Predictive Factors Of Resistance Research Articles

A new sensitive and fast assay for the detection of EGFR mutations in liquid biopsies.

A major perspective for the use of circulating tumor DNA (ctDNA) in the clinical setting of non-small cell lung cancer (NSCLC) is expected as predictive factor for resistance and response to EGFR TKI therapy and, especially, as a non-invasive alternative to tissue biopsy. However, ctDNA is both highly fragmented and mostly low concentrated in plasma and serum. On this basis, it is important to use a platform characterized by high sensitivity and linear performance in the low concentration range. This motivated us to evaluate the newly developed and commercially available SensiScreen® EGFR Liquid assay platform (PentaBase) with regard to sensitivity, linearity, repeatability and accuracy and finally to compare it to our already implemented methods. The validation was made in three independent European laboratories using two cohorts on a total of 68 unique liquid biopsies. Using artificial samples containing 1600 copies of WT DNA spiked with 50% - 0.1% of mutant copies across a seven-log dilution scale, we assessed the sensitivity, linearity, repeatability and accuracy for the p.T790M, p.L858R and exon 19 deletion assays of the SensiScreen® EGFR Liquid assay platform. The lowest value detectable ranged from 0.5% to 0.1% with R2≥0,97 indicating good linearity. High PCR efficiency was shown for all three assays. In 102 single PCRs each containing theoretical one copy of the mutant at initiating, assays showed repeatable positivity in 75.5% - 80.4% of reactions. At low ctDNA levels, as in plasma, the SensiScreen® EGFR Liquid assay platform showed better sensitivity than the Therascreen® EGFR platform (Qiagen) and equal performance to the ctEGFR Mutation Detection Kit (EntroGen) and the IOT® Oncomine cell-free nucleic acids assay (Thermo Fisher Scientific) with 100% concordance at the sequence level. For profiling clinical plasma samples, characterized by low ctDNA abundance, the SensiScreen® EGFR Liquid assay is able to identify down to 1 copy of mutant alleles and with its high sensitivity, linearity and accuracy it may be a competitive platform of choice.

Predictive value of KRAS mutation and excision repair cross-complementing 1 (ERCC1) protein overexpression in patients with colorectal cancer administered FOLFOX regimen

BackgroundRecent studies have reported that KRAS mutational status is correlated with ERCC1 expression level. The purpose of this study was to determine the clinical significance of the KRAS mutation and ERCC1 overexpression status as predictive factors for resistance against oxaliplatin-based treatment. MethodsWe retrospectively analyzed clinicopathologic features, KRAS mutation status, and ERCC1 overexpression status in 386 patients with colorectal cancer (CRC) who underwent curative-intent surgery. Of these patients, 84 were administered the FOLFOX regimen as a first-line or adjuvant treatment. Disease-free survival and overall survival in groups separated by KRAS and ERCC1 statuses were analyzed. ResultsWild-type KRAS and ERCC1 overexpression were observed in 25.5% of all patients. Among the 84 patients who were treated with the FOLFOX regimen, 73 patients were evaluated for KRAS and ERCC1 status. There were no significant differences in disease-free survival or overall survival in groups separated by KRAS mutation and ERCC1 expression status. Subgroup analysis of patients with wild-type KRAS showed that overall survival in the ERCC1 overexpression group was lower than that of patients in the ERCC1 underexpression group (p = 0.029); however, no significant difference was found in the mutant KRAS patient group (p = 0.671). ConclusionsOur results suggest that CRC with wild-type KRAS and ERCC1 overexpression might be associated with oxaliplatin resistance. When considering oxaliplatin-based chemotherapy, the status of both KRAS mutation and ERCC1 overexpression should be evaluated.

Abstract P6-10-22: miR363-3p mediates maintenance of breast cancer stem cells (BCSCs) and predicts resistance to neoadjuvant chemotherapy and disease recurrence

