Publications by authors named "Sara Lopez-Tarruella"

46 Publications

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts.

Sci Rep 2021 Mar 29;11(1):7064. Epub 2021 Mar 29.

Department of Medical Oncology, Hospital General Universitario Gregorio Marañón Instituto de Investigacion Sanitaria Gregorio Marañon (IiSGM), CIBERONC, Universidad Complutense, Dr Esquerdo 46, 28007, Madrid, Spain.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.
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http://dx.doi.org/10.1038/s41598-021-85962-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007714PMC
March 2021

Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors.

Sci Transl Med 2020 10;12(565)

CIMA and Clínica Universidad de Navarra and CIBERONC, Pamplona 31008, Spain.

Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.
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http://dx.doi.org/10.1126/scitranslmed.abb0391DOI Listing
October 2020

GEICAM Guidelines for the Management of Patients with Breast Cancer During the COVID-19 Pandemic in Spain.

Oncologist 2020 09 23;25(9):e1339-e1345. Epub 2020 Jul 23.

Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Departamento de Medicina, Universidad Complutense, Madrid, Spain.

Breast cancer (BC) is the most common cancer in women in Spain. During the COVID-19 pandemic caused by the SARS-CoV-2 virus, patients with BC still require timely treatment and follow-up; however, hospitals are overwhelmed with infected patients and, if exposed, patients with BC are at higher risk for infection and serious complications if infected. Thus, health care providers need to evaluate each BC treatment and in-hospital visit to minimize pandemic-associated risks while maintaining adequate treatment efficacy. Here we present a set of guidelines regarding available options for BC patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the lack of evidence about COVID-19 infection, these recommendations are mainly based on expert opinion, medical organizations' and societies' recommendations, and some published evidence. We consider this a useful tool to facilitate medical decision making in this health crisis situation we are facing. IMPLICATIONS FOR PRACTICE: This work presents a set of guidelines regarding available options for breast cancer (BC) patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the suddenness of this health crisis, specialists have to make decisions with little evidence at hand. Thus, these expert guidelines may be a useful tool to facilitate medical decision making in the context of a worldwide pandemic with no resources to spare.
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http://dx.doi.org/10.1634/theoncologist.2020-0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405405PMC
September 2020

Survival impact of primary tumor resection in de novo metastatic breast cancer patients (GEICAM/El Alamo Registry).

Sci Rep 2019 12 27;9(1):20081. Epub 2019 Dec 27.

GEICAM, Spanish Breast Cancer Research Group, Madrid, Spain.

The debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach's outcomes in patients included in a retrospective registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990-2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study's criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue [16.3%], bone [33.8%], or viscera [48.3%]). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.
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http://dx.doi.org/10.1038/s41598-019-55765-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934456PMC
December 2019

Poly (ADP-ribose) Polymerase Inhibition in Patients with Breast Cancer and BRCA 1 and 2 Mutations.

Drugs 2020 Feb;80(2):131-146

Medical Oncology Service, Departamento de Medicina, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

The poly-(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib, have recently been approved for use in patients with metastatic breast cancer (BC) and germline BRCA 1 or 2 mutations due to improved progression-free survival compared to chemotherapy. An increasing number of clinical trials are evaluating the role of PARP inhibitors (PARPi) in BC, alone and in combination with other therapies (including immunotherapy), as well as in earlier stages of the disease. This review describes the unique mechanism of action of these drugs and puts into clinical context the results of pivotal clinical trials. We also discuss the future development of PARPi in BC, their potential combination with other strategies, including chemotherapy and immune-checkpoint inhibitors, and the impact of these treatments in current genetic counselling.
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http://dx.doi.org/10.1007/s40265-019-01235-5DOI Listing
February 2020

Simulation modeling approaches to answer clinically relevant questions in breast cancer low-risk populations.

Ann Transl Med 2018 Nov;6(Suppl 1):S80

Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, CiberOnc, GEICAM, Madrid, Spain.

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http://dx.doi.org/10.21037/atm.2018.10.68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291602PMC
November 2018

Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase gene.

Cancer Manag Res 2018 11;10:4517-4522. Epub 2018 Oct 11.

Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain,

Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic test resulted negative. exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.
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http://dx.doi.org/10.2147/CMAR.S174470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190816PMC
October 2018

Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel.

Clin Cancer Res 2018 12 30;24(23):5820-5829. Epub 2018 Jul 30.

Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CIBERONC, GEICAM, Madrid, Spain.

