PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

Leiping Wang, Qunling Zhang, Jian Zhang, Si Sun, Haiyi Guo, Zhen Jia, Biyun Wang, Zhimin Shao, Zhonghua Wang, Xichun Hu, Leiping Wang, Qunling Zhang, Jian Zhang, Si Sun, Haiyi Guo, Zhen Jia, Biyun Wang, Zhimin Shao, Zhonghua Wang, Xichun Hu

Abstract

Background: Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or "addictive" to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab.

Methods: Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity.

Results: PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013).

Conclusions: PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib and trastuzumab.

Trial registration: ClinicalTrials.gov NCT00338247.

Figures

Figure 1
Figure 1
PTEN gene mutations. Sample 38, 46, 65, 68 have exon 20 missense mutations, H1047R (a); sample 2 has exon 9 missense mutation, E542K (b); sample 11 has exon 9 missense mutation, L540F (c); sample 54 has exon 20 missense mutation, T1052A (d).
Figure 2
Figure 2
PTEN expression. PTEN negative (IRS 0-3, a); Weak Positive (IRS 4-6, b); Positive (IRS 7-9, c); and Strong Positive (IRS 10-12, d).
Figure 3
Figure 3
Overall response rate (ORR) and clinical benefit rate (CBR) grouped by the status of PI3K pathway activation. The ORR was marginally significant between pathway activation group and wild type group; the CBR was statistically significant between pathway activation and wild type groups.
Figure 4
Figure 4
Progression-free survival with objective response, clinical benefit, and PI3K pathway activation. The difference in PFS between patients with response (CR+PR) and those without response (a); the difference in PFS between patients with clinical benefit (CR+PR+SD > 6 months) and those without benefit (b); the difference in PFS between patients with pathway activation and those with no activation (c), and pathway activation status with efficacy of the first Trastuzumab-containing regimen (d).

