Publications by authors named "Eduardo Diaz-Rubio"

147 Publications

Treatment breaks in first line treatment of advanced colorectal cancer: An individual patient data meta-analysis.

Cancer Treat Rev 2021 Sep 19;99:102226. Epub 2021 May 19.

MRC Clinical Trials Unit at UCL, United Kingdom. Electronic address:

Background: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break.

Patients And Methods: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken.

Results: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy).

Conclusion: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.
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http://dx.doi.org/10.1016/j.ctrv.2021.102226DOI Listing
September 2021

Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer.

J Natl Cancer Inst 2021 Jun 1. Epub 2021 Jun 1.

Department of Gastrointestinal Onocology, Keck School of Medicine at USC, Los Angeles, CA, USA.

Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.

Methods: PTS data of 9,277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemo, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs. chemotherapy alone). All statistical tests were 2-sided.

Results: Compared to right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 v 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67-0.76, P<.001) and PFS (median = 8.6 v 7.5 months; HRadj = 0.80, 95% CI = 0.75-0.84, P<.001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction<.001): left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53-0.66; PFS HRadj =0.68, 95% CI = 0.61-0.75), but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75-0.97, P = .01; PFS HRadj = 0.77, 95% CI = 0.67-0.88, P<.001), but not for right-sidedness.

Conclusions: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.
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http://dx.doi.org/10.1093/jnci/djab112DOI Listing
June 2021

Implementation of the Quality Oncology Practice Initiative Program in Spain: First Results and Implications.

JCO Oncol Pract 2021 Aug 23;17(8):e1162-e1169. Epub 2021 Feb 23.

Fundación ECO (Excelencia y Calidad en Oncología), Madrid, Spain.

Purpose: Measuring and tracking quality of care is highly relevant in today's health care. The Quality Oncology Practice Initiative (QOPI) program is a referral for evaluating oncology practices worldwide. Excellence and Quality in Oncology Foundation, a collaboration of oncology experts from major Spanish hospitals involved in cancer treatment, reached an agreement with QOPI to include Spanish hospitals in this program.

Methods: We analyzed the results of the QOPI Core module measures from 19 Spanish hospitals over nine rounds (from fall 2015 to fall 2019).

Results: Of the 19 hospitals, 15 completed more than one round; none participated in all nine (two hospitals participated in eight rounds). The highest scores were for pathology report confirming malignancy, documenting a plan of care for moderate or severe pain and chemotherapy dose, and chemotherapy administered to patients with metastatic solid tumor with performance status undocumented. Measures regarding a summary of chemotherapy treatment, tobacco use cessation counseling, and assessment of patient emotional well-being were among the lowest scored measures. Six of the 15 practices that participated repeatedly achieved a better score in their last round compared with their first. Overall, scores of Spanish hospitals improved from 67.79% in fall 2015 to 68.91% in fall 2019.

Conclusion: To our knowledge, this is the first study to evaluate QOPI scores in Spain. There was high variability in scores, with quality of care improving with repeated participation in some hospitals, but worsening in others. Excellence and Quality in Oncology Foundation will support practices to increase their participation to improve oncology care and implement strategies that address the areas for improvement.
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http://dx.doi.org/10.1200/OP.20.00683DOI Listing
August 2021

First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis.

Drugs Aging 2021 03 22;38(3):219-231. Epub 2021 Feb 22.

IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain.

Background: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited.

Objective: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy.

Methods: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety.

Results: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%).

Conclusions: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.
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http://dx.doi.org/10.1007/s40266-021-00834-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914239PMC
March 2021

FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial.

ESMO Open 2020 11;5(6):e000944

Instituto de Investigación Hospital Clinico San Carlos (IdISSC), CIBERONC, Hospital Clínico San Carlos, Medical Oncology Department, Madrid, Spain.

Purpose: 5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab.

Patients And Methods: VISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m, oxaliplatin 85 mg/m, leucovorin 400 mg/m and 5-fluorouracil 3200 mg/m) or FOLFOX (oxaliplatin 85 mg/m, leucovorin 400 mg/m, 5-fluorouracil 400 mg/m then 2400 mg/m) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS).

