Immunotherapy and targeted therapy for cervical cancer: An update

Expert Review of Anticancer Therapy

Volumn 16, Issue 1, 2016, Pages 83-98

  Menderes, Gulden ^a   Black, Jonathan ^a   Schwab, Carlton L ^a   Santin, Alessandro D ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Advanced cervical cancer; gene therapy; immunotherapy; targeted therapy; therapeutic vaccines

Indexed keywords

ALDESLEUKIN; ANTINEOPLASTIC AGENT; BEVACIZUMAB; BRONTICTUZUMAB; CETUXIMAB; CHIMERIC ANTIGEN RECEPTOR; CISPLATIN; DURVALUMAB; ERLOTINIB; GEFITINIB; IMIQUIMOD; INO 9012; IPILIMUMAB; LAPATINIB; LC 9018; LIRILUMAB; LISTERIOLYSIN O; MAMMALIAN TARGET OF RAPAMYCIN; NIVOLUMAB; PAZOPANIB; PHOSPHORYL LIPID A; SGN 00101; TEMSIROLIMUS; TICILIMUMAB; TOPOTECAN; UNCLASSIFIED DRUG; URELUMAB; VASCULOTROPIN; VGX 3100; Z 100; ANGIOGENESIS INHIBITOR; PROTEIN KINASE INHIBITOR;

BRACHYTHERAPY; CANCER GENE THERAPY; CANCER IMMUNOLOGY; CANCER IMMUNOTHERAPY; CANCER RADIOTHERAPY; DOWN REGULATION; FEMALE; HUMAN; IMMUNOGENICITY; IMMUNOSUPPRESSIVE TREATMENT; LACTOBACILLUS DELBRUECKII SUBSP. LACTIS; LACTOBACILLUS PLANTARUM; LISTERIA MONOCYTOGENES; MOLECULAR BIOLOGY; MOLECULARLY TARGETED THERAPY; MYCOBACTERIUM BOVIS BCG; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SALMONELLA ENTERICA; UPREGULATION; UTERINE CERVIX CANCER; VIRUS LIKE AGENT; WART VIRUS; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; METASTASIS; PATHOLOGY; PROCEDURES; PROGNOSIS; SURVIVAL RATE; UTERINE CERVICAL NEOPLASMS;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; FEMALE; HUMANS; IMMUNOTHERAPY; MOLECULAR TARGETED THERAPY; NEOPLASM METASTASIS; PROGNOSIS; PROTEIN KINASE INHIBITORS; SURVIVAL RATE; UTERINE CERVICAL NEOPLASMS;

EID: 84955172253     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/14737140.2016.1121108     Document Type: Review

References (129)

1. de Sanjose S, Serrano B, Castellsague X., et al. Human papillomavirus (HPV) and related cancers in the Global Alliance for Vaccines and Immunization (GAVI) countries. A WHO/ICO HPV Information Centre Report. Vaccine. 2012; 30 (Suppl 4): D1-83, vi.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65: 5-29.
3. Eskander RN, Tewari KS. Chemotherapy in the treatment of metastatic, persistent, and recurrent cervical cancer. Curr Opin Obstet Gynecol. 2014; 26: 314-321.
4. Monk BJ, Tewari KS. Evidence-based therapy for recurrent cervical cancer. J Clin Oncol. 2014; 32: 2687-2690.
5. Van Meir H, Kenter GG, Burggraaf J., et al. The need for improvement of the treatment of advanced and metastatic cervical cancer, the rationale for combined chemo-immunotherapy. Anticancer Agents Med Chem. 2014; 14: 190-203.
6. Bosch FX, Lorincz A, Munoz N., et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002; 55: 244-265.
7. Narisawa-Saito M, Kiyono T. Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 2007; 98: 1505-1511.
8. Patel D, Incassati A, Wang N., et al. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res. 2004; 64: 1299-1306.
9. Nakamura M, Bodily JM, Beglin M., et al. Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses. Virology. 2009; 387: 442-448.
10. Kim MK, Kim HS, Kim SH., et al. Human papillomavirus type 16 E5 oncoprotein as a new target for cervical cancer treatment. Biochem Pharmacol. 2010; 80: 1930-1935.
