0000000000004045
AUTHOR
Jose Alejandro Perez-fidalgo
Current questions for the treatment of advanced gastric cancer.
Abstract Background Gastric cancer remains a major health problem worldwide. Treatment of advanced gastric cancer is controversial and there is no standard regimen for first- or second-line chemotherapy (CT). This review aims to give an overview of the hot topics concerning treatment, prognostic factors and new strategies in advanced gastric cancer. Material and methods Seven questions of special clinical interest have been formulated previously to the literature review. With the aim of answering each of these questions, a specific search of the relevant trials and meta-analyses published or communicated from 1990 to date was performed. Results Patients treated with CT have a survival benef…
A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers.
Background: AZD5363 is a novel potent pan-AKT inhibitor (IC50of AKT1, AKT2 and AKT3 of 3, 7 and 7nM respectively) with preclinical activity across a range of models. Methods: The trial had an adaptive design that allowed changes in schedule based on toxicity, PK, and PD findings. AZD5363 was administered orally (PO) twice a day (BID). Three schedules were explored: continuous dosing (7/7), four days a week, (4/7) and two days a week (2/7). PD biomarkers including pAKT, pGSK3?, and pPRAS40 were measured by IHC in pre- and post-treatment tumor biopsies. Once a RP2D was established, two expansion cohorts of PIK3CA-mutant ER+ve breast (B) and gynecological (G) cancers were explored. Results: 47…
Correlation between classical prognostic factors and overexpression of HER2 and HER3 in localized gastric cancer
e14589 Background: Although HER2 overexpression has been identified as a predictive factor for targeted therapy in advanced gastric cancer (GC), little is known about its role in localized GC. Recent studies suggest that not only HER2 but also HER3 might have a role in prognosis in GC. Our study aimed to identify the prevalence of HER2 and HER3 overexpression in a series of localized GC and to describe correlations of these with traditional prognostic factors Methods: We performed a retrospective analysis of HER2 and HER3 overexpression in archived tumour samples in pts diagnosed with GC at stage I-III. HER2 was assessed with herceptest, (negative if 0 or 1+, or positive with 2+ or 3+). St…
A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients
Background Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods Epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K arra…
Balixafortide (a CXCR4 antagonist) + eribulin in HER2-negative metastatic breast cancer (MBC): Survival outcomes of the phase I trial.
2606 Background: Balixafortide (B) is a potent antagonist of the chemokine receptor CXCR4. Preclinical evidence suggests that disrupting CXCR4 dependent pathways prevents development of breast cancer metastases, enhances the cytotoxic effect of chemotherapy and immunotherapy, and counteracts tumor cell evasion of the immune system. Encouraging safety and efficacy data were published recently from the ongoing Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC (Pernas S. et al. Lancet Oncol. 2018; 19: 812−24). The objective response rate, median progression free survival and median overall survival (OS) for the expanded cohort (EC) and the overall efficacy popula…
An evaluation of the impact of technical bias on the concordance rate between primary and recurrent tumors in breast cancer.
Abstract Purpose Whether or not to biopsy the metastasis in recurrent breast cancer has become mired in controversy. Several studies have shown an important discordance of the immunohistochemical (IHC) determinations for ER, PR and HER2 between primary (PT) and recurrent tumors (RT). Yet it remains unknown within this what impact technical issues have. The aim of our study was to assess whether technical variability might have an impact on the concordance between PT and RT. Methods IHC determinations in paired biopsies from PT and RT were compared under routine vs study conditions. In the former, pathological analysis reproduced the conditions used in the routine of a University Pathology D…
Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer
Abstract There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable.” Alterations…
The GAIN-C study (BP25438): Randomized phase II trial of RG7160 (GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI alone in second-line KRAS wild type (WT) or mutant metastatic colorectal cancer (mCRC).
TPS3637 Background: GA201 is a novel, dual-acting, humanized, glycoengineered IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in combination with signal inhibition. GA201 demonstrates significantly enhanced in vitro/vivo activity compared to cetuximab (cet) both as a single agent and in combination with irinotecan, in both KRAS mutant and BRAF mutant models and promising clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011) including KRAS mutant mCRC. A randomized ph II program was launched: one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is presented here. Methods: Main inclusion criteria are prog…
The role of AXL as mechanism of resistance to trastuzumab and a prognostic factor in breast cancer HER2 positive: A translational approach
Abstract Background Breast cancer (BC) is a heterogeneous disease. HER2+ BC represents between 15-30% of cases. Trastuzumab (T), a monoclonal antibody, has been successfully improved clinical benefits in both adjuvant and in metastatic settings. Despite this evidence, many patients experience resistance to therapy. The objective of this study is to assess AXL as a potential mechanism of resistance and its implication as a prognostic factor. Methods We used three cell lines with acquired resistance to T. Resistant models were generated by treating parental cells (AU565, SKR3, BT474) with constant dose of T (15mg/mL) for 6 months. Cell viability was estimated by MTT assay. Proteins were asses…
Balixafortide (a CXCR4 antagonist) plus eribulin in HER2 negative metastatic breast cancer: Dose-response analysis of efficacy from phase I single-arm trial.
e15209 Background: Balixafortide (B) is a potent, selective antagonist of the chemokine receptor CXCR4. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in metastatic breast cancer (MBC). Efficacy and safety data were published recently from the Phase 1 trial investigating B + eribulin (E) in patients with HER2 negative MBC1. We report the final efficacy analyses from this trial, including assessment of dose-response. Methods: In this single-arm, dose escalation trial, patients (pts) received E + increasing doses of B using a 3+3 design in 3 parts: Part I (cohorts received low E doses); Part II (dose-escalation cohort for B [1−5.5mg/kg] + 1.4mg/m2 E); Ex…
A preclinical model for skin sensitization prediction of antineoplasic drugs.
e15643 Background: Skin side effects are common manifestations of antineoplastic drugs that are frequently observed in early clinical trials. Therefore, there is a need to identify skin toxic agents before clinical development in order to predict severe skin manifestations. In many cases, skin toxicity is due to sensitization, a key immunologic process mediating redness, swelling and itching that can lead to more severe skin alterations. Methods: We adapted three skin cellular in vitro techniques for cutaneous drug sensitization assessment of the Organization for Economic Cooperation and Development (OECD, 2012) in order to predict antineoplastic drug skin sensitization: 1) Direct peptide …
Mechanisms of skin toxicity of paclitaxel: An in vitro preclinical assessment.
e15511 Background: Paclitaxel skin toxicity is a frequent side effect extensively evaluated in the clinical setting. However little is known about the preclinical mechanisms that lead to this toxicity. The endpoint of this study was to analyse the cutaneous mechanisms that drive paclitaxel toxicity in a preclinical model. Methods: Primary human keratinocytes were co-cultured with human dermal fibroblast in collagen gel under air-liquid interface conditions to generate a multilayered 3D epidermis. Paclitaxel was added to 3D epidermis at 0.3 µM, 3 µM and 30 µM and total RNA and protein was extracted after 24h of incubation. Markers of cell senescence (p21 and p53), anti-apoptotic mediators (…