References

    1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–792. doi: 10.1056/NEJM200103153441101.
    1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–1684. doi: 10.1056/NEJMoa052122.
    1. Van Pelt AE, Mohsin S, Elledge RM, Hilsenbeck SG, Gutierrez MC, Lucci A Jr, Kalidas M, Granchi T, Scott BG, Allred DC. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer. 2003;4(5):348–353. doi: 10.3816/CBC.2003.n.040.
    1. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–726. doi: 10.1200/JCO.20.3.719.
    1. She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR, DeFeo-Jones D, Huber HE, Rosen N. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One. 2008;3(8):e3065..
    1. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127. doi: 10.1016/j.ccr.2004.06.022.
    1. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395–402. doi: 10.1016/j.ccr.2007.08.030.
    1. Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer. 2006;94(2):247–252. doi: 10.1038/sj.bjc.6602926.
    1. Fabi A, Metro G, Di Benedetto A, Nisticò C, Vici P, Melucci E, Antoniani B, Perracchio L, Sperduti I, Milella M. Clinical significance of PTEN and p-Akt co-expression in HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Oncology. 2010;78(2):141–149. doi: 10.1159/000312656.
    1. Pandolfi PP. Breast cancer--loss of PTEN predicts resistance to treatment. N Engl J Med. 2004;351(22):2337–2338. doi: 10.1056/NEJMcibr043143.
    1. Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21(2):255–62. doi: 10.1093/annonc/mdp304.
    1. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5(12):921–929. doi: 10.1038/nrc1753.
    1. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–619. doi: 10.1038/nrg1879.
    1. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–1947. doi: 10.1126/science.275.5308.1943.
    1. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000;100(4):387–390. doi: 10.1016/S0092-8674(00)80674-1.
    1. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell. 2007;12(2):104–107. doi: 10.1016/j.ccr.2007.07.014.
    1. Coughlin CM, Johnston DS, Strahs A, Burczynski ME, Bacus S, Hill J, Feingold JM, Zacharchuk C, Berkenblit A. Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy. Breast Cancer Res Treat. 2010;124(1):1–11. doi: 10.1007/s10549-010-1108-4.
    1. Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H. Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21(2):255–262. doi: 10.1093/annonc/mdp304.
    1. Moy B, Kirkpatrick P, Kar S, Goss P. Lapatinib. Nat Rev Drug Discov. 2007;6(6):431–432. doi: 10.1038/nrd2332.
    1. Scaltriti M, Chandarlapaty S, Prudkin L, Aura C, Jimenez J, Angelini PD, Sánchez G, Guzman M, Parra JL, Ellis C. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res. 2010;16(9):2688–2695. doi: 10.1158/1078-0432.CCR-09-3407.
    1. Mukohara T. Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer. Cancer Sci. in press .
    1. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733–2743. doi: 10.1056/NEJMoa064320.
    1. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008;26(34):5544–5552. doi: 10.1200/JCO.2008.16.2578.
    1. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538–5546. doi: 10.1200/JCO.2009.23.3734.
    1. Xia W, Husain I, Liu L, Bacus S, Saini S, Spohn J, Pry K, Westlund R, Stein SH, Spector NL. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers. Cancer Res. 2007;67(3):1170–1175. doi: 10.1158/0008-5472.CAN-06-2101.
    1. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008;68(22):9221–9230. doi: 10.1158/0008-5472.CAN-08-1740.
    1. Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol. 2008;26(7):1066–1072. doi: 10.1200/JCO.2007.13.9949.
    1. Koninki K, Barok M, Tanner M, Staff S, Pitkanen J, Hemmila P, Ilvesaro J, Isola J. Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells. Cancer Lett. 2010;294(2):211–219. doi: 10.1016/j.canlet.2010.02.002.
    1. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010;9(6):1489–1502. doi: 10.1158/1535-7163.MCT-09-1171.
    1. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–562. doi: 10.1038/nrc2664.
    1. Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res. 2005;7(5):R609–616. doi: 10.1186/bcr1262.
    1. Adélaïde J, Finetti P, Bekhouche I, Repellini L, Geneix J, Sircoulomb F, Charafe-Jauffret E, Cervera N, Desplans J, Parzy D. Integrated profiling of basal and luminal breast cancers. Cancer Res. 2007;67(24):11565–11575. doi: 10.1158/0008-5472.CAN-07-2536.
    1. Buttitta F, Felicioni L, Barassi F, Martella C, Paolizzi D, Fresu G, Salvatore S, Cuccurullo F, Mezzetti A, Campani D. PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol. 2006;208(3):350–355. doi: 10.1002/path.1908.
    1. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64(21):7678–7681. doi: 10.1158/0008-5472.CAN-04-2933.
    1. Li SY, Rong M, Grieu F, Iacopetta B. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat. 2006;96(1):91–95. doi: 10.1007/s10549-005-9048-0.
    1. Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res. 2007;13(2 Pt 1):408–414.
    1. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmström PO, Mansukhani M, Enoksson J. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65(7):2554–2559. doi: 10.1158/0008-5472-CAN-04-3913.
    1. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304(5670):554.. doi: 10.1126/science.1096502.
    1. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Bhanot UK, Hedvat CV, Traina TA, Solit D, Gerald W. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15(16):5049–5059. doi: 10.1158/1078-0432.CCR-09-0632.
    1. Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjold B, Rutqvist LE, Skoog L, Stal O. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007;13(12):3577–3584. doi: 10.1158/1078-0432.CCR-06-1609.
    1. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15(4):356–362. doi: 10.1038/ng0497-356.
    1. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, Bose S. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer. 2004;112(3):407–410. doi: 10.1002/ijc.20447.
    1. Bose S, Crane A, Hibshoosh H, Mansukhani M, Sandweis L, Parsons R. Reduced expression of PTEN correlates with breast cancer progression. Hum Pathol. 2002;33(4):405–409. doi: 10.1053/hupa.2002.124721.
    1. Tsutsui S, Inoue H, Yasuda K, Suzuki K, Higashi H, Era S, Mori M. Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology. 2005;68(4-6):398–404. doi: 10.1159/000086981.
    1. Lee JS, Kim HS, Kim YB, Lee MC, Park CS, Min KW. Reduced PTEN expression is associated with poor outcome and angiogenesis in invasive ductal carcinoma of the breast. Appl Immunohistochem Mol Morphol. 2004;12(3):205–210. doi: 10.1097/00129039-200409000-00004.
    1. Torres J, Navarro S, Rogla I, Ripoll F, Lluch A, Garcia-Conde J, Llombart-Bosch A, Cervera J, Pulido R. Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer. 2001;37(1):114–121. doi: 10.1016/S0959-8049(00)00366-X.
    1. Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66(3):1630–1639. doi: 10.1158/0008-5472.CAN-05-1182.
    1. Cizkova M, Bouchalova K, Trojanec R, Dziechciarkova M, Vacher S, Radova L. Impact of PIK3CA, PTEN and RPS6 status on lapatinib treatment outcome in advanced-stage breast cancer patients. 2010. SABCS conference, abs. P2-09-30.
    1. Campone M, Juin P, Andre F, Bachelot T. Resistance to HER2 inhibitors: Is addition better than substitution? Rationale for the hypothetical concept of drug sedimentation. Crit Rev Oncol Hematol. in press .
    1. Brünner-Kubath C, Shabbir W, Saferding V, Wagner R, Singer CF, Valent P, Berger W, Marian B, Zielinski CC, Grusch M. The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells. Breast Cancer Res Treat. in press .
    1. O'Brien NA, Wilcox K, McDermott M, Crown J, O'Donovan N, Slamon DJ. The role of the PI3K/AKT, RAS/MAPK and novel signaling pathways in resistance to HER2-targeted therapy. 2010. SABCS conference, abs. P4-01-06.
    1. Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J, Rimawi M, Schiff R, Arteaga C, Osborne CK, Chang JC. 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. J Clin Oncol. 2011;29(2):166–73. doi: 10.1200/JCO.2009.27.7814.
    1. Toi M, Iwata H, Fujiwara Y, Ito Y, Nakamura S, Tokuda Y, Taguchi T, Rai Y, Aogi K, Arai T, Watanabe J, Wakamatsu T, Katsura K, Ellis CE, Gagnon RC, Allen KE, Sasaki Y, Takashima S. Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer. 2009;101(10):1676–82. doi: 10.1038/sj.bjc.6605343.
    1. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res. 2007;13(20):6064–6069. doi: 10.1158/1078-0432.CCR-07-0266.
    1. Dupont Jensen J, Laenkholm AV, Knoop A, Ewertz M, Bandaru R, Weihua L, Hackl W, Barrett JC, Gardner H. PIK3CA mutations may be discordant between primary and corresponding metastatic disease in Breast Cancer. Clin Cancer Res. in press .
    1. Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001;14(7):672–676. doi: 10.1038/modpathol.3880371.
    1. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmström P, Memeo L. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA. 2007;104(18):7564–7569. doi: 10.1073/pnas.0702507104.

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