Genome-Wide DNA Copy Number Predictors of Lapatinib Sensitivity in Tumor-Derived Cell Lines

Total Page:16

File Type:pdf, Size:1020Kb

Genome-Wide DNA Copy Number Predictors of Lapatinib Sensitivity in Tumor-Derived Cell Lines 935 Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines Joel Greshock,1 Jie Cheng,2 David Rusnak,1 either EGFR or HER2, lapatinib treatment results in growth Anne Marie Martin,3 Richard Wooster,1 arrest and cell death (1), suggesting that it may be possible Tona Gilmer,1 Kwan Lee,2 Barbara L. Weber,1 to predict clinical response based on a tumor’s genetic in vitro and Tal Zaks3 profile. Although larger screens confirm strong associations between EGFR and HER2amplification with 1Translational Medicine Oncology, GlaxoSmithKline, King of lapatinib responsiveness, some tumor models seem to Prussia, Pennsylvania and 2Department of Biostatistics and Data 3 respond in the absence of these markers (2, 3). This Management and Medicines Development Center, Oncology, observation indicates that additional proteins may cooper- GlaxoSmithKline, Collegeville, Pennsylvania ate with HER2in promoting lapatinib responsiveness, thereby forming the basis of a more inclusive means of Abstract predicting clinical response. Such proteins may include the A common aim of pharmacogenomic studies that use linear cascades that constitute the mitogen-activated genome-wide assays on panels of cancers is the unbiased cascade, the stress-activated protein kinase cascade, protein discovery of genomic alterations that are associated with kinase C, and the Akt pathway (4). clinical outcome and drug response. Previous studies of Altered DNA copy number is a hallmark feature of the lapatinib, a selective dual-kinase inhibitor of epidermal cancer genome. A number of tumor suppressor genes have growth factor receptor (EGFR) and HER2 tyrosine kinases, been mapped to homozygous deletions, including RB1 and have shown predictable relationships between the activity SMAD4/DPC4 (5, 6). Similarly, oncogenic copy number of these target genes and response. Under the hypothesis amplifications have been described in such loci as PDGFRA, EGFR HER2 that additional genes may play a role in drug sensitivity, a , and (7–9). Until recent technolog- predictive model for lapatinib response was constructed ical advances, the assembly of more complete lists of genes from genome-wide DNA copy number data from 24 cancer whose copy number is altered in cancer has been limited by cell lines. An optimal predictive model which consists of nonsystematic techniques (10). However, the development aberrations at nine distinct genetic loci, includes gains of of high-resolution microarray-based genome-wide DNA HER2, EGFR, and loss of CDKN2A. This model achieved copy number has remedied this limitation. Although an area under the receiver operating characteristic curve earlier BAC clone–based platforms provided a resolution of f0.85 (80% confidence interval, 0.70–0.98; of f1 Mb (11), more recent oligonucleotide-based plat- P < 0.01), and correctly classified the sensitivity status forms such as Representational Oligonucleotide Microarray of 8 of 10 head and neck cancer cell lines. This study Analysis decreased probe spacing considerably (12). Single- shows that biomarkers predictive for lapatinib sensitivity, nucleotide polymorphism arrays (SNP chips) represent a including the previously described copy number gains of type of high-density oligonucleotide-based microarrays EGFR and HER2, can be discovered using novel genomic that have been adapted for DNA copy number analyses assays in an unbiased manner. Furthermore, these results (13) and perform comparably with traditional two-channel show the utility of DNA copy number profiles in pharma- arrays (14). cogenomic studies. [Mol Cancer Ther 2008;7(4):935–43] The increasing role of pharmacogenomics in oncology compound development and treatment has closely paral- Introduction leled the advent of high-throughput genomics platforms. A major attraction of using genome-wide assays is the Lapatinib is a potent, orally active dual kinase inhibitor of increased ability to more comprehensively characterize the epidermal growth factor receptor (EGFR) and HER2 genomic mechanisms of drug sensitivity. For example, tyrosine kinase receptors. In tumor cells that overexpress gross patterns in gene expression effectively show that in vitro response to a farnesyltransferase inhibitor of the Ras pathway is directly correlated with Ras pathway activity (15). Translational research focuses on the