Publications by authors named "José Luis Manzano"

43 Publications

Clinico-pathological factors related to metastatic pathway in localised melanoma.

Australas J Dermatol 2021 Oct 12. Epub 2021 Oct 12.

Departament of Dermatology, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

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http://dx.doi.org/10.1111/ajd.13728DOI Listing
October 2021

Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM).

J Immunother Cancer 2021 03;9(3)

Oncology Department, Consorci Hospital General Universitari de Valencia, Valencia, Comunitat Valenciana, Spain.

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities.
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http://dx.doi.org/10.1136/jitc-2020-001664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009216PMC
March 2021

Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial.

Eur J Cancer 2021 03 20;145:158-167. Epub 2021 Jan 20.

Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain. Electronic address:

Introduction: Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting.

Material And Methods: This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337).

Results: Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%).

Conclusions: These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.
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http://dx.doi.org/10.1016/j.ejca.2020.12.005DOI Listing
March 2021

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results.

BMC Cancer 2020 Nov 27;20(1):1164. Epub 2020 Nov 27.

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

Background: Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The "Tratamiento de Tumores Digestivos" group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years.

Methods: Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks).

Results: In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%).

Conclusions: the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term.

Trial Registration: EudraCT number: 2009-010192-24 . Clinicaltrials.gov number: NCT01043484 .
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http://dx.doi.org/10.1186/s12885-020-07661-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694337PMC
November 2020

Locally advanced head and neck squamous cell carcinoma and melanoma simultaneously treated with pembrolizumab: an unusual situation.

Eur J Dermatol 2020 Dec;30(6):743-744

Dermatology Department Hospital Universitari Germans Trias i Pujol, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain.

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http://dx.doi.org/10.1684/ejd.2020.3911DOI Listing
December 2020

Rectal neuroendocrine carcinoma: case report of a rare entity and perspective review of promising agents.

Drugs Context 2020 15;9. Epub 2020 May 15.

Medical Oncology Department, Catalan Institute of Oncology (ICO)-Badalona; Badalona-Applied Research Group in Oncology (B-ARGO)-Germans Trias i Pujol Institute (IGTP); Germans Trias i Pujol University Hospital (HUGTiP), Badalona, Barcelona, Spain.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumours, which can be classified into neuroendocrine tumours (NETs), neuroendocrine carcinomas (NECs) and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). To date, there is no consensus regarding the optimal therapy, which usually depends on the primary location and classification, according to morphological features of differentiation and proliferation rates. Nevertheless, multidisciplinary strategies combining medical treatments and locoregional strategies have yielded better efficacy results. Here, we report the case of a patient diagnosed with a nonfunctional rectal NECs with metastatic widespread to pelvic lymph nodes and bilateral lung metastases. The patient received three cycles of platinum-etoposide, concomitantly with palliative radiotherapy. Although CT scan after three cycles showed a significant partial response, there was an early fatal progression only 3 months after having stopped systemic therapy. As formerly described in the literature, this case highlights the aggressive behaviour of NECs, rare tumours that often present in advanced stages at diagnosis. Lately, new insights into the molecular biology of NECs have unveiled the possibility of using novel drugs, such as targeted agents or immunotherapy, in molecularly selected subgroups of patients. In this review, we discuss the current management of this rare entity and provide an overview of the most relevant molecular findings, whilst illustrating the potential value that prescreening panels can offer, searching for actionable targets (MSI/dMMR, PD-L1, BRAF) to guide therapy with promising agents that could fill a void in this disease.
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http://dx.doi.org/10.7573/dic.2020-2-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233296PMC
May 2020

Enhancement of Antiviral CD8 T-Cell Responses and Complete Remission of Metastatic Melanoma in an HIV-1-Infected Subject Treated with Pembrolizumab.

J Clin Med 2019 12 1;8(12). Epub 2019 Dec 1.

IrsiCaixa AIDS Research Institute, 08916 Badalona, Spain.