Abstract Background Increasing data support the role of BCSCs in recurrence and resistance to chemotherapy. However, detecting these cells specifically and targeting them therapeutically remain challenging. We set to identify miRNAs involved in chemoresistance of BCSCs in vitro and the results were assessed in the sera of healthy donors and breast cancer patients treated with neoadjuvant chemotherapy (NAC). Methods In vitro experiments were conducted in the MCF7 cell line grown as mammospheres (MS) in order to enrich a BCSC phenotype. After treatment with 5FU or Paclitaxel (Pac), microRNA profile of chemoresistant cells was analyzed by microarray. The results were compared to miRNAs found in immortalized non-tumorigenic MCF10A cells in order to exclude miRNAs related to normal stem cells. A signature of 6 miRNAs was identified. miR-363-3p, appearing the most relevant, was chosen for further assessment. By RT-qPCR, miR363-3p levels were 20- and 100-fold higher in ALDH+ sorted cells compared to ALDH- MCF7 and MDA-MB-231 cells, respectively. Moreover, overexpression of miR363-3p in MCF7 cells correlated with an increased number of ALDH+ cells and 1.5 more MS formed. In contrast, downregulation of miR363-3p levels induced a decrease in MS size and 2-fold reduction in number. Consistently, miR-363-3p downregulation decreased tumor growth and metastasis of MCF7 cells in an intraductal human-in-mice transplantation model. miRNA was quantified by RT-qPCR in tissue and sera collected prospectively from 40 breast cancer patients before and after NAC (anthracycline-taxane) and also from 25 healthy donors. Results Fifty percent of the patients had luminal A and B tumors (n=20), 32,5% (n=13) had triple negative breast cancer (TNBC), and 17.5% (n=7) had HER2 positive BC. Excluding one patient, who refused the surgical resection, 40% achieved pathological complete response (pCR). Six patients presented disease recurrence. In patients’ tumor before and after NAC, a higher level of miR363-3p was observed compared with benign tissue. In sera of the BC patients, miR363-3p levels were significantly higher than that of healthy donors. After NAC, the levels of miR363-3p remained high among patients who relapsed, whereas they were equivalent to the healthy donors in patients who remained in remission. No correlation between Ki-67, grade 1 or 2 and miR363-3p levels was observed. However, in grade 3 BC, low level of miR363-3p before and after NAC was correlated with pCR and remission. The level of miR363-3p correlated with remission and pCR in patients with TNBC and HER2 BC. Conclusions Assessment in the sera of patients and healthy donors confirms our previous data supporting the role of miR363-3p as predictive factor of resistance to neoadjuvant chemotherapy and disease recurrence. Further investigations are warranted to confirm the role of miR363-3p as a biomarker and potential therapeutic target. Citation Format: Stephanie Renaud, Athina Stravodimou, Maryse Fiche, Ioannis Xenarios, Scabia Valentina, Valerian Dormoy, Marie Galmiche, Cathrin Brisken, Jean-Francois Delaloye, Assia Treboux, Jean-Yves Meuwly, Nicolas Mermod, Khalil Zaman. miR363-3p mediates maintenance of breast cancer stem cells (BCSCs) and predicts resistance to neoadjuvant chemotherapy and disease recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-22.

Predictive value of ERCC1 and KRAS in colorectal cancer patients with FOLFOX chemotherapy.

588 Background: To determine the clinical significance of KRAS mutation and ERCC1 overexpression as a predictive factor of resistance in oxaliplatin based treatment. Methods: We retrospectively analyzed the clinicopathologic features, status of KRAS mutation and ERCC1 overexpression of 386 colorectal cancer patients who received curative intent surgery. Among them 84 patients were treated by FOLFOX regimen as the first line. Their disease-free survival and overall survival according to the KRAS and ERCC1 were analyzed. Results: About a quarter of patients (25.5%) were represented KRAS wild type with ERCC1 overexpression. Among the patients who treated by FOLFOX regimen, 73 patients were evaluated both of the KRAS and ERCC1. There were no significant differences of disease-free survival and overall survival according to KRAS status and ERCC1 expression each. Under the subgroup analysis, overall survival of ERCC1 overexpression group in wild type KRAS was poor than ERCC1 negative group (p=.029), but no significant difference was in mutant KRAS group (p=.671). Conclusions: Our results suggest that the KRAS wild type with ERCC1 overexpression would be associated with the resistance of oxaliplatin.If oxaliplatin based chemotherapy would beconsidered, status of KRAS mutation and ERCC1 overexpression should be evaluated.

Primary resistance to abiraterone acetate (AA) after docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC): A multicenter retrospective analysis.