discovery of Received 9/18/07; revised 12/19/07; accepted 1/10/08. rational predictive markers derived from such genomic The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked assays that could then be used for response enrichment in a advertisement in accordance with 18 U.S.C. Section 1734 solely to clinical setting. A growing number of these studies include indicate this fact. an effective predictor of bortezomib response in myelomas Requests for reprints: Tal Z. Zaks, Translational Medicine Oncology, that was retrospectively calculated and validated from gene GlaxoSmithKline, 1250 South Collegeville Road, UP 4W-4230, Collegeville, PA 19426. Phone: 610-917-5124; Fax: 610-917-4830. expression microarrays run on patient tissue collected from E-mail: [email protected] multiple independent clinical sites (16). Although genome- Copyright C 2008 American Association for Cancer Research. wide expression profiling is currently the most widespread doi:10.1158/1535-7163.MCT-07-2072 platform for pharmacogenomic studies, the mapping of Mol Cancer Ther 2008;7(4). April 2008 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2008 American Association for Cancer Research. 936 DNA Copy Number Predictors of Lapatinib Sensitivity specific DNA copy number alterations to multiple path- (ranging between 0.008 and 10 Amol/L). Cells were ways is also effective in delineating markers associated with harvested by trypsinization on day 7 and counted using a the responsiveness to targeted therapy (reviewed in ref. 17). particle counter (Z1, Beckman Coulter, Inc.). Growth Fixed genetic alterations such as DNA copy number gains inhibition was calculated as a percentage of the untreated and losses are appealing for clinical study because (a) they controls. Experiments were carried out twice or thrice in are relatively stable in vivo over time, and (b) they are duplicate for each cell line. The log of the fractional growth faithfully modeled in cell lines in vitro (18, 19). For example, inhibition was plotted against the log of the drug copy number studies have associated specific DNA copy concentration, and the IC50s were interpolated from the number alterations in ovarian carcinomas with carboplatin resulting linear regression curve fit (Calcusyn, Biosoft). IC50 response (20), whereas amplifications of the multidrug values <1.0 Amol/L were considered as sensitive, 1.0 to resistance gene MDR1 are correlated with therapeutic 2.5 Amol/L as intermediate, and values >2.5 Amol/L were resistance (21, 22). considered resistant. Proliferation data for several of these The growing use of targeted therapies in cancer treatment lines have been previously presented in ref. (2). reflects an increasing knowledge of key oncogenic path- SNP Chip/Transcript Analysis ways. Difficulties in predicting response to targeted DNA was extracted from each line using Mini DNeasy kit therapies are likely a consequence of the limited global (Qiagen, Inc.) and subsequently purified. For the 24 cell knowledge of altered genetic pathways in each cancer. lines of mixed tumor type composing the gtrainingh panel, Also, unique genomic profiles observed in each cancer two aliquots (250 ng each) were digested with the suggests the existence of many more contributing path- restriction enzyme XbaIorHindIII (New England Biolabs), ways than previously thought. For example, contrasting whereas a similar quantity of material was digested with sets of recurring alterations found to differentiate between Sty and Nsp enzymes for the 10 head and neck lines in the certain types of lung cancers indicate that common validation set. Digested DNA was subsequently ligated to oncogenic pathways may be subject to unique alterations an adaptor and amplified by PCR using Platinum Pfx DNA (23). Collectively, these results suggest that developing Polymerase (Invitrogen), yielding a product of f250 to genome-wide strategies to discover predictive models of 2,000 bp. For each enzyme digest, PCR was carried out in therapeutic response can be more sensitive than traditional four 100-AL aliquots, pooled, purified, quantified, normal- single-gene approaches. In this study, we present a model ized to 40 Ag/45 AL, and fragmented with DNase I to yield that takes advantage of global characterizations of DNA a size range of f25 to 200 bp. The fragmented products of copy number to accurately predict in vitro responses to the training set and test set were then labeled, denatured, lapatinib. The model, which emphasizes high-level copy and hybridized to the Affymetrix 100K and 500K chip, number alterations such as homozygous deletions and respectively (Affymetrix Inc.). Upon completion of hybrid- oncogenic amplifications, rediscovers the HER2 locus, ization, each assay was washed and stained using which is already a known predictor of clinical activity. Affymetrix fluidics stations. Image data were acquired Furthermore, this model discovers novel markers of using the GeneChip Scanner 3000. For all 34 cell lines, response that are capable of classifying a panel of non– transcript abundance was quantified in triplicate by using HER2-amplified
