Publications by authors named "Marta Schirripa"

61 Publications

Synaptophysin expression in mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis.

Eur J Cancer 2021 Feb 16;146:145-154. Epub 2021 Feb 16.

Unit of Oncology 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. Electronic address:

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier and log-rank tests.

Results: Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21-3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35-3.85, p = 0.001).

Conclusions: Among BRAFmt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.016DOI Listing
February 2021

Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

Pharmacogenomics J 2021 Feb 4. Epub 2021 Feb 4.

Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA, 90033, USA.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.
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http://dx.doi.org/10.1038/s41397-021-00207-xDOI Listing
February 2021

A polymorphism in the cachexia-associated gene INHBA predicts efficacy of regorafenib in patients with refractory metastatic colorectal cancer.

PLoS One 2020 24;15(9):e0239439. Epub 2020 Sep 24.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America.

Activin/myostatin signaling has a critical role not only in cachexia but also in tumor angiogenesis. Cachexia is a frequent complication among patients with advanced cancer and heavily pretreated patients. We aimed to evaluate the prognostic significance of cachexia-associated genetic variants in refractory metastatic colorectal cancer (mCRC) patients treated with regorafenib. Associations between twelve single nucleotide polymorphisms in 8 genes (INHBA, MSTN, ALK4, TGFBR1, ALK7, ACVR2B, SMAD2, FOXO3) and clinical outcome were evaluated in mCRC patients of three cohorts: a discovery cohort of 150 patients receiving regorafenib, a validation cohort of 80 patients receiving regorafenib and a control cohort of 128 receiving TAS-102. In the discovery cohort, patients with any G variant in FOXO3 rs12212067 had a significantly lower response rate (P = 0.031) and overall survival (OS) than those with a T/T in univariate analysis (4.5 vs. 7.6 months, hazard ratio [HR] = 1.63, 95% confidence interval [CI] = 1.09-2.46, P = 0.012). Among female patients, those with any G variant in INHBA rs2237432 had a significantly longer OS than those with an A/A in both univariate (7.6 vs. 4.3 months, HR = 0.57, 95%CI = 0.34-0.95, P = 0.021) and multivariable (HR = 0.53, 95%CI = 0.29-0.94, adjusted P = 0.031) analysis. This association was confirmed in female patients of the validation cohort, though without statistical significance (P = 0.059). Conversely, female patients with any G allele in the control group receiving TAS-102 did not show a longer OS. This was the first study evaluating the associations between polymorphisms in cachexia-associated genes and outcomes in refractory mCRC patients treated with regorafenib. Further studies should be conducted to confirm these associations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514061PMC
November 2020

Role of enterocyte-specific gene polymorphisms in response to adjuvant treatment for stage III colorectal cancer.

Pharmacogenet Genomics 2021 Jan;31(1):10-16

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

Objectives: The enterocyte subtype of colorectal cancer (CRC) responds favorably to oxaliplatin-based adjuvant treatment for stage III CRC. We examined the clinical significance of single-nucleotide polymorphisms (SNPs) in enterocyte-related genes MS4A12 and CDX2 in response to adjuvant treatment for stage III CRC.

Patients And Methods: A total of 350 patients with stage III CRC were included: 274 received adjuvant treatment with surgical resection (discovery cohort) and 76 received surgery alone (control cohort). In the discovery cohort, 68 patients received FOLFOX and 206 received oral fluoropyrimidine. SNPs were analyzed by PCR-based direct sequencing.

Results: In the discovery cohort, the MS4A12 rs4939378 G/G variant was associated with lower 5-year survival than any A allele [70% vs. 90%, univariate: hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.03-5.06, P = 0.035; multivariate: HR 2.58, 95% CI 1.15-5.76, P = 0.021]. Patients with the CDX2 rs3812863 G/G variant had better overall survival than those with any A allele, although this was not significant in multivariate analysis (5 year-survival: 95% vs. 82%, univariate: HR 0.34, 95% CI 0.12-0.97, P = 0.034; multivariate: HR 0.39, 95% CI 0.13-1.11, P = 0.078). The SNPs did not show significant association with overall survival in the control cohort, and significant interaction was observed between MS4A12 genotypes and groups (P = 0.007).

