Publications by authors named "John Crown"

178 Publications

Use of Circulating Tumour DNA (ctDNA) for Measurement of Therapy Predictive Biomarkers in Patients with Cancer.

J Pers Med 2022 Jan 13;12(1). Epub 2022 Jan 13.

Department of Medical Oncology, St Vincent's University Hospital, D04 T6F4 Dublin, Ireland.

Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis.
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http://dx.doi.org/10.3390/jpm12010099DOI Listing
January 2022

A method of separating extracellular vesicles from blood shows potential clinical translation, and reveals extracellular vesicle cargo gremlin-1 as a diagnostic biomarker.

Transl Oncol 2022 Jan 18;15(1):101274. Epub 2021 Nov 18.

School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, Dublin, Ireland; Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; Trinity St. James's Cancer Institute, Trinity College Dublin, Dublin, Ireland. Electronic address:

Extracellular vesicles (EVs) have potential as minimally invasive biomarkers. However, the methods most commonly used for EV retrieval rely on ultracentrifugation, are time-consuming, and unrealistic to translate to standard-of-care. We sought a method suitable for EV separation from blood that could be used in patient care. Sera from breast cancer patients and age-matched controls (n = 27 patients; n = 36 controls) were analysed to compare 6 proposed EV separation methods. The EVs were then characterised on 8 parameters. The selected method was subsequently applied to independent cohorts of sera (n = 20 patients; n = 20 controls), as proof-of-principle, investigating EVs' gremlin-1 cargo. Three independent runs with each method were very reproducible, within each given method. All isolates contained EVs, although they varied in quantity and purity. Methods that require ultracentrifugation were not superior for low volumes of sera typically available in routine standard-of-care. A CD63/CD81/CD9-coated immunobead-based method was most suitable based on EV markers' detection and minimal albumin and lipoprotein contamination. Applying this method to independent sera cohorts, EVs and their gremlin-1 cargo were at significantly higher amounts for breast cancer patients compared to controls. In conclusion, CD63/CD81/CD9-coated immunobeads may enable clinical utility of blood-based EVs as biomarkers.
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http://dx.doi.org/10.1016/j.tranon.2021.101274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605358PMC
January 2022

Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis.

Endocrinol Diabetes Metab Case Rep 2021 Oct 1;2021. Epub 2021 Oct 1.

Department of Endocrinology, St Vincent's University Hospital, Dublin, Ireland.

Summary: Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient's malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis.

Learning Points: Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy. Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4). Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis. Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption. A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.
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http://dx.doi.org/10.1530/EDM-21-0130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558892PMC
October 2021

A careful reassessment of anthracycline use in curable breast cancer.

NPJ Breast Cancer 2021 Oct 8;7(1):134. Epub 2021 Oct 8.

Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.

It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.
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http://dx.doi.org/10.1038/s41523-021-00342-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501074PMC
October 2021

Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma.

J Cancer 2021 4;12(15):4672-4685. Epub 2021 Jun 4.

National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin, Ireland.

The molecular, histopathological, genomic and transcriptomic characteristics of uveal melanoma (UM) have identified four molecular subgroups with different clinical outcomes. Despite the improvements in UM classification and biological pathology, current treatments do not reduce the occurrence of metastasis. The development of effective adjuvant and metastatic therapies for UM has been slow and extremely limited. Preclinical models that closely resemble the molecular and genetic UM subgroups are essential for translating molecular findings into improved clinical treatment. In this review, we provide a retrospective view of the existing preclinical models used to study UM, and give an overview of their strengths and limitations. We review targeted therapy clinical trial data to evaluate the gap in the translation of preclinical findings to human studies. Reflecting on the current high attrition rates of clinical trials for UM, preclinical models that effectively recapitulate the human situation and/or accurately reflect the subtype classifications would enhance the translational impact of experimental data and have crucial implications for the advancement of personalised medicine.
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http://dx.doi.org/10.7150/jca.53954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210544PMC
June 2021

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

Breast Cancer Res Treat 2021 Aug 14;189(1):269-283. Epub 2021 Jun 14.