Background: Pembrolizumab is an immune checkpoint inhibitor against programmed cell death protein-1 (PD-1) approved for therapy in metastatic melanoma. PD-1 expression is associated with a diminished functionality in HIV-1 specific-CD8 T cells. It is thought that PD-1 blockade could contribute to reinvigorate antiviral immunity and reduce the HIV-1 reservoir.

Methods: Upon metastatic melanoma diagnosis, an HIV-1-infected individual on stable suppressive antiretroviral regimen was treated with pembrolizumab. A PET-CT was performed before and one year after pembrolizumab initiation. We monitored changes in the immunophenotype and HIV-1 specific-CD8 T-cell responses during 36 weeks of treatment. Furthermore, we assessed changes in the viral reservoir by total HIV-1 DNA, cell-associated HIV-1 RNA, and ultrasensitive plasma viral load.

Results: Complete metabolic response was achieved after pembrolizumab treatment of metastatic melanoma. Activated CD8 T-cells expressing HLA-DR/CD38 transiently increased over the first nine weeks of treatment. Concomitantly, there was an augmented response of HIV-1 specific-CD8 T cells with TNF production and poly-functionality, transitioning from TNF to an IL-2 profile. Furthermore, a transient reduction of 24% and 32% in total HIV-1 DNA was observed at weeks 3 and 27, respectively, without changes in other markers of viral persistence.

Conclusions: These data demonstrate that pembrolizumab may enhance the HIV-1 specific-CD8 T-cell response, marginally affecting the HIV-1 reservoir. A transient increase of CD8 T-cell activation, TNF production, and poly-functionality resulted from PD-1 blockade. However, the lack of sustained changes in the viral reservoir suggests that viral reactivation is needed concomitantly with HIV-1-specific immune enhancement.
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http://dx.doi.org/10.3390/jcm8122089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947580PMC
December 2019

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

Tumor Expression of Cyclin-Dependent Kinase 5 (Cdk5) Is a Prognostic Biomarker and Predicts Outcome of Oxaliplatin-Treated Metastatic Colorectal Cancer Patients.

Cancers (Basel) 2019 Oct 11;11(10). Epub 2019 Oct 11.

Program of predictive and personalized cancer medicine (PMPPC) Germans Trias i Pujol Research Institute (IGTP), Ctra. Can Ruti-Camí de les escoles s/n, 08916 Badalona, Spain.

In recent years, an increasing number of studies have shown that elevated expression of cyclin dependent kinase (Cdk5) contributes to the oncogenic initiation and progression of many types of cancers. In this study, we investigated the expression pattern of Cdk5 in colorectal cancer (CRC) cell lines and in a large number of tumor samples in order to evaluate its relevance in this pathogenesis and possible use as a prognostic marker. We found that Cdk5 is highly expressed and activated in CRC cell lines and that silencing of the kinase decreases their migration ability. In tumor tissues, Cdk5 is overexpressed compared to normal tissues due to a copy number gain. In patients with localized disease, we found that high Cdk5 levels correlate with poor prognosis, while in the metastatic setting, this was only the case for patients receiving an oxaliplatin-based treatment. When exploring the Cdk5 levels in the consensus molecular subtypes (CMS), we found the lowest levels in subtype 1, where high Cdk5 again was associated with a poorer prognosis. In conclusion, we confirm that Cdk5 is involved in CRC and disease progression and that it could serve as a prognostic and predictive biomarker in this disease.
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http://dx.doi.org/10.3390/cancers11101540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826373PMC
October 2019

Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.

Oncologist 2019 01 23;24(1):38-46. Epub 2018 May 23.

Catalan Institute of Oncology (ICO), Bellvitge, Barcelona, Spain.

Background: Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials.

Materials And Methods: This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression).

Results: Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS.

Conclusion: The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting.

Implications For Practice: The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting.
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http://dx.doi.org/10.1634/theoncologist.2017-0622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324631PMC
January 2019

Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.

