Publications by authors named "Josep Tabernero"

409 Publications

High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer.

Clin Cancer Res 2021 Sep 30. Epub 2021 Sep 30.

Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO)

Purpose: amplification (amp) is recurrent in metastatic breast cancer (BC) and is associated with resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Multi-tyrosine kinase inhibitors (MTKI) and selective pan-FGFR inhibitors (FGFRi) are being developed for amp BC. High-level amplification and protein expression by IHC have identified BC responders to FGFRi or MTKI, respectively.

Experimental Design: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of seventeen BC patient-derived xenografts (PDXs) harboring amplification in and in ten patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.

Results: High mRNA levels but not copy number alteration (CNA) associated with FGFRi response. Treatment with MTKI showed higher response rates than with FGFRi (86% 53%), regardless of the mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRi or MTKI, and PDXs exclusively sensitive to MTKI exhibited an additional anti-angiogenic response. Consistently, clinical benefit of MTKI was not associated with high mRNA levels and it was observed in patients previously treated with anti-angiogenic drugs.

Conclusion: Tailored therapy with FGFRi in molecularly-selected metastatic BC based on high mRNA levels warrants prospective validation in luminal BC CDK4/6i-resistant patients and in TNBC patients without targeted therapeutic options.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1810DOI Listing
September 2021

The Porto European Cancer Research Summit 2021.

Mol Oncol 2021 Oct 13;15(10):2507-2543. Epub 2021 Sep 13.

Fédération of European Academies of Medicine, Brussels, Belgium.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.
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http://dx.doi.org/10.1002/1878-0261.13078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486569PMC
October 2021

Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective.

Ther Adv Med Oncol 2021 2;13:17588359211042224. Epub 2021 Sep 2.

Cancer Division, University College London Hospitals, London, UK.

Background: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres.

Methods: From the OnCovid repository ( = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT- not referred).

Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more 'Do not attempt cardio-pulmonary resuscitation' orders completed prior to (12.6% 3.7%) and during admission (50% 22.1%,  < 0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% 22.1%,  < 0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% 0%,  < 0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% 47.1%) and benzodiazepines (82.9% 41.2%) being used frequently for symptom control.

Conclusion: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population.
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http://dx.doi.org/10.1177/17588359211042224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419540PMC
September 2021

Single- and multiple-dose pharmacokinetics, potential for CYP3A inhibition, and food effect in patients with cancer and healthy subjects receiving ipatasertib.

Cancer Chemother Pharmacol 2021 Dec 1;88(6):921-930. Epub 2021 Sep 1.

Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.

Purpose: To examine the single- and multiple-dose pharmacokinetics (PK), CYP3A inhibition potential of ipatasertib, and effect of food on PK of ipatasertib in patients with refractory solid tumors and a dedicated food effect assessment in healthy subjects.

Methods: The Phase I dose-escalation study enrolled patients with solid tumors in a standard 3 + 3 design with a 1 week washout after the first dose, followed by once-daily dosing on a 3-week-on/1-week-off schedule. In the expansion cohort, the effect of ipatasertib on CYP3A substrate (midazolam) was assessed by examining the change in midazolam exposure when dosed in the absence and presence of steady-state ipatasertib at 600 mg. The effect of food on ipatasertib PK was studied with ipatasertib administered in fed or fasted state (6 patients from Phase I patient study and 18 healthy subjects from the dedicated food effect study).

Results: Ipatasertib was generally well tolerated at doses up to 600 mg given daily for 21 days. Ipatasertib showed rapid absorption (t, 0.5-3 h), was dose-proportional over a range of 200-800 mg, had a median half-life (range) of 45.0 h (27.8-66.9 h), and had approximately two-fold accumulation following once-daily dosing. Midazolam exposure (AUC) increased by 2.2-fold in the presence of ipatasertib. PK was comparable in subjects administered ipatasertib in a fed or fasted state.

Conclusion: Ipatasertib exhibited rapid absorption and was dose-proportional over a broad dose range. Ipatasertib appeared to be a moderate CYP3A inhibitor when administered at 600 mg and could be administered with or without food in clinical studies.