Department of Medical Oncology, University Hospital Waterford, Waterford, Ireland.

Purpose: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes.

Methods: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses.

Results: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications.

Conclusion: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.
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http://dx.doi.org/10.1007/s10549-021-06263-yDOI Listing
August 2021

Prognostic value of the 6-gene OncoMasTR test in hormone receptor-positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors.

Eur J Cancer 2021 07 2;152:78-89. Epub 2021 Jun 2.

UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, 4, Ireland; OncoMark Limited, Belfield, Dublin, 4, Ireland.

Aim: The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade.

Methods: Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones.

Results: OMm and OM (both with likelihood ratio statistic [LRS] P < 0.001; C indexes = 0.84 and 0.85, respectively) were more prognostic for DRFS and provided significant additional prognostic information to all other assessment tools/factors assessed (all LRS P ≤ 0.002). In addition, the OM correctly classified more patients with distant recurrences (DRs) into the high-risk category than other risk classification tools. Similar results were observed for IDFS.

Discussion: Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions.
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http://dx.doi.org/10.1016/j.ejca.2021.04.016DOI Listing
July 2021

NRG Oncology/NSABP B-47 menstrual history study: impact of adjuvant chemotherapy with and without trastuzumab.

NPJ Breast Cancer 2021 May 20;7(1):55. Epub 2021 May 20.

NSABP/NRG Oncology, Pittsburgh, PA, USA.

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.
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http://dx.doi.org/10.1038/s41523-021-00264-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137688PMC
May 2021

Endometrial Mesonephric-like Adenocarcinoma Presenting as an Ocular Lesion: A Case Report.

Int J Gynecol Pathol 2021 May 3. Epub 2021 May 3.

Department of Pathology, St. Vincent's University Hospital (S.A.L.N., A.D., S.K., D.G.) UCD School of Medicine and Medical Specialties (S.K., R.M.V., J.C., D.G.) Departments of Gynecological Oncology (R.M.V.) Oncology (J.C.), St. Vincent's University Hospital.

Endometrial mesonephric-like carcinoma (ML-CA) is a recently recognized subtype of aggressive endometrial adenocarcinoma that is morphologically and immunophenotypically similar to mesonephric carcinoma but not typically associated with mesonephric remnants. Here, we report a case of 58-yr-old female who had a past medical history of fibroids and of irregular menstrual bleeding for ~20 yr who presented with visual disturbance. On further investigation, she was found to have a large choroidal peri-papillary tumor of the right eye. A presumptive diagnosis of choroidal melanoma was made. Right eye enucleation was performed, and microscopy revealed moderately differentiated metastatic adenocarcinoma. Further work up was advised. A uterine mass was identified on imaging followed by endometrial biopsy that showed a morphologically and immunohistochemically similar tumor to that in the eye. A hysterectomy was carried out and a malignant neoplasm with varying morphologic patterns including gland formation, solid sheets of tumor cells, cribriform, glomeruloid, spindled and papillary areas was seen. The immunohistochemical profile showed diffuse strong positivity for AE1/AE3, TTF1, P16, and vimentin. CD56, GATA3, Napsin A, and CD10 were focally positive. The neoplastic cells were negative for the following markers ER, PR, WT1, calretinin, and synaptophysin. PDL-1 was negative and mismatch repair protein was proficient. An identical KRAS mutation was detected in both the uterine corpus and ocular tumors. The findings are in keeping with a uterine mesonephric-like adenocarcinoma with an ocular metastasis. An Oncomine Focus-Mutation profile, Thermo-Fisher Scientific Inc., a 60 gene oncologic panel, performed on the ocular tumor, revealed no further mutations.
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http://dx.doi.org/10.1097/PGP.0000000000000781DOI Listing
May 2021

Circulating tumor DNA (ctDNA) as a pan-cancer screening test: is it finally on the horizon?

Clin Chem Lab Med 2021 07 15;59(8):1353-1361. Epub 2021 Apr 15.

Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.