Conclusions: Our findings suggest that MS4A12 and CDX2 gene polymorphisms may predict outcome in stage III CRC. However, the clinical significance of SNPs for response to oxaliplatin may differ by tumor stage.
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http://dx.doi.org/10.1097/FPC.0000000000000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655616PMC
January 2021

Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes and are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether and SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients.

Patients And Methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) ( = 230, discovery cohort) and first-line FOLFIRI plus BEV ( = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing.

Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type , progression-free survival (PFS) was shorter for the rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07-5.03, = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27-6.94, = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant and rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09-0.62, = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the mutant, rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56-1.07, = 0.12) or the wild-type, rs7356 C/C variant subgroup.

Conclusion: SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.
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http://dx.doi.org/10.3390/cancers12071742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408001PMC
June 2020

KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population.

Clin Colorectal Cancer 2020 09 12;19(3):219-225. Epub 2020 May 12.

Department of Oncology, Veneto Institute of Oncology IOV IRCCS, Padua, Italy. Electronic address:

Background: Kirsten rat sarcoma viral oncogene (KRAS) G12C mutation occurs in about 4% of colorectal cancers (CRCs). Recently, KRAS G12C was identified to be a potential drug target and predictor of response to the novel on AMG510 target treatment. We described the clinicopathologic features and prognosis of KRAS G12C-mutated metastatic CRCs compared to other KRAS mutation.

Patients And Methods: Clinicopathologic features and outcome data of KRAS-mutated metastatic CRC (mCRC) patients referred to 3 Italian oncology units from January 2010 to December 2018 were collected. A cohort of KRAS-mutant mCRC patients referred to the Department of Medical Oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy) within the same time frame was included as external validation.

Results: A total of 839 KRAS-mutated mCRC cases were included in the main patient population. A total of 145 patients (17%) had KRAS G12C mutation. Our analyses showed that patients harboring KRAS G12C mutation were more likely to be men and to present lung and liver metastases, and were less likely to have peritoneal spread. KRAS G12C mutation was associated with shorter overall survival compared to other KRAS mutations (hazard ratio, 1.32; 95% confidence interval, 1.07-1.63; P = .009). Such results were confirmed in the external validation cohort.

Conclusion: The knowledge of the distinctive traits of KRAS G12C-mutated CRC patients is crucial to future translational research studies, clinical trial design, and proper interpretation of results.
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http://dx.doi.org/10.1016/j.clcc.2020.04.009DOI Listing
September 2020

Outcome of patients with colorectal cancer undergoing lung metastases resection: a single-institution retrospective analysis.

Tumori 2021 Feb 29;107(1):46-54. Epub 2020 Jun 29.

Department of Clinical and Experimental Oncology, Medical Oncology Unit 1, Istituto Oncologico Veneto (IRCSS), Padua, Italy.

Introduction: This study was undertaken to review a single-institution cohort of patients with metastatic colorectal cancer undergoing lung resection after a multidisciplinary evaluation and to investigate the main prognostic factors for survival.

Methods: Medical records of 129 patients undergoing lung metastasectomy for colorectal cancer with curative intent from 2001 to 2017 were reviewed. Tissue samples from the primary tumor were analyzed with a multiplex genotyping system for the detection of mutations in and genes. Survival analyses were carried out by the Kaplan-Meier method. Univariate and multivariable analyses were performed using the log-rank test and the Cox regression model.

Results: Postoperative morbidity and mortality were 13.2% and 0%, respectively. At a median follow-up time of 62.5 months, median overall survival was 90.5 months and median relapse-free survival was 42.8 months. Multivariable analysis for overall survival identified synchronous versus metachronous metastatic presentation as the only prognostic factor, whereas relapse-free survival was independently associated with synchronous versus metachronous metastatic presentation, number of metastases, and postoperative chemotherapy.