Medicine (Baltimore) 2017 Dec;96(52):e9523

Medical Oncology, Clínica Universidad de Navarra, Pamplona Instituto Valenciano de Oncología, Valencia Medical Oncology, Parc Taulí Sabadell Hospital Universitario, Sabadell Oncología Intercentros, Hospitales Universitarios Regional y Virgen de la Victoria (HURyVV) and Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga Onkologikoa, Instituto Oncológico de Kutxa, San Sebastian Instituto Catalán de Oncología, ICO-Badalona, Hospital Germans Trías I Pujol, Barcelona Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid Medical Oncology, Complejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria, Las Palmas de Gran Canaria Medical Oncology, Hospital Universitario La Paz, Madrid Medical Oncology, Hospital Virgen de la Salud, Toledo Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid Instituto Catalán de Oncología Girona, Girona Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida Medical Oncology, Hospital Universitario San Cecilio, Granada Medical Oncology, Complejo Hospitalario de Navarra, Pamplona Medical Oncology, Hospital Universitario Central de Asturias, Oviedo Medical Oncology, Hospital Universitario Nuestra Señora de Valme, Sevilla Medical Oncology, Hospital General Universitario de Elche, Alicante Medical Oncology, Complejo Hospitalario Torrecárdenas de Almería, Almería Medical Oncology, Hospital Marqués de Valdecilla, Santander Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca Medical Oncology, Hospital Universitario La Princesa, Madrid Medical Oncology, Complejo Hospitalario Universitario Ourense, Ourense Medical Oncology, Hospital Universitario 12 de Octubre, Madrid Medical Oncology, Hospital General Universitario de Valencia, Valencia Medical Oncology, Hospital Clínic Barcelona, Barcelona, Spain.

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.
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http://dx.doi.org/10.1097/MD.0000000000009523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393118PMC
December 2017

Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM).

Ann Transl Med 2017 Oct;5(19):389

Department of Oncology, Clínica Universitaria de Navarra, Pamplona, Spain.

Immunotherapy has become a key element in the treatment of several tumors, such as lung carcinoma and melanoma. Immunotherapy, unlike classical chemotherapy and targeted drugs, may yield long-term survival, even in patients who stop treatment due to toxicity. This fact has generated considerable excitement and a real shift in the paradigm of cancer treatment. However, only a small subset of patients benefit from immunotherapy. Survival curves show that most patients have progression of the disease in the first months after starting immunotherapy, followed by a slower decrease over the first 3 years, until curves reach a plateau. This early progression suggests the presence of mechanisms for primary resistance. In addition, some patients have tumor relapse after years of response, suggesting that there is also acquired resistance in a small subset of patients. Resistance mechanisms are now being elucidated. PD-L1 expression in tumor and immune cells correlates with higher chances of response, but melanoma patients with PD-L1 negative tumors can also respond. Several studies have demonstrated an increased probability of clinical benefit when tumors are infiltrated by CD8 T cells, have a high mutation burden or have an interferon gamma signature. But none of these factors has been implemented in the clinical practice, since more studies confirming their value are needed, as well as the development of standardized techniques.
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http://dx.doi.org/10.21037/atm.2017.08.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653511PMC
October 2017

Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC).

Eur J Endocrinol 2017 Oct 7;177(4):309-317. Epub 2017 Jul 7.

Medical Oncology Department, University of Barcelona, Hospital Clínic of Barcelona, Barcelona, Spain.

Background: Axitinib, an antiangiogenic multikinase inhibitor (MKI), was evaluated in the compassionate use programme (CUP) in Spain (October 2012-November 2014).

Subjects And Methods: 47 patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC,  = 34) or medullary thyroid cancer (MTC,  = 13) with documented disease progression were treated with axitinib 5 mg b.i.d. The primary efficacy endpoint was objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Progression-free survival (PFS) and adverse events (AEs) were secondary objectives. Regulatory authorities validated the CUP, and all patients signed informed consent form.