11. DiMaio D, Mattoon D. Mechanisms of cell transformation by papillomavirus E5 proteins. Oncogene. 2001; 20: 7866-7873.
12. Jabbar SF, Abrams L, Glick A., et al. Persistence of high-grade cervical dysplasia and cervical cancer requires the continuous expression of the human papillomavirus type 16 E7 oncogene. Cancer Res. 2009; 69: 4407-4414.
13. Romanczuk H, Howley PM. Disruption of either the E1 or the E2 regulatory gene of human papillomavirus type 16 increases viral immortalization capacity. Proc Natl Acad Sci USA. 1992; 89: 3159-3163.
14. Howley PM, Munger K, Romanczuk H., et al. Cellular targets of the oncoproteins encoded by the cancer associated human papillomaviruses. Princess Takamatsu Symp. 1991; 22: 239-248.
15. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 480: 480-489.
16. Topalian SL, Hodi FS, Brahmer JR., et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366: 2443-2454.
17. Yang W, Song Y, Lu YL., et al. Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia. Immunology. 2013; 139: 513-522.
18. Karim R, Jordanova ES, Piersma SJ., et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009; 15: 6341-6347.
19. Eskander RN, Tewari KS. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther. 2015; 37: 20-38.
20. Stern PL, van der Burg SH, Hampson IN., et al. Therapy of human papillomavirus-related disease. Vaccine. 2012; 30 (Suppl 5): F71-82.
21. Venuti A, Paolini F, Nasir L., et al. Papillomavirus E5: the smallest oncoprotein with many functions. Mol Cancer. 2011; 10: 140.
22. Ashrafi GH, Haghshenas MR, Marchetti B., et al. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. Int J Cancer. 2005; 113: 276-283.
23. Zhang B, Li P, Wang E., et al. The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-gamma. Virology. 2003; 310: 100-108.
24. Campo MS, Graham SV, Cortese MS., et al. HPV-16 E5 down-regulates expression of surface HLA class I and reduces recognition by CD8 T cells. Virology. 2010; 407: 137-142.
25. Stanley MA, Pett MR, Coleman N. HPV: from infection to cancer. Biochem Soc Trans. 2007; 35 (Pt 6): 1456-1460.
26. OBrien PM, Saveria Campo M. Evasion of host immunity directed by papillomavirus-encoded proteins. Virus Res. 2002; 88: 103-117.
27. Crosbie EJ, Einstein MH, Franceschi S., et al. Human papillomavirus and cervical cancer. Lancet. 2013; 382: 889-899.
28. Piersma SJ. Immunosuppressive tumor microenvironment in cervical cancer patients. Cancer Microenviron. 2011; 4: 361-375.
29. Diaz-Padilla I, Monk BJ, Mackay HJ., et al. Treatment of metastatic cervical cancer: future directions involving targeted agents. Crit Rev Oncol Hematol. 2013; 85: 303-314.
30. Badaracco G, Venuti A. Human papillomavirus therapeutic vaccines in head and neck tumors. Expert Rev Anticancer Ther. 2007; 7: 753-766.
31. Su JH, Wu A, Scotney E., et al. Immunotherapy for cervical cancer: Research status and clinical potential. BioDrugs. 2010; 24: 109-129.
32. Bolhassani A, Mohit E, Rafati S. Different spectra of therapeutic vaccine development against HPV infections. Hum Vaccin. 2009; 5: 671-689.
33. Cortes-Perez NG, Azevedo V, Alcocer-Gonzalez JM., et al. Cell-surface display of E7 antigen from human papillomavirus type-16 in Lactococcus lactis and in Lactobacillus plantarum using a new cell-wall anchor from lactobacilli. J Drug Target. 2005; 13: 89-98.
34. Sewell DA, Shahabi V, Gunn GR 3rd., et al. Recombinant Listeria vaccines containing PEST sequences are potent immune adjuvants for the tumor-associated antigen human papillomavirus-16 E7. Cancer Res. 2004; 64: 8821-8825.
35. Echchannaoui H, Bianchi M, Baud D., et al. Intravaginal immunization of mice with recombinant Salmonella enterica serovar Typhimurium expressing human papillomavirus type 16 antigens as a potential route of vaccination against cervical cancer. Infect Immun. 2008; 76: 1940-1951.
36. Hsieh CJ, Kim TW, Hung CF., et al. Enhancement of vaccinia vaccine potency by linkage of tumor antigen gene to gene encoding calreticulin. Vaccine. 2004; 22: 3993-4001.
