J Gynecol Oncol.  2013 Jan;24(1):66-82. 10.3802/jgo.2013.24.1.66.

Major clinical research advances in gynecologic cancer in 2012

• Suh DH
• Kim JW
• Kim K
• Kim HJ
• Lee KH

• KMID: 2288563
• DOI: http://doi.org/10.3802/jgo.2013.24.1.66

Abstract

Ten topics were chosen among major clinical research achievements in gynecologic oncology in 2012. For ovarian cancer, comprehensive review of the history of bevacizumab studies was followed by poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors and other molecular targeted agents such as epidermal growth factor receptor tyrosine kinase inhibitor and AMG 386. For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively. For endometrial cancer, targeted agents including mammalian target of rapamycin (mTOR) inhibitors and bevacizumab were discussed. Radiation therapy "sandwiched" between combination chemotherapy schedules for the treatment of uterine papillary serous carcinoma was also reviewed. Preoperative prediction of lymph node metastasis, definition of low-risk group, and recurrence and survival outcomes of laparoscopic approaches were addressed. For cervical cancer, we reviewed long-term benefit of human papillomavirus test and efficacy of paclitaxel/carboplatin versus paclitaxel/cisplatin in stage IVB, persistent or recurrent disease. In addition, the effect of three dimensional image-based high-dose rate brachytherapy was also reviewed. For vulvar cancer, the diagnostic value of sentinel lymph node biopsy was discussed. For breast cancer, positive results of three outstanding phase III randomized clinical trials, CLEOPATRA, EMILIA, and BOLERO-2 were introduced. Lastly, updates of major practice guidelines were summarized.

Keyword

Bevacizumab; PARP inhibitor; Low-risk endometrial cancer; Image-based high-dose rate brachytherapy; Practice guidelines

MeSH Terms

Achievement
Adenosine Diphosphate
Antibodies, Monoclonal, Humanized
Appointments and Schedules
Bevacizumab
Brachytherapy
Breast Neoplasms
Drug Therapy, Combination
Endometrial Neoplasms
Female
Humans
Lymph Nodes
Neoplasm Metastasis
Nitriles
Ovarian Neoplasms
Protein-Tyrosine Kinases
Pyrethrins
Receptor, Epidermal Growth Factor
Recombinant Fusion Proteins
Recurrence
Sentinel Lymph Node Biopsy
Sirolimus
Uterine Cervical Neoplasms
Vulvar Neoplasms
Adenosine Diphosphate
Antibodies, Monoclonal, Humanized
Nitriles
Protein-Tyrosine Kinases
Pyrethrins
Receptor, Epidermal Growth Factor
Recombinant Fusion Proteins
Sirolimus

Reference

1. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011. 365:2473–2483.

2. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011. 365:2484–2496.

3. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012. 30:2039–2045.

4. Aghajanian C, Blank SV, Goff BA, Judson PL, Nycum LR, Sovak MA, et al. An updated safety analysis of OCEANS, a randomized, double-blind, phase III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or placebo (PL) followed by BV or PL to disease progression (PD) in patients with platinum-sensitive (Plat-S) recurrent ovarian cancer. J Clin Oncol. 2012. 30:abstr 5054.

5. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol. 2012. 30:abstr LBA 5002.

6. Kristensen G, Berton-Rigaud D, Hilpert F, Reuss A, Bover I, Raspagliesi F, et al. The effect of bevaxizumab (BEV) plus chemotherapy (CT) for platinum-resistant ovarian cancer (OC) with ascites: analysis of the AURELIA trial. Int J Gynecol Cancer. 2012. 22:8 suppl 3. E103.

7. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009. 374:1331–1338.

8. Gonzalez-Martin A, Gladieff L, Tholander B, Stroyakovsky D, Gore ME, Segalla JGM, et al. Safety of front-line bevacizumab (BEV) combined with weekly paclitaxel (wPAC) and q3w carboplatin (C) for ovarian cancer (OC): Results from OCTAVIA. J Clin Oncol. 2012. 30:abstr 5017.

