensitive patients displayed dramatically lower ERCC1 expression than treatment-resistant cases did. Furthermore, the Kaplan-Meier plots revealed lower ERCC1 expression was significantly associated with better survival. Multivariate analysis further showed that the ERCC1 expression was an independent predictor of NPC patients' survival. CONCLUSIONS: ERCC1 expression might be a useful predictive marker in patients with locoregionally advanced NPC receiving cisplatin-based concurrent chemoradiotherapy.

ERCC1 as predictive biomarker to platinum-based chemotherapy in adrenocortical carcinomas.

OBJECTIVE: Platinum-based chemotherapy (PBC) is the most effective cytotoxic treatment for advanced adrenocortical carcinoma (ACC). Excision repair cross complementing group 1 (ERCC1) plays a critical role in the repair of platinum-induced DNA damage. Two studies investigating the role of ERCC1 immunostaining as a predictive marker for the response to PBC in ACC had reported conflicting results. Both studies used the ERCC1-antibody clone 8F1 that later turned out to be not specific. The aim of this study was to evaluate the predictive role of ERCC1 with a new specific antibody in a larger series of ACC. DESIGN AND METHODS: 146 ACC patients with available FFPE slides were investigated. All patients underwent PBC (median cycles = 6), including cisplatin (n = 131) or carboplatin (n = 15), in most cases combined with etoposide (n = 144), doxorubicin (n = 131) and mitotane (n = 131). Immunostaining was performed with the novel ERCC1-antibody clone 4F9. The relationship between ERCC1 expression and clinicopathological parameters, as well as best objective response to therapy and progression-free survival (PFS) during PBC was evaluated. RESULTS: High ERCC1 expression was observed in 66% of ACC samples. During PBC, 43 patients experienced objective response (29.5%), 49 stable disease (33.6%), 8 mixed response (5.5%) and 46 progressive disease (31.5%) without any relationship with the ERCC1 immunostaining. No significant correlation was also found between ERCC1 expression and progression-free survival (median 6.5 vs 6 months, P = 0.33, HR = 1.23, 95% CI = 0.82-2.0). CONCLUSION: ERCC1 expression is not directly associated with sensitivity to PBC in ACC. Thus, other predictive biomarkers are required to support treatment decisions in patients with ACC.

Prognostic implication of ERCC1 protein expression in resected oropharynx and oral cavity cancer.

BACKGROUND: Excision repair cross complement group 1 (ERCC1) expression is a predictive biomarker for platinum-containing treatment in squamous cell carcinoma of head and neck (SCCHN). However, the prognostic significance after surgical resection is not well understood. METHODS: Oropharynx (n=143) or oral cavity (n=61) SCCHN patients undergoing surgery were included. ERCC1 protein expression and HPV status were assessed by ERCC1 and p16 immunohistochemistry. RESULTS: The ERCC1, over-expressed in 66.7% of patients, was associated with oral cavity cancer (P<0.001), well differentiation (P=0.036), and HPV negativity (P<0.001). In TCGA database, ERCC1 mRNA upregulation was enriched in HPV-negative and oral cavity cancers, and associated with HRAS mutation (P<0.001). The prognostic role of ERCC1 was not different according to HPV status. High ERCC1 expression showed a trend toward poor prognosis in patients with an advanced stage (P=0.079) with marginal significance. CONCLUSIONS: The ERCC1 expression was not prognostic in surgically resected oropharynx/oral cavity SCCHN, irrespective of HPV status. However, it could provide additional prognostic information for advanced stage patients.

XPG genetic polymorphisms and clinical outcome of patients with advanced non-small cell lung cancer under platinum-based treatment: a meta-analysis of 12 studies.