Trail Registration: NCT01090960 (registered March 23, 2010); NCT02536391 (registered August 31, 2015).
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http://dx.doi.org/10.1007/s00280-021-04344-9DOI Listing
December 2021

Molecular Subtyping Combined with Biological Pathway Analyses to Study Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer.

Clin Cancer Res 2021 Aug 23. Epub 2021 Aug 23.

Department of Physiology and Medical Physics, Precision Cancer Medicine Group, Royal College of Surgeons in Ireland, Dublin, Ireland.

Purpose: Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers.

Experimental Design: Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment.

Results: Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal expression is associated with REG resistance.

Conclusions: Subtype classification systems represent canonical "" (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0818DOI Listing
August 2021

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials.

Eur J Cancer 2021 Sep 9;155:168-178. Epub 2021 Aug 9.

Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Electronic address:

Purpose: Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline.

Methods: Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application.

Results: We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3-12.7) for ICIs cohort and 7.7 m (95% CI, 6.6-8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS - ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64-0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%-90%).

Conclusions: PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.
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http://dx.doi.org/10.1016/j.ejca.2021.05.040DOI Listing
September 2021

Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study.

Curr Med Res Opin 2021 Oct 28;37(10):1769-1778. Epub 2021 Jul 28.

Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Background: Vascular endothelial growth factor (VEGF)-D was identified as a potential predictive biomarker for ramucirumab efficacy in second-line metastatic colorectal cancer using a research use only (RUO) assay. We describe results with a new assay for detecting VEGF-D in human plasma.

Methods: In RAISE (Clinical Trial Registration: NCT01183780), 1072 patients were randomized 1:1 to ramucirumab or placebo plus FOLFIRI. All patients were then randomized 1:2 to marker exploratory (ME) and marker confirmatory (MC) groups, and those with plasma samples were analyzed accordingly. A new assay validated for investigational use only (IUO) was used to measure VEGF-D levels in plasma, which were analyzed for correlation with overall and progression-free survival (OS/PFS). IUO assay data were compared with historical RUO assay data.

Results: ME subset analyses determined the optimal cutpoint of 5.4 ng/mL for defining high/low VEGF-D subgroups. In the combined ME/MC placebo arms, OS/PFS were numerically greater for patients with low vs high VEGF-D (OS: 12.8 vs 11.1 months; PFS: 5.6 vs 4.2 months). In patients with high VEGF-D, ramucirumab vs placebo demonstrated a numerically greater improvement in OS and PFS. Differential efficacy by VEGF-D level was statistically significant for PFS, but not OS.

Conclusion: In patients with high VEGF-D, ramucirumab demonstrated a greater improvement in OS and PFS vs placebo; however, baseline VEGF-D level was not predictive of ramucirumab OS benefit using VEGF-D assay for IUO. The RAISE intent-to-treat results remain valid.
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http://dx.doi.org/10.1080/03007995.2021.1940908DOI Listing
October 2021

Up-to-date role of aflibercept in the treatment of colorectal cancer.

Expert Opin Biol Ther 2021 Oct 13;21(10):1315-1324. Epub 2021 Jun 13.

Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

: Colorectal cancer (CRC) is a major public health problem. Despite major progress understanding the biological basis of this tumor added to the incorporation of optimized diagnostic and therapeutic strategies, prognosis after progression on first-line standard treatment remains poor. Several antiangiogenic treatments have demonstrated improvement in overall survival (OS) in the second-line treatment being aflibercept, a fully humanized recombinant protein, one of them. The results of the VELOUR study showed that the addition of aflibercept to second-line FOLFIRI improved OS and progression-free survival.: A literature review of published clinical studies was performed in order to discuss the clinical data on aflibercept in mCRC from early drug development to real-world data.: The combination of aflibercept with FOLFIRI provides a statistical improvement in OS and in all the efficacy endpoints analyzed in the VELOUR trial, showing efficacy independently on time to progression, molecular status, prior biological treatment, or age. Further studies are needed to find new biomarkers and molecular characterization in order to better select patients that could benefit from this treatment.
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http://dx.doi.org/10.1080/14712598.2021.1935231DOI Listing
October 2021

FRESCO-2: a global Phase III study investigating the efficacy and safety of fruquintinib in metastatic colorectal cancer.