206 Background: AA improves survival in mCRPC patients pre-treated with docetaxel. All patients eventually become resistant at different interval times, but some of them show an early progression and should be considered as primary resistant (PRES). To date, no factors have been identified as predictive of primary resistance. Methods: The clinical outcomes of a consecutive series of patients treated with AA after docetaxel failure in 19 Italian Hospitals within a Named Patient Program (NPP) was previously reported (BJU 2014). In the present analysis, we focus on patients who achieved an investigator-assessed PFS ≤ 3 months (PRES) and those with PFS ≥ 12 months (long term responders, LR). The main aim is to determine clinical characteristics associated with primary resistance. Results: Among the 265 patients enrolled in the NPP, we identified 97 PRES (37%) and 71 LP (27%). Poor performance status, visceral metastases, presence of pain, low baseline haemoglobin level, increased LDH and ALP levels, and short time from diagnosis to AA therapy were significantly associated with early progression (Table). Conclusions: Several clinical parameters appear to correlate with early progression under AA. Their role as potential predictive factors of resistance deserve further exploration in order to develop alternative treatment strategies. [Table: see text]

Predictive Factors of Surgery in Peptic Stenosis of the Bulb

The bulb ulcer stenosis, becoming exceptional in developed countries, remains frequent in our country despite the use of the antisecretory. The purpose of our study was to study epidemiological, diagnostic, and evolutionary complication particularities, and to find potential predictive factors of resistance of ulcer stenosis of the bulb to the pump inhibitors Proton through a recent series. This is a retrospective and descriptive study involving 105 patients, treated for ulcer stenosis of the bulb between January 2007 and December 2012. All our patients had received inhibitors of Proton pump, parenterally for 7 days. They were divided into 2 groups according to their response to treatment: the first group (G1) was sensitive and the second (G2) was resistant. All patients of the G2 were operated. We had compared the two groups. There was no statistically significant difference concerning age, sex, blood group and smoking between the two groups. In univariate study, the age of the epigastralgies was greater than or equal to 9 years; the clapotage fasting, dilation and gastric atony, objectified by the oesogastroduodenal transit were significantly associated with the failure of medical treatment. Only gastric atony and seniority of the disease over 9 years were independent risk factors of resistance to the Proton pump inhibitors in multivariate study.

Predictive factors of resistance to trastuzumab as neoadjuvant therapy in women with HER2-positive breast cancer.

168 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel plus weekly trastuzumab before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 status did not affect the pCR rate. Although membranous pIGF1-R expression did not affect pCR rate in hormone receptor-positive patients (66.7% vs. 50.0%), hormone receptor-positive patients with positive membranous pIGF1-R tended to show higher pCR rate compared with negative pIGF1-R (41.2% vs. 0%). PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.

PD-0015 Influence of BRAF V600E and Different Kras Mutations on Outcome of Metastatic Colorectal Cancer Patients Treated with First- Line Therapy

ABSTRACT Introduction KRAS mutation status in codons 12 and 13 is recognized as a predictive factor for resistance to anti- EGFR monoclonal antibodies. Recent retrospective studies suggested that patients (pts) with different KRAS mutations (KRAS mts) respond different to specific systemic therapy and also pts with KRAS mt in codon 13 might respond to anti- EGFR monoclonal antibodies but with lower response rates than pts with KRAS wild-type (KRAS wt) tumors. Methods Objective response (OR), time to progression (TTP), overall survival (OS) and BRAF status in metastatic colorectal cancer (mCRC) pts treated with first- line therapy according to KRAS status, were retrospectively analyzed. Results In total 176 mCRC pts who received first- line therapy between May 2009 and October 2010 were included in retrospective analysis. The median age was 62 years (27- 86), M/F 61/39 %. The most common received therapies were XELIRI/bevacizumab and XELOX/cetuximab in 29.5 % and in 22.1 % of pts respectively. KRAS mts were found in 63 pts (35.8 %), mt KRAS in codon 12 in 53 pts (84%) and mt KRAS in codon 13 in 10 pts (16%). BRAF V600E mt was detected in 13 of 176 pts (7.4%). OR in wt KRAS/wt BRAF pts was 54% (CR 14.7 %, PR 39.3 %) and in wt KRAS/mt BRAF pts was 38.5% (CR 15.4 %, PR 23.1 %), difference (diff) was not statistically significant (p= 0.378). Median OS of wt KRAS/wt BRAF pts and wt KRAS/mt BRAF pts was 107.4 months (mo) (95% CI: 82- 132.9 mo) and 45 mo (95% CI: 28.4- 61.5 mo) respectively, diff was statistically significant (p= 0.042). TTP in wt KRAS/ wt BRAF pts and wt KRAS/mt BRAF pts was 16 mo (95% CI: 10.7- 21.2 mo) and 12 mo (95% CI: 4.0 -15.0 mo) respectively, diff was not statistically significant (p= 0.558). OR in codon 12 mt pts was 47% (CR 20.7%, PR 26.3%) and in codon 13 mt pts was 33% (CR 11%, PR 22%),dif was not statistically significant (p= 0.08). TTP in mt codon 12 pts and mt codon 13 pts was 13.5 mo (95% CI: 9.0- 18.0 months) and 9.3 mo (95% CI: 5.1- 13.5 mo) respectively, diff was not statistically significant (p= 0.106). Conclusion Mt BRAF pts have statistically significantly worse prognosis than wt BRAF pts, with lower response rates and progress earlier during systemic treatment. Codon 13 mt KRAS pts have lower response rate and progress earlier than KRAS codon 12 mt pts. Definitive role of mt BRAF and different KRAS mts are needed to be defined to select pts, who will benefit from specific combination of systemic therapy.