Conclusions: This study shows particularly favorable survival outcomes for patients undergoing lung metastasectomy. The validity of some of the main prognostic factors was confirmed and a positive effect of postoperative chemotherapy on relapse-free survival was shown. Contrary to other reports, the presence of mutations was not associated with significant survival differences. Further studies are needed in order to clarify the interactions between molecular, clinical, and pathologic characteristics and treatment-related factors.
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http://dx.doi.org/10.1177/0300891620930793DOI Listing
February 2021

Retreatment With Anti-EGFR Antibodies in Metastatic Colorectal Cancer Patients: A Multi-institutional Analysis.

Clin Colorectal Cancer 2020 09 11;19(3):191-199.e6. Epub 2020 Apr 11.

Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. Electronic address:

Background: On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti-epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice.

Patients And Methods: A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type-status tissue samples, who had received a first-line anti-EGFR-based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated.

Results: A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of < 3 months (rechallenge group), > 2 prior therapy lines and a longer anti-EGFR-free interval were associated with higher ORR, but not with longer PFS or OS.

Conclusion: Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.
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http://dx.doi.org/10.1016/j.clcc.2020.03.009DOI Listing
September 2020

Thyroid hormones ratio is a major prognostic marker in advanced metastatic colorectal cancer: Results from the phase III randomised CORRECT trial.

Eur J Cancer 2020 07 20;133:66-73. Epub 2020 May 20.

Department of Oncology, Unit of Oncology 1, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. Electronic address:

Background: Free triiodothyronine (FT3)/free thyroxine (FT4) ratio is an index estimating the peripheral activity of thyroid hormones. In a previous experience, we identified a prognostic role for FT3/FT4 ratio in chemorefractory patients treated with regorafenib. Therefore, we planned this post hoc analysis of the phase III CORRECT trial of regorafenib versus placebo.

Methods: Seven hundred fifty-eight out of 760 randomised patients (503 in the regorafenib and 255 in the placebo arm) were evaluable for the present analyses, based on availability of FT3 and FT4 baseline values. Co-primary objectives were to explore the predictive role of FT3/FT4 ratio in patients treated with regorafenib compared with placebo and to validate the prognostic value of FT3/FT4 ratio in the CORRECT trial.

Results: For patients randomised to regorafenib, median overall survival (OS) was 4.0, 7.5 and 9.8 months in low, intermediate and high FT3/FT4 ratio subgroups, respectively. Hazard ratio (HR) for OS was 0.40 (p < 0.0001) when comparing intermediate versus low and 0.32 (p < 0.0001) when comparing high versus low FT3/FT4 ratio. In the placebo arm, median OS was 3.3, 5.6 and 7.7 months, in the three subgroups. HR for OS was 0.47 (p < 0.0001) when comparing intermediate versus low and 0.33 (p < 0.0001) when comparing high versus low. FT3/FT4 ratio retained its association with OS in the multivariate model in both arms.

Conclusions: While rejecting the predictive effect of baseline FT3/FT4 ratio, present data strengthen the prognostic role of the ratio, pave the way for direct clinical application, underline the need for a better biological understanding and suggest possible therapeutic implications for thyroid hormones.
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http://dx.doi.org/10.1016/j.ejca.2020.04.023DOI Listing
July 2020

A polymorphism within the R-spondin 2 gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab: data from FIRE-3 and TRIBE trials.

Eur J Cancer 2020 05 16;131:89-97. Epub 2020 Apr 16.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab.

Patients And Methods: 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated.

Results: RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009).

Conclusion: Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status.
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http://dx.doi.org/10.1016/j.ejca.2020.02.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513926PMC
May 2020

Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis.

Int J Cancer 2020 Oct 24;147(8):2303-2315. Epub 2020 Apr 24.

Charité Comprehensive Cancer Center, Berlin, Germany.