Future Oncol 2021 Aug 17;17(24):3151-3162. Epub 2021 May 17.

Division of Hematology & Oncology, Vanderbilt-Ingram Cancer Center, 2220 Pierce Ave, 777 PRB, Nashville, TN 37232, USA.

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.
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http://dx.doi.org/10.2217/fon-2021-0202DOI Listing
August 2021

KEYNOTE-859: a Phase III study of pembrolizumab plus chemotherapy in gastric/gastroesophageal junction adenocarcinoma.

Future Oncol 2021 Aug 12;17(22):2847-2855. Epub 2021 May 12.

PLA Cancer Centre of Nanjing, Jinling Hospital, Nanjing, 34210002, China.

Current guidelines recommend two-drug cytotoxic chemotherapy with a fluoropyrimidine (fluorouracil or capecitabine) and a platinum-based agent (oxaliplatin or cisplatin) as first-line treatment for advanced gastric cancer. Pembrolizumab monotherapy has demonstrated durable antitumor activity in patients with advanced programmed death ligand 1-positive (combined positive score ≥1) gastric/gastroesophageal junction adenocarcinoma. Accumulating evidence indicates that combining pembrolizumab with standard-of-care chemotherapy for the treatment of advanced or metastatic cancer improves clinical outcomes. We describe the rationale for and the design of the randomized, double-blind, placebo-controlled, Phase III KEYNOTE-859 study, which is investigating pembrolizumab in combination with chemotherapy as first-line treatment for patients with human epidermal growth factor receptor 2-negative advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma. The planned sample size is 1542 patients, and the primary end point is overall survival. NCT03675737 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2021-0176DOI Listing
August 2021

Determinants of enhanced vulnerability to coronavirus disease 2019 in UK patients with cancer: a European study.

Eur J Cancer 2021 06 6;150:190-202. Epub 2021 Apr 6.

Policlinico Universitario Campus Bio-Medico, Rome, Italy.

Background: Despite high contagiousness and rapid spread, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to heterogeneous outcomes across affected nations. Within Europe (EU), the United Kingdom (UK) is the most severely affected country, with a death toll in excess of 100,000 as of January 2021. We aimed to compare the national impact of coronavirus disease 2019 (COVID-19) on the risk of death in UK patients with cancer versus those in continental EU.

Methods: We performed a retrospective analysis of the OnCovid study database, a European registry of patients with cancer consecutively diagnosed with COVID-19 in 27 centres from 27th February to 10th September 2020. We analysed case fatality rates and risk of death at 30 days and 6 months stratified by region of origin (UK versus EU). We compared patient characteristics at baseline including oncological and COVID-19-specific therapy across UK and EU cohorts and evaluated the association of these factors with the risk of adverse outcomes in multivariable Cox regression models.

Findings: Compared with EU (n = 924), UK patients (n = 468) were characterised by higher case fatality rates (40.38% versus 26.5%, p < 0.0001) and higher risk of death at 30 days (hazard ratio [HR], 1.64 [95% confidence interval {CI}, 1.36-1.99]) and 6 months after COVID-19 diagnosis (47.64% versus 33.33%; p < 0.0001; HR, 1.59 [95% CI, 1.33-1.88]). UK patients were more often men, were of older age and have more comorbidities than EU counterparts (p < 0.01). Receipt of anticancer therapy was lower in UK than in EU patients (p < 0.001). Despite equal proportions of complicated COVID-19, rates of intensive care admission and use of mechanical ventilation, UK patients with cancer were less likely to receive anti-COVID-19 therapies including corticosteroids, antivirals and interleukin-6 antagonists (p < 0.0001). Multivariable analyses adjusted for imbalanced prognostic factors confirmed the UK cohort to be characterised by worse risk of death at 30 days and 6 months, independent of the patient's age, gender, tumour stage and status; number of comorbidities; COVID-19 severity and receipt of anticancer and anti-COVID-19 therapy. Rates of permanent cessation of anticancer therapy after COVID-19 were similar in the UK and EU cohorts.

Interpretation: UK patients with cancer have been more severely impacted by the unfolding of the COVID-19 pandemic despite societal risk mitigation factors and rapid deferral of anticancer therapy. The increased frailty of UK patients with cancer highlights high-risk groups that should be prioritised for anti-SARS-CoV-2 vaccination. Continued evaluation of long-term outcomes is warranted.
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http://dx.doi.org/10.1016/j.ejca.2021.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023206PMC
June 2021

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival.

NPJ Precis Oncol 2021 Apr 28;5(1):33. Epub 2021 Apr 28.

American Society of Clinical Oncology (ASCO), Alexandria, VA, USA.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E-05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E-04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients' treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).
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http://dx.doi.org/10.1038/s41698-021-00171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080819PMC
April 2021

The Transcription Factor SLUG Uncouples Pancreatic Cancer Progression from the RAF-MEK1/2-ERK1/2 Pathway.

Cancer Res 2021 Jul 26;81(14):3849-3861. Epub 2021 Apr 26.

Preclinical Research Programs, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Activating mutations in some isoforms of RAS or RAF are drivers of a substantial proportion of cancers. The main Raf effector, MEK1/2, can be targeted with several highly specific inhibitors. The clinical activity of these inhibitors seems to be mixed, showing efficacy against mutant BRAF-driven tumors but not KRAS-driven tumors, such as pancreatic adenocarcinomas. To improve our understanding of this context-dependent efficacy, we generated pancreatic cancer cells resistant to MEK1/2 inhibition, which were also resistant to KRAS and ERK1/2 inhibitors. Compared with parental cells, inhibitor-resistant cells showed several phenotypic changes including increased metastatic ability . The transcription factor SLUG, which is known to induce epithelial-to-mesenchymal transition, was identified as the key factor responsible for both resistance to MEK1/2 inhibition and increased metastasis. Slug, but not similar transcription factors, predicted poor prognosis of pancreatic cancer patients and induced the transition to a cellular phenotype in which cell-cycle progression becomes independent of the KRAS-RAF-MEK1/2-ERK1/2 pathway. SLUG was targeted using two independent strategies: (i) inhibition of the MEK5-ERK5 pathway, which is responsible for upregulation of SLUG upon MEK1/2 inhibition, and (ii) direct PROTAC-mediated degradation. Both strategies were efficacious in preclinical pancreatic cancer models, paving the path for the development of more effective therapies against pancreatic cancer. SIGNIFICANCE: This study demonstrates that SLUG confers resistance to MEK1/2 inhibitors in pancreatic cancer by uncoupling tumor progression from KRAS-RAF-MEK1/2-ERK1/2 signaling, providing new therapeutic opportunities. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/14/3849/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-4263DOI Listing
July 2021

José "Pepe" Baselga, MD, PhD: In Memoriam (1959-2021).

Cancer Discov 2021 Jul 21;11(7):1614-1616. Epub 2021 Apr 21.

Paris-Saclay University and Gustave Roussy Cancer Campus, Villejuif, France.

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http://dx.doi.org/10.1158/2159-8290.CD-21-0458DOI Listing
July 2021

Precision oncology in metastatic colorectal cancer - from biology to medicine.

Nat Rev Clin Oncol 2021 08 16;18(8):506-525. Epub 2021 Apr 16.

Department of Oncology, University of Torino, Candiolo, Italy.

Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.
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http://dx.doi.org/10.1038/s41571-021-00495-zDOI Listing
August 2021

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials.

JAMA Oncol 2021 Jun;7(6):895-902

David Geffen School of Medicine, University of California, Los Angeles.

Importance: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.

Objective: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.

Design, Setting, And Participants: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.

Interventions: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.

Main Outcomes And Measures: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.

Results: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.

Conclusions And Relevance: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.

Trial Registration: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.
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http://dx.doi.org/10.1001/jamaoncol.2021.0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017478PMC
June 2021

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score.

J Immunother Cancer 2021 03;9(3)

Department of Medical Oncology, Catalan Institute of Oncology, University Hospital Josep Trueta, Girona, Spain.

Background: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study.

Methods: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets.

Results: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611).