Co-expression of erythropoietin receptor with human epidermal growth factor 2 may counteract trastuzumab inhibition in gastric cancer

Gastric cancer has high prevalence and high modality worldwide. For many years, few improvements in the efficacy of treatments were reported for advanced gastric cancer settings. Although a novel molecular target agent trastuzumab, in combination with chemotherapy, prolongs overall survival time in advanced gastric cancer, resistance to this drug still exists among human epidermal growth factor receptor-2 (HER2) positive patients. HER2 and erythropoietin receptor (EPOR) downstream signaling pathway have some common factors like Akt, Erk and STATs. Also there exist evidences that EPOR may express on some solid tumors and probably promote tumor progression. So it is reasonable for us to hypothesis that HER2 and EPOR may be co-expressed in the same gastric cancer cell and if so, EPOR signaling pathway may overlaps that with HER2 and promotes HER2 induced signal transduction to cell proliferation. In clinical settings, a stimulation of EPOR will play antagonistic effects on trastuzumab-induced anti-tumor activity to HER2-positive gastric cancer patients. Co-expression of EPOR and HER2 is a predictive factor for resistance of trastuzumab in gastric cancer.

S1347 Predictive Factors of Resistance to Enteral Nutrition

S1347 Predictive Factors of Resistance to Enteral Nutrition

Abstract 2697: Analysis of the correlation between gene expression of IGF-pathway components and benefit from cetuximab (Erbitux™) in metastatic colorectal cancer patients

Abstract OBJECTIVE: There is considerable evidence showing cross-talk between the epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) pathways. This analysis was carried out to examine the correlation between the gene expression levels of IGF pathway components and the clinical benefit from the anti-EGFR monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC) patients; and to look for the factors contributing to non-benefit from cetuximab in K-Ras wild type (WT) patients, further seeking the treatment options for this sub-population. EXPERIMENTAL DESIGN: Gene expression profiling data for the components of IGF pathway and K-Ras mutational status are available from 70 pre-treatment tumor biopsies from patients with refractory mCRC receiving cetuximab monotherapy (Khambata-Ford et al., 2007). RESULTS: In this cohort of mCRC, patients with tumors expressing high level of IGF-IR or GRB7 were associated with longer progression-free survival (PFS) with cetuximab than patients with low expression levels of these genes. In addition, patients with tumors that express low level of insulin inducible gene 2 (INSIG2), insulin receptor (INSR), IGF-1 or IGF binding protein 3 (IGFBP3) were found to have a longer PFS and higher disease control rate than patients with high expression levels of these genes. For example, median PFS was 115 days in INSIG2 low-expressing tumors and 58 days in INSIG2 high-expressing tumors (log-rank p=0.0029, hazard ratio=0.45); and the disease control rate was 51.4% and 11.4%, respectively, for patients with INSIG2 low-expressing tumors vs. INSIG2 high-expressing tumors (Fisher exact p=0.0006). Furthermore, among patients with K-Ras WT tumors, a significant difference in disease control rate was observed for INSIG2 low- and high-expressing tumors (76.2 % vs. 18.2 %, Fisher exact p=0.0002). Additionally, patients with K-Ras WT tumors that have a high gene expression of IGF-1R had a significantly higher disease control rate (62.5%) than patients with low expression (26.3%) (Fisher exact p=0.03) and longer PFS (log-rank p= 0.01, hazard ratio=2.45, and median PFS, 122 days vs. 60 days, respectively). CONCLUSION: A statistically significant association was observed between the gene expression of some key components of the IGF pathway and benefit from cetuximab in mCRC. In patients with K-Ras WT tumors, high expression of IGF-1R and GRB7 are potential predictive factors for clinical benefit whereas low expression of IGF-1 and INSIG2 are potential predictive factors for resistance to cetuximab. Our data suggest that IGF pathway plays an important role in benefit from the anti-EGFR therapy cetuximab, and that targeting IGF-1R/IR may prove valuable treatment option in K-Ras WT mCRC patients that not benefit from cetuximab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2697.