Results: Axitinib was administered as first-line therapy in 17 patients (36.2%), as second-line in 18 patients (38.3%) and as third/fourth-line in 12 patients (25.5%). With a median follow-up of 11.5 months (0-24.3), ORR was 27.7% (DTC: 29.4% and MTC: 23.1%) and median PFS was 8.1 months (95% CI: 4.1-12.2) (DTC: 7.4 months (95% CI: 3.1-11.8) and MTC: 9.4 months (95% CI: 4.8-13.9)). Better outcomes were reported with first-line axitinib, with an ORR of 53% and a median PFS of 13.6 months compared with 16.7% and 10.6 months as second-line treatment. Twelve (25.5%) patients required dose reduction to 3 mg b.i.d. All-grade AEs included asthenia (53.2%), diarrhoea (36.2%), hypertension (31.9%) and mucositis (29.8%); grade 3/4 AEs included anorexia (6.4%), diarrhoea (4.3%) and cardiac toxicity (4.3%).

Conclusion: Axitinib had a tolerable safety profile and clinically meaningful activity in refractory and progressive thyroid cancer regardless of histology as first-line therapy. To our knowledge, this is the first time that cross-resistance between MKIs is suggested in thyroid cancer, highlighting the importance of prospective sequential clinical studies.
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http://dx.doi.org/10.1530/EJE-17-0243DOI Listing
October 2017

First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD).

Eur J Cancer 2017 08 19;81:191-202. Epub 2017 Jun 19.

Maimonides Institute of Biomedical Research, IMIBIC, Spain, Reina Sofía Hospital, University of Córdoba, Spanish Cancer Network, (RTICC), Instituto de Salud Carlos III, Avenida Menéndez Pidal, s/n, ES-14004, Córdoba, Spain.

Background: In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.

Methods: Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients.

Results: Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm.

Conclusions: In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).
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http://dx.doi.org/10.1016/j.ejca.2017.04.024DOI Listing
August 2017

Optimization of Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer.

Mol Cancer Ther 2017 09 16;16(9):1999-2007. Epub 2017 Jun 16.

Department of Medical Oncology, Catalan Institute of Oncology (ICO), Translational Research Laboratory, ICO-Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain.

In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR- ( = 255) or bevacizumab- ( = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, , and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing and (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti-EGFR cohort ( < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in / wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the scenario (HR = 1.53; CI 95%, 1.12-2.09 for PFS, and HR = 1.9; CI 95%, 1.33-2.72 for OS). Although the rate of mutations observed among techniques is different, and mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0153DOI Listing
September 2017

Resistant mechanisms to BRAF inhibitors in melanoma.

Ann Transl Med 2016 Jun;4(12):237

Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.

Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.
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http://dx.doi.org/10.21037/atm.2016.06.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930524PMC
June 2016

Curcumin mediates oxaliplatin-acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-κB signalling pathway.

Sci Rep 2016 Apr 19;6:24675. Epub 2016 Apr 19.

Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Can Ruti Campus, Ctra. Can Ruti- Camí de les escoles s/n, 08916, Badalona, Spain.

Resistance to oxaliplatin (OXA) is a complex process affecting the outcomes of metastatic colorectal cancer (CRC) patients treated with this drug. De-regulation of the NF-κB signalling pathway has been proposed as an important mechanism involved in this phenomenon. Here, we show that NF-κB was hyperactivated in in vitro models of OXA-acquired resistance but was attenuated by the addition of Curcumin, a non-toxic NF-κB inhibitor. The concomitant combination of Curcumin + OXA was more effective and synergistic in cell lines with acquired resistance to OXA, leading to the reversion of their resistant phenotype, through the inhibition of the NF-κB signalling cascade. Transcriptomic profiling revealed the up-regulation of three NF-κB-regulated CXC-chemokines, CXCL8, CXCL1 and CXCL2, in the resistant cells that were more efficiently down-regulated after OXA + Curcumin treatment as compared to the sensitive cells. Moreover, CXCL8 and CXCL1 gene silencing made resistant cells more sensitive to OXA through the inhibition of the Akt/NF-κB pathway. High expression of CXCL1 in FFPE samples from explant cultures of CRC patients-derived liver metastases was associated with response to OXA + Curcumin. In conclusion, we suggest that combination of OXA + Curcumin could be an effective treatment, for which CXCL1 could be used as a predictive marker, in CRC patients.
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http://dx.doi.org/10.1038/srep24675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835769PMC
April 2016

Appendiceal mixed adenoneuroendocrine carcinomas, a rare entity that can present as a Krukenberg tumor: case report and review of the literature.

World J Surg Oncol 2015 Nov 26;13:325. Epub 2015 Nov 26.

Medical Oncology Department, Institut Català d'Oncologia Badalona (Hospital Germans Trias i Pujol), Carretera del Canyet s/n, 08916, Badalona, Barcelona, Spain.

Background: Mixed adenoneuroendocrine carcinoma is a rare tumor recently recognized as a new category in the last World Health Organization (WHO) classification of appendiceal tumors (2010). This term has been proposed to designate carcinomas of the appendix that arise by progression from a pre-existing goblet cell carcinoid. Mixed adenoneuroendocrine carcinomas are more aggressive tumors than typical goblet cell carcinoids and usually present with peritoneal spreading and ovarian masses. Staging, some histological features, and completeness of surgery are factors that determine its evolution.

Case Presentation: We report the case of a mixed adenoneuroendocrine carcinoma--signet ring cell subtype--that presented as a Krukenberg tumor of unknown primary.

Conclusion: The review of literature is focused on the most recent WHO pathologic classification of appendiceal tumors containing goblet cell clusters, which seems to correlate with prognosis. A management proposal for mixed adenoneuroendocrine carcinomas reported in previous literature is also discussed. This ranges from right hemicolectomy to cytoreduction plus hyperthermic intraperitoneal chemotherapy, in both cases usually followed by intravenous chemotherapy.
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http://dx.doi.org/10.1186/s12957-015-0740-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661956PMC
November 2015

Epigenetic mechanisms involved in melanoma pathogenesis and chemoresistance.

Ann Transl Med 2015 Sep;3(15):209

1 Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Catalonia, Spain ; 2 Medical Oncology Service, Catalan Institute of Oncology, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.

The discovery of highly recurrent mutations in melanoma, such as BRAF(V600E), completely changed the clinical management including therapy of melanoma patients. In the era of Personalized Medicine targeted melanoma therapies showed high response rates, currently evidenced by BRAF inhibitors or immune-stimulating therapies. In addition to genetic biomarkers, epigenetic knowledge in melanoma has undergone a major step forward in recent years. In particular, epigenetics is unveiling new perspectives to fight this disease, providing an encouraging number of DNA methylation based biomarkers that will likely improve patient stratification for prognosis and treatment. In this regard, putative targetable biomarkers or those with predictive value for the outcome of currently applied therapies are promising tools for future precision oncology strategies. In addition, the progress made in genetic and epigenetic profiling technologies and their reconfiguration to real-time clinical screening approaches makes personalized medicine in melanoma an achievable objective in upcoming years.
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http://dx.doi.org/10.3978/j.issn.2305-5839.2015.06.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583598PMC
September 2015

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance.

Mol Cancer Ther 2015 Aug 16;14(8):1767-76. Epub 2015 Jul 16.

Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Catalonia, Spain. Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP). Badalona, Catalonia, Spain. Oncology Unit, Hospital CIMA Sanitas, Barcelona, Catalonia, Spain.

Oxaliplatin was the first platinum drug with proven activity against colorectal tumors, becoming a standard in the management of this malignancy. It is also considered for the treatment of pancreatic and gastric cancers. However, a major reason for treatment failure still is the existence of tumor intrinsic or acquired resistance. Consequently, it is important to understand the molecular mechanisms underlying the appearance of this phenomenon to find ways of circumventing it and to improve and optimize treatments. This review will be focused on recent discoveries about oxaliplatin tumor-related resistance mechanisms, including alterations in transport, detoxification, DNA damage response and repair, cell death (apoptotic and nonapoptotic), and epigenetic mechanisms.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0636DOI Listing
August 2015

Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis.

BMC Cancer 2015 Jul 4;15:495. Epub 2015 Jul 4.

