Publications by authors named "Asunción Díaz-Serrano"

10 Publications

  • Page 1 of 1

Necitumumab for the treatment of advanced non-small-cell lung cancer.

Future Oncol 2019 Mar 3;15(7):705-716. Epub 2018 Dec 3.

Medical Oncology Department, Hospital Universitario 12 de Octubre. Madrid, Spain.

Personalized patient-precise medicine is being gradually incorporated into clinical practice for the treatment of non-small-cell lung cancer (NSCLC). The EGFR pathway has been explored as a druggable target with monoclonal antibodies such as cetuximab or necitumumab. Necitumumab is a humanized IgG1 anti-EGFR. In the Phase III SQUIRE trial, necitumumab used as first-line therapy in combination with cisplatin and gemcitabine showed a reduction in risk-of-death and a better disease control rate in advanced squamous NSCLC. Thus, necitumumab is now a new first-line treatment option in squamous NSCLC. However, further biomarker research is needed to improve patient selection. Moreover, necitumumab associated with other immunotherapy and targeted agents is currently an important area of research that may yield better outcomes for NSCLC patients.
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http://dx.doi.org/10.2217/fon-2018-0594DOI Listing
March 2019

Targeting EGFR in Lung Cancer: Current Standards and Developments.

Drugs 2018 Jun;78(9):893-911

Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.

Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.
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http://dx.doi.org/10.1007/s40265-018-0916-4DOI Listing
June 2018

Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab.

Oncologist 2018 09 26;23(9):1092-1102. Epub 2018 Apr 26.

Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain

Background: HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab.

Patients And Methods: Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed.

Results: Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS.

Conclusion: Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab.

Implications For Practice: This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.
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http://dx.doi.org/10.1634/theoncologist.2017-0379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192610PMC
September 2018

Efficacy and safety of chemotherapy in older versus non-older patients with advanced gastric cancer: A real-world data, non-inferiority analysis.

J Geriatr Oncol 2018 05 11;9(3):254-264. Epub 2017 Dec 11.

Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, Murcia, Spain.

Objective: Advanced gastric cancer (AGC) is a common neoplasm in older adults. Nevertheless, there are few specific management data in the literature. The aim of this study was to assess non-inferiority of survival and efficacy-related outcomes of chemotherapy used in older vs non-older patients with AGC.

Materials And Methods: We recruited 1485 patients from the AGAMENON registry of AGC treated with polychemotherapy between 2008-2017. A statistical analysis was conducted to prove non-inferiority for overall survival (OS) associated with the use of chemotherapy schedules in individuals ≥70 vs.<70years. The fixed-margin method was used (hazard ratio [HR]<1.176) that corresponds to conserving at least 85% efficacy.

Results: 33% (n=489) of the cases analyzed were ≥70 years. Two-agent chemotherapies and combinations with oxaliplatin (48% vs. 29%) were used more often in the older patients, as were modified schedules and/or lower doses. Toxicity grade 3-4 was comparable in both groups, although when looking at any grade, there were more episodes of enteritis, renal toxicity, and fatigue in older patients. In addition, toxicity was a frequent cause for discontinuing treatment in older patients. The response rate was similar in both groups. After adjusting for confounding factors, the non-inferiority of OS associated with schedules administered to the older vs. younger subjects was confirmed: HR 1.02 (90% CI, 0.91-1.14), P (non inferiority)=0.018, as well as progression-free survival: HR 0.97 (90% CI, 0.87-1.08), P(non-inferiority)=0.001.

Conclusion: In this AGC registry, the use of chemotherapy with schedules adapted to patients ≥70 years provided efficacy that was not inferior to that seen in younger cases, with comparable adverse effects.
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http://dx.doi.org/10.1016/j.jgo.2017.11.008DOI Listing
May 2018

Prospective Clinical Integration of an Amplicon-Based Next-Generation Sequencing Method to Select Advanced Non-Small-Cell Lung Cancer Patients for Genotype-Tailored Treatments.

Clin Lung Cancer 2018 01 23;19(1):65-73.e7. Epub 2017 Jun 23.

Medical Oncology Department, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain; Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

Introduction: A substantial fraction of non-small-cell lung cancers (NSCLCs) harbor targetable genetic alterations. In this study, we analyzed the feasibility and clinical utility of integrating a next-generation sequencing (NGS) panel into our routine lung cancer molecular subtyping algorithm.

Patients And Methods: After routine pathologic and molecular subtyping, we implemented an amplicon-based gene panel for DNA analysis covering mutational hot spots in 22 cancer genes in consecutive advanced-stage NSCLCs.

Results: We analyzed 109 tumors using NGS between December 2014 and January 2016. Fifty-six patients (51%) were treatment-naive and 82 (75%) had lung adenocarcinomas. In 89 cases (82%), we used samples derived from lung cancer diagnostic procedures. We obtained successful sequencing results in 95 cases (87%). As part of our routine lung cancer molecular subtyping protocol, single-gene testing for EGFR, ALK, and ROS1 was attempted in nonsquamous and 3 squamous-cell cancers (n = 92). Sixty-nine of 92 samples (75%) had sufficient tissue to complete ALK and ROS1 immunohistochemistry (IHC) and NGS. With the integration of the gene panel, 40 NSCLCs (37%) in the entire cohort and 30 NSCLCs (40%) fully tested for ALK and ROS1 IHC and NGS had actionable mutations. KRAS (24%) and EGFR (10%) were the most frequently mutated actionable genes. Ten patients (9%) received matched targeted therapies, 6 (5%) in clinical trials.

