Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2011

Open Access 01-12-2011 | Research article

Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases

Authors: Barbara Adamo, Allison M Deal, Emily Burrows, Joseph Geradts, Erika Hamilton, Kimberly L Blackwell, Chad Livasy, Karen Fritchie, Aleix Prat, J Chuck Harrell, Matthew G Ewend, Lisa A Carey, C Ryan Miller, Carey K Anders

Published in: Breast Cancer Research | Issue 6/2011

Login to get access

Abstract

Introduction

Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs.

Methods

p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method.

Results

Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival.

Conclusions

The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.
Appendix
Available only for authorised users
Literature
1.
Kirsch D, Loeffler J: Brain metastases in patients with breast cancer: new horizons. Clin Breast Cancer. 2005, 6: 115-124. 10.3816/CBC.2005.n.013.CrossRefPubMed
2.
Boogerd W, Vos V, Hart A, Baris G: Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol. 1993, 15: 165-174. 10.1007/BF01053937.CrossRefPubMed
3.
Lin N, Bellon J, Winer E: CNS metastases in breast cancer. J Clin Oncol. 2004, 22: 3608-3617. 10.1200/JCO.2004.01.175.CrossRefPubMed
4.
Gasper L: Recursive Partioning Analysis (RPA) of prognostic factors in three Radiation Oncology Treatment Group (RTOG) brain metastasis trials. Int J Radiat Oncol Biol Phys. 1997, 37: 745-751. 10.1016/S0360-3016(96)00619-0.CrossRef
5.
Engel J: Determinants and prognosis of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys. 2003, 55: 1186-1195. 10.1016/S0360-3016(02)04476-0.CrossRefPubMed
6.
Isakoff S, Engelman J, Irie H, Luo J, Brachmann S, Pearline R, Cantley L, Brugge J: Breast cancer-associated PI3KA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005, 65: 10992-11000. 10.1158/0008-5472.CAN-05-2612.CrossRefPubMed
7.
Bunney T, Katan M: Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer. 2010, 10: 342-352. 10.1038/nrc2842.CrossRefPubMed
8.
Dillon R, White D, Muller W: The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer. Oncogene. 2007, 26: 1338-1345. 10.1038/sj.onc.1210202.CrossRefPubMed
9.
Levine D, Bogomolniy F, Yee C, Lash A, Barakat R, Borgen P, Boyd J: Frequent mutation of the PI3KCA gene in ovarian and breast cancers. Hum Cancer Biol. 2005, 11: 2875-2878.
10.
Li S, Rong M, Grieu F, Iacopetta B: PI3KCA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat. 2006, 96: 91-95. 10.1007/s10549-005-9048-0.CrossRefPubMed
11.
Tokunaga E, Kimura Y, Mashino K, Oki E, Kotaoka A, Ohno S, Morita M, Kakeji Y, Baba H, Maehara Y: Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer. 2006, 13: 137-144. 10.2325/jbcs.13.137.CrossRefPubMed
12.
Vivanco I, Sawyers C: The phosphotidylinositol-3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002, 2: 489-501. 10.1038/nrc839.CrossRefPubMed
13.
Sansal I, Sellers W: The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004, 22: 2954-2963. 10.1200/JCO.2004.02.141.CrossRefPubMed
14.
Bose S, Chandran S, Mirocha J, Bose N: The AKT pathway in human breast cancer: a tissue-array-based analysis. Modern Pathol. 2006, 19: 238-245. 10.1038/modpathol.3800525.CrossRef
15.
Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT: An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008, 68: 6084-6091. 10.1158/0008-5472.CAN-07-6854.CrossRefPubMedPubMedCentral
16.
Kesari S, Ramakrishna N, Sauvageot C, Stiles C, Wen P: Targeted molecular therapy of malignant gliomas. Curr Oncol Rep. 2006, 8: 58-70. 10.1007/s11912-006-0011-y.CrossRefPubMed
17.
18.
Andersen JN, Sathyanarayanan S, Di Bacco A, Chi A, Zhang T, Chen AH, Dolinski B, Kraus M, Roberts B, Arthur W, Klinghoffer RA, Gargano D, Li L, Feldman I, Lynch B, Rush J, Hendrickson RC, Blume-Jensen P, Paweletz CP: Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors. Sci Transl Med. 2010, 2: 43-55.
19.
Harrell J, Prat A, Parker J, Fan C, He X, Carey L, Anders C, Ewend M, Perou C: Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat. 2011,
20.
Zhang XHF, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massagué J: Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009, 16: 67-78. 10.1016/j.ccr.2009.05.017.CrossRefPubMedPubMedCentral
21.
Anders CK, Deal AM, Khorram C, Meng H, Burrows E, Livasy C, Fritchie K, Ewend MG, Perou CM, Carey LA: The prognostic contribution of intrinsic breast cancer subtype, race, and age among patients with brain metastases. J Clin Oncol. 2010, 28: abstr 1027
22.
Nam B-H, Kim SY, Han H-S, Kwon Y, Lee KS, Kim TH, Ro J: Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res. 2008, 10: 1-8.CrossRef
23.
Niwinska A, Murawska M, Pogoda K: Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT). Ann Oncol. 2010, 21: 942-948. 10.1093/annonc/mdp407. Epub 2009 Oct 19CrossRefPubMed
24.
Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J, Garay JP, Cosgrove D, Tamaki A, Konishi H, Konishi Y, Mohseni M, Wang G, Rosen DM, Denmeade SR, Higgins MJ, Vitolo MI, Bachman KE, Park BH: Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci USA. 2009, 106: 2835-2840. 10.1073/pnas.0813351106.CrossRefPubMedPubMedCentral
25.
Engelman J: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009, 9: 550-562. 10.1038/nrc2664.CrossRefPubMed
26.
Bader A, Kang S, Zhao L, Vogt P: Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005, 5: 921-929. 10.1038/nrc1753.CrossRefPubMed
27.
Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W, Moynahan ME: PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009, 15: 5049-5059. 10.1158/1078-0432.CCR-09-0632.CrossRefPubMed
28.
Liedtke C, Cardone L, Tordai A, Yan K, Gomez HL, Figureoa LJ, Hubbard RE, Valero V, Souchon EA, Symmans WF, Hortobagyi GN, Bardelli A, Pusztai L: PIK3CA-activating mutations and chemotherapy sensitivity in stage II-III breast cancer. Breast Cancer Res. 2008, 10: R27-10.1186/bcr1984.CrossRefPubMedPubMedCentral
29.
Brugge J, Hung M, Mills G: A new mutational aktivation in the PI3K pathway. Cancer Cell. 2007, 12: 104-107. 10.1016/j.ccr.2007.07.014.CrossRefPubMed
30.
Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R: PI3KCA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mututally exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005, 65: 2554-2559. 10.1158/0008-5472-CAN-04-3913.CrossRefPubMed
31.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al: High frequency mutations of the PI3KCA gene in human cancers. Science. 2004, 304: 554-10.1126/science.1096502.CrossRefPubMed
32.
Aleskandarany M, Rakha E, Ahmed M, Powe D, Ellis I, Green A: Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat. 2010
33.
Aleskandarany M, Rakha E, Ahmed M, Powe D, Paish E, Macmillan R, Ellis I, Green A: PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Res Treat. 2010, 122: 45-53. 10.1007/s10549-009-0508-9.CrossRefPubMed
34.
Akcakanat A, Sahin A, Shaye A, Velasco M, Meric-Bernstam F: Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases. Cancer. 2008, 112: 2352-2358. 10.1002/cncr.23456.CrossRefPubMedPubMedCentral
35.
Capodanno A, Camerini A, Orlandini C, Baldini E, Resta M, Bevilacqua G, Collecchi P: Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma. Hum Pathol. 2009, 40: 1408-1417. 10.1016/j.humpath.2009.02.005.CrossRefPubMed
36.
Fedele CG, Ooms LM, Ho M, Vieusseux J, O'Toole SA, Millar EK, Lopez-Knowles E, Sriratana A, Gurung R, Baglietto L, Giles GG, Bailey CG, Rasko JE, Shields BJ, Price JT, Majerus PW, Sutherland RL, Tiganis T, McLean CA, Mitchell CA: Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci USA. 2010, 107: 22231-22236. 10.1073/pnas.1015245107.CrossRefPubMedPubMedCentral
37.
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC: Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009, 16: 115-125. 10.1016/j.ccr.2009.06.006.CrossRefPubMedPubMedCentral
38.
Pérez-Tenorio G, Alkhori L, Olsson B, Waltersson M, Nordenskjöld B, Rutqvist L, Skoog L, Stål O: PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007, 13: 3577-3584. 10.1158/1078-0432.CCR-06-1609.CrossRefPubMed
39.
Brogi E, Murray M, Nehhozina T, Akram M, Cranor M, Seidman A: Clinical and pathologic characteristics of brain metastases of breast carcinoma: a study of 74 patients. San Antonio Breast Cancer Symposium. 2006, Abstract 4003
40.
Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011, 5: 5-23. 10.1016/j.molonc.2010.11.003.CrossRefPubMed
41.
Garcia-Echeverria C, Sellers W: Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008, 27: 5511-5526. 10.1038/onc.2008.246.CrossRefPubMed
42.
Baselga J: Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist. 2011, 16 (suppl 1): 12-9.CrossRefPubMed
Metadata
Title
Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases
Authors
Barbara Adamo
Allison M Deal
Emily Burrows
Joseph Geradts
Erika Hamilton
Kimberly L Blackwell
Chad Livasy
Karen Fritchie
Aleix Prat
J Chuck Harrell
Matthew G Ewend
Lisa A Carey
C Ryan Miller
Carey K Anders
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3071

Other articles of this Issue 6/2011

Breast Cancer Research 6/2011 Go to the issue

Research article

Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer

Research article

A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines

Research article

A genome-wide linkage study of mammographic density, a risk factor for breast cancer

Research article

Lack of EGFR-activating mutations in European patients with triple-negative breast cancer could emphasise geographic and ethnic variations in breast cancer mutation profiles

Review

β1-integrins signaling and mammary tumor progression in transgenic mouse models: implications for human breast cancer

Review

The microenvironment in breast cancer progression: biology and implications for treatment
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits