Clinical analysis of chemo-resistance risk factors in endometriosis associated ovarian cancer

Clinical analysis of chemo-resistance risk factors in endometriosis associated ovarian cancer Background: To analyze the clinical characteristics and chemo-resistance related factors of patients with resistant and non-resistant endometriosis-associated ovarian cancer (ovarian clear cell carcinoma and endometrioid carcinoma) by reviewing the data of epithelial ovarian cancer patients who received initial treatment in our hospital over a 12-year period. Results: Among the 304 patients, 17.1% were seen with platinum-based drug resistance. The ROC curve of continuous variables was drawn according to resistance situation, then they were grouped by age (< 48 or ≥ 48 years), tumor size (< 7 cm or ≥ 7 cm) and Ca125 (< 90 and ≥ 90 U/ml). In univariate analysis, age ≥ 48 years, initial symptom of abdominal distension or weight loss, abnormal preoperative serum Ca125, Ca125 < 90 U/ml, advanced FIGO stage, absence of endometriosis, bilateral tumors, lack of lymphadenectomy, positive lymph nodes, unsatisfactory initial cytoreduction surgery and history of breast cancer were all related to drug resistance in ovarian cancer. In multivariate analysis, advanced stage, lack of lymphadenectomy, positive lymph nodes and history of breast cancer were independent risk factors related to platinum-based drug resistance (P <0.05). Conclusion: For patients of endometriosis-related ovarian cancer, platinum-based drug resistance were associated with advanced FIGO stage, lack of lymphadenectomy, positive lymph nodes and history of breast cancer. Keywords: Chemo-resistance, Risk factors, Endometriosis associated ovarian cancer Background of OCCC were with unilateral pelvic mass of early stage, At present, many scholars regard endometriosis-associated their prognosis was better than other types of EOC. The ovarian cancer(EAOC) as a special pathological type of 5-year survival rate of OCCC patients with early stage was epithelial ovarian cancer(EOC), including ovarian clear cell higher than 80% [3]. However, the prognosis of those with carcinoma (OCCC) and endometrioid carcinoma. Studies advanced stage was poorer than that of other EOCs with have reported that the clinical features and prognosis of the 5-year survival rate about 20%, which might be related patients with EAOC were different from those with other to the resistance to platinum-based chemotherapy [4]. The EOCs. Compared with ovarian serous carcinoma, the onset clinical risk factors of chemo-resistance in patients with age of OCCC was younger (55 vs 64 years; median age) [1]. EAOC have not been reported. By retrospectively analyzing A study comparing early ovarian cancer and advanced ovar- the data of EOC patients who received initial treatment in ian cancer (I/II vs. III/IV) reported that 57–81% of OCCC our hospital over a 12-year period, this study intended to were diagnosed in early stage (I/II) [2]. Since most patients analyze the clinical features and chemo-resistance related factors of patients with resistant and non-resistant EAOC (OCCC and endometrioid carcinoma), expecting to provide * Correspondence: wangshu219@hotmail.com; XiangY@pumch.cn; references for the guidance of clinical treatments and the langjh@hotmail.com prediction of survival outcomes. Tong Ren and Ting-Ting Sun contributed equally to this work. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 ShuaiFuYuan, DongCheng District, Beijing 100730, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ren et al. Journal of Ovarian Research (2018) 11:40 Page 2 of 7 Table 1 Clinical and morphological characteristics of patients with or without chemo-resistance Variable Category Number(%) Chemo-sensitive(%) Chemoresistance(%) P 304 252(82.9%) 52(17.1%) Age < 48 129(42.43) 114(45.24) 15(28.85) 0.0294* ≥48 175(57.57) 138(54.76) 37(71.15) Menopausal status Pre 161(52.96) 139(55.16) 22(42.31) 0.0909 Post 143(47.04) 113(44.84) 30(57.69) Gravidity < 1 35(11.51) 31(12.3) 4(7.69) 0.3431 > = 1 269(88.49) 221(87.7) 48(92.31) Parity < 1 51(16.78) 46(18.25) 5(9.62) 0.1290 > = 1 253(83.22) 206(81.75) 47(90.38) Abdominal pain No 210(69.08) 174(69.05) 36(69.23) 0.9016 Yes 93(30.59) 77(30.56) 16(30.77) Bloating No 243(79.93) 208(82.54) 35(67.31) 0.0125* Yes 61(20.07) 44(17.46) 17(32.69) Palpable mass No 223(73.36) 182(72.22) 41(78.85) 0.3253 Yes 81(26.64) 70(27.78) 11(21.15) Incidental finding No 256(84.21) 208(82.54) 48(92.31) 0.0786 Yes 48(15.79) 44(17.46) 4(7.69) Irregular menstruation No 275(90.46) 226(89.68) 49(94.23) 0.3094 Yes 29(9.54) 26(10.32) 3(5.77) Postmenopausal bleeding No 285(93.75) 235(93.25) 50(96.15) 0.4316 Yes 19(6.25) 17(6.75) 2(3.85) Emaciation No 294(96.71) 248(98.41) 46(88.46) 0.0002* Yes 10(3.29) 4(1.59) 6(11.54) Abnormal vaginal discharge No 302(99.34) 250(99.21) 52(100) 0.5192 Yes 2(0.66) 2(0.79) 0(0) Ca125 in normal range(< 35 U/L) No 249(81.91) 199(78.97) 50(96.15) 0.0034* Yes 55(18.09) 53(21.03) 2(3.85) CA125group < 90 112(36.84) 104(41.27) 8(15.38) 0.0004* ≥90 192(63.16) 148(58.73) 44(84.62) Early or late Stage FIGO I + II 185(60.86) 175(69.44) 10(19.23) <.0001* FIGO III + IV 119(39.14) 77(30.56) 42(80.77) FIGO stage I 141(46.38) 136(53.97) 5(9.62) <.0001* II 44(14.47) 39(15.48) 5(9.62) III 104(34.21) 69(27.38) 35(67.31) IV 15(4.93) 8(3.17) 7(13.46) Tumor size group < 7 80(26.32) 66(26.19) 14(26.92) 0.9130 ≥7 224(73.68) 186(73.81) 38(73.08) Pathology Grade G1 45(24.19) 44(28.03) 1(3.45) 0.0128* G2 59(31.72) 49(31.21) 10(34.48) G3 82(44.09) 64(40.76) 18(62.07) Pathology type Endometrioid 186(61.18) 157(62.30) 29(55.77) 0.435 Clear cell 118(38.82) 95(37.70) 23(44.23) Endometriosis No 235(77.30) 188(74.6) 47(90.38) 0.0134* Yes 69(22.70) 64(25.4) 5(9.62) Ren et al. Journal of Ovarian Research (2018) 11:40 Page 3 of 7 Table 1 Clinical and morphological characteristics of patients with or without chemo-resistance (Continued) Variable Category Number(%) Chemo-sensitive(%) Chemoresistance(%) P Side of tumor Unilateral 212(69.74) 183(72.62) 29(55.77) 0.0160* Bilateral 92(30.26) 69(27.38) 23(44.23) LN metastasis No 213(70.07) 195(77.38) 18(34.62) <.0001* Yes 40(13.16) 24(9.52) 16(30.77) unclear 51(16.78) 33(13.1) 18(34.62) LN dissection No 51(16.78) 33(13.1) 18(34.62) 0.0002* Yes 253(83.22) 219(86.9) 34(65.38) Residual disease No 231(75.99) 207(82.14) 24(46.15) <.0001* Yes 73(24.01) 45(17.86) 28(53.85) TH No 297(97.7) 246(97.62) 51(98.08) 0.8411 Yes 7(2.3) 6(2.38) 1(1.92) Tubal ligation No 290(95.39) 243(96.43) 47(90.38) 0.0583 Yes 14(4.61) 9(3.57) 5(9.62) Sterilization surgery No 283(93.09) 237(94.05) 46(88.46) 0.1481 Yes 21(6.91) 15(5.95) 6(11.54) Endometrial disorder No 252(82.89) 208(82.54) 44(84.62) 0.7174 Yes 52(17.11) 44(17.46) 8(15.38) Variable endometrial disorder No 252(82.89) 207(82.14) 45(86.54) 0.7998 EP 27(8.88) 23(9.13) 4(7.69) EIN 22(7.24) 19(7.54) 3(5.77) EC 3(0.99) 3(1.19) 0(0) Breast cancer No 296(97.37) 248(98.41) 48(92.31) 0.0123* Yes 8(2.63) 4(1.59) 4(7.69) HT No 250(82.24) 208(82.54) 42(80.77) 0.7610 Yes 54(17.76) 44(17.46) 10(19.23) DM No 286(94.08) 236(93.65) 50(96.15) 0.4862 Yes 18(5.92) 16(6.35) 2(3.85) According to the classification system of FIGO staging (2013 version) Abbreviation: Ca125 cancer antigen 125, EM endometriosis, LN lymph node, TH total hysterectomy, EP endometrial polyps, EIN endometrial intraepithelial neoplasm, EC endometrial cancer, HT hypertension, DM diabetic mellitus *P < 0.05 Results Ca125 < 90 U/L (84.62% vs 58.73%, P = 0.0004), more ad- A total of 304 patients diagnosed with EAOC and treated vanced FIGO stage(III + IV) (80.77% vs 30.56%, P < 0.001), in PUMCH were identified, 52(17.1%) of which were seen more high-grade tumor(62.07% vs 40.76%; P = 0.0128), with platinum-based drug resistance and the rest fewer coexisting endometriosis (9.62% vs 25.4%, P = 252(82.9%) were in the non-resistant