The detection of cancer at an early stage while it is curable by surgical resection is widely believed to be one of the most effective strategies for reducing cancer mortality. Hence, the intense interests in the development of a simple pan-cancer screening test. Lack of sensitivity and specificity when combined with the low prevalence of most types of cancer types in the general population limit the use of most of the existing protein biomarkers for this purpose. Like proteins, tumor DNA also can be released into the circulation. Such circulating tumor DNA (ctDNA) can be differentiated from normal cell DNA by the presence of specific genetic alteration such as mutations, copy number changes, altered methylation patterns or being present in different sized fragments. Emerging results with test such as CancerSEEK or GRAIL suggest that the use of ctDNA can detect cancer with specificities >99%. Sensitivity however, is cancer type and stage-dependent, varying from approximately 40% in stage I disease to approximately 80% in stage III disease. It is important to stress however, that most of the studies published to date have used patients with an established diagnosis of cancer while the control population were healthy individuals. Although the emerging results are promising, evidence of clinical utility will require demonstration of reduced mortality following evaluation in a prospective randomized screening trial.
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http://dx.doi.org/10.1515/cclm-2021-0171DOI Listing
July 2021

First use of tofacitinib to treat an immune checkpoint inhibitor-induced arthritis.

BMJ Case Rep 2021 Feb 4;14(2). Epub 2021 Feb 4.

EULAR Centre for Arthritis and Rheumatic Disease, St. Vincent's University Hospital, Dublin, Ireland

Immune checkpoint inhibitors have revolutionised cancer treatment; however, immune-related adverse events do occur, with up to 7% developing inflammatory arthritis. Common rheumatoid arthritis therapies such as methotrexate, prednisolone and biologics have been used to treat this arthritis in small, uncontrolled case series with varying success. In this case of personalised medicine, we report the first use of tofacitinib, a small molecular inhibitor of the Janus kinase-signal transducer and activator of transcription pathway, to treat checkpoint inhibitor-related inflammatory arthritis. This resulted in a rapid clinical response and complete, sustained remission of the arthritis with associated marked reduction in synovial molecular and cellular immune response.
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http://dx.doi.org/10.1136/bcr-2020-238851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868229PMC
February 2021

MYC as a target for cancer treatment.

Cancer Treat Rev 2021 Mar 19;94:102154. Epub 2021 Jan 19.

Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland.

The MYC gene which consists of 3 paralogs, C-MYC, N-MYC and L-MYC, is one of the most frequently deregulated driver genes in human cancer. Because of its high prevalence of deregulation and its causal role in cancer formation, maintenance and progression, targeting MYC is theoretically an attractive strategy for treating cancer. As a potential anticancer target, MYC was traditionally regarded as undruggable due to the absence of a suitable pocket for high-affinity binding by low molecular weight inhibitors. In recent years however, several compounds that directly or indirectly inhibit MYC have been shown to have anticancer activity in preclinical tumor models. Amongst the most detailed investigated strategies for targeting MYC are inhibition of its binding to its obligate interaction partner MAX, prevention of MYC expression and blocking of genes exhibiting synthetic lethality with overexpression of MYC. One of the most extensively investigated MYC inhibitors is a peptide/mini-protein known as OmoMYC. OmoMYC, which acts by blocking the binding of all 3 forms of MYC to their target promoters, has been shown to exhibit anticancer activity in a diverse range of preclinical models, with minimal side effects. Based on its broad efficacy and limited toxicity, OmoMYC is currently being developed for evaluation in clinical trials. Although no compound directly targeting MYC has yet progressed to clinical testing, APTO-253, which partly acts by decreasing expression of MYC, is currently undergoing a phase I clinical trial in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.
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http://dx.doi.org/10.1016/j.ctrv.2021.102154DOI Listing
March 2021

Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors.

Br J Cancer 2021 03 21;124(7):1249-1259. Epub 2021 Jan 21.

National Institute of Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland.

Background: Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations.

Methods: In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data.

Results: All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance.

Conclusions: Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.
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http://dx.doi.org/10.1038/s41416-020-01257-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007737PMC
March 2021

A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer.

Breast Cancer Res 2021 01 15;23(1). Epub 2021 Jan 15.

Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Background: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).

Methods: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).

Results: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).

Conclusions: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).

Trial Registration: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
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http://dx.doi.org/10.1186/s13058-020-01382-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811234PMC
January 2021

Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer.

Cancers (Basel) 2020 Nov 27;12(12). Epub 2020 Nov 27.

Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.

Castrate-resistant prostate cancer (CRPC) is challenging to treat with the androgen receptor (AR), the main target and key focus of resistance. Understanding the mechanisms of AR interaction with co-regulators will identify new therapeutic targets to overcome AR resistance mechanisms. We previously identified the serum response factor (SRF) as a lead target in an in vitro model of CRPC and showed that SRF expression in tissues of CRPC patients was associated with shorter survival. Here, we tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in CRPC. Inhibition of SRF with the small-molecule inhibitor CCG1423 resulted in enhanced response to enzalutamide in vitro and reduced tumour volume of LuCaP 35CR, a CRPC patient-derived xenograft model. Nuclear localisation of AR post-CCG1423 was significantly decreased and was associated with decreased α-tubulin acetylation in vitro and decreased prostate specific antigen (PSA) levels in vivo. SRF immunoreactivity was tested in metastatic tissues from CRPC patients to investigate its role in enzalutamide response. Kaplan-Meier curves showed that high SRF expression was associated with shorter response to enzalutamide. Our study supports the use of SRF inhibitors to improve response to enzalutamide.
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http://dx.doi.org/10.3390/cancers12123540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760758PMC
November 2020

Effects of HER Family-targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer.

Clin Cancer Res 2021 02 29;27(3):807-818. Epub 2020 Oct 29.

National Institute for Cellular Biotechnology, Dublin City University, Dublin, Leinster, Ireland.

Purpose: Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC.

Experimental Design: Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2 (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry-based protocols.

Results: Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy ( = 0.03) and associated with trastuzumab response ( = 0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC , but it did not consistently correlate with HER2 expression in HER2 or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone.

Conclusions: TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854527PMC
February 2021

The novel low molecular weight MYC antagonist MYCMI-6 inhibits proliferation and induces apoptosis in breast cancer cells.

Invest New Drugs 2021 04 14;39(2):587-594. Epub 2020 Oct 14.

UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

Background The MYC oncogene is one of the most frequently altered driver genes in cancer. MYC is thus a potential target for cancer treatment as well as a biomarker for the disease. However, as a target for treatment, MYC has traditionally been regarded as "undruggable" or difficult to target. We set out to evaluate the efficacy of a novel MYC inhibitor known as MYCMI-6, which acts by preventing MYC from interacting with its cognate partner MAX. Methods MYCMI-6 response was assessed in a panel of breast cancer cell lines using MTT assays and flow cytometry. MYC gene amplification, mRNA and protein expression was analysed using the TCGA and METABRIC databases. Results MYCMI-6 inhibited cell growth in breast cancer cell lines with IC values varying form 0.3 μM to >10 μM. Consistent with its ability to decrease cell growth, MYCMI-6 was found to induce apoptosis in two cell lines in which growth was inhibited but not in two cell lines that were resistant to growth inhibition. Across all breast cancers, MYC was found to be amplified in 15.3% of cases in the TCGA database and 26% in the METABRIC database. Following classification of the breast cancers by their molecular subtypes, MYC was most frequently amplified and exhibited highest expression at both mRNA and protein level in the basal subtype. Conclusions Based on these findings, we conclude that for patients with breast cancer, anti-MYC therapy is likely to be most efficacious in patients with the basal subtype.
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http://dx.doi.org/10.1007/s10637-020-01018-wDOI Listing
April 2021

Targeting p53 for the treatment of cancer.

Semin Cancer Biol 2020 Jul 31. Epub 2020 Jul 31.

Department of Medical Oncology, St Vincent's University Hospital, Dublin, Ireland.

Dysfunction of the TP53 (p53) gene occurs in most if not all human malignancies. Two principal mechanisms are responsible for this dysfunction; mutation and downregulation of wild-type p53 mediated by MDM2/MDM4. Because of its almost universal inactivation in malignancy, p53 is a highly attractive target for the development of new anticancer drugs. Although multiple strategies have been investigated for targeting dysfunctional p53 for cancer treatment, only 2 of these have so far yielded compounds for testing in clinical trials. These strategies include the identification of compounds for reactivating the mutant form of p53 back to its wild-type form and compounds for inhibiting the interaction between wild-type p53 and MDM2/MDM4. Currently, multiple p53-MDM2/MDM4 antagonists are undergoing clinical trials, the most advanced being idasanutlin which is currently undergoing testing in a phase III clinical trial in patients with relapsed or refractory acute myeloid leukemia. Two mutant p53-reactivating compounds have progressed to clinical trials, i.e., APR-246 and COTI-2. Although promising data has emerged from the testing of both MDM2/MDM4 inhibitors and mutant p53 reactivating compounds in preclinical models, it is still unclear if these agents have clinical efficacy. However, should any of the compounds currently being evaluated in clinical trials be shown to have efficacy, it is likely to usher in a new era in cancer treatment, especially as p53 dysfunction is so prevalent in human cancers.
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http://dx.doi.org/10.1016/j.semcancer.2020.07.005DOI Listing
July 2020

Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer.

Br J Cancer 2020 10 27;123(8):1219-1222. Epub 2020 Jul 27.

National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland.

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P = 0.07), while more significantly pronounced in copy number gains (P = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 (P = 0.02) and in Chr17 (P = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].
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http://dx.doi.org/10.1038/s41416-020-0999-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553955PMC
October 2020

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

J Clin Oncol 2020 09 17;38(27):3138-3149. Epub 2020 Jul 17.

Graduate School of Medicine, Gunma University, Gunma, Japan.

Purpose: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.

Methods: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).

Results: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% 29.2%; 043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; .0004). The most common all-grade adverse events were diarrhea (N+C 83% L+C 66%) and nausea (53% 42%). Discontinuation rates and HRQoL were similar between groups.

Conclusion: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
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http://dx.doi.org/10.1200/JCO.20.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499616PMC
September 2020

Drugging "undruggable" genes for cancer treatment: Are we making progress?

Int J Cancer 2021 01 7;148(1):8-17. Epub 2020 Aug 7.

Department of Medical Oncology, St Vincent's University Hospital, Dublin 4, Ireland.

RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as "undruggable." Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.
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http://dx.doi.org/10.1002/ijc.33197DOI Listing
January 2021

Immune checkpoint inhibitors: Key trials and an emerging role in breast cancer.

Semin Cancer Biol 2020 Jul 2. Epub 2020 Jul 2.

National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. Electronic address:

This review focuses on immune checkpoint inhibitors - immunomodulatory agents that aim to relieve tumour-mediated immune-cell suppression. Immune checkpoint proteins can be expressed on the tumour-cell or immune-cell populations. Immune checkpoint proteins dampen the immune response by inactivating immune cells capable of tumour destruction. Blockade of immune checkpoints has shown impressive results in a range of solid cancers, particularly melanoma and non-small cell lung cancer. The potential benefit of this class of drugs is widespread across most cancer types and an unprecedented number of clinical studies are underway to examine the benefit of these agents. The aims of this review are to: provide an overview of the key early immune checkpoint inhibitor trials involving drugs targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in multiple disease types; provide an overview of emerging therapies aimed at these targets; and provide a detailed exploration of the status of immune checkpoint inhibitors in breast cancer.
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http://dx.doi.org/10.1016/j.semcancer.2020.06.016DOI Listing
July 2020

Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index.

J Clin Oncol 2020 09 2;38(25):2883-2891. Epub 2020 Jul 2.

Unit of Medical Statistics, Biometry and Bioinformatics Giulio A. Maccacaro Department of Clinical Sciences and Community Health & DSRC, University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Purpose: Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel-based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI).

Patients And Methods: We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (ClinicalTrials.gov identifier: NCT00174655; N = 2,887) comparing non-docetaxel- to docetaxel-containing chemotherapy. BMI (kg/m) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status.