Purpose: Prognostic value of pathologic complete response (pCR) and extent of pathologic response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC.

Patients And Methods: One-hundred and ninety patients with stage I-III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan-Meier method.

Results: Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14-0.62; = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10-0.63; = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS.

Conclusions: Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279513PMC
December 2018

Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial.

Lancet Oncol 2018 06 26;19(6):812-824. Epub 2018 Apr 26.

Breast Cancer Unit and Gynaecological Tumours, Ramon y Cajal University Hospital, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Baselga Oncology Institute, Quiron Group, Madrid and Barcelona, Spain. Electronic address:

Background: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer.

Methods: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual.

Findings: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia.

Interpretation: The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials.

Funding: Polyphor.
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http://dx.doi.org/10.1016/S1470-2045(18)30147-5DOI Listing
June 2018

Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification.

Clin Cancer Res 2018 04 29;24(8):1845-1852. Epub 2018 Jan 29.

Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Universidad Complutense, CiberOnc, GEICAM, Madrid, Spain.

Triple-negative breast cancer (TNBC) requires the iden- tification of reliable predictors of response to neoadjuvant chemotherapy (NACT). For this purpose, we aimed to evaluate the performance of the TNBCtype-4 classifier in a cohort of patients with TNBC treated with neoadjuvant carboplatin and docetaxel (TCb). Patients with TNBC were accrued in a nonrandomized trial of neoadjuvant carboplatin AUC 6 and docetaxel 75 mg/m for six cycles. Response was evaluated in terms of pathologic complete response (pCR, ypT0/is ypN0) and residual cancer burden by Symmans and colleagues. Lehmann's subtyping was performed using the TNBCtype online tool from RNAseq data, and germline sequencing of a panel of seven DNA damage repair genes was conducted. Ninety-four out of the 121 patients enrolled in the trial had RNAseq available. The overall pCR rate was 44.7%. Lehmann subtype distribution was 34.0% BL1, 20.2% BL2, 23.4% M, 14.9% LAR, and 7.4% were classified as ER+. Response to NACT with TCb was significantly associated with Lehmann subtype ( = 0.027), even in multivariate analysis including tumor size and nodal involvement, with BL1 patients achieving the highest pCR rate (65.6%), followed by BL2 (47.4%), M (36.4%), and LAR (21.4%). BL1 was associated with a significant younger age at diagnosis and higher ki67 values. Among our 10 germline mutation carriers, 30% were BL1, 40% were BL2, and 30% were M. TNBCtype-4 is associated with significantly different pCR rates for the different subtypes, with BL1 and LAR displaying the best and worse responses to NACT, respectively. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899625PMC
April 2018

Evaluation of Breast Cancer Patients with Genetic Risk in a University Hospital: Before and After the Implementation of a Heredofamilial Cancer Unit.

J Genet Couns 2018 08 15;27(4):854-862. Epub 2017 Dec 15.

Servicio de Oncología Médica, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.

The identification of patients at risk for breast cancer by genetic testing has proven to reduce breast cancer mortality. In 2010, due to a lack of systematization in hereditary cancer assistance in our center, we implemented a multidisciplinary Heredofamilial Cancer Unit (HFCU). We analyze if the HFCU improved the rates of referrals and preventive management of breast cancer patients with genetic risk. We retrospectively compared family history records, referrals of high-risk patients to genetic counseling, and detection and management of patients with BRCA1/2 mutations in two cohorts of breast cancer patients diagnosed before (first period: 2007-2010) and after the creation of the HFCU (second period: 2010-2013). In the first period, 893 patients were included, and 902 were included in the second. Due to the inability to establish their genetic risk, 142 patients (15.9%) vs. 70 (7.8%) were excluded from analysis (p < 0.001). Among the evaluable patients, 194 (25.8%) vs. 223 (26.8%) fulfilled one or more risk criteria (p = 0.65). Family history documentation in patient's medical records (92.4 vs. 97.8%, p < 0.001) and referral rate (26.3 vs. 52%, p < 0.0001) significantly increased in the second period. Eight BRCA1/2 mutations were detected among patients referred in the first period and 17 among those referred to the HFCU. The rate of preventive surgeries in patients with BRCA mutations significantly increased in the second period (25 vs. 76.5%, p = 0.03). In conclusion, there was a clear improvement in family history records, referrals, and preventive surgeries in breast cancer patients with genetic risk after the implementation of the HFCU.
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http://dx.doi.org/10.1007/s10897-017-0187-3DOI Listing
August 2018

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer.