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty-seven fresh and 55 formalin-fixed paraffin-embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI-like, BRAF-like, TGFB activated-like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa-like and CMS classification with overall survival. Fifty-one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF-like and MSI-like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal-like, based on the CMS and the TGFBa-like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell-intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5-18.5, P = .0048; TGFBa-like vs TGFBi-like, HR = 2.5, 95% CI = 1.1-5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC.
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http://dx.doi.org/10.1002/ijc.33003DOI Listing
October 2020

The heterogeneous clinical and pathological landscapes of metastatic -mutated colorectal cancer.

Cancer Cell Int 2020 29;20:30. Epub 2020 Jan 29.

1Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy.

Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of mutations. Because of the great aggressiveness of -mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing mutations is needed.
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http://dx.doi.org/10.1186/s12935-020-1117-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990491PMC
January 2020

Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes.

Oncologist 2020 06 22;25(6):481-487. Epub 2020 Jan 22.

Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua University Hospital, Padua, Italy.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking.

Patients And Methods: Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of "super" responders and "clearly" refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS).

Results: In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463).

Conclusion: A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy.

Implications For Practice: Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability-high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.
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http://dx.doi.org/10.1634/theoncologist.2019-0611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288636PMC
June 2020

CK7 and consensus molecular subtypes as major prognosticators in BRAF mutated metastatic colorectal cancer.

Br J Cancer 2019 10 2;121(7):593-599. Epub 2019 Sep 2.

Surgical Pathology & Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.

Background: BRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among BRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes.

Methods: Data and tissue specimens from 155 BRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS).

Results: CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS.

Conclusion: The present study provides new evidence on how several well-established biomarkers perform in a homogenousBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis.
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http://dx.doi.org/10.1038/s41416-019-0560-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889398PMC
October 2019

High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

Front Oncol 2019 12;9:622. Epub 2019 Jul 12.

Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.

Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months). Plasma samples from mCRC patients were collected prior to (baseline samples = 60) and/or during regorafenib treatment ( = 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA). In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 [95%CI: 1.01-3.13], = 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 [95%CI: 1.83-6.57], < 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; [95%CI: 1.63-5.46; < 0.0001). Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib.
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http://dx.doi.org/10.3389/fonc.2019.00622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640154PMC
July 2019

A validated prognostic classifier for BRAF-mutated metastatic colorectal cancer: the 'BRAF BeCool' study.

Eur J Cancer 2019 09 19;118:121-130. Epub 2019 Jul 19.

S.C.D.U. Medical Oncology, A.O. Ordine Mauriziano Hospital, Department of Oncology, University of Turin, Turin, Italy.

Background: Despite the well-known negative prognostic value of the BRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined.

Methods: Two large retrospective series of BRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated.

Results: A total of 395 BRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a 'complete' score (0-16) including all significant covariates and a 'simplified' score (0-9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0-4), intermediate (5-8) and high (9-16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44-3.22, p < .001) and 6.6 months (HR for high vs low risk: 4.72, 95% CI: 2.72-8.20, p < .001). Similar results were observed also after adjusting for the type of first-line treatment and adopting the simplified score. The simplified prognostic score derived from the exploratory set was then applied to the validation set for external confirmation.

Conclusions: These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.
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http://dx.doi.org/10.1016/j.ejca.2019.06.008DOI Listing
September 2019

Class 1, 2, and 3 -Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization.

Clin Cancer Res 2019 07 9;25(13):3954-3961. Epub 2019 Apr 9.

Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.

Purpose: mutations are grouped in activating -independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and -dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of -mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.

Experimental Design: Data from 117 patients with (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test.

Results: Class 3 -mutated mCRC was more frequently left sided ( = 0.0028), pN0 ( = 0.0159), and without peritoneal metastases ( = 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with wt, was 2.38 [95% confidence interval (CI), 1.61-3.54] for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 ( < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in -mutated class 2 ( = 0.033) compared with class 3 cases.