Recommended publications
  • TYKERB  Decreases in Left Ventricular Ejection Fraction (LVEF) Have Been Reported
    HIGHLIGHTS OF PRESCRIBING INFORMATION ---------------------------WARNINGS AND PRECAUTIONS------------------- These highlights do not include all the information needed to use TYKERB Decreases in left ventricular ejection fraction (LVEF) have been reported. safely and effectively. See full prescribing information for TYKERB. Confirm normal LVEF before starting TYKERB and continue evaluations TYKERB® (lapatinib) tablets, for oral use during treatment. (5.1) Initial U.S. Approval: 2007 TYKERB has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as WARNING: HEPATOTOXICITY clinically indicated. Discontinue and do not restart TYKERB if patients See full prescribing information for complete boxed warning. experience severe changes in liver function tests. (5.2) Hepatotoxicity has been observed in clinical trials and postmarketing Dose reduction in patients with severe hepatic impairment should be experience. The hepatotoxicity may be severe and deaths have been considered. (2.2, 5.3, 8.7) reported. Causality of the deaths is uncertain. (5.2) Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if --------------------------------INDICATIONS AND USAGE--------------------------- severe. (5.4) TYKERB is a kinase inhibitor indicated in combination with: (1) TYKERB has been associated with interstitial lung disease and pneumonitis. capecitabine for the treatment of patients with advanced or metastatic breast Discontinue TYKERB if patients experience severe pulmonary symptoms. cancer whose tumors overexpress human epidermal growth factor receptor 2 (5.5) (HER2) and who have received prior therapy, including an anthracycline, a TYKERB may prolong the QT interval in some patients. Consider taxane, and trastuzumab. electrocardiogram (ECG) and electrolyte monitoring.
    [Show full text]
  • Combining Paclitaxel and Lapatinib As Second-Line Treatment for Patients with Metastatic Transitional Cell Carcinoma: a Case Series
    ANTICANCER RESEARCH 32: 3949-3952 (2012) Combining Paclitaxel and Lapatinib as Second-line Treatment for Patients with Metastatic Transitional Cell Carcinoma: A Case Series STÉPHANE CULINE, ZINEB SELLAM, LINDA BOUAITA, ELIAS ASSAF, CATHERINE DELBALDO, MURIEL VERLINDE-CARVALHO and DAMIEN POUESSEL Department of Medical Oncology, Henri Mondor Hospital, Créteil, France Abstract. Background: Current first-line cisplatin-based trial comparing vinflunine with best supportive care (BSC) combination chemotherapy regimens provide interesting to BSC alone, an estimated difference in overall survival response rates but limited impact on survival for patients with (OS) of 2 months was reached in the intent-to-treat metastatic transitional cell carcinoma of the urothelium. Such population. However, a significant difference in OS was only results leave a significant patient population in need of salvage seen after removing patients who had major protocol therapy. Patients and Methods: As the epidermal growth factor violations (2). Therefore therapy for patients who fail first- receptors 1 and 2 (EGFR and HER2) are frequently line cisplatin-based chemotherapy remains a highly unmet overexpressed in urothelial carcinoma, we explored the medical need. feasibility of a combination of paclitaxel (80 mg/m2/week) and In a phase II study led by the French Genito-Urinary lapatinib (1,500 mg orally daily) for six patients who were Tumor group (GETUG), the activity of weekly paclitaxel as treated after failure of first-line platinum-based chemotherapy. second-line chemotherapy was assessed in 45 patients with Results: Only one out of six patients was able to receive the MTCCU. A low objective response rate (9%) along with a full doses during the first six weeks of treatment, while grade high rate of stabilization (38%) suggested limited impact as 2 or 3 diarrhea events required lapatinib dose reduction (one a single agent (3).