Results: The intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively.

Conclusions: First-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.
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http://dx.doi.org/10.1136/esmoopen-2020-000944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640586PMC
November 2020

Behavioural and structural interventions in cancer prevention: towards the 2030 SDG horizon.

Mol Oncol 2021 03 15;15(3):801-808. Epub 2020 Oct 15.

Servicio Oncologia Medica, Hospital Clinico San Carlos, Madrid, Spain.

Traditionally, the prevention of cancer (and other chronic diseases) has been considered primarily linked to personal responsibility, for which interventions must be based on health education information enabling individuals to make knowledge-based decisions to improve their lifestyle. However, lifestyle is conditioned by environmental factors (including dimensions such as the context of economics, transport, urbanism, agriculture or education) that may render healthy behavioural choices either easier or, alternatively, impossible. This article reviews the conceptual underpinnings of the behavioural-structural dichotomy. We believe that it is advisable to opt for multilevel strategies that take into account all the determinants of health, using structural and behavioural approaches, rather than only the latter, as has been done until now.
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http://dx.doi.org/10.1002/1878-0261.12805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931131PMC
March 2021

SOD3 induces a HIF-2α-dependent program in endothelial cells that provides a selective signal for tumor infiltration by T cells.

J Immunother Cancer 2020 06;8(1)

Department of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid, Spain

Background: Tumor-infiltrating lymphocytes (TILs), mainly CD8 cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium.

Results: Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4 and CD8 T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4 and CD8 effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8 T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8 TIL density and disease-free survival. SOD3 expression was also linked to a T cell-inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program.

Conclusion: Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically "cold" into "hot" tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8 T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type-specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.
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http://dx.doi.org/10.1136/jitc-2019-000432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319787PMC
June 2020

Association Between Baseline Circulating Tumor Cells, Molecular Tumor Profiling, and Clinical Characteristics in a Large Cohort of Chemo-naïve Metastatic Colorectal Cancer Patients Prospectively Collected.

Clin Colorectal Cancer 2020 09 6;19(3):e110-e116. Epub 2020 Mar 6.

Medical Oncology IMIBIC, Reina Sofía Hospital, University of Córdoba, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III, Córdoba, Spain.

Background: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population.

Patients And Methods: A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients.

Results: Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels.

Conclusions: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors.

Trial Registration Number: VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.
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http://dx.doi.org/10.1016/j.clcc.2020.02.014DOI Listing
September 2020

Tumour location and efficacy of first-line EGFR inhibitors in wild-type metastatic colorectal cancer: retrospective analyses of two phase II randomised Spanish TTD trials.

ESMO Open 2019 1;4(6):e000599. Epub 2019 Dec 1.

Medical Oncology Service, Hospital General Universitario Gregorio Maranon, Madrid, Spain.

Purpose: Metastatic colorectal cancer (mCRC) is a group of distinct diseases, with clinical and molecular differences between right-sided and left-sided tumours driving varying prognosis.

Methods: Patients with /-wild type (wt) mCRC treated in first line with epidermal growth factor receptor inhibitors (EGFR-Is) (cetuximab or panitumumab) plus oxaliplatin or irinotecan-based chemotherapy from two phase II randomised trials conducted by the Spanish Cooperative for the Treatment of Digestive Tumours group were included in this retrospective study. The main objective was to analyse the prognostic effect of primary tumour location on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Results: Patients with -wt right-sided tumours (n=52) had significantly lower efficacy as compared with patients with -wt left-sided tumours (n=209); confirmed ORR (25% vs 47%, respectively; OR 0.4, 95% CI 0.2 to 0.8, p=0.004); and shorter median PFS (7.2 vs 9.9 months; HR 0.6, 95% CI 0.4 to 0.9, p=0.0157) and OS (13.6 vs 27.7 months; HR 0.5, 95% CI 0.3 to 0.7, p<0.0001). Similar results were observed in the -wt populations. The further classification of left-sided tumours as colon or rectum delivered similar survival outcomes, as well as a tendency to diminished ORR in patients with rectum tumours.

Conclusion: We observed significantly improved efficacy outcomes in patients with /-wt mCRC treated with first-line EGFR-I plus chemotherapy in left-sided primary tumours as compared with right-sided primary tumours.

Trial Registration Numbers: NCT01161316 and NCT00885885.
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http://dx.doi.org/10.1136/esmoopen-2019-000599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890384PMC
June 2020

Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer.

JAMA Netw Open 2019 09 4;2(9):e1911750. Epub 2019 Sep 4.

Hasselt University, Diepenbeek, Belgium.

Importance: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS).

Objective: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer.

Design, Setting, And Participants: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer.

Main Outcomes And Measures: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS.

Results: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78).

Conclusions And Relevance: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.11750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755539PMC
September 2019

Working towards a consensus on the oncological approach of breakthrough pain: a Delphi survey of Spanish experts.

J Pain Res 2019 29;12:2349-2358. Epub 2019 Jul 29.

Jefe del Servicio de Oncología Médica, Instituto Valenciano de Oncología, Valencia, Spain.

Purpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients.

Patients And Methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of ≥7, and agreement among panelists as an interquartile range (IQR) of ≤3.

Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient's quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl.

Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research.
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http://dx.doi.org/10.2147/JPR.S203903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681159PMC
July 2019

A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients.

Br J Cancer 2019 08 31;121(5):378-383. Epub 2019 Jul 31.

IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC, Instituto de Salud Carlos III, Córdoba, Spain.

Background: Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients.

Methods: KRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy.

Results: Sixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7-4.3) and median OS of 12.5 months (95% CI 6.7-15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3-4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each).

Conclusions: The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.
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http://dx.doi.org/10.1038/s41416-019-0537-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738054PMC
August 2019

Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing.

Sci Rep 2019 07 8;9(1):9814. Epub 2019 Jul 8.

Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, IdISSC, CIBERONC, Madrid, Spain.

Attenuated adenomatous polyposis (AAP) is a heterogeneous syndrome in terms of clinical manifestations, heritability and etiology of the disease. Genetic heterogeneity and low penetrance alleles are probably the best explanation for this variability. Certainly, it is known that APC and MUTYH are high penetrance predisposition genes for adenomatous polyposis, but they only account for 5-10% of AAP. Other new predisposition genes, such as POLE, POLD1, NTHL1, AXIN2 or MSH3, have been recently described and have been associated with AAP, but their relative contribution is still not well defined. In order to evaluate the genetic predisposition to AAP in a hospital based population, germline DNAs from 158 AAP subjects were screened for genetic variants in the coding regions and intron-exon boundaries of seven associated genes through a next-generation sequencing (NGS) custom gene panel. Splicing, segregation studies, somatic mutational screening and RNA quantitative expression assays were conducted for selected variants. In four of the probands the adenoma susceptibility could be explained by actionable mutations in APC or MUTYH, and one other patient was a double carrier of two truncating variants in both POLE and NTHL1. Furthermore, 16 additional patients harbored uncertain significance variants in the remaining tested genes. This report gives information about the contribution of the newly described adenomatous polyposis predisposition genes in a Spanish attenuated polyposis cohort. Our results highly support the convenience of NGS multigene panels for attenuated polyposis genetic screening and reveals POLE frameshift variants as a plausible susceptibility mechanism for AAP.
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http://dx.doi.org/10.1038/s41598-019-46403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614360PMC
July 2019

Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples.

Sci Rep 2019 06 20;9(1):8976. Epub 2019 Jun 20.

Laboratorio de Investigación Traslacional, IdISSC, Hospital Clínico San Carlos, CIBERONC, Madrid, Spain.

