Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer

Annals of Oncology

Volumn 23, Issue 12, 2012, Pages 3007-3016

  Mohd, M S N ^a,b   Crown, J ^c   Hennessy, B T ^a,b  

^a BEAUMONT HOSPITAL   (Ireland)

^b OUR LADY OF LOURDES HOSPITAL   (Ireland)

^c ST VINCENT S UNIVERSITY HOSPITAL   (Ireland)

Author keywords

Breast cancer; Everolimus; Her2; Mtor; Overcoming resistance; Restoring sensitivity

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 1 [4 [(5 CYCLOPROPYL 1H PYRAZOL 3 YL)AMINO]PYRROLO[2,1 F][1,2,4]TRIAZIN 2 YL] N (6 FLUORO 3 PYRIDINYL) 2 METHYL 2 PYRROLIDINECARBOXAMIDE; 5 (2,4 DIHYDROXY 5 ISOPROPYLPHENYL) 4 (4 MORPHOLINOMETHYLPHENYL) 3 ISOXAZOLECARBOXYLIC ACID ETHYLAMIDE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; BUPARLISIB; CAPECITABINE; CIXUTUMUMAB; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; EVEROLIMUS; GANETESPIB; IMETELSTAT; INK 128; LAPATINIB; LETROZOLE; LINSITINIB; MK 2006; NAVELBINE; NERATINIB; PACLITAXEL; PERTUZUMAB; PICTILISIB; PLACEBO; TEMSIROLIMUS; TRASTUZUMAB; TRASTUZUMAB EMTANSINE; UNCLASSIFIED DRUG; XL 147;

ADVANCED CANCER; ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; BLOOD BRAIN BARRIER; BRAIN METASTASIS; BREAST CANCER; CANCER ADJUVANT THERAPY; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; CANCER RECURRENCE; CANCER RESISTANCE; CANCER RISK; CANCER STAGING; CANCER SURVIVAL; CELL METABOLISM; CELL PROLIFERATION; CELL SURVIVAL; CENTRAL NERVOUS SYSTEM METASTASIS; COMPLEMENT ALTERNATIVE PATHWAY; DIMERIZATION; DISEASE FREE SURVIVAL; DRUG BINDING; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; DRUG SENSITIVITY; DRUG TARGETING; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; EVIDENCE BASED PRACTICE; FATIGUE; GENE AMPLIFICATION; GENE DOSAGE; HUMAN; HYPERGLYCEMIA; IMMUNE RESPONSE; INTRACELLULAR SIGNALING; LEUKOPENIA; LYMPHOCYTOPENIA; METASTASIS POTENTIAL; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MUCOSA INFLAMMATION; NEUTROPENIA; ONCOGENE NEU; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK BENEFIT ANALYSIS; RISK REDUCTION; STOMATITIS; TREATMENT DURATION; TREATMENT FAILURE; TREATMENT RESPONSE; UPREGULATION;

EID: 84869781977     PISSN: 09237534     EISSN: 15698041     Source Type: Journal    
DOI: 10.1093/annonc/mds200     Document Type: Review

References (92)