    [Show full text]
  • HER2-Positive Male Breast Cancer: an Update
    Breast Cancer: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW HER2-positive male breast cancer: an update Laura Ottini1 Abstract: Although rare, male breast cancer (MBC) remains a substantial cause for morbidity Carlo Capalbo2 and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, Piera Rizzolo1 and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer Valentina Silvestri1 (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor Giuseppe Bronte3 (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor Sergio Rizzo3 receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 Antonio Russo3 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant 1 Department of Experimental therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents Medicine, “Sapienza” University of ® Rome, Rome, Italy; 2Medical Oncology, a very interesting molecular target and a number of compounds (trastuzumab [Herceptin ; IDI-IRCCS, Rome, Italy; 3Department F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb®, GlaxoSmithKline, London, of Surgical and Oncological Sciences, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody Section of Medical Oncology, University of Palermo, Palermo, Italy which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist.
    [Show full text]
  • Lapatinib Has Been Associated with Hepatotoxicity
    HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ---------------- These highlights do not include all the information needed to use • Decreases in left ventricular ejection fraction have been reported. TYKERB safely and effectively. See full prescribing information for Confirm normal LVEF before starting TYKERB and continue evaluations TYKERB. during treatment. (5.1) • Lapatinib has been associated with hepatotoxicity. Monitor liver function TYKERB (lapatinib) tablets tests before initiation of treatment, every 4 to 6 weeks during treatment, Initial U.S. Approval: 2007 and as clinically indicated. Discontinue and do not restart TYKERB if patients experience severe changes in liver function tests. (5.2) WARNING: HEPATOTOXICITY • Dose reduction in patients with severe hepatic impairment should be See full prescribing information for complete boxed warning. considered. (2.2, 5.3, 8.7) Hepatotoxicity has been observed in clinical trials and postmarketing • Diarrhea, including severe diarrhea, has been reported during treatment. experience. The hepatotoxicity may be severe and deaths have been Manage with anti-diarrheal agents, and replace fluids and electrolytes if reported. Causality of the deaths is uncertain. [See Warnings and severe. (5.4) Precautions (5.2).] • Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue TYKERB if patients experience severe pulmonary symptoms. (5.5) ---------------------------RECENT MAJOR CHANGES -------------------- Boxed Warning. Month YEAR • Lapatinib prolongs the QT interval in some patients. Consider ECG and Hepatotoxicity. (5.2, 17.6) Month YEAR electrolyte monitoring. (5.6) Interstitial lung disease and pneumonitis. (5.5) August 2007 • Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB.
    [Show full text]
  • Fasting Potentiates the Anticancer Activity of Tyrosine Kinase Inhibitors by Strengthening MAPK Signaling Inhibition
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 14 Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition Irene Caffa1, Vito D’Agostino2, Patrizia Damonte1, Debora Soncini1, Michele Cea1, Fiammetta Monacelli1, Patrizio Odetti1,3, Alberto Ballestrero1,3, Alessandro Provenzani2, Valter D. Longo4,5 and Alessio Nencioni1,3 1 Department of Internal Medicine, University of Genoa, Genoa, Italy 2 Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy 3 IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 4 Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 5 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy Correspondence to: Valter D. Longo, email: [email protected] Correspondence to: Alessio Nencioni, email: [email protected] Keywords: tyrosine kinase inhibitors, fasting, MAPK pathway, E2F transcription factors, cell cycle regulation Received: March 04, 2015 Accepted: March 11, 2015 Published: March 18, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown.