KRAS mutations are common in colorectal cancer (CRC). In this setting, mutation status determination in circulating-free DNA from blood samples (liquid biopsy) has been shown to be a viable alternative to tissue testing. The objective of this study was to compare the sensitivity of two liquid biopsy methods for detecting KRAS mutations in plasma samples from metastatic CRC patients. Samples with a positive (KRAS-MUT+) result and a mutant allelic fraction (MAF) < 5% according to the OncoBEAM RAS CRC assay were pairly analyzed by the Idylla ctKRAS Mutation Test (n = 116). In a cohort of 71 patients with at least 1 year of follow-up, the progression-free survival (PFS) was determined according to MAF values. Idylla detected KRAS mutations in 81/116 OncoBEAM KRAS-MUT+ samples with MAF < 5% and in 48/79 samples with MAF < 1%. Concordance between OncoBEAM and Idylla significantly improved at higher MAF values. PFS rates at 6 and 12 months tended to be lower in patients with MAF levels between 1% and 5% than in those with levels <1%. OncoBEAM demonstrated greater sensitivity for plasma detection of KRAS mutations than Idylla. Importantly, our data identified a "gray zone" below 1% MAF where Idylla showed reduced KRAS mutation detection, highlighting the importance of an accurate method to provide the mutational status of CRC patients.
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http://dx.doi.org/10.1038/s41598-019-45616-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586620PMC
June 2019

Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.

J Med Genet 2019 07 19;56(7):453-460. Epub 2019 Mar 19.

Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Background: monoallelic germ-line variants confer a breast cancer risk comparable to the average pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify variants in without incurring overprediction-is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in , analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.

Methods: Alternative splicing was characterised in RNAs extracted from blood, breast and /ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in c.212-1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant.

Results: We identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies.

Conclusions: PVS1 is not necessarily warranted for splice site variants targeting four acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed / without further evidences. Our study puts a warning in up to five genetic variants that are currently reported as in ClinVar.
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http://dx.doi.org/10.1136/jmedgenet-2018-105834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591742PMC
July 2019

The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper.

Crit Rev Oncol Hematol 2019 Feb 19;134:39-45. Epub 2018 Dec 19.

Women Cancer Center, Azienda Socio Sanitaria Territoriale di Cremona, University of Trieste, Italy.

Background: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease.

Methods: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with ≥ 5 CTCs were classified as Stage IV, those with < 5 CTCs as Stage IV Survival was analyzed using Kaplan-Meier curves and the log rank test.

Results: For all patients, Stage IV patients had longer median overall survival than those with Stage IV (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IV vs. 18.7 months Stage IV, p < 0.0001). Moreover, patients with Stage IV disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location.

Conclusions: We confirm the identification of two subgroups of MBC, Stage IV and Stage IV, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.
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http://dx.doi.org/10.1016/j.critrevonc.2018.12.004DOI Listing
February 2019

Nasoethmoidal Intestinal-Type Adenocarcinoma Treated with Cetuximab: Role of Liquid Biopsy and BEAMing in Predicting Response to Anti-Epidermal Growth Factor Receptor Therapy.

Oncologist 2019 03 2;24(3):293-300. Epub 2019 Jan 2.

Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.

Sinonasal intestinal-type adenocarcinomas (SNS-ITAC) are very rare tumors that resemble colorectal cancer in many of their pathological and molecular characteristics. Indeed, in most published series, 10%-14% of SNS-ITAC harbor mutations in . There is no standard systemic treatment in recurrent or metastatic SNS-ITAC, and there is no evidence of the use of any targeted agent in this entity. We present the case of a recurrent nasoethmoidal ITAC informed as and wild-type by standard real-time polymerase chain reaction methods and treated with first-line cetuximab and irinotecan without response. Circulating tumor cells coupled to highly sensitive DNA analyses unveiled a mutation in exon 2 codon 12. Subsequent studies in the primary tumor using BEAMing detected a mutation in the same codon, confirming the mutated status of the tumor, and possibly explaining the absence of treatment response. This case exemplifies how liquid biopsy can aid in the correct and real-time molecular characterization of tumors even in a rare nonmetastatic cancer of the head and neck. KEY POINTS: Sinonasal intestinal type adenocarcinomas (SNS-ITAC) are rare tumors that commonly develop after a prolonged exposure to organic dusts (wood, leather, etc.), and that resemble colorectal cancer in some of their morphological and molecular characteristics. mutations have been described in 10%-14% in most series. However, its predictive value for guiding treatment decisions with targeted therapies (i.e., anti-epidermal growth factor receptor [EGFR] therapy) has not been defined.The first case of an SNS-ITAC treated with anti-EGFR therapy (cetuximab) is reported. Analysis of DNA from circulating tumor cells (CTCs) unveiled a mutation in not detected by standard methods in the primary tumor. However, analysis using BEAMing detected a mutation in the primary tumor in the same codon of originally detected in CTCs, altogether possibly explaining the lack of treatment response.Liquid biopsy may allow for an accurate molecular diagnosis in rare, organ-confined tumors where few therapeutic options exist. Highly sensitive molecular diagnostics may aid in better characterizing rare entities harboring potentially druggable targets.
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http://dx.doi.org/10.1634/theoncologist.2018-0387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519763PMC
March 2019

Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer.

Br J Cancer 2018 12 23;119(12):1464-1470. Epub 2018 Nov 23.

Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Liquid biopsy offers a minimally invasive alternative to tissue-based evaluation of mutational status in cancer. The goal of the present study was to evaluate the aggregate performance of OncoBEAM RAS mutation analysis in plasma of colorectal cancer (CRC) patients at 10 hospital laboratories in Spain where this technology is routinely implemented.

Methods: Circulating cell-free DNA from plasma was examined for RAS mutations using the OncoBEAM platform at each hospital laboratory. Results were then compared to those obtained from DNA extracted from tumour tissue from the same patient.

Results: The overall percentage agreement between plasma-based and tissue-based RAS mutation testing of the 236 participants was 89% (210/236; kappa, 0.770 (95% CI: 0.689-0.852)). Re-analysis of tissue from all discordant cases by BEAMing revealed two false negative and five false positive tumour tissue RAS results, with a final concordance of 92%. Plasma false negative results were found more frequently in patients with exclusive lung metastatic disease.

Conclusions: In this first prospective real-world RAS mutation performance comparison study, a high overall agreement was observed between results obtained from plasma and tissue samples. Overall, these findings indicate that the plasma-based BEAMing assay is a viable solution for rapid delivery of RAS mutation status to determine mCRC patient eligibility for anti-EGFR therapy.
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http://dx.doi.org/10.1038/s41416-018-0293-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288144PMC
December 2018

Trabectedin for reversing platinum resistance and resensitization to platinum in patients with recurrent ovarian cancer.

Future Oncol 2019 Jan 22;15(3):271-280. Epub 2018 Nov 22.

Department of Medical Oncology, University Hospital San Carlos, Madrid, Spain.

Aims: We evaluated trabectedin in patients with platinum-resistant/refractory and partially platinum-sensitive recurrent ovarian cancer and the outcomes after reintroduction of platinum.

Methods: Twenty-seven patients (platinum-resistant/refractory n = 24/PPS; n = 3) treated with trabectedin were retrospectively analyzed.

Results: Trabectedin resulted in an objective response rate (ORR) of 18.2% with a 59.1% of disease control rate (ORR plus stable disease). The median progression-free and overall survival were 3.0 and 21.3 months, respectively. Subsequently, 17 patients were retreated with platinum and yield an ORR of 41.2% and DCR of 47.0%. The median progression-free and overall survival after platinum rechallenge were 5.0 and 14.7 months, respectively.

Conclusion: Our results suggest that trabectedin may contribute to resensitize tumor cells to platinum rechallenge.
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http://dx.doi.org/10.2217/fon-2018-0554DOI Listing
January 2019

Clinicopathological differences and survival outcomes with first-line therapy in patients with left-sided colon cancer and rectal cancer: Pooled analysis of 2879 patients from AGITG (MAX), COIN, FOCUS2, OPUS, CRYSTAL and COIN-B trials in the ARCAD database.

