Translational Research in Oncology

Montevideo, Uruguay

Translational Research in Oncology

Montevideo, Uruguay
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Mackey J.R.,University of Alberta | Ramos-Vazquez M.,Centro Oncologico Of Galicia Jose Antonio Quiroga Y Pineiro | Lipatov O.,Bashkortostan Republic Ministry of Health | McCarthy N.,ICON Cancer Care Wesley | And 16 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. Patients and Methods: In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) -negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. Results: Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. Conclusion: Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes. © 2014 by American Society of Clinical Oncology.

O'Shaughnessy J.,Baylor Charles mmons Cancer Center | Hellerstedt B.,Texas Oncology Round Rock | Schwartzberg L.,Accelerated Community Oncology Research Network | Yardley D.A.,Sarah Cannon Research Institute | And 14 more authors.
Journal of Clinical Oncology | Year: 2014

Purpose: There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. Patients and Methods: Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m2 and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. Results: Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. Conclusion: The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation. © 2014 by American Society of Clinical Oncology.

Mackey J.R.,Cross Cancer Institute | Martin M.,Complutense University of Madrid | Pienkowski T.,European Health Center | Rolski J.,Podkarpackie Centrum Onkologii | And 26 more authors.
The Lancet Oncology | Year: 2013

Background: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. Methods: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with, number NCT00688740. Findings: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. Interpretation: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. Funding: Sanofi. © 2013 Elsevier Ltd.

Hecht J.R.,University of California at Los Angeles | Bang Y.-J.,Seoul National University | Qin S.K.,Nanjing Bayi Hospital | Chung H.C.,Yonsei University | And 20 more authors.
Journal of Clinical Oncology | Year: 2016

Purpose: To evaluate the efficacy of adding lapatinib to capecitabine and oxaliplatin (CapeOx) in patients with previously untreated human epidermal growth factor receptor 2 (HER2) -amplified advanced gastroesophageal adenocarcinoma. Patients and Methods: Patients with HER2-positive advanced gastroesophageal adenocarcinoma were randomly assigned at a one-to-one ratio to CapeOx plus lapatinib 1,250mg or placebo daily. Primary end point was overall survival (OS) in patientswith centrally confirmed HER2 amplification in the primary efficacy population. Results: A total of 545 patients were randomly assigned, and 487 patients comprised the primary efficacy population. Median OS in the lapatinib and placebo arms was 12.2 (95% CI, 10.6 to 14.2) and 10.5 months (95% CI, 9.0 to 11.3), respectively, which was not significantly different (hazard ratio, 0.91; 95% CI, 0.73 to 1.12). Median progression-free survival in the lapatinib and placebo arms was 6.0 (95% CI, 5.6 to 7.0) and 5.4 months (95% CI, 4.4 to 5.7), respectively (hazard ratio, 0.82; 95% CI, 0.68 to 1.00; P = .0381). Response rate was significantly higher in the lapatinib arm: 53% (95% CI, 46.4 to 58.8) compared with 39% (95% CI, 32.9 to 45.3) in the placebo arm (P = .0031). Preplanned exploratory subgroup analyses showed OS in the lapatinib arm was prolonged in Asian and younger patients. No correlation was observed between HER2 immunohistochemistry status and survival. There were increased toxicities in the lapatinib arm, particularly diarrhea. Conclusion: Addition of lapatinib to CapeOx did not increase OS in patients with HER2-amplified gastroesophageal adenocarcinoma. There were clear differences in the effect of lapatinib depending on region and age. Future studies could examine this correlation. © 2016 by American Society of Clinical Oncology. All rights reserved.

Harbeck N.,Ludwig Maximilians University of Munich | Huang C.-S.,National Taiwan University Hospital | Hurvitz S.,University of California at Los Angeles | Hurvitz S.,Translational Research in Oncology | And 19 more authors.
The Lancet Oncology | Year: 2016

Background: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. Methods: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with, NCT01125566. Findings: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). Interpretation: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. Funding: Boehringer Ingelheim. © 2016 Elsevier Ltd.