9. Arnold D, Andre T, Bennouna J, Sastre J, Osterlund PJ, Greil R, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012. 30:abstr CRA 3503.

10. Previs R, Perry L, Sperling J, Brevis K, McCann G, Moore K, et al. Bevacizumab beyond progression is not associated with prolonged progression-free survival in epithelial ovarian cancer. Int J Gynecol Cancer. 2012. 22:8 suppl 3. E220.

11. Patel AG, Sarkaria JN, Kaufmann SH. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A. 2011. 108:3406–3411.

12. Konstantinopoulos PA, Cannistra SA. Comparing poly (ADP-ribose) polymerase inhibitors with standard chemotherapy in BRCA-mutated, recurrent ovarian cancer: lessons learned from a negative trial. J Clin Oncol. 2012. 30:347–350.

13. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010. 28:3239–3247.

14. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008. 105:17079–17084.

15. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012. 30:372–379.

16. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010. 376:245–251.

17. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010. 28:2512–2519.

18. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol. 2001. 19:3312–3322.

19. Yang D, Khan S, Sun Y, Hess K, Shmulevich I, Sood AK, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011. 306:1557–1565.

20. Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008. 451:1116–1120.

21. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012. 366:1382–1392.

22. Vergote IB, Joly F, Katsaros D, Coens C, Reinthaller A, Hall M, et al. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a GCIG and EORTC-GCG study. J Clin Oncol. 2012. 30:abstr LBA 5000.

23. Colombo N, Kutarska E, Dimopoulos M, Bae DS, Rzepka-Gorska I, Bidzinski M, et al. Randomized, open-label, phase III study comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, or primary peritoneal cancer. J Clin Oncol. 2012. 30:3841–3847.

24. Kowalski RJ, Giannakakou P, Hamel E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). J Biol Chem. 1997. 272:2534–2541.

25. Altmann KH, Wartmann M, O'Reilly T. Epothilones and related structures: a new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta. 2000. 1470:M79–M91.

26. Ten Bokkel Huinink WW, Sufliarsky J, Smit WM, Spanik S, Wagnerova M, Hirte HW, et al. Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a phase I, open-label, dose-escalation study. J Clin Oncol. 2009. 27:3097–3103.

27. Zhang L, Yang N, Park JW, Katsaros D, Fracchioli S, Cao G, et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res. 2003. 63:3403–3412.

28. Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007. 25:5180–5186.

29. Herbst RS, Hong D, Chap L, Kurzrock R, Jackson E, Silverman JM, et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol. 2009. 27:3557–3565.

30. Mita AC, Takimoto CH, Mita M, Tolcher A, Sankhala K, Sarantopoulos J, et al. Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin Cancer Res. 2010. 16:3044–3056.

31. Karlan BY, Oza AM, Richardson GE, Provencher DM, Hansen VL, Buck M, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 2012. 30:362–371.

32. Mahner S. Phase III HECTOR study: recurring platinum sensitive ovarian cancer [Internet]. 2012. cited 2012 Nov 25. Cancer Intelligence;Available from: http://ecancer.org/tv/conference/157/1688.

33. Koensgen D, Stengel D, Belau A, Klare P, Oskay-Oezcelik G, Steck T, et al. Topotecan and carboplatin in patients with platinum-sensitive recurrent ovarian cancer: results of a multicenter NOGGO: phase I/II study. Cancer Chemother Pharmacol. 2008. 62:393–400.

34. Rose PG, Monk BJ, Provencher D, Hartney J, Legenne P, Lane S. An open-label, single-arm phase II study of intravenous weekly (days 1 and 8) topotecan in combination with carboplatin (day 1) every 21 days as second-line therapy in patients with platinum-sensitive relapsed ovarian cancer. Gynecol Oncol. 2011. 120:38–42.