Medical Oncology Department, Gregorio Marañon Hospital, Calle Doctor Esquerdo 46, 28007, Madrid, Spain.

Background: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice.

Methods: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected.

Results: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone.

Conclusions: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.
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http://dx.doi.org/10.1186/s12885-015-1512-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490650PMC
July 2015

PKM2 Subcellular Localization Is Involved in Oxaliplatin Resistance Acquisition in HT29 Human Colorectal Cancer Cell Lines.

PLoS One 2015 8;10(5):e0123830. Epub 2015 May 8.

Translational research in digestive tumours group, Laboratory of Molecular Cancer Biology, Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Badalona, Spain; Medical Oncology Service, Catalan Institute of Oncology (ICO) University Hospital Germans Trias I Pujol, Badalona, Spain.

Chemoresistance is the main cause of treatment failure in advanced colorectal cancer (CRC). However, molecular mechanisms underlying this phenomenon remain to be elucidated. In a previous work we identified low levels of PKM2 as a putative oxaliplatin-resistance marker in HT29 CRC cell lines and also in patients. In order to assess how PKM2 influences oxaliplatin response in CRC cells, we silenced PKM2 using specific siRNAs in HT29, SW480 and HCT116 cells. MTT test demonstrated that PKM2 silencing induced resistance in HT29 and SW480 cells and sensitivity in HCT116 cells. Same experiments in isogenic HCT116 p53 null cells and double silencing of p53 and PKM2 in HT29 cells failed to show an influence of p53. By using trypan blue stain and FITC-Annexin V/PI tests we detected that PKM2 knockdown was associated with an increase in cell viability but not with a decrease in apoptosis activation in HT29 cells. Fluorescence microscopy revealed PKM2 nuclear translocation in response to oxaliplatin in HCT116 and HT29 cells but not in OXA-resistant HTOXAR3 cells. Finally, by using a qPCR Array we demonstrated that oxaliplatin and PKM2 silencing altered cell death gene expression patterns including those of BMF, which was significantly increased in HT29 cells in response to oxaliplatin, in a dose and time-dependent manner, but not in siPKM2-HT29 and HTOXAR3 cells. BMF gene silencing in HT29 cells lead to a decrease in oxaliplatin-induced cell death. In conclusion, our data report new non-glycolytic roles of PKM2 in response to genotoxic damage and proposes BMF as a possible target gene of PKM2 to be involved in oxaliplatin response and resistance in CRC cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425499PMC
February 2016

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features.

BMC Cancer 2015 Feb 26;15:60. Epub 2015 Feb 26.

Medical Oncology, Reina Sofía Hospital, University of Córdoba, Maimonides Institute of Biomedical Research (IMIBIC); Spanish Cancer Network (RTICC), Instituto de Salud Carlos III, Córdoba, Spain.

Background: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging.

Methods: Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0).

Results: Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02).

Conclusions: The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies.

Trial Registry: Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.
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http://dx.doi.org/10.1186/s12885-015-1053-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343271PMC
February 2015

The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies.

Nat Genet 2015 Mar 9;47(3):250-6. Epub 2015 Feb 9.

Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.
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http://dx.doi.org/10.1038/ng.3218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930244PMC
March 2015

Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study.

PLoS One 2012 12;7(10):e47345. Epub 2012 Oct 12.

Department of Medical Oncology, Hospital Clínico San Carlos (HCSC), Red Temática de Investigación Cooperativa en Cáncer, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria del HCSC (IdISSC), Madrid, Spain.

Background: In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.

Methodology/principal Findings: KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p=0.0038; HR: 1.40; 95% CI:1.12-1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p=0.0002; HR: 1.55; 95% CI: 1.23-1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p=0.0054; OR: 1.77; 95% CI: 1.18-2.64).

Conclusions/significance: This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470549PMC
April 2013

A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines.

Mol Cancer Ther 2009 Apr;8(4):771-8

Medical Oncology Service, Hospital Universitari Germans Trias i Pujol, Institut Catala Oncologia, Badalona 08916, Barcelona, Spain.