37. Liao JB, Publicover J, Rose JK., et al. Single-dose, therapeutic vaccination of mice with vesicular stomatitis virus expressing human papillomavirus type 16 E7 protein. Clin Vaccine Immunol. 2008; 15: 817-824.
38. Lee DW, Anderson ME, Wu S., et al. Development of an adenoviral vaccine against E6 and E7 oncoproteins to prevent growth of human papillomavirus-positive cancer. Arch Otolaryngol Head Neck Surg. 2008; 134: 1316-1323.
39. Zhou L, Zhu T, Ye X., et al. Long-term protection against human papillomavirus e7-positive tumor by a single vaccination of adeno-associated virus vectors encoding a fusion protein of inactivated e7 of human papillomavirus 16/18 and heat shock protein 70. Hum Gene Ther. 2010; 21: 109-119.
40. Daemen T, Riezebos-Brilman A, Regts J., et al. Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model: effects of the route of immunization. Antivir Ther. 2004; 9: 733-742.
41. Davidson EJ, Faulkner RL, Sehr P., et al. Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7). Vaccine. 2004; 22: 2722-2729.
42. Baldwin PJ, van der Burg SH, Boswell CM., et al. Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a therapeutic vaccination for vulval and vaginal intraepithelial neoplasia. Clin Cancer Res. 2003; 9: 5205-5213.
43. Radaelli A, De Giuli Morghen C, Zanotto C., et al. A prime/boost strategy by DNA/fowlpox recombinants expressing a mutant E7 protein for the immunotherapy of HPV-associated cancers. Virus Res. 2012; 170: 44-52.
44. Sharma C, Dey B, Wahiduzzaman M., et al. Human papillomavirus 16 L1-E7 chimeric virus like particles show prophylactic and therapeutic efficacy in murine model of cervical cancer. Vaccine. 2012; 30: 5417-5424.
45. Kaufmann AM, Nieland JD, Jochmus I., et al. Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer. 2007; 121: 2794-2800.
46. Vambutas A, DeVoti J, Nouri M., et al. Therapeutic vaccination with papillomavirus E6 and E7 long peptides results in the control of both established virus-induced lesions and latently infected sites in a pre-clinical cottontail rabbit papillomavirus model. Vaccine. 2005; 23: 5271-5280.
47. Chen W, Huang L. Induction of cytotoxic T-lymphocytes and antitumor activity by a liposomal lipopeptide vaccine. Mol Pharm. 2008; 5: 464-471.
48. Sharma RK, Elpek KG, Yolcu ES., et al. Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors. Cancer Res. 2009; 69: 4319-4326.
49. Kim TG, Kim CH, Won EH., et al. CpG-ODN-stimulated dendritic cells act as a potent adjuvant for E7 protein delivery to induce antigen-specific antitumour immunity in a HPV 16 E7-associated animal tumour model. Immunology. 2004; 112: 117-125.
50. Cui Z, Huang L. Liposome-polycation-DNA (LPD) particle as a carrier and adjuvant for protein-based vaccines: therapeutic effect against cervical cancer. Cancer Immunol Immunother. 2005; 54: 1180-1190.
51. Frazer IH, Quinn M, Nicklin JL., et al. Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX adjuvant in women with cervical intraepithelial neoplasia. Vaccine. 2004; 23: 172-181.
52. Liao CW, Chen CA, Lee CN., et al. Fusion protein vaccine by domains of bacterial exotoxin linked with a tumor antigen generates potent immunologic responses and antitumor effects. Cancer Res. 2005; 65: 9089-9098.
53. Goldstone SE, Palefsky JM, Winnett MT., et al. Activity of HspE7, a novel immunotherapy, in patients with anogenital warts. Dis Colon Rectum. 2002; 45: 502-507.
54. Derkay CS, Smith RJ, McClay J., et al. HspE7 treatment of pediatric recurrent respiratory papillomatosis: final results of an open-label trial. Ann Otol Rhinol Laryngol. 2005; 114: 730-737.
55. Roman LD, Wilczynski S, Muderspach LI., et al. A phase II study of Hsp-7 (SGN-00101) in women with high-grade cervical intraepithelial neoplasia. Gynecol Oncol. 2007; 106: 558-566.
56. Vici P, Mariani L, Pizzuti L., et al. Immunologic treatments for precancerous lesions and uterine cervical cancer. J Exp Clin Cancer Res. 2014; 33: 29.