Correlation of insulin-like growth factor 1 (IGF-1) expression and clinical outcome in K-RAS wild-type colorectal cancer patients treated with cetuximab-irinotecan

4017 Background: K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. Recent data suggested that in presence of IGF-1 system altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested in order to verify the ability of IGF-1 to identify a sub-group of patients more likely to benefit from EGFR-targeted antibodies treatment. Methods: IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. Results: Sixty-two patients were analyzed. IGF-1 was negative in 21 patients (34%). and overexpressed in the remaining 41 cases (66%). In IGF-1 negative and IGF-1 positive tumors we observed progressive disease in 6 (29%) and 26 (63%) patients respectively (p = 0.01). Median time to progression was 7.7 months in patients showing IGF-1 negative tumors and 2.3 months for IGF-1 expressing tumors (p = 0.005). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 7 (50%) and 1 (5%) cases respectively (p = 0.004). Median time to progression in IGF-1 negative tumors was 11 months and 3.2 months in IGF-1 positive colorectal cancers (p = 0.03). Conclusions: IGF-1 proved to be a reliable predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal tumors in this setting. No significant financial relationships to disclose.

Prospective observational study (ZORES Study) on analysis of genetic mutations and enzymatic activity of Farnesyl Pyrophosphate Synthetase (FPPS) as predictive factor of resistance to amino-bisphosphonates (N-BP) in patients with bone metastases from solid tumors

Prospective observational study (ZORES Study) on analysis of genetic mutations and enzymatic activity of Farnesyl Pyrophosphate Synthetase (FPPS) as predictive factor of resistance to amino-bisphosphonates (N-BP) in patients with bone metastases from solid tumors

S.07.07 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study

S.07.07 Predictive factors of resistance to antidepressant treatment: results from a European multicentre study

Expression of HER-2/NEU oncoprotein in familial and non-familial breast cancer.

The HER-2/neu proto-oncogene amplification or oncoprotein overexpression is an important prognostic factor and a predictive factor for resistance to endocrine therapy and adjuvant chemotherapy in breast cancers. Moreover, it is an entry criterion in the assessment of patients for whom Herceptin (Trastuzumab) treatment is considered. The overexpression rate of HER-2/neu oncoprotein has been identified in 10% to 40% of human breast cancers. In Taiwan, a higher grade of pathobiologic characteristics of familial breast cancer was also noted than that found in the non-familial group. It is worthwhile to evaluate whether the overexpression is more frequent in familial breast cancers. Fifty-six familial and 111 non-familial breast cancers were studied between 1990 and 1999 to assess both the overexpression of HER-2/neu oncoprotein immunohistochemically and the correlation with the histological type, grade and stage of breast carcinoma. The overexpression rate is higher in the familial breast cancer group (50.0%) when compared with non-familial breast cancer group (36.9%), which did not prove to be statistically significant (P = 0.1068). However, when the infiltrating ductal carcinomas of both groups are compared, it is statistically significant (52.3% vs. 33.7%, P = 0.0429). Overexpression correlated with node status and histological grade of infiltrating ductal carcinomas in non-familial and overall breast cancers. It also correlated with nuclear pleomorphism and mitotic counts, but not tubule formation or tumor size. All 3 cases of Paget's disease revealed overexpression, whereas all 12 cases of mucinous and one case of metaplastic carcinoma and one case of medullary carcinoma were negative. The overexpression rate was higher both in familial and non-familial intraductal carcinomas (57.1% vs. 73.3%, P = 0.4716). No statistical difference was identified between the 2 subsets. A case of infiltrating ductal carcinoma combined with intraductal carcinoma revealed heterogeneous staining in the component of ductal carcinoma in situ, while the invasive component did not. This suggests that overexpression decreases within individual tumors as they evolve from in situ to invasive lesioins. The HER-2/neu may imply a different role in intraductal carcinoma, Paget's disease and invasive duct carcinoma. Although the overexpression rate of HER-2/neu oncoprotein of familial breast cancer was not significantly higher than that of the non-familial group, it is appropriate to evaluate the rate of HER-2/neu overexpression according to the histological type of breast cancers from familial breast cancer and non-familial breast cancer. The prognoses will be needed for future evaluation.