group. Table 1 0.0134), more bilateral tumors (44.23% vs 27.38%, P = showed the demographic and clinical characteristics of all 0.0160), more positive LNs (30.77% vs 9.52%, P <0.001), the patients. In this study, based on the ROC curve of fewer lymphadenectomy (34.62% vs 13.1%, P = 0.0002), chemo-resistance, the above continuous variables were more residual tumor > 1 cm and more history of breast grouped by age, tumor size and Ca125 level[age: < 48 or ≥ cancer (7.69% vs 1.59%, P = 0.0123). Meanwhile, there was 48 years; tumor size: < 7 cm or ≥ 7 cm; Ca125: < 90 U/L no statistically significant difference seen in menopause sta- or ≥90 U/L],as seeninFig. 1.Univariateanalysisshowed tus, number of pregnancies and labors, tumor size, histo- that compared with the non-resistant group, there were logic type, coexisting endometrial lesions, history of more patients with age ≥ 48 years in the chemo-resistant hysterectomy or tubal sterilization and history of diabetes group (71.15% vs 54.76%, P = 0.0294), more with symptoms mellitus or hypertension, as showed in Table 1 (P >0.05). of abdominal distension (32.69% vs 17.46%, P = 0.0125) and In multivariate analysis however, only FIGO stage (P = emaciation (11.54% vs 1.59%, P = 0.0002), fewer with nor- 0.004), positive LNs (P = 0.040), lymph nodes resection mal level of Ca125 (3.85% vs 21.03%, P = 0.0034) but more (P = 0.016) and history of breast cancer (P = 0.044) were Ren et al. Journal of Ovarian Research (2018) 11:40 Page 4 of 7 Fig. 1 ROC curve for age of disease onset, tumor size, pre-surgery Ca125 in the occurrence of chemo-resistance independent risk factors of platinum-based drug investigated the clinicopathological risk factors of resistance, while onset age, initial symptoms, Ca125 platinum-based chemoresistance. Univariate analysis showed level, coexisting endometriosis and residual tumors were that age, higher level of Ca125, advanced FIGO stage, not, as seen in Table 2. high-grade tumor, absence of endometriosis, bilateral tumors, lack of lymphadenectomy, positive LNs, residual Discussion lesion > 1 cm and history of breast cancer were related to This study regarded OCCC and ovarian endometrioid chemoresistance. However, multivariate analysis showed carcinoma as a whole of EAOC for the first time and that FIGO stage, lack of lymphadenectomy, positive LNs and history of breast cancer were independent risk factors associated with drug resistance to platinum in patients Table 2 Multivariate analysis of risk factors of chemo-resistance with such type of EOC. among endometriosis related ovarian cancer patients A large number of previous studies focused on the B S.E. P OR(95%CI) drug resistance in OCCC. Some retrospective studies Age .337 .395 .393 1.4(0.65~ 3.04) have shown that OCCC was resistant to traditional plati- Bloating −.057 .401 .886 0.94(0.43~ 2.07) num-based chemotherapy regimens with an objective ef- Emaciation 1.447 .791 .067 4.25(0.9~ 20.02) fective rate of 11–27%, while the response rate of serous Ca125 in normal range .728 .797 .361 2.07(0.43~ 9.87) adenocarcinoma (SAC) was 73–81%, significantly higher than that of OCCC [5–7]. Utsunomiya et al. found that EM −.016 .573 .978 0.98(0.32~ 3.03) the effective rate of paclitaxel plus carboplatin (TC) FIGO stage 1.422 .497 .004* 4.15(1.57~ 10.97) regimen in patients with OCCC was not high either [8]. LN metastasis .980 .477 .040* 2.66(1.05~ 6.78) Rauh-Hain et al. reported that the response rate of 121 LN dissection 1.059 .440 .016* 2.88(1.22~ 6.82) OCCC patients treated with first-line platinum-based Residual disease .396 .405 .328* 1.49(0.67~ 3.29) chemotherapy regimens was 79 and 24% of the patients Breast cancer 1.851 .918 .044* 6.37(1.05~ 38.49) relapsed within 6 months after the last cycle of chemo- therapy of initial treatments [9]. Moreover, their results Constant −5.388 1.018 .000 showed that unsatisfactory cytoreductive surgery and *The difference reached statistical