PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations.

PURPOSE Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance. PATIENTS AND METHODS Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. RESULTS Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response. CONCLUSION PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.

[1]  Razelle Kurzrock,et al.  Risks and benefits of phase 1 oncology trials, revisited. , 2005, The New England journal of medicine.

[2]  J. Lee,et al.  Screening for PIK3CA mutations, PTEN loss, and RAS/RAF mutations in early-phase protocols with PI3K/mTOR pathway inhibitors. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  D. Bodurka,et al.  Phase I clinical trials in 85 patients with gynecologic cancer: the M. D. Anderson Cancer Center experience. , 2010, Gynecologic oncology.

[4]  L. Tanoue,et al.  Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma , 2010 .

[5]  A. Jimeno,et al.  Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. , 2010 .

[6]  L. Tanoue,et al.  Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer , 2012 .

[7]  K. Flaherty,et al.  Inhibition of mutated, activated BRAF in metastatic melanoma. , 2010, The New England journal of medicine.

[8]  H. Koeppen,et al.  Application of COLD-PCR for improved detection of KRAS mutations in clinical samples , 2009, Modern Pathology.

[9]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[10]  Mingming Jia,et al.  COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer , 2009, Nucleic Acids Res..

[11]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Enomoto,et al.  PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. , 2008, Cancer letters.

[13]  G. Mills,et al.  Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. , 2009, Cancer research.

[14]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[15]  Francesca Molinari,et al.  Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. , 2010, The Journal of clinical investigation.

[16]  Seiichiro Yamamoto,et al.  Risks and benefits of phase 1 oncology trials, 1991 through 2002. , 2005, The New England journal of medicine.

[17]  A. Lash,et al.  Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers , 2005, Clinical Cancer Research.

[18]  三宅 貴仁.  PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences , 2008 .

[19]  Razelle Kurzrock,et al.  Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies Patients on Lower Doses Do Not Fare Worse , 2010, Clinical Cancer Research.

[20]  M Van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. , 2000, Journal of the National Cancer Institute.

[21]  S. Antoniu.  Crizotinib for EML4-ALK positive lung adenocarcinoma: a hope for the advanced disease? , 2011, Expert opinion on therapeutic targets.

[22]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.

[23]  A. D. Van den Abbeele,et al.  Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. , 2002, The New England journal of medicine.

[24]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[25]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[26]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[27]  R. Kurzrock,et al.  PIK3CA, KRAS, and BRAF mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. , 2010 .

[28]  Alona Muzikansky,et al.  First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Sigrid Stroobants,et al.  Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study , 2001, The Lancet.

[30]  Hong Wang,et al.  PIK3CA and PTEN Mutations in Uterine Endometrioid Carcinoma and Complex Atypical Hyperplasia , 2006, Clinical Cancer Research.

[31]  Razelle Kurzrock,et al.  PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors , 2011, Molecular Cancer Therapeutics.

[32]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[33]  D. Bodurka,et al.  A Phase I Trial of Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies , 2011, Clinical Cancer Research.