Eur J Cancer 2018 11 27;103:205-213. Epub 2018 Sep 27.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Purpose: Patients with left-sided colon tumours have better survival and respond differently to biologics compared with patients with right-sided tumours. Left-sided colon tumours and rectal cancers are often grouped together. Herein, we examined the clinicopathological differences and outcomes between left-sided colon and rectal cancers.

Patients And Methods: Data from 2879 metastatic colorectal cancer patients enrolled on six first-line clinical trials during 2004-2010 were pooled. Patients were included if the primary tumour origin was clearly defined. Progression-free survival (PFS) and overall survival (OS) were compared in the two groups after adjusting for patient and tumour characteristics, metastatic sites and the first-line regimen.

Results: In total, 1374 patients with metastatic left-sided colon cancer and 1505 patients with metastatic rectal cancers were evaluated. Left-sided colon cancer patients were more likely to be female (40.1% versus 32.6%; P < 0.0001) and older (31.0% ≥ 70 years versus 25.8%; P = 0.0033) compared with rectal cancers patients. Patients with left-sided colon cancer had higher rates of liver metastases (80.9% versus 72.3%, P < 0.0001) but lower rates of lung metastases (34.2% versus 53.8%, P < 0.0001). KRAS mutations were slightly less frequent among left-sided tumours (34.8% versus 40.5%; P = 0.0103). Patients with left-sided tumours had approximately similar PFS (median 7.4 versus 6.9 months; hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.87-1.03; P = 0.1998) and OS (median 17.4 versus 16.6 months; HR 0.99, 95% CI 0.91-1.07; P = 0.7597) compared with rectal cancer patients.

Conclusion: The site of tumour origin within the left side was not prognostic of outcomes. Moreover, neither bevacizumab nor cetuximab impacted, differently, the findings of the comparisons in outcomes between patients with left-sided colon tumours or rectal cancers.
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http://dx.doi.org/10.1016/j.ejca.2018.08.020DOI Listing
November 2018

Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.

PLoS One 2018 26;13(9):e0203885. Epub 2018 Sep 26.

Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.

Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203885PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157886PMC
March 2019

Consensus statement on essential patient characteristics in systemic treatment trials for metastatic colorectal cancer: Supported by the ARCAD Group.

Eur J Cancer 2018 09 22;100:35-45. Epub 2018 Jun 22.

Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Patient characteristics and stratification factors are key features influencing trial outcomes. However, there is substantial heterogeneity in reporting of patient characteristics and use of stratification factors in phase 3 trials investigating systemic treatment of metastatic colorectal cancer (mCRC). We aimed to develop a minimum set of essential baseline characteristics and stratification factors to include in such trials.

Methods: We performed a modified, two-round Delphi survey among international experts with wide experience in the conduct and methodology of phase 3 trials of systemic treatment of mCRC.

Results: Thirty mCRC experts from 15 different countries completed both consensus rounds. A total of 14 patient characteristics were included in the recommended set: age, performance status, primary tumour location, primary tumour resection, prior chemotherapy, number of metastatic sites, liver-only disease, liver involvement, surgical resection of metastases, synchronous versus metachronous metastases, (K)RAS and BRAF mutation status, microsatellite instability/mismatch repair status and number of prior treatment lines. A total of five patient characteristics were considered the most relevant stratification factors: RAS/BRAF mutation status, performance status, primary tumour sidedness and liver-only disease.

Conclusions: This survey provides a minimum set of essential baseline patient characteristics and stratification factors to include in phase 3 trials of systemic treatment of mCRC. Inclusion of these patient characteristics and strata in study protocols and final study reports will improve interpretation of trial results and facilitate cross-study comparisons.
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http://dx.doi.org/10.1016/j.ejca.2018.05.010DOI Listing
September 2018

Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis.

J Natl Cancer Inst 2018 06;110(6):560-567

Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker.

Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided.

Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008).

Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.
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http://dx.doi.org/10.1093/jnci/djy018DOI Listing
June 2018

Bevacizumab-based first-line chemotherapy in elderly patients with metastatic colorectal cancer: an individual patient data based meta-analysis.

Oncotarget 2018 Feb 20;9(12):10272-10283. Epub 2017 Dec 20.

Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany.

Background: The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients (≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials.

Results: Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70-88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials.

Materials And Methods: PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age.

Conclusions: This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.
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http://dx.doi.org/10.18632/oncotarget.23475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828201PMC
February 2018

SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α.

Nat Commun 2018 02 8;9(1):575. Epub 2018 Feb 8.

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin, 3, Madrid, 28049, Spain.

One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2α (HIF-2α) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2α ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2α levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.
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http://dx.doi.org/10.1038/s41467-018-03079-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805714PMC
February 2018

Personalizing Survival Predictions in Advanced Colorectal Cancer: The ARCAD Nomogram Project.

J Natl Cancer Inst 2018 06;110(6):638-648

Mayo Clinic, Rochester, MN.

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database.

Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257).

Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals.

Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.
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http://dx.doi.org/10.1093/jnci/djx253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005015PMC
June 2018

Role of GALNT12 in the genetic predisposition to attenuated adenomatous polyposis syndrome.

PLoS One 2017 2;12(11):e0187312. Epub 2017 Nov 2.

Laboratorio de Oncología Molecular, CIBERONC, IdISSC, Hospital Clínico San Carlos, Madrid, Spain.

The involvement of GALNT12 in colorectal carcinogenesis has been demonstrated but it is not clear to what extent it is implicated in familial CRC susceptibility. Partially inactivating variant, NM_024642.4:c.907G>A, p.(D303N), has been previously detected in familial CRC and proposed as the causative risk allele. Since phenotypes of the described carrier families showed not only CRC but also a polyp history, we hypothesized that GALNT12 could be involved in adenoma predisposition and consequently, in hereditary polyposis CRC syndromes. For that purpose, we have screened the GALNT12 gene in germline DNA from 183 unrelated attenuated polyposis patients. c.907G>A, p.(D303N) was detected in 4 cases (MAF = 1.1%) and no other candidate variants were found. After segregation studies, LOH analyses, glycosylation pattern tests and case-control studies, our results did not support the role of c.907G>A, p.(D303N) as a high-penetrance risk allele for polyposis CRC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667827PMC
December 2017

Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database.

J Clin Oncol 2017 Jun 17;35(17):1929-1937. Epub 2017 Apr 17.

Lindsay A. Renfro, Axel Grothey, and Daniel J. Sargent, Mayo Clinic, Rochester, MN; Richard M. Goldberg, The Ohio State University, Columbus, OH; Alberto Sobrero, Ospedale San Martino, Genoa; Alfredo Falcone, University Hospital of Pisa, Pisa, Italy; Richard Adams, Cardiff University, Cardiff; Matthew T. Seymour, St James's Hospital and University of Leeds, Leeds, United Kingdom; Volker Heinemann, University of Munich, Munich; Hans-Joachim Schmoll, University Clinic Halle (Saale), Halle; Rainer Porschen, Klinikum Bremen-Ost Klinik für Innere Medizin, Bremen; Carsten Bokemeyer, University Hospital, Hamburg-Eppendorf, Germany; Jean-Yves Douillard, Centre René Gauducheau, Nantes; Christophe Tournigand, University of Paris Est Creteil; Christophe Tournigand, Assistance Hopitaux Publique de Paris Henri-Mondor Hospital, Créteil; Benoist Chibaudel and Aimery de Gramont, Franco-British Institute, Levallois-Perret, France; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Charles S. Fuchs; Dana-Farber Cancer Institute, Boston, MA; Eduardo Diaz-Rubio, Hospital Clínico San Carlos, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain; Paulo M. Hoff, Hospital Sírio-Libanês and University of São Paulo, São Paulo, Brazil; Fairooz F. Kabbinavar and J. Randolph Hecht, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA; Niall C. Tebbutt, Austin Health, Heidelberg, Victoria, Australia; Cornelis J.A. Punt, University of Amsterdam, Amsterdam, the Netherlands; John Souglakos, University of Crete, Heraklion, Greece; Eric Van Cutsem, University Hospital Leuven, Leuven, Belgium; and Leonard Saltz, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.
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http://dx.doi.org/10.1200/JCO.2016.71.5771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466009PMC
June 2017

Tumor burden monitoring using cell-free tumor DNA could be limited by tumor heterogeneity in advanced breast cancer and should be evaluated together with radiographic imaging.