Conclusions: For the first time, different clinical and pathologic features and outcome data were reported according to the three mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0311DOI Listing
July 2019

Benefit from anti-EGFRs in and wild-type metastatic transverse colon cancer: a clinical and molecular proof of concept study.

ESMO Open 2019 8;4(2):e000489. Epub 2019 Mar 8.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Objective: Primary tumour location is regarded as a reliable surrogate of colorectal cancer biology. Sensitivity to anti-EGFRs (Epidermal Growth Factor Receptor) of metastatic transverse colon cancers (mTCCs) has usually been assumed similar to right-sided tumours; however, evidence about the clinical behaviour of mTCC is limited. Thus, to verify sensitivity of mTCC to anti-EGFRs we conducted the present study.

Methods: Patients with wild-type microsatellite stable (MSS) mTCC receiving anti-EGFR monotherapy, or in combination with irinotecan if clearly irinotecan-refractory, were included. Hypothesising an overall response rate (ORR) of 35%, 11 patients, of whom at least 3 were responders, were necessary to be able to reject the null hypothesis of an ORR of 5%, with α and β errors of 0.05 and 0.20. PRESSING panel and consensus molecular subtypes (CMS) were assessed on tumour samples, whereas in-silico data were obtained from TCGA dataset.

Results: Among nine eligible patients, four and three achieved response and disease stabilisation (ORR 44%). At a median follow-up of 23.1 months, median progression-free survival and overall survival were 7.3 (95% CI 3.9 to NA) and 15.0 months (95% CI 10.0 to NA), respectively. A amplification and an S303F substitution were detected in patients with rapid disease progression, while others had PRESSING panel-negative tumours with CMS2 or CMS4 subtypes.

Conclusions: wild-type MSS mTCCs may be sensitive to anti-EGFRs, as confirmed by molecular analyses.
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http://dx.doi.org/10.1136/esmoopen-2019-000489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435314PMC
March 2019

Phase II randomised study of maintenance treatment with bevacizumab or bevacizumab plus metronomic chemotherapy after first-line induction with FOLFOXIRI plus Bevacizumab for metastatic colorectal cancer patients: the MOMA trial.

Eur J Cancer 2019 03 5;109:175-182. Epub 2019 Feb 5.

Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address:

Background: Alternating induction and maintenance phases is a common strategy in metastatic colorectal cancer (mCRC). Metronomic chemotherapy (metroCT) may represent a well-tolerated chemotherapy backbone for maximising bevacizumab effect during maintenance. The MOMA trial was designed to compare metroCT plus bevacizumab versus bevacizumab alone as maintenance following 4 months of induction with FOLFOXIRI plus bevacizumab.

Patients And Methods: In this phase II study, patients with unresectable mCRC were randomised to receive up to 8 cycles of FOLFOXIRI plus bevacizumab, followed by bevacizumab (arm A) or the same regimen followed by bevacizumab plus metroCT (capecitabine 500 mg/three times per day and cyclophosphamide 50 mg/die, arm B) until disease progression. The primary end-point was progression-free survival (PFS). According to the Rubinstein and Korn's design, to detect a hazard ratio[HR] of 0.75 favouring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events and 222 patients were required.

Results: Between May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomised in 16 Italian centres. At a median follow-up of 47.8 months, 210 and 164 progression and death events were registered. The primary end-point was not met. Median PFS was 10.3 and 9.4 months in arm B and A, respectively (HR: 0.94 [70% confidence interval {CI}: 0.82-1.09], p = 0.680). No significant differences were reported in terms of overall survival (OS) (median OS arm B/A: 22.5/28 months; HR: 1.16 [95%CI: 0.99-1.37], p = 0.336). Response rate with FOLFOXIRI plus bevacizumab was 63% (arm B/A: 58%/68%). In the liver-limited subgroup, the secondary resection rate was 49% (arm B/A: 45%/55%).

Conclusions: The addition of metroCT to maintenance with bevacizumab does not significantly improve PFS of mCRC patients. The activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS/BRAF mutations treated with a 4-months induction.