35. Katsumata N, Yasuda M, Isonishi S, Michimae H, Kimura E, Aoki D, et al. Long-term follow-up of a rancomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. J Clin Oncol. 2012. 30:abstr 5003.

36. Kim K, Ryu SY. Major clinical research advances in gynecologic cancer 2009. J Gynecol Oncol. 2009. 20:203–209.

37. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011. 474:609–615.

38. Levy-Lahad E. Is it necessary to screen everybody for inherited cancer? when, why and how. Ann Oncol. 2012. 23:suppl 9. ix34.

39. Suh DH, Kim K, Kim JW. Major clinical research advances in gynecologic cancer in 2011. J Gynecol Oncol. 2012. 23:53–64.

40. Claes K. Challenges of dealing with next generation sequencing for hereditary cancer in clinical practice. Ann Oncol. 2012. 23:suppl 9. ix33.

41. Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012. 307:382–390.

42. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol. 2008. 26:20–25.

43. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 2003. 97:2187–2195.

44. Buller RE, Shahin MS, Geisler JP, Zogg M, De Young BR, Davis CS. Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res. 2002. 8:1196–1202.

45. Heravi-Moussavi A, Anglesio MS, Cheng SW, Senz J, Yang W, Prentice L, et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med. 2012. 366:234–242.

46. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004. 116:281–297.

47. Colombo N, Peiretti M, Castiglione M. Non-epithelial ovarian cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009. 20:Suppl 4. 24–26.

48. Bahubeshi A, Tischkowitz M, Foulkes WD. miRNA processing and human cancer: DICER1 cuts the mustard. Sci Transl Med. 2011. 3:111ps46.

49. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, Tsimberidou AM, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012. 30:777–782.

50. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005. 11:2875–2878.

51. Miyake T, Yoshino K, Enomoto T, Takata T, Ugaki H, Kim A, et al. PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. Cancer Lett. 2008. 261:120–126.

52. Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, et al. PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res. 2006. 12:5932–5935.

53. Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010. 120:2858–2866.

54. Emons G, Heyl W. Hormonal treatment of endometrial cancer. J Cancer Res Clin Oncol. 2000. 126:619–623.

55. Humber CE, Tierney JF, Symonds RP, Collingwood M, Kirwan J, Williams C, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 2007. 18:409–420.

56. Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011. 29:3278–3285.

57. Fleming G. New therapies to treat advanced endometrial cancer [Internet]. 2012. cited 2012 Nov 25. Cancer Intelligence;Available from: http://ecancer.org/tv/pubdate/1676.

58. Togami S, Sasajima Y, Oi T, Ishikawa M, Onda T, Ikeda S, et al. Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER2) and hormone receptor expression in uterine papillary serous carcinoma. Cancer Sci. 2012. 103:926–932.

59. Lupe K, D'Souza DP, Kwon JS, Radwan JS, Harle IA, Hammond JA, et al. Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer. Gynecol Oncol. 2009. 114:94–98.

60. Obermair A, Mileshkin L, Bolz K, Kondalsamy-Chennakesavan S, Cheuk R, Vasey P, et al. Prospective, non-randomized phase 2 clinical trial of carboplatin plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous carcinoma. Gynecol Oncol. 2011. 120:179–184.

61. Geller MA, Ivy J, Dusenbery KE, Ghebre R, Isaksson Vogel R, Argenta PA. A single institution experience using sequential multi-modality adjuvant chemotherapy and radiation in the "sandwich" method for high risk endometrial carcinoma. Gynecol Oncol. 2010. 118:19–23.

62. Geller MA, Ivy JJ, Ghebre R, Downs LS Jr, Judson PL, Carson LF, et al. A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a "Sandwich" method for stage III, IV, and recurrent endometrial cancer. Gynecol Oncol. 2011. 121:112–117.

63. Einstein MH, Frimer M, Kuo DY, Reimers LL, Mehta K, Mutyala S, et al. Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma. Gynecol Oncol. 2012. 124:21–25.