Results: There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; = .21) and 1.27 (95% CI, 1.01 to 1.60; = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; = .007) and 1.63 (95% CI, 1.27 to 2.09; < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted = .06) and OS (adjusted = .04).

Conclusion: This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.
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http://dx.doi.org/10.1200/JCO.19.01771DOI Listing
September 2020

Metastatic uveal melanoma: A valid indication for liver resection.

J BUON 2020 Mar-Apr;25(2):1161-1165

Department of Hepatobiliary and Liver Transplant Surgery, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland.

Purpose: Owing to its relative resistance to chemotherapeutics, prognosis following the diagnosis of metastatic uveal melanoma has remained disappointing. On this basis, liver resection in cases of isolated hepatic metastases has been postulated as a viable treatment option. Herein we performed an analysis of patients who underwent hepatic metastatectomy for uveal melanoma and compared their outcomes to those undergoing resection for colorectal cancer liver metastases (CRLM) in the same time period.

Methods: From 2008 to 2018, all patients referred to our unit with hepatic metastases were included for analysis. Performing a 3:1 matched cohort analysis, patients with metastatic uveal melanoma were matched for age, sex, operative approach, tumour number and size to those undergoing resection for CRLM. Clinicopathological data was sought from a prospectively maintained database and reviewed along with 30-day post-operative morbidity and mortality.

Results: Fifteen patients underwent hepatic metastasectomy for primary uveal melanoma. A further 45 patients undergoing hepatectomy for metastatic colorectal cancer acted as the control group. No in-hospital mortality was noted with four patients (26.6%) developing post-operative morbidity. The median follow-up period following melanoma resection was 27 months (range 5-211) with 1-, 3- and 5- year overall survival for this cohort of 86.6%, 53.3% and 40%, respectively. There was no difference in overall survival between the melanoma and CRLM group (p =0.80).

Conclusion: In patients presenting with hepatic metastases from uveal melanoma, this present study supports the rationale to proceed to surgery with acceptable morbidity and mortality.
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February 2021

Targeting c-Met in triple negative breast cancer: preclinical studies using the c-Met inhibitor, Cpd A.

Invest New Drugs 2020 10 22;38(5):1365-1372. Epub 2020 Apr 22.

Molecular Therapeutics for Cancer in Ireland, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.

Introduction Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer that carries a poorer prognosis. There remains a need to identify novel drivers of TNBC, which may represent targets to treat the disease. c-Met overexpression is linked with decreased survival and is associated with the basal subtype of breast cancer. Cpd A, a kinase inhibitor selective/specific for Met kinase has demonstrated preclinical anti-cancer efficacy in TNBC. We aimed to assess the anti-cancer efficacy of Cpd A when combined with Src kinase, ErbB-family or hepatocyte growth factor (HGF) inhibitors in TNBC cell lines. Methods We determined the anti-proliferative effects of Cpd A, rilotumumab, neratinib and saracatinib tested alone and in combination in a panel of TNBC cells by acid phosphatase assays. We performed reverse phase protein array analysis of c-Met and IGF1Rβ expression and phosphorylation of c-Met (Y1234/1235) in TNBC cells and correlated their expression/phosphorylation with Cpd A sensitivity. We examined the impact of Cpd A, neratinib and saracatinib tested alone and in combination on invasive potential and colony formation.Results TNBC cells are not inherently sensitive to Cpd A, and neither c-Met expression nor phosphorylation are biomarkers of sensitivity to Cpd A. Cpd A enhanced the anti-proliferative effects of neratinib in vitro; however, this effect was limited to cell lines with innate sensitivity to Cpd A. Cpd A had limited anti-invasive effects but it reduced colony formation in the TNBC cell line panel.Conclusions Despite Cpd A having a potential role in reducing cancer cell metastasis, identification of strong predictive biomarkers of c-Met sensitivity would be essential to the development of a c-Met targeted treatment for an appropriately selected cohort of TNBC patients.
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http://dx.doi.org/10.1007/s10637-020-00937-yDOI Listing
October 2020

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

Oncologist 2020 12 10;25(12):e1837-e1845. Epub 2020 Mar 10.