Trial Registration: www.clinicaltrials.gov NCT02271464.
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http://dx.doi.org/10.1016/j.ejca.2018.12.028DOI Listing
March 2019

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients.

Pharmacogenomics J 2019 12 6;19(6):556-563. Epub 2019 Feb 6.

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.
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http://dx.doi.org/10.1038/s41397-019-0077-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867961PMC
December 2019

Early modifications of circulating microRNAs levels in metastatic colorectal cancer patients treated with regorafenib.

Pharmacogenomics J 2019 10 28;19(5):455-464. Epub 2019 Jan 28.

Institute of Clinical Physiology, CNR, Pisa, Italy.

Biomarkers able to improve the cost/benefit ratio are urgently needed for metastatic colorectal cancer patients that are eligible to receive regorafenib. Here, we measured plasma levels of ten circulating microRNAs (c-miRNAs) and we investigated their early changes during treatment, as well as possible correlation with clinical outcome. Ten literature-selected c-miRNAs were quantified by qRT-PCR on plasma samples collected at baseline (d1) and after 15 days of treatment (d15). C-miRNAs showing significant changes were further analyzed to establish correlations with outcome. A decision tree-based approach was employed to define a c-miRNA signature able to predict the outcome. Results achieved in an exploratory cohort were tested in a validation group. In the exploratory cohort (n = 34), the levels of c-miR-21 (p = 0.06), c-miR-141 (p = 0.04), and c-miR-601 (p = 0.01) increased at d15 compared with d1. A c-miRNA signature involving c-miR-21, c-miR-221, and c-miR-760 predicted response to treatment (p < 0.0001) and was significantly associated to PFS (HR = 10.68; 95% CI 3.2-35.65; p < 0.0001). In the validation cohort (n = 36), the increase in c-miR-21 (p = 0.02) and c-miR-601 (p = 0.02) levels at d15 was confirmed, but the associations with outcome were not. Our data indicate that early changes of c-miRNA levels might be influenced by regorafenib treatment. However, further studies are needed to establish the predictive power of such modifications.
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http://dx.doi.org/10.1038/s41397-019-0075-3DOI Listing
October 2019

Safety and Tolerability of c-MET Inhibitors in Cancer.

Drug Saf 2019 02;42(2):211-233

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA, 90033, USA.

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.
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http://dx.doi.org/10.1007/s40264-018-0780-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491978PMC
February 2019

Role of CCL5 and CCR5 gene polymorphisms in epidermal growth factor receptor signalling blockade in metastatic colorectal cancer: analysis of the FIRE-3 trial.

Eur J Cancer 2019 01 14;107:100-114. Epub 2018 Dec 14.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA.

Background: Epidermal growth factor receptor signalling blockade increases CCL5 expression that regulates either the anti-tumour immune response or tumour progression. We investigated the potential role of CCL5/CCR5 axis in cetuximab-based treatment in metastatic colorectal cancer (mCRC) patients.

Patients And Methods: Genomic DNA was extracted from 491 samples of two different cohorts with KRAS wild-type mCRC from the FIRE-3 trial: an evaluation cohort of 244 patients receiving cetuximab plus FOLFIRI and a control cohort of 247 patients receiving bevacizumab plus FOLFIRI. Single-nucleotide polymorphisms (SNPs) of CCL5 and CCR5 genes were analysed by polymerase chain reaction-based direct sequencing.

Results: Patients in the evaluation cohort with any CCL5 rs2280789G allele had shorter overall survival (OS) compared with those with the A/A variant (hazard ratio 1.56, P = 0.024). Patients carrying any CCR5 rs1799988T allele had a trend toward lower response rate than those with the C/C variant (68 vs. 81%, P = 0.078). In the analysis based on primary tumour location (left-sided [L]: right-sided [R]), remarkable differences in outcomes were observed between patients with L-CCR5 SNPs C/C variant (L-C/C), L-any T, R-T/T and R-any C as follows: median OS, 38.5, 30.6, 27.1 and 15.8 months, P < 0.001; response rate, 91, 66, 92 and 48%, P < 0.001. Median OS for CCL5 SNPs including L-A/A, L-any G, R-A/A and R-any G groups were 38.3, 21.7, 21.9 and 18.3 months, P < 0.001. The findings were not significant in the control cohort.