    [Show full text]
  • Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach
    www.nature.com/scientificreports OPEN Identifcation of candidate repurposable drugs to combat COVID‑19 using a signature‑based approach Sinead M. O’Donovan1,10, Ali Imami1,10, Hunter Eby1, Nicholas D. Henkel1, Justin Fortune Creeden1, Sophie Asah1, Xiaolu Zhang1, Xiaojun Wu1, Rawan Alnafsah1, R. Travis Taylor2, James Reigle3,4, Alexander Thorman6, Behrouz Shamsaei4, Jarek Meller4,5,6,7,8 & Robert E. McCullumsmith1,9* The COVID‑19 pandemic caused by the novel SARS‑CoV‑2 is more contagious than other coronaviruses and has higher rates of mortality than infuenza. Identifcation of efective therapeutics is a crucial tool to treat those infected with SARS‑CoV‑2 and limit the spread of this novel disease globally. We deployed a bioinformatics workfow to identify candidate drugs for the treatment of COVID‑19. Using an “omics” repository, the Library of Integrated Network‑Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID‑19 drugs and publicly available SARS‑CoV‑2 infected cell lines to identify novel therapeutics. We identifed a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID‑19, the remaining 12 have antiviral properties and 6 have antiviral efcacy against coronaviruses specifcally, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug fndings are discordant with (i.e., reverse) SARS‑CoV‑2 transcriptome signatures generated in vitro, and a subset are also identifed in transcriptome signatures generated from COVID‑19 patient samples, like the MEK inhibitor selumetinib. Overall, our fndings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID‑19 and identify promising novel targets that are worthy of further investigation.
    [Show full text]
  • Votrient, INN-Pazopanib
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Votrient 200 mg film-coated tablets Votrient 400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Votrient 200 mg film-coated tablets Each film-coated tablet contains 200 mg pazopanib (as hydrochloride). Votrient 400 mg film-coated tablets Each film-coated tablet contains 400 mg pazopanib (as hydrochloride). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Votrient 200 mg film-coated tablets Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side. Votrient 400 mg film-coated tablets Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Renal cell carcinoma (RCC) Votrient is indicated in adults for the first-line treatment of advanced renal cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease. Soft-tissue sarcoma (STS) Votrient is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy. Efficacy and safety has only been established in certain STS histological tumour subtypes (see section 5.1). 4.2 Posology and method of administration Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products. 2 Posology Adults The recommended dose of pazopanib for the treatment of RCC or STS is 800 mg once daily. Dose modifications Dose modification (decrease or increase) should be in 200 mg decrements or increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions.
    [Show full text]
  • BC Cancer Benefit Drug List September 2021
    Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal
    [Show full text]
  • Activity of Lapatinib Is Independent of EGFR Expression Level in HER2-Overexpressing Breast Cancer Cells
    1846 Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells Dongwei Zhang,1,2 Ashutosh Pal,3 overexpressed (i.e., HER2-positive) in 20% to 30% of breast William G. Bornmann,3 Fumiyuki Yamasaki,1,2 cancers (4, 5). EGFR and HER2 are known to drive tumor Francisco J. Esteva,1,4 Gabriel N. Hortobagyi,4 growth and progression and have emerged as promising Chandra Bartholomeusz,1,2 and Naoto T. Ueno1,2,4 targets for cancer therapy. A number of small molecules that target individual or 1Breast Cancer Translational Research Laboratory, dual ErbB receptors have been developed and tested in Departments of 2Stem Cell Transplantation and Cellular 3 4 clinical trials. Lapatinib, a dual inhibitor of EGFR and Therapy, Experimental Diagnostic Imaging, and Breast HER2 tyrosine kinases, has already been approved by the Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas US Food and Drug Administration as a treatment for HER2-positive metastatic breast cancer (6, 7). Lapatinib as a single agent or in combination with trastuzumab or Abstract capecitabine exhibited activity against HER2-positive ad- Epidermal growth factor receptor (EGFR/ErbB1) and HER2 vanced or metastatic breast cancer that has progressed after (ErbB2/neu), members of the ErbB receptor tyrosine kinase trastuzumab therapy (8–10). The activity of lapatinib in family, are frequently overexpressed in breast cancer and inflammatory breast cancer was evaluated in an interna- are known to drive tumor growth and progression, making tional Phase II trial (11). Although lapatinib showed them promisingtargetsfor cancer therapy.