PURPOSE: A number of studies on the relationship between xeroderma pigmentosum group G (XPG) polymorphisms and clinical outcomes in non-small cell cancer (NSCLC) have led to inconclusive results. This meta-analysis evaluates the predictive value of XPG polymorphisms on the treatment response rate and overall survival of patients with NSCLC. METHODS: To measure the correlative strength of the relationship between XPG polymorphisms and outcomes of patients with NSCLC, we searched electronic databases, including PubMed and China National Knowledge Infrastructure, to retrieve studies up to August 2016. We also employed pooled odds ratios (ORs) and hazard ratios (HRs) corresponding to 95% confidence intervals (95% CIs). RESULTS: Twelve studies involving 2877 patients with NSCLC were included: 8 studies involving 1473 patients examined the correlation between XPG polymorphisms and tumor response rate and 7 studies involving 2329 patients reported on the correlation of XPG polymorphisms with overall survival. None of the XPG His1104Asp(C>G)/His46His(C>T) polymorphisms exhibited a correlation with treatment response rate or overall survival. However, in a further stratified analysis by ethnicity, carriers of the 1104G allele were associated with good response among Asians in the homozygote model (GG vs. CC: OR = 1.57, 95% CI: 1.05-2.34, P = 0.027). Meanwhile, further stratified by ethnicity, His46His polymorphism was not associated with RR and OS in any genetic models. CONCLUSIONS: No strong evidence was found to support the use of XPG polymorphisms as tumor response and prognostic factors of patients with NSCLC receiving a platinum-based treatment regimen, which is attributed to marginal association. Studies with large-scale and multiple ethnicities need to be conducted to verify the conclusion.

A phase II single institution single arm prospective study with paclitaxel, ifosfamide and cisplatin (TIP) as first-line chemotherapy in high-risk germ cell tumor patients with more than ten years follow-up and retrospective correlation with ERCC1, Topoisomerase 1, 2A, p53 and HER-2 expression.

PURPOSE: One half of high-risk germ cell tumor (HRGCT) patients relapse after standard chemotherapy. This phase II study evaluated prospectively the toxicity and efficacy in first-line of the paclitaxel-ifosfamide-cisplatin combination (TIP) in HRGCT patients and tried to identify biomarkers that may allow patient-tailored treatments. METHODS: Between October 1997- September 2000, 28 chemo-naive HRGCT patients were enrolled. Patients received 4 cycles of TIP (paclitaxel 175 mg/m(2) day 1/; ifosfamide 1.2 g/m(2)/day, days 1-5; Mesna 1.2 g/m(2)/day, days 1-5; and cisplatin 20 mg/m(2)/day, days 1-5 every 3 weeks). A non-randomized comparison was made between HRGCT patients treated in the same period with first-line TIP and bleomycin-etoposide-cisplatin (BEP) (28 patients vs 20). In 17 HRGCT patients treated between 1998-2006, ERCC1, Topoisomerase 1 and 2A, p53 and HER-2 expression was retrospectively analysed by immunohistochemistry (IHC) (7 patients with TIP, 10 with BEP), and correlations were made with response to chemotherapy and survival. RESULTS: With a median follow-up of 72 months [range 48+...89+], 5-year disease free survival (DFS) was 55%, with 95% CI 36-72, and the overall survival (OS) was 63%, with 95% CI 44-78. In June 2015, with a median follow-up of 196.47 months (range 177.30-209.27) (>15 years), 12 [%?] patients were alive and disease-free, and 16 [%?] had died (12 specific causes). There was no significant correlation between the expression of ERCC1, Topoisomerase 1 and 2A, HER-2 and p53 and response to treatment. CONCLUSION: Long-term follow-up showed no difference in OS between TIP vs BEP as first-line therapy. Both regimens had mild toxicity.

Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Trabectedin is a promising antitumour agent for synovial sarcoma.

Synovial sarcoma (SS) is an aggressive soft tissue tumour with poor prognosis. Using five human SS cell lines, we examined the cytotoxic effects of trabectedin (ET-743; Yondelis(®)), a novel marine natural product, which was approved in Europe for the treatment of soft tissue sarcomas (STS). The significant growth inhibitory effects were observed in all SS cell lines below nanomolar concentration of trabectedin. Furthermore, trabectedin significantly suppressed the tumour growth in xenograft models. Flow cytometer analysis in vitro and immunohistochemical analysis in vivo revealed its effect of cell cycle inhibition and apoptosis induction. We also examined the expression of ERCC1, 5 and BRCA1 in SS cell lines and clinical samples, and majority of them showed highly trabectedin-sensitive pattern as previously reported in other cancers. Our preclinical data indicated that trabectedin could be a promising therapeutic option for patients with SS.