64. Fields AL, Einstein MH, Novetsky AP, Gebb J, Goldberg GL. Pilot phase II trial of radiation "sandwiched" between combination paclitaxel/platinum chemotherapy in patients with uterine papillary serous carcinoma (UPSC). Gynecol Oncol. 2008. 108:201–206.

65. Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008. 100:1707–1716.

66. Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009. 373:125–136.

67. Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol. 2008. 109:11–18.

68. Boronow RC. Surgical staging of endometrial cancer: evolution, evaluation, and responsible challenge--a personal perspective. Gynecol Oncol. 1997. 66:179–189.

69. Boronow RC, Morrow CP, Creasman WT, Disaia PJ, Silverberg SG, Miller A, et al. Surgical staging in endometrial cancer: clinical-pathologic findings of a prospective study. Obstet Gynecol. 1984. 63:825–832.

70. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group Study. Cancer. 1987. 60:2035–2041.

71. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol. 1991. 40:55–65.

72. Milan M, Java J, Walker J, Parker L, Metzinger D, Coleman R. Incidence of nodal metastasis in endometrioid endometrial cancer risk groups: a Gynecologic Oncology Groups multicenter review. Gynecol Oncol. 2011. 120:Suppl 1. S4.

73. Convery PA, Cantrell LA, Di Santo N, Broadwater G, Modesitt SC, Secord AA, et al. Retrospective review of an intraoperative algorithm to predict lymph node metastasis in low-grade endometrial adenocarcinoma. Gynecol Oncol. 2011. 123:65–70.

74. Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas LR, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol. 2012. 127:5–10.

75. Kang S, Lee JM, Lee JK, Kim JW, Cho CH, Kim SM, et al. How low is low enough? Evaluation of various risk-assessment models for lymph node metastasis in endometrial cancer: a Korean multicenter study. J Gynecol Oncol. 2012. 23:251–256.

76. Kang S, Kang WD, Chung HH, Jeong DH, Seo SS, Lee JM, et al. Preoperative identification of a low-risk group for lymph node metastasis in endometrial cancer: a Korean gynecologic oncology group study. J Clin Oncol. 2012. 30:1329–1334.

77. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol. 2009. 27:5331–5336.

78. Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol. 2012. 30:695–700.

79. Berchuck A, Secord AA, Havrilesky LJ. Minimally invasive surgery for endometrial cancer: the horse is already out of the barn. J Clin Oncol. 2012. 30:681–682.

80. Wright JD, Burke WM, Wilde ET, Lewin SN, Charles AS, Kim JH, et al. Comparative effectiveness of robotic versus laparoscopic hysterectomy for endometrial cancer. J Clin Oncol. 2012. 30:783–791.

81. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005. 97:1072–1079.

82. Castle PE, Glass AG, Rush BB, Scott DR, Wentzensen N, Gage JC, et al. Clinical human papillomavirus detection forecasts cervical cancer risk in women over 18 years of follow-up. J Clin Oncol. 2012. 30:3044–3050.

83. Kitagawa R, Katsumata N, Shibata T, Nakanishi T, Nishimura S, Ushijima K, et al. A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical cancer: Japan Clinical Oncology Group study (JCOG 0505). J Clin Oncol. 2012. 30:abstr 5006.

84. Levenback CF, Ali S, Coleman RL, Gold MA, Fowler JM, Judson PL, et al. Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study. J Clin Oncol. 2012. 30:3786–3791.

85. Levenback C, Coleman RL, Burke TW, Bodurka-Bevers D, Wolf JK, Gershenson DM. Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer. Gynecol Oncol. 2001. 83:276–281.

86. Rob L, Robova H, Pluta M, Strnad P, Kacirek J, Skapa P, et al. Further data on sentinel lymph node mapping in vulvar cancer by blue dye and radiocolloid Tc99. Int J Gynecol Cancer. 2007. 17:147–153.