1. Ferlay J, Shin HR, Bray F et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-2917
2. Moon YW, Park S, Sohn JH et al. Clinical significance of progesterone receptor and HER2 status in estrogen receptor-positive, operable breast cancer with adjuvant tamoxifen. J Cancer Res Clin Oncol 2011; 137: 1123-1130.
3. Dowsett M, Houghton J, Iden C et al. Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol 2006; 17: 818-826.
4. Parise CA, Bauer KR, Brown MM et al. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999-2004. Breast J 2009; 15: 593-602.
5. Knoop AS, Bentzen SM, Nielsen MM et al. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol 2001; 19: 3376-3384.
6. Hubalek M, Brunner C, Mattha K et al. Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. Wien Klin Wochenschr 2010; 160: 506-512.
7. Al-Kuraya K, Schraml P, Torhorst J et al. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 2004; 64: 8534-8540.
8. Chia S, Norris B, Speers C et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of nodenegative breast cancers. J Clin Oncol 2008; 26: 5697-5704.
9. Sanna G, Franceschelli L, Rotmensz N et al. Brain metastases in patients with advanced breast cancer. Anticancer Res 2007; 27: 2865-2869.
10. Heitz F, Harter P, Lueck HJ et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur J Cancer 2009; 45: 2792-2798.
11. Musolino A, Ciccolallo L, Panebianco M et al. Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study. Cancer 2011; 117: 1837-1846.
12. Ross JS, Slodkowska EA, Symmans WF et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009; 14: 320-368.
13. Aebi S, Davidson T, Gruber G et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 (Suppl 5): v9-v14.
14. Cardoso F, Senkus-Konefka E, Fallowfield L et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21(Suppl 5): v15-v19.
15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Breast Cancer. 2011; Fort Washington, PA.
16. Carter P, Presta L, Gorman CM et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992; 89: 4285-4289.
17. Petrelli F, Borgonovo K, Cabiddu M et al. Neoadjuvant chemotherapy and concomitant trastuzumab in breast cancer: a pooled analysis of two randomized trials. Anticancer Drugs 2010; 22: 128-135.
18. Dahabreh IJ, Linardou H, Siannis F et al. Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 2008; 13: 620-630.
19. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-792.
20. Montagna E, Cancello G, D'Agostino D et al. Central nervous system metastases in a cohort of metastatic breast cancer patients treated with trastuzumab. Cancer Chemother Pharmacol 2009; 63: 275-280.
21. Ono M, Ando M, Yunokawa M et al. Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer. Int J Clin Oncol 2009; 14: 48-52.
22. Stemmler HJ, Schmitt M, Willems A et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007; 18: 23-28.
23. Pohlmann PR, Mayer IA, Mernaugh R. Resistance to Trastuzumab in Breast Cancer. Clin Cancer Res 2009; 15: 7479-7491.
24. Muthuswamy SK. Trastuzumab resistance: all roads lead to SRC. Nat Med 2011; 17: 416-418.
25. Gelmon KA, Mackey J, Verma S et al. Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer 2004; 5: 52-58.
26. Garcia-Saenz JA, Martin M, Puente J et al. Trastuzumab associated with successive cytotoxic therapies beyond disease progression in metastatic breast cancer. Clin Breast Cancer 2005; 6: 325-329.
27. Fabi A, Metro G, Ferretti G et al. Do HER-2 positive metastatic breast cancer patients benefit from the use of trastuzumab beyond disease progression? A mono-institutional experience and systematic review of observational studies. Breast 2008; 17: 499-505.
28. von Minckwitz G, du Bois A, Schmidt M et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol 2009; 27: 1999-2006.
29. Mannocci A, De Feo E, de Waure C et al. Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies. Tumori 2010; 96: 385-391.
30. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733-2743.
31. Burstein HJ, Sun Y, Dirix LY et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2010; 28: 1301-1307.
32. Chandarlapaty S, Scaltriti M, Angelini P et al. Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene 2010; 29: 325-334.
33. Scaltriti M, Rojo F, Ocana A et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 2007; 99: 628-638.
34. Sperinde J, Jin X, Banerjee J et al. Quantitation of p95HER2 in paraffin sections by using a p95-specific antibody and correlation with outcome in a cohort of trastuzumab-treated breast cancer patients. Clin Cancer Res 2010; 16: 4226-4235.
35. Wood ER, Truesdale AT, McDonald OB et al. A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004; 64: 6652-6659.
36. Scaltriti M, Chandarlapaty S, Prudkin L et al. 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: 2688-2695.
37. Burris HA, III, Rugo HS, Vukelja SJ et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011; 29: 398-405.
38. Krop I, LoRusso P, Miller KD et al. A phase 2 study of the HER2 anitbody-drug conjugate trastuzumab-DM1 (T-MD1) in patients (PTS) with HER2-positive metastatic breast cancer (MBC) previously treated with tratuzumab, lapatinib, and chemotherapy. Ann Clin Oncol 2010; 21: viii-97.
39. Blackwell KL, Burstein HJ, Storniolo AM et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumabrefractory metastatic breast cancer. J Clin Oncol 2010; 28: 1124-1130.
40. Baselga J, Bradbury I, Eidtmann H et al. First results of the NeoALTTO trial (BIG 01-06/EGF 106903): a phase III randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Presented at the 33rd Annual San Antonio Breast Cancer Symposium, December 8-12, 2010; San Antonio, TX.
41. Baselga J, Cortes J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012 366: 109-119.
42. Schneeweiss A, Chia S, Hickish T et al. Neoadjuvant pertuzumab and trastuzumab concurrent or sequential with an anthracycline-containing or concurrent with an anthracycline-free standard regimen: a randomized phase II study (TRYPHAENA). Presented at the 34th Annual San Antonio Breast Cancer Symposium, December 6-10, 2011, San Antonio, TX.
43. Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, openlabel, phase 2 trial. Lancet Oncol 2012; 13: 25-32.
44. Cortes J, Fumoleau P, Bianchi GV et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012; 30: 1594-1600.
45. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335-348.
46. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671-688.
47. Tokunaga E, Kimura Y, Mashino K et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006; 13: 137-144.