Prognostic role of excision repair cross complementing-1 and topoisomerase-1 expression in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer is the most lethal gynecologic cancer worldwide and chemoresistance is one of the major causes of treatment failure. We investigated whether ERCC1, TAU, TOPO2A, TOPO1, P53, and C-MYC expression could be used as predictors for treatment outcomes. MATERIALS AND METHODS: Immunohistochemical staining was used to examine the expression of these biomarkers in resected tumor specimens from 38 patients treated in our institute. Clinicopathological data including demographics, staging, histological type, treatment response, expression of the biomarkers, and patient outcomes were analyzed. RESULTS: The median follow-up period was 47.5 months (range, 10-135 months) and the median overall survival was 56.0 months. Patients who did not have expression of ERCC1, and those who had expression of TOPO1 had significantly better overall survival. Cox regression analysis also confirmed that these two biomarkers were significant independent factors predicting survival (ERCC1, hazard ratio 5.51, 95% confidence interval: 2.02-14.00, p = 0.001; TOPO1, hazard ratio 0.22, 95% confidence interval: 0.06-0.77, p = 0.017). CONCLUSION: We concluded that poor overall survival was significantly associated with positive ERCC1 and negative TOPO1 expression. The results might be the consequence of chemoresistance to platinum and camptothecins, both of which are commonly used regimens in the treatment of epithelial ovarian cancer.

Excision Repair Cross-complementation Group 1 is a Prognostic Biomarker in Patients with Colorectal Cancer Receiving Chemotherapy.

BACKGROUND: Conflicting results about the association between expression level of excision repair cross-complementation group 1 (ERCC1) and clinical outcome in patients with colorectal cancer (CRC) receiving chemotherapy have been reported. Thus, we searched the available articles and performed the meta-analysis to elucidate the prognostic role of ERCC1 expression in patients with CRC. METHODS: A thorough literature search using PubMed (Medline), Embase, Cochrane Library, Web of Science databases, and Chinese Science Citation Database was conducted to obtain the relevant studies. Pooled hazard ratios (HR s) or odds ratios (OR s) with 95% confidence intervals (CI s) were calculated to estimate the results. RESULTS: A total of 11 studies were finally enrolled in this meta-analysis. Compared with patients with lower ERCC1 expression, patients with higher ERCC1 expression tended to have unfavorable overall survival (OS) (HR = 2.325, 95% CI: 1.720-3.143, P < 0.001), progression-free survival (PFS) (HR = 1.917, 95% CI: 1.366-2.691, P < 0.001) and poor response to chemotherapy (OR = 0.491, 95% CI: 0.243-0.990, P = 0.047). Subgroup analyses by treatment setting, ethnicity, HR extraction, detection methods, survival analysis, and study design demonstrated that our results were robust. CONCLUSIONS: ERCC1 expression may be taken as an effective prognostic factor predicting the response to chemotherapy, OS, and PFS. Further studies with better study design and longer follow-up are warranted in order to gain a deeper understanding of ERCC1's prognostic value.

Problems of variable biomarker evaluation in stratified medicine research--A case study of ERCC1 in non-small-cell lung cancer.

OBJECTIVES: Consistency of procedures for the evaluation of a predictive biomarker (including sample collection, processing, assay and scoring system) based on adequate evidence is necessary to implement research findings in clinical practice. As a case study we evaluated how a particular predictive biomarker, ERCC1, was assessed in research on platinum-based chemotherapy in non-small-cell lung cancer and what motivated the choice of procedure. MATERIALS AND METHODS: A systematic review of studies completed since 2007 and ongoing was undertaken. Questionnaires on details of ERCC1 evaluation procedures and the rationale for their choice were sent to contacts of identified studies. RESULTS: Thirty-three studies of platinum-based chemotherapy in non-small-cell lung cancer using ERCC1 were identified. A reply to the questionnaire was received for 16 studies. Procedures for ERCC1 evaluation varied substantially and included reverse transcriptase quantitative polymerase chain reaction (nine studies), immunohistochemistry (five studies) and other methods (multiple methods-two studies, NER polymorphism-one study). In five studies ERCC1 use was planned, but not undertaken. In nine data was insufficient to identify the procedure. For each assay there was variation across studies in the details of the laboratory techniques, scoring systems and methods for obtaining samples. CONCLUSIONS: We found large variation across studies in ERCC1 evaluation procedures. This will limit the future comparability of results between these different studies. To enable evidence-based clinical practice, consensus is needed on a validated procedure to assess a predictive biomarker in the early phase of research. We believe that ERCC1 is not untypical of biomarkers being investigated for stratified medicine.

Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer.

INTRODUCTION: Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. PATIENTS AND METHODS: ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient's disease-free survival was assessed. RESULTS: We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. CONCLUSION: Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.

Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer.

PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.