87. de Hullu JA, Hollema H, Piers DA, Verheijen RH, van Diest PJ, Mourits MJ, et al. Sentinel lymph node procedure is highly accurate in squamous cell carcinoma of the vulva. J Clin Oncol. 2000. 18:2811–2816.

88. Mahner S, Jueckstock JK, Hilpert F, Lubbe D, Harter P, Gregorio ND, et al. Impact of adjuvant therapy in lymphnode positive vulvar cancer: the AGO CARE 1 study. J Clin Oncol. 2012. 30:abstr 5007.

89. Ling CC, Schell MC, Working KR, Jentzsch K, Harisiadis L, Carabell S, et al. CT-assisted assessment of bladder and rectum dose in gynecological implants. Int J Radiat Oncol Biol Phys. 1987. 13:1577–1582.

90. Haie-Meder C, Potter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol. 2005. 74:235–245.

91. Potter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere M, Dimopoulos J, et al. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006. 78:67–77.

92. Potter R, Fidarova E, Kirisits C, Dimopoulos J. Image-guided adaptive brachytherapy for cervix carcinoma. Clin Oncol (R Coll Radiol). 2008. 20:426–432.

93. Guedea F, Venselaar J, Hoskin P, Hellebust TP, Peiffert D, Londres B, et al. Patterns of care for brachytherapy in Europe: updated results. Radiother Oncol. 2010. 97:514–520.

94. Tan LT. Implementation of image-guided brachytherapy for cervix cancer in the UK: progress update. Clin Oncol (R Coll Radiol). 2011. 23:681–684.

95. Narayan K, van Dyk S, Bernshaw D, Rajasooriyar C, Kondalsamy-Chennakesavan S. Comparative study of LDR (Manchester system) and HDR image-guided conformal brachytherapy of cervical cancer: patterns of failure, late complications, and survival. Int J Radiat Oncol Biol Phys. 2009. 74:1529–1535.

96. Shin KH, Kim TH, Cho JK, Kim JY, Park SY, Kim DY, et al. CT-guided intracavitary radiotherapy for cervical cancer: Comparison of conventional point A plan with clinical target volume-based three-dimensional plan using dose-volume parameters. Int J Radiat Oncol Biol Phys. 2006. 64:197–204.

97. Charra-Brunaud C, Harter V, Delannes M, Haie-Meder C, Quetin P, Kerr C, et al. Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: results of the French STIC prospective study. Radiother Oncol. 2012. 103:305–313.

98. Sadozye AH, Reed N. A review of recent developments in image-guided radiation therapy in cervix cancer. Curr Oncol Rep. 2012. 14:519–526.

99. Viswanathan AN, Dimopoulos J, Kirisits C, Berger D, Potter R. Computed tomography versus magnetic resonance imaging-based contouring in cervical cancer brachytherapy: results of a prospective trial and preliminary guidelines for standardized contours. Int J Radiat Oncol Biol Phys. 2007. 68:491–498.

100. Potter R, Georg P, Dimopoulos JC, Grimm M, Berger D, Nesvacil N, et al. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol. 2011. 100:116–123.

101. Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene. 2007. 26:3637–3643.

102. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012. 366:109–119.

103. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009. 9:463–475.

104. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004. 5:317–328.

105. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009. 69:9330–9336.

106. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012. 367:1783–1791.

107. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012. 366:520–529.

108. Johnston SR. Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res. 2006. 12:1061s–1068s.

109. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009. 284:6361–6369.

110. Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O'Reilly T, Evans DB, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005. 11:5319–5328.

111. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009. 27:2630–2637.

112. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology [Internet]. 2012. cited 2012 Dec 25. Fort Washington, PA: National Comprehensive Cancer Network;Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

113. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012. 62:147–172.

114. American College of Obstetricians and Gynecologists (ACOG). Management of gynecologic issues in women with breast cancer [Internet]. 2012. cited 2012 Dec 25. Washington, DC: ACOG;Available from: http://www.guideline.gov/content.aspx?id=36055&search=gynecologic+issues+in+women+with+breast+cancer.