    [Show full text]
  • T-DM1 As a New Treatment Option for Patients with Metastatic HER2-Positive Breast Cancer in Clinical Practice
    ANTICANCER RESEARCH 35: 5085-5090 (2015) T-DM1 as a New Treatment Option for Patients with Metastatic HER2-positive Breast Cancer in Clinical Practice LAURA L. MICHEL1,2, JUSTO LORENZO BERMEJO3, ADAM GONDOS4, FREDERIK MARMÉ1,2 and ANDREAS SCHNEEWEISS1,2 1National Center for Tumor Diseases and 2Department of Obstetrics and Gynecology, University Hospital, Heidelberg, Germany; 3Institute of Medical Biometry and Informatics, University of Heidelberg, Germany; 4Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany Abstract. Aim: To compare results of trastuzumab- targeted approach (1, 2). Within the last few years, additional emtansine (T-DM1) treatment in our clinical practice with HER2-directed agents such as the monoclonal antibody data from phase III clinical trials. Patients and Methods: A pertuzumab and the dual epidermal growth factor receptor retrospective chart review of all 23 patients with metastatic (EGFR)/HER2 tyrosine kinase inhibitor, lapatinib, were human epidermal growth factor receptor 2 (HER2)-positive developed to overcome resistance to trastuzumab and provide breast cancer who were started on T-DM1 until April 2014 additional treatment options for these patients (3, 4). was performed. Results: Four patients (17.4%) received The newest agent, which was approved by the Food and T-DM1 as first-line, three (13.0%) as second-line, six Drug Administration (FDA) in February 2013 for HER2- (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line positive metastatic breast cancer is trastuzumab-emtansine therapy. Overall, the response rate (ORR) was 26.0%, (T-DM1, Roche, Basel). T-DM1 represents a new generation disease control rate 78.3% and median progression-free of cytotoxic drugs.
    [Show full text]
  • Changing the Destiny of HER2 Expressing Solid Tumors
    International Journal of Molecular Sciences Review Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors Alice Indini 1 , Erika Rijavec 1 and Francesco Grossi 2,* 1 Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; [email protected] (A.I.); [email protected] (E.R.) 2 Medical Oncology Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy * Correspondence: [email protected] or [email protected] Abstract: HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer.
    [Show full text]
  • 5Th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 5)5
    SPECIAL ARTICLE 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)5 F. Cardoso1*, S. Paluch-Shimon2, E. Senkus3, G. Curigliano4, M. S. Aapro5, F. André6, C. H. Barrios7, J. Bergh8, G. S. Bhattacharyya9, L. Biganzoli10, F. Boyle11, M.-J. Cardoso1,12, L. A. Carey13, J. Cortés14,15, N. S. El Saghir16, M. Elzayat17, A. Eniu18, L. Fallowfield19, P. A. Francis20, K. Gelmon21, J. Gligorov22, R. Haidinger23, N. Harbeck24,X.Hu25, B. Kaufman26, R. Kaur27, B. E. Kiely28, S.-B. Kim29, N. U. Lin30, S. A. Mertz31, S. Neciosup32, B. V. Offersen33, S. Ohno34, O. Pagani35, A. Prat36,37,38, F. Penault-Llorca39,40, H. S. Rugo41, G. W. Sledge42, C. Thomssen43, D. A. Vorobiof44, T. Wiseman45,B.Xu46, L. Norton47, A. Costa48,49 & E. P. Winer30 1Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal; 2Sharett Division of Oncology, Hadassah University Hospital, Jerusalem, Israel; 3Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 4Department of Oncology and Hemato-Oncology, European Institute of Oncology, IRCCS, Division of Early Drug Development, University of Milan, Milan, Italy; 5Breast Center, Clinique de Genolier, Genolier, Switzerland; 6Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; 7Latin American Cooperative Oncology Group (LACOG), Grupo Oncoclínicas, Porto Alegre, Brazil; 8Department of Oncology-Pathology, Karolinska Institute & University Hospital, Stockholm, Sweden; 9Department of Medical Oncology, Salt Lake City Medical Centre,
    [Show full text]