University of California San Francisco, San Francisco, California, USA.

Lessons Learned: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components.

Background: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor.

Methods: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study.

Results: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076.

Conclusion: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.
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http://dx.doi.org/10.1634/theoncologist.2020-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186410PMC
December 2020

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples.

J Transl Med 2020 02 22;18(1):99. Epub 2020 Feb 22.

Medical Oncology Lab, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin, Ireland.

Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance.

Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development.

Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors.

Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.
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http://dx.doi.org/10.1186/s12967-020-02273-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036178PMC
February 2020

Modelling of pancreatic cancer biology: transcriptomic signature for 3D PDX-derived organoids and primary cell line organoid development.

Sci Rep 2020 02 17;10(1):2778. Epub 2020 Feb 17.

National Institute for Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin 9, Ireland.

With a five-year survival rate of 9%, pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all cancers. The rapid mortality makes PDAC difficult to research, and inspires a resolve to create reliable, tractable cellular models for preclinical cancer research. Organoids are increasingly used to model PDAC as they maintain the differentiation status, molecular and genomic signatures of the original tumour. In this paper, we present novel methodologies and experimental approaches to develop PDAC organoids from PDX tumours, and the simultaneous development of matched primary cell lines. Moreover, we also present a method of recapitulating primary cell line cultures to organoids (CLOs). We highlight the usefulness of CLOs as PDAC organoid models, as they maintain similar transcriptomic signatures as their matched patient-derived organoids and patient derived xenografts (PDX)s. These models provide a manageable, expandable in vitro resource for downstream applications such as high throughput screening, functional genomics, and tumour microenvironment studies.
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http://dx.doi.org/10.1038/s41598-020-59368-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026166PMC
February 2020

Combined targeting EGFR and SRC as a potential novel therapeutic approach for the treatment of triple negative breast cancer.

Ther Adv Med Oncol 2020 28;12:1758835919897546. Epub 2020 Jan 28.

National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.

Background: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Epidermal growth factor receptor (EGFR) has been shown to be over-expressed in TNBC and represents a rational treatment target.

Methods: We examined single agent and combination effects for afatinib and dasatinib in TNBC. We then determined IC and combination index values using Calcusyn. Functional analysis of single and combination treatments was performed using reverse phase protein array and cell cycle analysis. Finally, we determined the anticancer effects of the combination .

Results: A total of 14 TNBC cell lines responded to afatinib with IC values ranging from 0.008 to 5.0 µM. Three cell lines, belonging to the basal-like subtype of TNBC, were sensitive to afatinib. The addition of afatinib enhanced response to the five other targeted therapies in HCC1937 and HDQP1 cells. The combination of afatinib with dasatinib caused the greatest growth inhibition in both cell lines. The afatinib/dasatinib combination was synergistic and/or additive in 13/14 TNBC cell lines. Combined afatinib/dasatinib treatment induced G1 cell cycle arrest. Reverse phase protein array results showed the afatinib/dasatinib combination resulted in efficient inhibition of both pERK(T202/T204) and pAkt(S473) signalling in BT20 cells, which was associated with the greatest antiproliferative effects. High baseline levels of pSrc(Y416) and pMAPK(p38) correlated with sensitivity to afatinib, whereas low levels of B-cell lymphoma 2 (Bcl2) and mammalian target of rapamycin (mTOR) correlated with synergistic growth inhibition by combined afatinib and dasatinib treatment. , the combination treatment inhibited tumour growth in a HCC1806 xenograft model.

Conclusions: We demonstrate that afatinib combined with dasatinib has potential clinical activity in TNBC but warrants further preclinical investigation.
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http://dx.doi.org/10.1177/1758835919897546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987485PMC
January 2020

NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2.

J Clin Oncol 2020 02 10;38(5):444-453. Epub 2019 Dec 10.

NRG Oncology, Pittsburgh, PA.

Purpose: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer.

Patients And Methods: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks.

Results: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx.

Conclusion: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
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http://dx.doi.org/10.1200/JCO.19.01455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007289PMC
February 2020
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