Breast Care (Basel) 2017 Oct 19;12(5):296-302. Epub 2017 Oct 19.

Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Universidad Complutense de Madrid, CiberOnc, Madrid, Spain.

After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity.
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http://dx.doi.org/10.1159/000481656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704690PMC
October 2017

Frequency of breast cancer with hereditary risk features in Spain: Analysis from GEICAM "El Álamo III" retrospective study.

PLoS One 2017 6;12(10):e0184181. Epub 2017 Oct 6.

Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Purpose: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain.

Methods: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria.

Results: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria.

Conclusions: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184181PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630120PMC
October 2017

Ribociclib for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer.

Future Oncol 2017 Oct 31;13(24):2137-2149. Epub 2017 Jul 31.

Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), Universidad Complutense, CiberOnc, GEICAM, Madrid, Spain.

CDK4/6 inhibitors are a promising new class of drugs for hormone-receptor-positive breast cancer and have been shown to overcome and delay hormone resistance in advanced breast cancer. Ribociclib, a selective oral inhibitor of CDK4/6, was approved by the US FDA for first-line treatment of hormone-receptor-positive/HER2-negative metastatic breast cancer. This review summarizes the clinical evidence available for ribociclib, from preclinical data to the pivotal studies, with a special focus on toxicity and its management. In addition, this article reviews potential new combinations under study, as well as ongoing clinical trials both in the metastatic and early setting. Finally, this review compares ribociclib activity and toxicity with those of the drugs of the same class (palbociclib and abemaciclib).
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http://dx.doi.org/10.2217/fon-2017-0183DOI Listing
October 2017

Neratinib for the treatment of HER2-positive early stage breast cancer.

Expert Rev Anticancer Ther 2017 08 26;17(8):669-679. Epub 2017 Jun 26.

c Instituto de Investigación Sanitaria Gregorio Maranon (IiSGM), Universidad Complutense, CiberOnc, GEICAM , Madrid , Spain.

Introduction: Despite the advances in the treatment of HER2-positive breast cancer, resistance to actual chemotherapeutic regimens eventually occurs. Neratinib, an orally available pan-inhibitor of the ERBB family, represents an interesting new option for early-stage HER2-positive breast cancer. Areas covered: In this article, the development of neratinib, with a special focus on its potential value in the treatment of early-stage HER2-positive breast cancer, has been reviewed. For this purpose, a literature search was conducted, including preclinical studies, early-phase trials in advanced cancer with neratinib in monotherapy and in combination, and phase II and large phase III trials in the early setting. Management of neratinib-induced toxicity, future perspectives for the drug, and ongoing trials are also discussed in this review. Expert commentary: Neratinib is emerging as a promising oral drug for the treatment of HER2-positive breast cancer. Although FDA and EMA approval is derived from the extended adjuvant treatment, this setting may not be the ideal scenario to obtain the beneficial effects of neratinib. Confirmatory data in the neoadjuvant setting and subgroup analysis from the ExTENET trial might bring some light into the best setting for neratinib therapy. Data from confirmatory trials in the metastatic setting are also required.
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http://dx.doi.org/10.1080/14737140.2017.1338954DOI Listing
August 2017

Multicenter analysis of neoadjuvant docetaxel, carboplatin, and trastuzumab in HER2-positive breast cancer.

Breast Cancer Res Treat 2017 02 31;162(1):181-189. Epub 2016 Dec 31.

Hospital Clínico San Carlos, Madrid, Spain.

Purpose: In an era where neoadjuvant dual blockade is emerging as the standard of care for early and locally advanced HER2-positive breast cancer, we aimed to identify predictors of response to single-blockade chemotherapy.

Methods: This retrospective analysis reviewed all the incident stage I-III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in three institutions. pCR was defined as the absence of invasive tumor in breast and axillary nodes (ypT0/isypN0).

Results: From 2008 to 2015, 84 patients receiving neoadjuvant TCH were identified within our institutions. The mean age at diagnosis was 51.8 years. 59.5% of the patients were hormone receptor (HR) positive, lymph node involvement occurred in 67.9%, and clinical distribution was 2.4, 65.5, and 32.1% for stage I, II, and III, respectively. pCR rate was 47.6%; there was a significantly lower response in HR-positive patients compared to HR-negative ones (34 vs 67.6%, p = 0.005). pCR rate was associated with tumor size, whereas differences did not reach significance either for stage or for nodal status. Multivariate analysis found that only HR status was associated with response (p = 0.003). At a median follow-up of 31.7 months, disease-free survival, distant disease-free survival, and overall survival were 78.6, 85.7, and 94%, respectively. Breast-conserving surgery was performed in 44% of the patients. Overall, TCH was well tolerated, with low rates of grade 3-4 adverse events, and neither late toxicities nor cardiac dysfunctions were reported.