Conclusion: Genetic variants of CCL5 and CCR5 SNPs may predict outcomes in mCRC patients receiving cetuximab-based treatment depending on tumour location.
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http://dx.doi.org/10.1016/j.ejca.2018.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367121PMC
January 2019

Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.

Int J Cancer 2019 05 14;144(10):2567-2577. Epub 2018 Dec 14.

Division of Medical Oncology Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.
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http://dx.doi.org/10.1002/ijc.31968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497849PMC
May 2019

Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study.

Clin Colorectal Cancer 2018 09 8;17(3):e601-e615. Epub 2018 Jun 8.

Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy. Electronic address:

Background: The impact of free triiodothyronine (FT)/free thyroxine (FT) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT/FT ratio in patients with advanced cancer. We evaluated the impact of FT/FT ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib.

Methods: Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT, FT, and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT/FT ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari.

Results: In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT/FT ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models.

Conclusions: High baseline FT/FT ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect.
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http://dx.doi.org/10.1016/j.clcc.2018.05.013DOI Listing
September 2018

Another Chapter of the : Is Primary Tumor Location a Prognostic Feature in Mutant Metastatic Colorectal Cancer?

Oncologist 2019 02 17;24(2):e77-e79. Epub 2018 Aug 17.

Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy.

Background: The prognostic value of primary tumor location (PTL) in patients with metastatic colorectal cancer (mCRC) was reported by recent analyses in wild-type patients. Here, we investigated the prognostic value of PTL in mutated mCRC patients.

Materials And Methods: PTL was defined as left or right if distal or proximal to the splenic flexure. Primary endpoint was overall survival (OS) according to PTL. Subgroup analyses were conducted according to time to metastases and mutation subtypes.

Results: Five hundred sixty-four patients were included. Left- and right-sided cases were 65% and 35%, respectively. No difference in OS was detected according to PTL (hazard ratio [HR] = 0.99, = .964). No difference in OS was observed in right versus left when looking at synchronous (HR 0.92, = .557) or metachronous (HR 1.07, = .807) patients.

Conclusion: No OS difference was detected in mutated mCRC. Molecular and clinical features able to improve prognosis and treatment strategies in this setting are needed.
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http://dx.doi.org/10.1634/theoncologist.2018-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369947PMC
February 2019

Potential role of PIN1 genotypes in predicting benefit from oxaliplatin-based and irinotecan-based treatment in patients with metastatic colorectal cancer.

Pharmacogenomics J 2018 09 21;18(5):623-632. Epub 2018 Jun 21.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P < 0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P = 0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45-0.91, P = 0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47-0.78, P < 0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62-1.02, P = 0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.
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http://dx.doi.org/10.1038/s41397-018-0030-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151284PMC
September 2018

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

Clin Colorectal Cancer 2018 09 14;17(3):e471-e488. Epub 2018 Mar 14.

Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA. Electronic address:

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-β 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 χ 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.
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http://dx.doi.org/10.1016/j.clcc.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110978PMC
September 2018

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

Clin Colorectal Cancer 2018 06 27;17(2):e395-e414. Epub 2018 Feb 27.

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. Electronic address:

Background: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib.

Patients And Methods: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing.

Results: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026).

Conclusion: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy.
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http://dx.doi.org/10.1016/j.clcc.2018.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493703PMC
June 2018

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials.

Br J Cancer 2018 04 13;118(7):955-965. Epub 2018 Mar 13.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori - Via Venezian, 1, 20100, Milano, Italy.

Background: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.

Methods: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.

Results: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).

Conclusions: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.
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http://dx.doi.org/10.1038/s41416-018-0015-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931102PMC
April 2018