57. Matijevic M, Hedley ML, Urban RG., et al. Immunization with a poly (lactide co-glycolide) encapsulated plasmid DNA expressing antigenic regions of HPV 16 and 18 results in an increase in the precursor frequency of T cells that respond to epitopes from HPV 16, 18, 6 and 11. Cell Immunol. 2011; 270: 62-69.
58. Garcia F, Petry KU, Muderspach L., et al. ZYC101a for treatment of high-grade cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2004; 103: 317-326.
59. Martinon F, Brochard P, Ripaux M., et al. Improved protection against simian immunodeficiency virus mucosal challenge in macaques primed with a DNA vaccine and boosted with the recombinant modified vaccinia virus Ankara and recombinant Semliki Forest virus. Vaccine. 2008; 26: 532-545.
60. Cheng WF, Hung CF, Hsu KF., et al. Cancer immunotherapy using Sindbis virus replicon particles encoding a VP22-antigen fusion. Hum Gene Ther. 2002; 13: 553-568.
61. Hsu KF, Hung CF, Cheng WF., et al. Enhancement of suicidal DNA vaccine potency by linking Mycobacterium tuberculosis heat shock protein 70 to an antigen. Gene Ther. 2001; 8: 376-383.
62. Kim TW, Hung CF, Juang J., et al. Enhancement of suicidal DNA vaccine potency by delaying suicidal DNA-induced cell death. Gene Ther. 2004; 11: 336-342.
63. Herd KA, Harvey T, Khromykh AA., et al. Recombinant Kunjin virus replicon vaccines induce protective T-cell immunity against human papillomavirus 16 E7-expressing tumour. Virology. 2004; 319: 237-248.
64. Varnavski AN, Young PR, Khromykh AA. Stable high-level expression of heterologous genes in vitro and in vivo by noncytopathic DNA-based Kunjin virus replicon vectors. J Virol. 2000; 74: 4394-4403.
65. Mikyskova R, Indrova M, Simova J., et al. Treatment of minimal residual disease after surgery or chemotherapy in mice carrying HPV16-associated tumours: Cytokine and gene therapy with IL-2 and GM-CSF. Int J Oncol. 2004; 24: 161-167.
66. Bergot AS, Kassianos A, Frazer IH., et al. New Approaches to Immunotherapy for HPV Associated Cancers. Cancers (Basel). 2011; 3: 3461-3495.
67. Bellone S, El-Sahwi K, Cocco E., et al. Human papillomavirus type 16 (HPV-16) virus-like particle L1-specific CD8+ cytotoxic T lymphocytes (CTLs) are equally effective as E7-specific CD8+ CTLs in killing autologous HPV-16-positive tumor cells in cervical cancer patients: implications for L1 dendritic cell-based therapeutic vaccines. J Virol. 2009; 83: 6779-6789.
68. Santin AD, Bellone S, Gokden M., et al. Vaccination with HPV-18 E7-pulsed dendritic cells in a patient with metastatic cervical cancer. N Engl J Med. 2002; 346: 1752-1753.
69. Santin AD, Hermonat PL, Ravaggi A., et al. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes. J Virol. 2000; 74: 4729-4737.
70. Santin AD, Hermonat PL, Ravaggi A., et al. Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells. Clin Cancer Res. 2001; 7 (3 Suppl): 804s-810s.
71. Santin AD, Hermonat PL, Ravaggi A., et al. Induction of human papillomavirus-specific CD4(+) and CD8(+) lymphocytes by E7-pulsed autologous dendritic cells in patients with human papillomavirus type 16-and 18-positive cervical cancer. J Virol. 1999; 73: 5402-5410.
72. Santin AD, Bellone S, Palmieri M., et al. HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities. Gynecol Oncol. 2006; 100: 469-478.
73. Santin AD, Bellone S, Palmieri M., et al. Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial. J Virol. 2008; 82: 1968-1979.
74. Santin AD, Hermonat PL, Ravaggi A., et al. Development, characterization and distribution of adoptively transferred peripheral blood lymphocytes primed by human papillomavirus 18 E7-pulsed autologous dendritic cells in a patient with metastatic adenocarcinoma of the uterine cervix. Eur J Gynaecol Oncol. 2000; 21: 17-23.