48. Tokunaga E, Kataoka A, Kimura Y et al. The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 2006; 42: 629-635.
49. Wu Y, Mohamed H, Chillar R et al. Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer. Breast Cancer Res 2008; 10: R3.
50. Wang L, Zhang Q, Zhang J et al. PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer 2011; 11: 248.
51. Razis E, Bobos M, Kotoula V et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat 2011; 128: 447-456.
52. Nagata Y, Lan KH, Zhou X et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6: 117-127.
53. Fujita T, Doihara H, Kawasaki K et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006; 94: 247-252.
54. Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007; 12: 395-402.
55. Esteva FJ, Guo H, Zhang S et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab response and survival in patients with HER2-positive metastatic breast cancer. Am J Pathol 2010; 177: 1647-1656.
56. Eichhorn PJ, Gili M, Scaltriti M et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/ phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 2008; 68: 9221-9230.
57. O'Brien NA, Browne BC, Chow L et al. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther 2010; 9: 1489-1502.
58. Kataoka Y, Mukohara T, Shimada H et al. 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: 255-262.
59. Dave B, Migliaccio I, Gutierrez MC et al. 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: 166-173.
60. Vazquez-Martin A, Oliveras-Ferraros C, Colomer R et al. Low-scale phosphoproteome analyses identify the mTOR effector p70 S6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (Tykerb) in human breast carcinoma cells. Ann Oncol 2008; 19: 1097-1109.
61. Gijsen M, King P, Perera T et al. HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol 2010; 8: e1000563.
62. Nencioni A, Cea M, Garuti A et al. Grb7 upregulation is a molecular adaptation to HER2 signaling inhibition due to removal of Akt-mediated gene repression. PLoS ONE 2010; 5: e9024.
63. Brunner-Kubath C, Shabbir W, Saferding V et al. The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells. Breast Cancer Res Treat 2011; 129: 387-400.
64. Goltsov A, Faratian D, Langdon SP et al. Compensatory effects in the PI3K/PTEN/ AKT signaling network following receptor tyrosine kinase inhibition. Cell Signal 2011; 23: 407-416.
65. Lu CH, Wyszomierski SL, Tseng LM et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13: 5883-5888.
66. Miller TW, Forbes JT, Shah C et al. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 2009; 15: 7266-7276.
67. Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-8030.
68. Junttila TT, Akita RW, Parsons K et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009; 15: 429-440.
69. Yao E, Zhou W, Lee-Hoeflich ST et al. Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res 2009; 15: 4147-4156.
70. Garcia-Garcia C, Ibrahim YH, Serra V et al. Dual mTORC1/2 and HER2 Blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 2012; 18: 2603-2612.
71. Andre F, Campone M, O'Regan R et al. Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 2010; 28: 5110-5115.
72. Jerusalem G, Fasolo A, Massacesi C et al. Maintenance with everolimus (RAD001) and trastuzumab (T) after discontinuation of chemotherapy in heavily pre-treated HER-2+ metastatic breast cancer (MBC) patients (pts): pooled data of extension cohorts of phase Ib/II studies. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 4-8, 2010.
73. Dalenc F, Campone M, Hupperets P et al. Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER-2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: a multicenter phase II clinical trial. Presented at the American Society of Clinical Oncology Annual Meeting, June 4-8, 2010; Chicago, IL.
74. Campone M, Gianni L, Massacesi C et al. Trastuzumab (H) and everolimus (RAD001) containing regimens are safe and active when reintroduced in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) pre-treated with lapatinib [abstract]. Eur J Cancer. 2010; 8(3):186.
75. Jerusalem G, Fasolo A, Dieras V et al. Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2011; 125: 447-455.
76. Morrow PK, Wulf GM, Ensor J et al. Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. J Clin Oncol 2011; 29: 3126-3132.
77. Ellard SL, Clemons M, Gelmon KA et al. Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163. J Clin Oncol 2009; 27: 4536-4541.
78. Tabernero J, Rojo F, Calvo E et al. Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008; 26: 1603-1610.
79. Tanaka C, O'Reilly T, Kovarik JM et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008; 26: 1596-1602.
80. Clayton AJ, Danson S, Jolly S et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer 2004; 91: 639-643.
81. Krueger DA, Care MM, Holland K et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: 1801-1811.
82. Jahanzeb M, Mortimer JE, Yunus F et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer. Oncologist 2002; 7: 410-417.
83. Burstein HJ, Harris LN, Marcom PK et al. Trastuzumab and vinorelbine as firstline therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21: 2889-2895.
84. Chan A, Martin M, Untch M et al. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial. Br J Cancer 2006; 95: 788-793.
85. Papaldo P, Fabi A, Ferretti G et al. A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease. Ann Oncol 2006; 17: 630-636.
86. Burstein HJ, Keshaviah A, Baron AD et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer 2007; 110: 965-972.
87. De Maio E, Pacilio C, Gravina A et al. Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial. BMC Cancer 2007; 7: 50.
88. Schilling G, Bruweleit M, Harbeck N et al. Phase II trial of vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer. a prospective, open label, non-controlled, multicenter phase II trial (to investigate efficacy and safety of this combination chemotherapy). Invest New Drugs 2009; 27: 166-172.
89. Nahta R, Yuan LX, Zhang B et al. Insulin-like growth factor-I receptor/ human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res 2005; 65: 11118-11128.
90. Lu Y, Zi X, Zhao Y et al. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93: 1852-1857.
91. Modi S, Stopeck A, Linden H et al. HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 2011; 17: 5132-5139.
92. Goldblatt EM, Erickson PA, Gentry ER et al. Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab. Breast Cancer Res Treat 2009; 118: 21-32