We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatin-resistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r=-0.846, P=0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P=0.026). High PK-M2 levels were associated with high p53 levels (P=0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatin-treated colorectal cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-08-0882DOI Listing
April 2009

Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy.

Int J Cancer 2009 Jun;124(12):2905-10

Medical Oncology Service, Hospital Universitari Germans Trias i Pujol, Institut Català d'Oncologia, Badalona, Barcelona, Spain.

Recently, the copper efflux transporters ATP7B and ATP7A have been implicated in the transport of and resistance to platinum drugs in breast and ovarian cancers. Because of the extensive use of oxaliplatin in colorectal cancer (CRC), we examined the expression of both transporters in tumors from CRC patients treated with oxaliplatin/5FU and sought to determine whether their expression can predict clinical outcome in these patients. ATP7B and ATP7A levels were determined by quantitative real-time PCR in 50 primary tumors of previously untreated patients with advanced colorectal adenocarcinoma who were subsequently treated with oxaliplatin/5FU. Additionally, ATP7B protein expression was assessed by immunohistochemical staining using a tissue microarray. Patients with the lowest mRNA expression levels of ATP7B had a significantly longer time to progression (TTP) (p = 0.0009) than patients with the highest levels (12.14 months vs. 6.43 months) who also had an increased risk of progression (HR = 3.56; 95% CI, 1.6-7.9; p = 0.002). Furthermore, patients with low levels of both protein and mRNA of ATP7B derived the maximum benefit from oxaliplatin/5FU with the longest TTP as compared with patients with high levels of ATP7B protein and mRNA (14.64 months vs. 4.63 months, respectively, p = 0.01) and showed a nonsignificant trend toward a lower response rate (37.5% and 75%, respectively). In conclusion, ATP7B mRNA and protein expression in colorectal tumors is associated with clinical outcome to oxaliplatin/5FU. Prospective studies are required to evaluate the role of this marker in tailoring chemotherapy.
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http://dx.doi.org/10.1002/ijc.24273DOI Listing
June 2009

Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma.

Eur J Cancer 2009 Mar 29;45(5):732-5. Epub 2009 Jan 29.

Clínica Universitaria de Navarra, Pamplona, Spain.

This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naïve patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.
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http://dx.doi.org/10.1016/j.ejca.2008.12.005DOI Listing
March 2009

Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer.

Mol Cancer Ther 2009 Jan;8(1):194-202

Medical Oncology Service, Institut Català Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona 08916, Barcelona, Spain.

Oxaliplatin is a third-generation platinum agent used in colorectal cancer treatment. Oxaliplatin resistance acquisition is a complex process mainly based on alteration of genes and pathways involved in its mechanism of action. Therefore, our purpose was to perform a gene expression screening in an in vitro model to identify genes that could play a role in oxaliplatin resistance acquisition processes. Four colorectal cancer cell lines and their oxaliplatin-resistant derived sublines were compared. Microarray analysis was done using Human 19K Oligo Array Slides. RNA from cells were hybridized with a commercial RNA reference sample and labeled with both fluorochromes Cy3 and Cy5. Data were analyzed by hierarchical clustering method. Subsequently, quantitative real-time PCR (qRT-PCR) was used to corroborate microarray data, considering as positively validated those genes that showed significant differences in expression levels between groups and a correlation between microarray and qRT-PCR data. By microarray analysis, 32 candidate genes were identified. After validation process by qRT-PCR, the genes AKT1, CDK5, TRIP, GARP, RGS11, and UGCGL1 were positively validated. The 3 first genes proved to be involved in regulation of nuclear factor-kappabeta antiapoptotic transcription factor previously related to drug resistance, and the other 3 genes are novel finds. We have identified 6 genes related to oxaliplatin resistance acquisition. These findings are of paramount importance to understand these processes better and open new lines of study to elucidate the relevance of this pharmacogenomic approach into the clinic.
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http://dx.doi.org/10.1158/1535-7163.MCT-08-0659DOI Listing
January 2009
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