75. Peralta-Zaragoza O, Bermudez-Morales VH, Perez-Plasencia C., et al. Targeted treatments for cervical cancer: a review. Onco Targets Ther. 2012; 5: 315-328.
76. Okawa T, Kita M, Arai T., et al. Phase II randomized clinical trial of LC9018 concurrently used with radiation in the treatment of carcinoma of the uterine cervix. Its effect on tumor reduction and histology. Cancer. 1989; 64: 1769-1776.
77. Okawa T, Niibe H, Arai T., et al. Effect of LC9018 combined with radiation therapy on carcinoma of the uterine cervix. A phase III, multicenter, randomized, controlled study. Cancer. 1993; 72: 1949-1954.
78. Chao A, Lin CT, Lai CH. Updates in systemic treatment for metastatic cervical cancer. Curr Treat Options Oncol. 2014; 15: 1-13.
79. Noda K, Ohashi Y, Sugimori H., et al. Phase III double-blind randomized trial of radiation therapy for stage IIIb cervical cancer in combination with low-or high-dose Z-100: treatment with immunomodulator, more is not better. Gynecol Oncol. 2006; 101: 455-463.
80. Sugiyama T, Fujiwara K, Ohashi Y., et al. Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: a JGOG study. Ann Oncol. 2014; 25: 1011-1017.
81. Callahan MK, Wolchok JD. At the bedside: CTLA-4-and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013; 94: 41-53.
82. Hodi FS, ODay SJ, McDermott DF., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-723.
83. Lyford-Pike S, Peng S, Young GD., et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013; 73: 1733-1741.
84. Robert C, Ribas A, Wolchok JD., et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384: 1109-1117.
85. Tewari KS, Monk BJ. New strategies in advanced cervical cancer: from angiogenesis blockade to immunotherapy. Clin Cancer Res. 2014; 20: 5349-5358.
86. Zsiros E, Tsuji T, Odunsi K. Adoptive T-cell therapy is a promising salvage approach for advanced or recurrent metastatic cervical cancer. J Clin Oncol. 2015; 33: 1521-1522.
87. Dudley ME, Wunderlich JR, Robbins PF., et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002; 298: 850-854.
88. Dudley ME, Wunderlich JR, Yang JC., et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005; 23: 2346-2357.
89. Stevanovic S, Draper LM, Langhan MM., et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015; 33: 1543-1550.
90. Shi H, Sun M, Liu L., et al. Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects. Mol Cancer. 2014; 13: 219.
91. Maude SL, Teachey DT, Porter DL., et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015; 125: 4017-4023.
92. Sharma C, Khan MA, Mohan T., et al. A synthetic chimeric peptide harboring human papillomavirus 16 cytotoxic T lymphocyte epitopes shows therapeutic potential in a murine model of cervical cancer. Immunol Res. 2014; 58: 132-138.
93. Markman M. The promise and perils of targeted therapy of advanced ovarian cancer. Oncology. 2008; 74: 1-6.
94. Murdoch D, Sager J. Will targeted therapy hold its promise An evidence-based review. Curr Opin Oncol. 2008; 20: 104-111.
95. Arteaga CL, Baselga J. Impact of genomics on personalized cancer medicine. Clin Cancer Res. 2012; 18: 612-618.
96. Ojesina AI, Lichtenstein L, Freeman SS., et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014; 506: 371-375.
97. Crook T, Wrede D, Tidy JA., et al. Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours. Lancet. 1992; 339: 1070-1073.
98. McIntyre JB, Wu JS, Craighead PS., et al. PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy. Gynecol Oncol. 2013; 128: 409-414.
99. Kang S, Kim HS, Seo SS., et al. Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma. Gynecol Oncol. 2007; 105: 662-666.
100. Wingo SN, Gallardo TD, Akbay EA., et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS One. 2009; 4: e5137.
101. Kim H, Muller WJ. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. Exp Cell Res. 1999; 253: 78-87.
102. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Euro J Cancer (Oxford, England: 1990). 2001; 37 (Suppl 4): S9-15.
103. Mendelsohn J, Fan Z. Epidermal growth factor receptor family and chemosensitization. J Natl Cancer Inst. 1997; 89 (5): 341-343.
104. Corvo R, Antognoni P, Sanguineti G. Biological predictors of response to radiotherapy in head and neck cancer: recent advances and emerging perspectives. Tumori. 2001; 87: 355-363.