Conclusions: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.
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http://dx.doi.org/10.1136/jitc-2020-002277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985977PMC
March 2021

and inhibition as treatment strategies in V600E metastatic colorectal cancer.

Ther Adv Med Oncol 2021 22;13:1758835921992974. Epub 2021 Feb 22.

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Catalunya, Spain.

Introduction: driver mutations are found in up to 15% of patients with colorectal cancer (CRC) and lead to constitutive activation of kinase and sustained pathway signaling. mutations define a sub-population characterized by a poor prognosis and dismal median survival. Following successful outcomes with inhibition in mutant metastatic melanoma, this approach was evaluated in metastatic colorectal cancer (mCRC). The development and combination of targeted therapies against multiple signaling pathways has proved particularly successful, with improved survival and response rates.

Areas Covered: This review addresses the development of therapeutic strategies with inhibitors targeting MAPK/ERK and signaling in V600E mutated mCRC, focusing on encorafenib, binimetinib and cetuximab. A pharmacological and clinical review of these drugs and the therapeutic approaches behind their optimization are presented.

Expert Opinion: Exploiting knowledge of the mechanisms of resistance to inhibitors has been crucial to developing effective therapeutic strategies in mutant mCRC. The BEACON trial is a successful example of this approach, using encorafenib and cetuximab with or without binimetinib in patients with previously treated V600E mutant mCRC, showing an impressive improvement in clinical outcomes and tolerable toxicity compared with chemotherapy, establishing a new standard of care in this setting.
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http://dx.doi.org/10.1177/1758835921992974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903827PMC
February 2021

Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study.

Gastric Cancer 2021 07 13;24(4):970-977. Epub 2021 Mar 13.

University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.

Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here.

Methods: Pa tients with mGC/mGEJC treated with  ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC).

Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received  ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI.

Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.
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http://dx.doi.org/10.1007/s10120-021-01156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205879PMC
July 2021

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment.

Nat Commun 2021 03 8;12(1):1503. Epub 2021 Mar 8.

Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain.

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8 T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
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http://dx.doi.org/10.1038/s41467-021-21789-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940606PMC
March 2021

Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study.

Clin Cancer Res 2021 May 18;27(9):2515-2522. Epub 2021 Feb 18.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Purpose: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the status by metastatic sites in patients with a single metastatic site.

Experimental Design: Data from previous Spanish and Japanese studies investigating the concordance of the status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden.

Results: Patients had metastases in the liver ( = 151), peritoneum ( = 25), or lung ( = 45) with concordance rates of 91% (95% confidence interval, 85%-95%), 88% (68%-97%), and 64% (49%-78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number ( = 0.004), and sample collection interval ( = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10.

Conclusions: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' status with only peritoneal or lung metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3677DOI Listing
May 2021

Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design.

Future Oncol 2021 Jun 11;17(16):1977-1985. Epub 2021 Feb 11.

Department of Digestive Oncology, University Hospitals Leuven & KU Leuven, Ijzerenberglaan 19, 3020, Herent, Belgium.

Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.
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http://dx.doi.org/10.2217/fon-2020-1238DOI Listing
June 2021

Quantifying the Long-term Survival Benefit of Pembrolizumab for Patients With Advanced Gastric Cancer-Reply.

JAMA Oncol 2021 Apr;7(4):633

Vall d'Hebron University Hospital (HUVH) and Institute of Oncology (VHIO), Barcelona, Spain.

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http://dx.doi.org/10.1001/jamaoncol.2020.8011DOI Listing
April 2021

Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study.

J Clin Oncol 2021 02;39(4):273-284

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with V600E-mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data.

Methods: In this open-label, phase III trial, 665 patients with V600E-mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients.

Results: Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively.

Conclusion: In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with V600E mCRC.
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http://dx.doi.org/10.1200/JCO.20.02088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078423PMC
February 2021

A CT-based Radiomics Signature Is Associated with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Radiology 2021 04 26;299(1):109-119. Epub 2021 Jan 26.