Conclusions: Neoadjuvant TCH, an anthracycline-free single-blockade regimen, achieved a pCR of 47.6%. Further molecular analyses are required in order to identify stronger predictive markers of pCR and thus for an accurate selection of patients who do not benefit from dual blockade.
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http://dx.doi.org/10.1007/s10549-016-4098-zDOI Listing
February 2017

Endocrine therapy for hormone treatment-naïve advanced breast cancer.

Breast 2016 Aug 18;28:161-6. Epub 2016 Jun 18.

Medical Oncology Department, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense de Madrid, C/Dr Esquerdo 46, Madrid 28009, Spain. Electronic address:

A proportion of patients with hormone receptor-positive locally advanced or metastatic breast cancer will not have received prior endocrine therapy. However, there are limited clinical data specifically in these patients. We conducted a review of randomized phase II and III clinical studies of anastrozole, letrozole, exemestane, palbociclib, and fulvestrant to determine the evidence base supporting use of specific endocrine therapies in this patient population. From our findings, there is a paucity of clinical studies in patients with endocrine therapy-naïve disease; however, it appears that first-line treatment effects are consistent between patients who have and have not received prior endocrine treatment.
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http://dx.doi.org/10.1016/j.breast.2016.05.015DOI Listing
August 2016

Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts.

Clin Cancer Res 2017 Feb 14;23(3):649-657. Epub 2016 Jun 14.

Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

Purpose: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC.

Experimental Design: The study population includes 190 patients with stage I-III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated.

Results: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event.

Conclusions: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline-taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649-57. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156592PMC
February 2017

Phase 2 Study of Trabectedin in Patients With Hormone Receptor-Positive, HER-2-Negative, Advanced Breast Carcinoma According to Expression of Xeroderma Pigmentosum G Gene.

Clin Breast Cancer 2016 10 14;16(5):364-371. Epub 2016 May 14.

Institut Gustave Roussy, Villejuif, France.

Background: Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m as a 3-hour intravenous infusion every 3 weeks in hormone receptor-positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression.

Patients And Methods: Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups. The primary efficacy end point was progression-free survival (PFS) rate at 16 weeks (PFS4); secondary efficacy end points were overall response rate (ORR), duration of response, PFS, overall survival, and safety of trabectedin in this patient population.

Results: Forty-four patients were treated, 21 with high XPG and 23 with low XPG. Four high-XPG and 6 low-XPG patients experienced PFS4; the criterion for further recruitment (> 6 patients experienced PFS4) was thus not met, and recruitment was stopped. One high-XPG patient had a partial response (ORR, 5%). One low-XPG patient had a complete response, and 2 low-XPG patients had partial responses (ORR, 13%). Comparison of efficacy parameters between high-XPG and low-XPG patients showed no statistically significant differences. ORR in the efficacy population was 9.3%, median PFS was 1.9 months, and overall survival was 11.8 months. The safety of trabectedin in breast carcinoma was similar to that shown in other indications.

Conclusion: Trabectedin as single agent had limited activity in hormone-positive, HER-2-negative advanced breast cancer. XPG mRNA expression was not predictive of trabectedin efficacy.
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http://dx.doi.org/10.1016/j.clbc.2016.05.005DOI Listing
October 2016

Emerging Therapeutic Options for HER2-Positive Breast Cancer.

Am Soc Clin Oncol Educ Book 2016 ;35:e64-70

From the Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.

The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2 directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant setting. New promising drugs have been approved to broaden the horizon of HER2-positive breast cancer such as pertuzumab or T-DM1, but we need new options to further improve the management of these diseases. In this review, we cover new strategies that are currently under evaluation for the treatment of patients with HER2-positive breast cancer, including new tyrosine kinase inhibitors (neratinib, ONT-380), new antibody-drug conjugates targeting HER2 (MM-302), and new indications of already approved drugs (T-DM1), as well as the potential dual combinations of anti-HER2 therapy with phosphoinositide 3-kinase/mTOR or cell cycle inhibitors (palbociclib, abemaciclib). Last but not least, we briefly review a new paradigm of emerging approaches that involve the host immune response, HER2 breast cancer vaccines, and other immune strategies, including immune checkpoint inhibition.
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http://dx.doi.org/10.1200/EDBK_159167DOI Listing
January 2017

Frequency of germline DNA genetic findings in an unselected prospective cohort of triple-negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial.