105. Kersemaekers AM, Fleuren GJ, Kenter GG., et al. Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin Cancer Res. 1999; 5: 577-586.
106. Bellone S, Frera G, Landolfi G., et al. Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for Cetuximab-mediated therapy in recurrent/metastatic disease. Gynecol Oncol. 2007; 106: 513-520.
107. Santin AD, Sill MW, McMeekin DS., et al. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2011; 122: 495-500.
108. Farley J, Sill MW, Birrer M., et al. Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix and evaluation of epidermal growth factor receptor immunohistochemical expression: a Gynecologic Oncology Group study. Gynecol Oncol. 2011; 121: 303-308.
109. Kurtz JE, Hardy-Bessard AC, Deslandres M., et al. Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: A phase II GINECO trial. Gynecol Oncol. 2009; 113: 16-20.
110. Yamanaka I, Koizumi M, Baba T., et al. Epidermal growth factor increased the expression of alpha2beta1-integrin and modulated integrin-mediated signaling in human cervical adenocarcinoma cells. Exp Cell Res. 2003; 286: 165-174.
111. Goncalves A, Fabbro M, Lhomme C., et al. A phase II trial to evaluate gefitinib as second-or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol Oncol. 2008; 108: 42-46.
112. Schilder RJ, Sill MW, Lee YC., et al. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Int J Gynecol Cancer. 2009; 19: 929-933.
113. Nogueira-Rodrigues A, Moralez G, Grazziotin R., et al. Phase 2 trial of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced cervical cancer. Cancer. 2014; 120: 1187-1193.
114. Perez-Regadera J, Sanchez-Munoz A, De-la-Cruz J., et al. Negative prognostic impact of the coexpression of epidermal growth factor receptor and c-erbB-2 in locally advanced cervical cancer. Oncology. 2009; 76: 133-141.
115. Van Meerten E, Franckena M, Wiemer E., et al. Phase I study of cisplatin, hyperthermia, and lapatinib in patients with recurrent carcinoma of the uterine cervix in a previously irradiated area. The Oncologist. 2015; 20: 241-242.
116. Monk BJ, Mas Lopez L, Zarba JJ., et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clinical Oncology: Official Journal Am Soc Clin Oncol. 2010; 28: 3562-3569.
117. Molinolo AA, Marsh C, El Dinali M., et al. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res. 2012; 18: 2558-2568.
118. Feng W, Duan X, Liu J., et al. Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions. Int J Clin Exp Pathol. 2009; 2: 249-260.
119. Tinker AV, Ellard S, Welch S., et al. Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol. 2013; 130: 269-274.
120. Fujimoto J, Toyoki H, Sato E., et al. Clinical implication of expression of vascular endothelial growth factor-C in metastatic lymph nodes of uterine cervical cancers. Br J Cancer. 2004; 91: 466-469.
121. Choi CH, Song SY, Choi JJ., et al. Prognostic significance of VEGF expression in patients with bulky cervical carcinoma undergoing neoadjuvant chemotherapy. BMC Cancer. 2008; 8: 295.
122. Braicu EI, Gasimli K, Richter R., et al. Role of serum VEGFA, TIMP2, MMP2 and MMP9 in monitoring response to adjuvant radiochemotherapy in patients with primary cervical cancer-results of a companion protocol of the randomized NOGGO-AGO phase III clinical trial. Anticancer Res. 2014; 34: 385-391.
123. Yang YC, Wang KL, Su TH., et al. Concurrent cisplatin-based chemoradiation for cervical carcinoma: tumor response, toxicity, and serum cytokine profiles. Cancer Investigation. 2006; 24: 390-395.
124. Monk BJ, Sill MW, Burger RA., et al. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clinical Oncology: Official Journal Am Soc Clin Oncol. 2009; 27: 1069-1074.
125. Zighelboim I, Wright JD, Gao F., et al. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013; 130: 64-68.
126. Schefter TE, Winter K, Kwon JS., et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys. 2012; 83: 1179-1184.
127. Schefter T, Winter K, Kwon JS., et al. RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys. 2014; 88: 101-105.
128. Tewari KS, Sill MW, Long HJ 3rd., et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014; 370: 734-743.
129. Rational molecular assessment innovative drug selection project. A European Project supported through the Seventh Framework Programme for Research and Technological Development. 2015 [ cited 2015 Oct 18[. Available from: www.raids-fp7.eu/project-overview.html