From the Radiomics Group, Vall d'Hebron Institute of Oncology (VHIO), Cellex Center, Natzaret 115-117, Barcelona 08035, Spain (M.L., A.G.R., R.P.L.); Oncology Data Science (ODysSey) Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain (C.V., G.V., R.D.); Institute of Radiology, Foundation IRCCS Polyclinic San Matteo, Pavia, Italy (M.V.R.); Department of Radiology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain (J.L.); Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain (I.M., J.M.L., M.O.d.O., C.H., J.M., M.G., R.M.B., C.S., J.R., E.E., I.B., E.M.C., A.O., E.F., J.T., J.C., E.G.); Department of Molecular Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain (R.F., P.N.); Computer Vision Center, Department of Computer Science, Autonomous University of Barcelona, Cerdanyola del Vallès, Spain (D.G.); Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Autonomous University of Barcelona, Institució Catalana de Recerca i Estudis Avançats (ICREA) and CIBERONC, Barcelona, Spain (C.R.P., J.S.); Department of Radiology, Vall d'Hebron University Hospital, Barcelona, Spain (M.E., R.P.L.); and Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain (J.T.).

Background Reliable predictive imaging markers of response to immune checkpoint inhibitors are needed. Purpose To develop and validate a pretreatment CT-based radiomics signature to predict response to immune checkpoint inhibitors in advanced solid tumors. Materials and Methods In this retrospective study, a radiomics signature was developed in patients with advanced solid tumors (including breast, cervix, gastrointestinal) treated with anti-programmed cell death-1 or programmed cell death ligand-1 monotherapy from August 2012 to May 2018 (cohort 1). This was tested in patients with bladder and lung cancer (cohorts 2 and 3). Radiomics variables were extracted from all metastases delineated at pretreatment CT and selected by using an elastic-net model. A regression model combined radiomics and clinical variables with response as the end point. Biologic validation of the radiomics score with RNA profiling of cytotoxic cells (cohort 4) was assessed with Mann-Whitney analysis. Results The radiomics signature was developed in 85 patients (cohort 1: mean age, 58 years ± 13 [standard deviation]; 43 men) and tested on 46 patients (cohort 2: mean age, 70 years ± 12; 37 men) and 47 patients (cohort 3: mean age, 64 years ± 11; 40 men). Biologic validation was performed in a further cohort of 20 patients (cohort 4: mean age, 60 years ± 13; 14 men). The radiomics signature was associated with clinical response to immune checkpoint inhibitors (area under the curve [AUC], 0.70; 95% CI: 0.64, 0.77; < .001). In cohorts 2 and 3, the AUC was 0.67 (95% CI: 0.58, 0.76) and 0.67 (95% CI: 0.56, 0.77; < .001), respectively. A radiomics-clinical signature (including baseline albumin level and lymphocyte count) improved on radiomics-only performance (AUC, 0.74 [95% CI: 0.63, 0.84; < .001]; Akaike information criterion, 107.00 and 109.90, respectively). Conclusion A pretreatment CT-based radiomics signature is associated with response to immune checkpoint inhibitors, likely reflecting the tumor immunophenotype. © RSNA, 2021 See also the editorial by Summers in this issue.
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http://dx.doi.org/10.1148/radiol.2021200928DOI Listing
April 2021

Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH.

Med Clin (Barc) 2021 05 16;156(9):463.e1-463.e30. Epub 2021 Jan 16.

Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España. Electronic address:

Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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http://dx.doi.org/10.1016/j.medcli.2020.09.022DOI Listing
May 2021

Efficacy of Pembrolizumab Monotherapy for Advanced Gastric/Gastroesophageal Junction Cancer with Programmed Death Ligand 1 Combined Positive Score ≥10.

Clin Cancer Res 2021 Apr 14;27(7):1923-1931. Epub 2021 Jan 14.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California.

Purpose: Pembrolizumab demonstrated efficacy in PD-L1-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (G/GEJ) cancer in the first-, second-, and third-line setting in KEYNOTE-062, KEYNOTE-061, and KEYNOTE-059, respectively. To better delineate the specificity of CPS as a predictor of clinical outcomes, we analyzed pembrolizumab efficacy in patients with CPS ≥ 10 in these trials.

Patients And Methods: Included were patients with CPS ≥ 10 tumors from KEYNOTE-059 cohort 1 (pembrolizumab, = 46; ), KEYNOTE-061 (pembrolizumab, = 53; chemotherapy, = 55; ), and KEYNOTE-062 (pembrolizumab, = 92; chemotherapy, = 90; primary). Efficacy outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR).

