Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers
Bhuvanesh Dave,Ilenia Migliaccio,M. Carolina Gutierrez,Meng Fen Wu,Gary C. Chamness,Helen Wong,Archana Narasanna,Anindita Chakrabarty,Susan G. Hilsenbeck,Jian Huang,Mothaffar F. Rimawi,Rachel Schiff,Carlos L. Arteaga,C. Kent Osborne,Jenny C. Chang +14 more
Reads0
Chats0
TLDR
Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib, and these observations support clinical trials with the combination of both agents.Abstract:
Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel fo...read more
Citations
More filters
Journal Article
Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.
TL;DR: It is reported that PTEN activation contributes to trastuzumab's antitumor activity and PTEN deficiency is a powerful predictor for trastzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.
Journal ArticleDOI
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
José Baselga,José Baselga,Ian Bradbury,Holger Eidtmann,Serena Di Cosimo,Serena Di Cosimo,Evandro de Azambuja,Claudia Aura,Henry L. Gomez,Phuong Dinh,Karine Fauria,Veerle Van Dooren,Gursel Aktan,Aron Goldhirsch,Tsai Wang Chang,Zsolt Horváth,Maria Antonia Coccia-Portugal,Julien Domont,Ling Min Tseng,Georg Kunz,Joohyuk Sohn,Vladimir Semiglazov,Guillermo Lerzo,Marketa Palacova,Volodymyr Probachai,Lajos Pusztai,Michael Untch,Richard D. Gelber,Martine Piccart-Gebhart +28 more
TL;DR: Dual inhibition of Her2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting, and the two anti-HER2 agents given together would be better than single-agent therapy.
Journal ArticleDOI
ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.
TL;DR: Current paradigms of targeting ERBB receptors with cancer therapeutics and the understanding of mechanisms of action and resistance to these drugs are discussed.
Journal ArticleDOI
Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.
TL;DR: Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies.
Journal ArticleDOI
Targeted therapies for breast cancer
Michaela J. Higgins,José Baselga +1 more
TL;DR: Clinical development of combinatorial approaches that act on the secondary mutations and/or compensatory pathways in resistant tumors may markedly improve on the effects of targeted agents used alone.
References
More filters
Journal ArticleDOI
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer
Edward H. Romond,Edith A. Perez,John Bryant,Vera J. Suman,Charles E. Geyer,Nancy E. Davidson,Elizabeth Tan-Chiu,Silvana Martino,Soonmyung Paik,Peter A. Kaufman,Sandra M. Swain,Thomas M. Pisansky,Louis Fehrenbacher,Leila A. Kutteh,Victor G. Vogel,Daniel W. Visscher,Greg Yothers,Robert B. Jenkins,Ann M. Brown,S. R. Dakhil,Eleftherios P. Mamounas,Wilma L. Lingle,Pamela M. Klein,James N. Ingle,Norman Wolmark +24 more
TL;DR: Tastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer.
Journal ArticleDOI
The use of confidence or fiducial limits illustrated in the case of the binomial
C. J. Clopper,E. S. Pearson +1 more
Journal ArticleDOI
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Charles E. Geyer,John K. Forster,Deborah Lindquist,Stephen Chan,C. Gilles Romieu,Tadeusz Pienkowski,Agnieszka Jagiełło-Gruszfeld,John Crown,Arlene Chan,Bella Kaufman,Dimosthenis Skarlos,Mario Campone,Neville Davidson,Mark S. Berger,Cristina Oliva,Stephen D. Rubin,S. Stein,David Cameron +17 more
TL;DR: Lapatinib plus capecitabine is superior to cape citabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.
Journal Article
Prognostic and predictive factors in breast cancer by immunohistochemical analysis
TL;DR: Although available studies suggest that estrogen and progesterone receptors might indeed be helpful in making treatment decisions, their clinical usefulness is still controversial, and there are important unresolved technical issues, such as how to prepare the tissue, which reagents to use and, most importantly, how to interpret the results.
Journal ArticleDOI
Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy
Xiaoxian Li,Michael T. Lewis,Jian Huang,Carolina Gutierrez,C. Kent Osborne,Meng Fen Wu,Susan G. Hilsenbeck,Anne Pavlick,Xiaomei Zhang,Gary C. Chamness,Helen Wong,Jeffrey M. Rosen,Jenny C. Chang +12 more
TL;DR: These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
Related Papers (5)
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial
Luca Gianni,Tadeusz Pienkowski,Young Hyuck Im,L Roman,Ling Ming Tseng,Mei Ching Liu,Ana Lluch,Elżbieta Starosławska,Juan de la Haba-Rodriguez,Seock-Ah Im,Jose Luiz Pedrini,Brigitte Poirier,Paolo Morandi,Vladimir Semiglazov,Vichien Srimuninnimit,Giulia Bianchi,Tania Szado,Jayantha Ratnayake,Graham Ross,Pinuccia Valagussa +19 more