BMC Cancer 2017 03 22;17(1):210. Epub 2017 Mar 22.

Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.

Background: Accurate measurement of tumor burden in breast cancer disease is essential to improve the clinical management of patients. In this study, we evaluate whether the fluctuations in the fraction of PIK3CA mutant allele correlates with tumor response according to RECIST criteria and tumor markers quantification.

Methods: Eighty six plasma samples were analyzed by digital PCR using Rare Mutation Assays for E542K, E545K and H1047R. Mutant cfDNA and tumor markers CA15-3 and CEA were compared with radiographic imaging.

Results: The agreement between PIK3CA mutation status in FFPE samples and circulating tumor DNA (ctDNA) was moderate (K = 0.591; 95% IC = 0.371-0.811). Restricting the analysis to the metastatic patients, we found a good agreement between PIK3CA mutation status assessed in liquid and solid biopsy (K = 0.798 95%; IC = 0.586-1). ctDNA showed serial changes with fluctuations correlating with tumor markers 15.3 and CEA in 7 out of 8 cases with Pearson correlation coefficients ranging from 0.99 to 0.46 and from 0.99 to 0.38 respectively. Similarly, fluctuations in the fraction of PIK3CA mutant allele always correlated with changes in lesion size seen on images, although in two cases it did not correlate with treatment responses as defined by RECIST criteria.

Conclusion: oncogenic mutation quantification in plasma samples can be useful to monitor treatment outcome. However, it might be limited by tumor heterogeneity in advanced disease and it should be evaluated together with radiographic imaging.
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http://dx.doi.org/10.1186/s12885-017-3185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362993PMC
March 2017

Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.

Lancet Oncol 2016 Dec 12;17(12):1709-1719. Epub 2016 Oct 12.

Department of Oncology, Mayo Clinic, Rochester, MN, USA.

Background: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy.

Methods: We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location [colon vs rectum], previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases.

Findings: Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 [41%] of 1371 vs 3312 [36%] of 9169 patients; p=0·0003), have colon primary tumours (1116 [84%] of 1334 patients vs 5603 [66%]; p<0·0001), and have performance status of 2 (136 [10%] vs 521 [6%]; p<0·0001). We recorded a higher proportion of patients with mutated BRAF in patients with peritoneal-only (eight [18%] of 44 patients with available data) and peritoneal metastatic colorectal cancer with other sites of metastasis (34 [12%] of 289), compared with patients with non-peritoneal metastatic colorectal cancer (194 [9%] of 2230; p=0·028 comparing the three groups). Overall survival (adjusted HR 0·75, 95% CI 0·63-0·91; p=0·003) was better in patients with isolated non-peritoneal sites than in those with isolated peritoneal metastatic colorectal cancer. Overall survival of patients with two of more non-peritoneal sites of metastasis (adjusted HR 1·04, 95% CI 0·86-1·25, p=0.69) and those with peritoneal metastatic colorectal cancer plus one other site of metastasis (adjusted HR 1·10, 95% CI 0·89-1·37, p=0·37) was similar to those with isolated peritoneal metastases. Compared with patients with isolated peritoneal metastases, those with peritoneal metastases and two or more additional sites of metastasis had the shortest survival (adjusted HR 1·40; CI 1·14-1·71; p=0·0011).

Interpretation: Patients with peritoneal metastatic colorectal cancer have significantly shorter overall survival than those with other isolated sites of metastases. In patients with several sites of metastasis, poor survival is a function of both increased number of metastatic sites and peritoneal involvement. The pattern of metastasis and in particular, peritoneal involvement, results in prognostic heterogeneity of metastatic colorectal cancer.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(16)30500-9DOI Listing
December 2016
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