Results: In KEYNOTE-059, median follow-up was 6 months, median OS was 8 months [95% confidence interval (CI), 5.8-11.1], ORR was 17%, and median (range) DOR was 21 months (3+ to 35+). In KEYNOTE-061, median follow-up was 9 months, median OS (pembrolizumab vs. chemotherapy) was 10 versus 8 months (HR, 0.64; 95% CI, 0.41-1.02), median PFS was 3 months versus 3 months (HR, 0.86; 95% CI, 0.56-1.33), ORR was 25% versus 9%, and median (range) DOR was not reached (4 to 26+ months) versus 7 months (3-7). In KEYNOTE-062, median follow-up was 11 months, median OS (pembrolizumab vs. chemotherapy) was 17 months versus 11 months (HR, 0.69; 95% CI, 0.49-0.97), median PFS was 3 months versus 6 months (HR, 1.09, 95% CI; 0.79-1.49), ORR was 25% versus 38%, and median (range) DOR was 19 months (1+ to 34+) versus 7 months (2+ to 30+).

Conclusions: This comprehensive analysis showed consistent improvements toward more favorable clinical outcomes with pembrolizumab across lines of therapy in patients with CPS ≥ 10 G/GEJ cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2980DOI Listing
April 2021

Prognostic variables in low and high risk stage III colon cancers treated in two adjuvant chemotherapy trials.

Eur J Cancer 2021 02 17;144:101-112. Epub 2020 Dec 17.

Department of Gastroenterology and GI Oncology, Sorbonne Paris Cité, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France.

Background: Stratification of patients with stage III colon cancer into low (TN) and high (T and/or N) risk groups is used to guide the duration of adjuvant chemotherapy. We determined the relative contribution of clinical and molecular features to survival by risk group.

Materials & Methods: Stage III colon cancer (N = 5337) patients from two adjuvant trials of FOLFOX ± cetuximab [N0147 (Alliance), PETACC-8] were risk grouped, then subgrouped by clinical features and molecular variables [KRAS and BRAF/mismatch repair (MMR) combined variable]. Distributions of disease-free survival (DFS), overall survival (OS), and survival after recurrence (SAR) were estimated. In multivariable Cox models, backward elimination was performed for analysis of candidate predictors of outcomes. Relative contributions of model-selected variables to outcomes by risk group were calculated using χ2.

Results: Among low risk tumours, mutant KRAS and male gender were significantly associated with poorer OS multivariately. In high risk tumours, significantly poorer OS was observed for right sidedness and for mutant KRAS and BRAF/pMMR, subgroups. Specifically, BRAF/pMMR (OS: HR = 1.75; 95% CI: 1.36-2.24; P<.0001) and right- versus left-sidedness were associated with significantly poorer DFS, OS (HR = 1.56; 95% CI: 1.31-1.83; P<.0001), and SAR (HR = 1.64; 95% CI: 1.37-1.95; P<.0001). Poor prognosis of mutant KRAS for DFS and OS was similar among risk groups. BRAF/MMR and sidedness were associated with poorer SAR in both low and high risk tumours. Age, gender, and KRAS were the top three relative contributors to DFS and OS among low risk tumours; sidedness ranked first for DFS and OS, and second to BRAF/MMR for SAR among high risk tumours.

Conclusion: Sidedness and BRAF/MMR contributed the most to survival outcomes among high risk tumours and should be interpreted in the context of risk group.
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http://dx.doi.org/10.1016/j.ejca.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855426PMC
February 2021

The Effective Targeting of KRAS Elusiveness.

Cancer Cell 2020 12;38(6):785-787

Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. Electronic address:

Developing therapies to directly target KRAS is challenging. In The New England Journal of Medicine, Hong et al. report a promising KRAS-targeting therapy phase I trial. However, a deeper understanding of the underlying biology of each histological context might well be required to optimize the potential benefit of this class of agents.
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http://dx.doi.org/10.1016/j.ccell.2020.11.012DOI Listing
December 2020
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