Breast Cancer Res Treat 2016 04 15;156(3):507-515. Epub 2016 Apr 15.

Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Universitario Gregorio Marañón, Madrid, Spain.

We describe the status and frequency of germline DNA genetic findings in an unselected prospective cohort of triple negative breast cancer patients participating in a platinum-based neoadjuvant chemotherapy trial. Study population includes 124 consecutive patients with stage II-III TNBC from a trial exploring the antitumor activity of neoadjuvant carboplatin/docetaxel chemotherapy enrolled between 2012 and March 2015, to determine the frequency of germline DNA genetic mutations. 17.1 % of the patients with germline DNA tested had deleterious mutations in any of the analyzed genes (12.38 % in BRCA1, 1.9 % in BRCA2 and BARD1 and 0.95 % in RAD51D). Attending the intrinsic subtype, all the BRCA1/2 carriers tested had basal-like subtype. Among wild-type (WT) patients, 70.11 % had basal subtype, 16.09 % HER2 enriched, 1.15 % Luminal B, and 4.60 % Normal-like. Mean age at diagnosis was significantly lower in mutation-carriers compared with no carriers (43.72 vs 53.10, p = 0.004). 3 BRCA1/2 carriers were detected between 51 and 60 years, and only one deleterious mutation (BARD1) over 60 years. A positive familiar history of breast and ovarian cancer was more frequent in patients with deleterious mutations (39.39 vs 17.94 %, p = 0.043). Our study confirms the prevalence of BRCA1/2 mutations in TNBC patients. TNBC should therefore be considered by itself as a criterion for BRCA1/2 genetic testing. Determination of other breast cancer predisposition genes implicated in homologous recombination should also be discussed in this population. However, no definitive conclusions can be reached due to the low prevalence and the uncertain clinical impact of most of the genes included.
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http://dx.doi.org/10.1007/s10549-016-3792-1DOI Listing
April 2016

S-1 versus taxanes for HER2-negative metastatic breast cancer.

Lancet Oncol 2016 Jan 24;17(1):11-2. Epub 2015 Nov 24.

Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Dr Esquerdo 46, 28007 Madrid, Spain.

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http://dx.doi.org/10.1016/S1470-2045(15)00470-2DOI Listing
January 2016

Supervised physical exercise improves VO2max, quality of life, and health in early stage breast cancer patients: a randomized controlled trial.

Breast Cancer Res Treat 2015 Sep 21;153(2):371-82. Epub 2015 Aug 21.

Physical Activity and Sport Science Faculty, Technical University of Madrid, Calle Martín Fierro, 7, C.P.: 28040, Madrid, Spain,

Breast cancer patients suffer impairment in cardiorespiratory fitness after treatment for primary disease, affecting patients' health and survival. The aim of this study was to evaluate the ability of a pragmatic exercise intervention to improve cardiorespiratory fitness of breast cancer patients after primary treatment. Between February 2013 and December 2014, 94 women with early stage (I-III) breast cancer, 1-36 months post-chemotherapy, and radiotherapy were randomly assigned to an intervention program (EX) combining supervised aerobic and resistance exercise (n = 44) or usual care (CON) (n = 45) for 12 weeks. Primary study endpoint was VO2max. Secondary endpoints were muscle strength, shoulder range of motion, body composition, and quality of life (QoL). Assessments were undertaken at baseline, 12-week, and 6-month follow-ups. Eighty-nine patients aged 29-69 years were assessed at baseline and 12 weeks. The EX group showed significant improvements in VO2max, muscle strength, percent fat, and lean mass (p ≤ 0.001 in all cases) and QoL compared with usual care (CON). Apart from body composition, improvements were maintained for the EX at 6-month follow-up. There were no adverse events during the testing or exercise intervention program. A combined exercise intervention produced considerable improvement in cardiorespiratory fitness, physical function, and quality of life in breast cancer patients previously treated with chemotherapy and radiation therapy. Importantly, most of these benefits were maintained 6 months after ceasing the supervised exercise intervention.
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http://dx.doi.org/10.1007/s10549-015-3541-xDOI Listing
September 2015

Optimizing Adjuvant Taxanes in Early Breast Cancer.

J Clin Oncol 2015 Jul 22;33(21):2334-6. Epub 2015 Jun 22.

Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1200/JCO.2015.61.9312DOI Listing
July 2015

Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy.

Clin Cancer Res 2015 Sep 26;21(17):3995-4003. Epub 2015 May 26.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.

Experimental Design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.

Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001).

Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558260PMC
September 2015

Circulating tumor cells following first chemotherapy cycle: an early and strong predictor of outcome in patients with metastatic breast cancer.

Oncologist 2013 19;18(8):917-23. Epub 2013 Jul 19.

Medical Oncology Service, Instituto de Investigación Sanitaria Hospital Gregorio Marañón, Universidad Complutense, Madrid, Spain.

We investigated the prognostic significance of circulating tumor cells (CTCs) determined immediately before the second cycle of chemotherapy in patients with metastatic breast cancer (MBC). The CTC counts were taken at baseline, before the first cycle of chemotherapy (CTC-0), and on day 21 before commencing the second cycle of chemotherapy (CTC-21) in consecutive MBC patients. The study's primary objectives were to analyze relationships between CTC-21 count and overall survival (OS). Based on the current literature, the CTC measurements were dichotomized as 0-4 versus ≥ 5 CTCs. Of 117 patients recruited, 99 were evaluable. Patients with 0-4 CTCs on day 21 had a significantly better OS than those with ≥ 5 CTCs (median OS: 38.5 months vs. 8.7 months). They also had a significantly better progression-free survival (PFS; median: 9.4 months vs. 3.0 months) and clinical benefit rate (77% vs. 44%). The OS of patients whose baseline CTCs were ≥ 5 but dropped to <5 on day 21 was apparently similar to those who had <5 CTCs at baseline. In a Cox regression analysis, CTC-21 was the only independent variable significantly predicting OS and PFS. Our data indicate that CTCs determined immediately before the second cycle of chemotherapy is an early and strong predictor of treatment outcome in MBC patients.
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http://dx.doi.org/10.1634/theoncologist.2012-0479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755928PMC
May 2014

Evaluation of a heredofamilial cancer unit in increasing family history collection and genetic counseling referrals among Spanish oncologists at a university hospital.

J Genet Couns 2014 Feb 16;23(1):108-13. Epub 2013 Jun 16.

Servicio de Oncología Médica; Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Calle Maiquez 7, 28007, Madrid, Spain,

A comprehensive family history is essential to identify patients at risk for hereditary cancer who could benefit from genetic counseling (GC). In a previous study, we observed a low occurrence of family history record (FHR) collection rate and GC referral among oncologists at our institution. The present work analyzes whether the implementation of a heredofamilial cancer unit (HFCU) would improve these parameters. We retrospectively compared the FHR rate in clinical records, National Cancer Institute (NCI) general criteria for hereditary cancer suspicion, GC referrals and FHR quality in two cohorts: cohort 1 (patients diagnosed before HFCU creation) and cohort 2 (after HFCU creation). Of 1,175 patients (590 cohort 1 and 585 cohort 2), FHRs were consigned in 27.3 % and 52.5 % of patients, respectively (p < 0.001). The GC referral of patients with any NCI criterion was 13.6 % xin cohort 1 vs. 40.5 % in cohort 2 (p < 0.001). FHR quality improved in terms of the total number of relatives (164 vs. 314, p = 0.1, N.S.) and number of healthy relatives consigned (80 vs. 191, p < 0.01). Nine mutations (6 BRCA, 1 MEN1, 2 Lynch), 4 unknown significance variants (all in BRCA) and 2 with no mutation were identified among patients referred from cohort 2. We conclude that the creation of a heredofamilial cancer unit has changed both FHR and GC referrals among oncologists at our institution, although continuous educational efforts are required.
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http://dx.doi.org/10.1007/s10897-013-9617-zDOI Listing
February 2014

Chemotherapy: Maintenance therapy in breast cancer--many questions remain.

Nat Rev Clin Oncol 2013 Jul 28;10(7):370-2. Epub 2013 May 28.

Gregorio Marañon Research Institute, Complutense University of Madrid, Calle del Doctor Esquerdo 46, 28007 Madrid, Spain.

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http://dx.doi.org/10.1038/nrclinonc.2013.87DOI Listing
July 2013

Zooming in on the schedule of bone-modifying drugs.

Lancet Oncol 2013 Jun 16;14(7):575-6. Epub 2013 May 16.

Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.

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http://dx.doi.org/10.1016/S1470-2045(13)70209-2DOI Listing
June 2013