Miriana Moran

Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer.

ABSTRACT Several studies have reported that epidermal growth factor receptor (EGFR)-related molecules may serve as predictors of cetuximab treatment for metastatic colorectal cancer (mCRC), such as EGFR gene copy number (GCN), expression of 2 ligands of EGFR, amphiregulin (AREG) and epiregulin (EREG), and EGFR CA simple sequence repeat 1 (CA-SSR1) polymorphism; however, these biomarkers still remain not useful in clinical practice since they have been evaluated using cohorts with patients treated in various settings of chemotherapy. We therefore analyzed associations of mRNA expression of AREG and EREG, EGFR GCN, and CA-SSR1 polymorphism [short (S;≤ 19) / long (L; ≥ 20)] with clinical outcomes in 77 Japanese patients with KRAS exon 2 wild-type mCRC enrolled in phase II trials of FOLFOX (n = 28/57, UMIN000004197) or SOX (n = 49/67, UMIN000007022) plus cetuximab as first-line therapy. High AREG expression correlated with significantly better progression-free survival (median 11.6 vs. 66 months, HR 0.52, P = 0.037); moreover, it remained statistically significant in multivariate analysis (HR: 0.48, P = 0.027). S/S genotype of CA-SSR1 predicted severe skin toxicity (P = 0.040). Patients with both AREG-low and EGFR low-GCN had significantly shorter overall survival than the others (median 22.2 vs. 42.8 months, HR 2.34, P = 0.042). The multivariate analysis showed that molecular status with both AREG-low and EGFR low-GCN was a predictor of worse survival (P = 0.006). In conclusion, AREG mRNA expression and EGFR CA-SSR1 polymorphism predict survival and skin toxicity, respectively, of initial chemotherapy with cetuximab. Our results also suggest potential prognostic value of the combined assessment of AREG and EGFR GCN for first-line cetuximab treatment.

Prognostic Value of ACVRL1 Expression in Metastatic Colorectal Cancer Patients Receiving First-line Chemotherapy With Bevacizumab: Results From the Triplet Plus Bevacizumab (TRIBE) Study.

Micro‐Abstract: ACVRL1 (activin receptor like‐protein 1) mediates tumor angiogenesis; however, its utility as a predictive or prognostic biomarker in colorectal cancer is unclear. We present the first evidence from a phase III study that intratumoral ACVRL1 expression is associated with tumor response and survival among metastatic colorectal cancer patients undergoing first‐line bevacizumab chemotherapy. These results could guide the selection of colorectal cancer patients for chemotherapy and antiangiogenic therapy. Background: No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like‐protein 1) encodes for ALK1, a member of the transforming growth factor‐&bgr; receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway‐related genes to identify molecular markers in the TRIBE study. Materials and Methods: Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin‐fixed paraffin‐embedded specimens were examined for expression of VEGF‐A, VEGF‐B, VEGF‐C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal χ2 approach was used to determine the messenger RNA levels associated with progression‐free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. Results: High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5‐fluorouracil, leucovorin, oxaliplatin, irinotecan]‐bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5‐fluorouracil, leucovorin, irinotecan]‐bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI‐bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI‐bevacizumab and of OS in patients receiving FOLFIRI‐bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1‐year survival (P < .05) among all colorectal cancer stages. Conclusion: ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Immune-related Genes to Dominate Neutrophil-lymphocyte Ratio (NLR) Associated With Survival of Cetuximab Treatment in Metastatic Colorectal Cancer

Background Few clinical studies have investigated the association between neutrophil‐lymphocyte ratio (NLR) and treatment with cetuximab‐based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune‐related genes affect the NLR remain unclear. Patients and Methods In 77 patients with KRAS exon2 wild‐type mCRC from prospective trials of first‐line chemotherapy with cetuximab, expression levels of 354 immune‐related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2‐sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR‐low and NLR‐high groups among all measured genes. Results NLR data were available for 71 patients. The NLR was associated with progression‐free survival and overall survival (r = −0.24; P = .040 and r = −0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan‐Meier curve of NLR‐low versus NLR‐high differed significantly for both progression‐free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2‐sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR‐low and NLR‐high groups (t test P‐value < .005; false discovery rate P‐value < .15). Conclusion NLR is significantly associated with survival in patients with mCRC treated with first‐line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR. Micro‐Abstract Our study, using data of prospective trials, demonstrated that the neutrophil‐lymphocyte ratio (NLR) was associated with survival time in patients with KRAS wild‐type metastatic colorectal cancer treated with first‐line chemotherapy with cetuximab. The expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR‐low and NLR‐high groups. Genes encoding for activities on macrophages may affect the NLR.

Expression of genes involved in vascular morphogenesis and maturation predicts efficacy of bevacizumab-based chemotherapy in patients undergoing liver resection

Angiogenesis-related gene expression is associated with the efficacy of anti-VEGF therapy. We tested whether intratumoral mRNA expression levels of genes involved in vascular morphogenesis and early vessel maturation predict response, recurrence-free survival (RFS), and overall survival (OS) in a unique cohort of patients with colorectal liver metastases (CLM) treated with bevacizumab-based chemotherapy followed by curative liver resection. Intratumoral mRNA was isolated from resected bevacizumab-pretreated CLM from 125 patients. In 42 patients, a matching primary tumor sample collected before bevacizumab treatment was available. Relative mRNA levels of 9 genes (ACVRL1, EGFL7, EPHB4, HIF1A, VEGFA, VEGFB, VEGFC, FLT1, and KDR) were analyzed by RT-PCR and evaluated for associations with response, RFS, and OS. P values for the associations between the individual dichotomized expression level and RFS were adjusted for choosing the optimal cut-off value. In CLM, high expression of VEGFB, VEGFC, HIF1A, and KDR and low expression of EGFL7 were associated with favorable RFS in multivariable analysis (P < 0.05). High ACVRL1 levels predicted favorable 3-year OS (P = 0.041) and radiologic response (PR = 1.093, SD = 0.539, P = 0.002). In primary tumors, low VEGFA and high EGFL7 were associated with radiologic and histologic response (P < 0.05). High VEGFA expression predicted shorter RFS (10.1 vs. 22.6 months; HR = 2.83, P = 0.038). High VEGFB (46% vs. 85%; HR = 5.75, P = 0.009) and low FLT1 (55% vs. 100%; P = 0.031) predicted lower 3-year OS rates. Our data suggest that intratumoral mRNA expression of genes involved in vascular morphogenesis and early vessel maturation may be promising predictive and/or prognostic biomarkers. Mol Cancer Ther; 15(11); 2814–21. ©2016 AACR.

Performance comparison of the Vysis automated versus manual ALK gene rearrangement assays on archived FFPE and cytology specimens.

e20056Background: The Vysis ALK Break Apart FISH Probe assay (ALK FISH) detects ALK gene chromosome 2p23 rearrangements in NSCLC FFPE tissue by fluorescence in situ hybridization (FISH) and involve...