Mackey J.R.,Cross Cancer Institute | Pienkowski T.,Center of Oncology of Poland | Crown J.,Dublin City University | Sadeghi S.,University of California at Los Angeles | And 15 more authors.
Annals of Oncology | Year: 2016

Background: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with nodepositive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. Patients and methods: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC→T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. Results: The 10-year DFS rates were 66.5% in the AC→T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC→T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC→T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. Conclusion: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC→T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. Trial Registration: Identifier NCT00312208. © The Author 2016.

Au H.-J.,University of Alberta | Eiermann W.,FrauenklinikvomRoten Kreuz | Robert N.J.,Us Oncology Research | Pienkowski T.,European Health Center | And 16 more authors.
Oncologist | Year: 2013

Background. This study aims to describe and compare health- related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast can-cer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone. Methods. Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC-T) or one of two trastu- zumab-containing regimens: adjuvant doxorubicin and cyclophos- phamidefollowed bydocetaxel plustrastuzumabadministeredfor1 year (AC-TH) or six cycles of docetaxel pluscarboplatin combined with trastuzumab administered for 1 year (TCH). The European Or-ganization for Research andTreatment of Cancer (EORTC)Qualityof Life Questionnaire C30 and BR-23 were administered at baseline, thestartofcycle4(mid),andtheendofchemotherapy(EOC),aswell as at 6,12, and 24 months after chemotherapy. Results. Compliance rates for the EORTC questionnaires were acceptable at 72%-93% of eligible patients out to the 12- month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients com-pared with AC->TH and AC-T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC-TH regimen, but was otherwise similar between arms. All treatment arms re-covered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and fol-low-up. Conclusion. HRQL outcomes for adjuvant docetaxel and trastu- zumab-based regimens are favorable and support TCH as a more tolerable treatment option. © AlphaMed Press 2013.

PubMed | Novartis, Yonsei University, Translational Research in Oncology, Nanjing Bayi Hospital and 11 more.
Type: | Journal: Molecular cancer therapeutics | Year: 2016

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2-amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx fluorescence in situ hybridization (FISH) and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4674 patients in a central laboratory for eligibility (1995 cases) and for confirmation of local HER2 results (333 cases). Of 1995 adenocarcinomas screened centrally, 322 (16.1%) had HER2 amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%) 487 patients (89%) were centrally confirmed as having HER2 amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2. In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low.

Fresco R.,Translational Research in Oncology | Spera G.,Translational Research in Oncology | Meyer C.,Translational Research in Oncology | Cabral P.,University of the Republic of Uruguay | Mackey J.R.,University of Alberta
Oncologist | Year: 2015

Background. Medical imaging is commonly required in breast cancer (BC) clinical trials to assess the efficacy and/or safety of study interventions. Despite the lack of definitive epidemiological data linking imaging radiation with cancer development in adults, concerns exist about the risks of imaging radiation-induced malignancies (IRIMs) in subjects exposed to repetitive imaging.We estimated the imaging radiation dose and IRIM risk in subjects participating in BC trials. Materials and Methods. The imaging protocol requirements in 10 phase III trials in the adjuvant and advanced settings were assessed to estimate the effective radiation dose received by a typical and fully compliant subject in each trial. For each study, the excess lifetime attributable cancer risk (LAR) was calculated using the National Cancer Institute’s Radiation Risk Assessment Tool, version 3.7.1. Dose and risk calculations were performed for both imaging intensive and nonintensive approaches to reflect the variability in imaging performed within the studies. Results. Thetotal effective imaging radiationdosewas 0.4-262.2 mSvinadjuvanttrialsand26-241.3mSvinmetastatic studies.The dose variability resulted fromdiffering protocol requirements and imaging intensity approaches,with computed tomography,multigated acquisition scans, and bone scans as the major contributors. The mean LAR was 1.87-2,410/100,000 in adjuvant trials (IRIM: 0.0002%-2.41% of randomized subjects) and 6.9-67.3/100,000 in metastatic studies (IRIM: 0.007%-0.067% of subjects). Conclusion. IRIMs are infrequent events. In adjuvant trials, aligning the protocol requirements with the clinical guidelines’ surveillance recommendations and substituting radiating procedures with equivalent nonradiating ones would reduce IRIM risk. No significant risk has been observed in metastatic trials, and potential concerns on IRIMs are not justified. © AlphaMed Press 2015.

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