Conclusion: The combination of IHC tests for ALK and ROS1 and amplicon-based NGS is applicable in routine clinical practice, enabling patient selection for genotype-tailored treatments.
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http://dx.doi.org/10.1016/j.cllc.2017.06.008DOI Listing
January 2018

On the Effect of Triplet or Doublet Chemotherapy in Advanced Gastric Cancer: Results From a National Cancer Registry.

J Natl Compr Canc Netw 2016 11;14(11):1379-1388

From Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, UMU, IMIB, Murcia, Spain; Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain; Medical Oncology Department, Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain; Medical Oncology Department, Hospital General Universitario de Elche, Alicante, Spain; Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain; Hematology and Medical Oncology Department, Hospital Universitario de Ciudad Real, Cuidad Real, Spain; Medical Oncology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain; Medical Oncology Department, Hospital General de Ciudad Real, Ciudad Real, Spain; Medical Oncology Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain; Pharmacy Department, Hospital Universitario Central de Asturias, Oviedo, Spain; Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain; Medical Oncology Department, Hospital Universitario Parc Tauli, Sabadell, Spain; Medical Oncology Department, Hospital Galdakao-Usansolo, Usansolo, Spain; Medical Oncology Department, Hospital Universitario del Mar, Barcelona, Spain; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Medical Oncology Department, Hospital Universitario Son Espases, Mallorca, Spain; Medical Oncology Department, Hospital Universitario Doce de Octubre, Madrid, Spain; Medical Oncology Department, Complejo Hospitalario de Orense, Spain; and Medical Oncology Department, Hospital Universitario de Valdecilla, Santander, Spain.

Background: There is currently no consensus regarding first-line chemotherapy for patients with advanced gastric cancer (AGC) who are ineligible to receive trastuzumab. The objective of this study was to evaluate the efficacy and tolerance of triplets versus doublets by analyzing a national gastric cancer registry.

Patients And Method: Patients with AGC treated with polychemotherapy without associating trastuzumab were included from 2008 through 2016. The effect of triplets versus doublets was compared using 3 methods: Cox proportional hazards regression, propensity score matching (PSM), and coarsened exact matching (CEM).

Results: A total of 970 patients were recruited (doublets: n=569; triplets: n=401). In the multivariate Cox model, the use of triplets was associated with better overall survival (OS), with a hazard ratio (HR) of 0.84 (95% CI, 0.72-0.98; P=.035). After PSM, the sample contained 340 pairs. A significant increase in OS, 11.14 months (95% CI, 9.60-12.68) versus 9.60 months (95% CI, 8.44-10.75), was seen in favor of triplets (HR, 0.77; 95% CI, 0.65-0.92; stratified log-rank test, P=.004). The effect appeared to be comparable for anthracycline-based (HR, 0.78; 95% CI, 0.64-0.94) or docetaxel-based triplets (HR, 0.78; 95% CI, 0.60-1.009). The trend was similar after applying the CEM algorithm, with an HR of 0.78 (95% CI, 0.63-0.97; P=.03). Triplet therapy was viable and relative dose intensities exceeded 85%, except for cisplatin in DCX (docetaxel, cisplatin, capecitabine). Triplets had more severe toxicity overall, especially hematologic, hepatic, and mucosal adverse events.

Conclusions: With the limitations of a retrospective study that examines a heterogeneous set of chemotherapy regimens, we found that triplets are feasible in daily practice and are associated with a discreet benefit in efficacy at the expense of a moderate increase in toxicity.
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http://dx.doi.org/10.6004/jnccn.2016.0148DOI Listing
November 2016

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer.

Gastric Cancer 2017 May 6;20(3):465-474. Epub 2016 Sep 6.

Medical Oncology Department, Hospital Universitario Vall d'Hebron and VHIO-Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC.

Methods: This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression.

Results: The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001-1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2.

Conclusion: Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.
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http://dx.doi.org/10.1007/s10120-016-0639-8DOI Listing
May 2017

The safety and efficacy of ramucirumab for the treatment of metastatic colorectal cancer.

Expert Rev Anticancer Ther 2016 Jun 14;16(6):585-95. Epub 2016 May 14.

a Medical Oncology Division , Hospital Universitario 12 de Octubre , Madrid , Spain.

Introduction: Ramucirumab (IMC-1121B, LY3009806) is a fully humanized monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR2), the principal mediator of VEGF-A downstream effects in cancer angiogenesis. Ramucirumab has been recently approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first line bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. This approval was based on the results of the RAISE phase III placebo-controlled trial. This study demonstrated that the addition of ramucirumab to irinotecan-based chemotherapy significantly improved progression-free and overall survival of patients with mCRC, with manageable toxicity.

Areas Covered: The aim of this drug profile is to briefly summarize the pharmacology, clinical efficacy, safety and tolerability of ramucirumab in the context of metastatic colorectal cancer, and to provide some perspective regarding the role of the drug in clinical practice. Expert commentary: Pending issues that shall be addressed in the upcoming years include the optimization of ramucirumab dosing schedule, assessment of its role with other chemotherapy regimens or in other treatment settings, comparative evaluation of this agent with other antiangiogenics, and identification of predictive biomarkers to improve the therapeutic index and cost-effectiveness of this drug.
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http://dx.doi.org/10.1080/14737140.2016.1182430DOI Listing
June 2016