significance. P values were cultivated by Cox regression analysis. The overall test of the above model showed the wide dissemination of tumors were significantly associ- model was significance, p < 0.0001 a ated with platinum resistance by multivariate logistic According to the classification system of FIGO staging (2013 version) Abbreviation: Ca125 cancer antigen 125, EM endometriosis, LN lymph node regression analysis. On the other hand, Liang et al. have Ren et al. Journal of Ovarian Research (2018) 11:40 Page 5 of 7 reported that advanced stage, poor differentiation, LN In addition, the up-regulation of growth factor signaling positivity, CA125 level > 1000 U/mL and suboptimal pathway is related to drug resistance in tumor. As cell sur- cytoreductive surgery would lead to drug resistance or face receptor tyrosine kinase, epidermal growth-factor re- partial sensitivity to chemotherapy during the treatment ceptor (EGFR) can activate the mitogen-activated protein of OCCC. These results were not in full accord with kinase pathway, thus inhibiting the apoptosis induced by the findings of this study [10]. chemotherapy drugs [17]. An immunohistochemical study The mechanism of drug resistance to chemotherapy in showed that EGFR could be found in 61% of CCC, and OCCC was complex, which might be related to the low the overexpression of EGFR might be related to chemo- proliferation rate of the tumors, the increase of damage therapy resistance and poor prognosis of ovarian cancer to DNA repair activity, the up-regulation of growth [18]. Siddiqui GK et al. reported that in factor signaling pathway and the abnormal expression of platinum-resistant group, the proportion of patients microtubule-disaggregated protein, etc. Studies have shown with high expression of VEGF in tumor tissues was that the high resistance of OCCC to chemotherapy might significantly higher than it in the platinum-sensitive group be related to its low cell proliferation rate [4]. Itamochi et (86% vs 2%), suggesting that the resistance of EOC to al. reported that the doubling time for tumor cells of platinum-based chemotherapy was related to VEGR OCCC was significantly longer than that of SAC (61.4 vs expression [19]. Mabuchi S et al. confirmed in vitro that 29.8 h) [11]. Ki-67 protein was expressed at various stages the expression of VEGF in cisplatin-resistant OCCC cell of the cell cycle, representing the proliferative activity of lines was significantly higher than that in cisplatin-sensitive the cells, and its expression in OCCC was significantly OCCC cell lines, suggesting that the generation of drug lower than that in SAC. In addition, the Ki-67 labelling resistance might be related to the angiogenesis in the index (LI) in patients that are resistant to platinum-based tumors [20]. According to previous literatures, the chemotherapy was significantly lower than it in those sensi- expression of HER2 in OCCC was much higher than it tive (15.3% vs 30.2%) [4]. As known, platinum-based drugs in other major histological types of EOCs, and tumors inhibited the proliferation of tumor cells mainly by with overexpression of HER2 showed low sensitivity to hindering the replication of DNA. Therefore, the low traditional anti-tumor drugs, leading to the poor progno- proliferation rate of OCCC cells enabled them to some sis of these patients [21, 22]. extent to be tolerant to platinum-based drugs targeting Studies about the drug resistance in ovarian endometrioid on DNA, which suggested that the chemoresistance of carcinoma was limited. Pylväs-Eerola et al. have reported OCCC might be associated with its low proliferation that the preoperative level of 8-hydroxy-2-deoxyguanosine rate [12]. in patients were significantly associated with chemoresis- Previous studies have showed tumors lack of DNA tance of ovarian endometrioid carcinoma, which could be mismatch repair (MMR) system were highly resistant to used as a factor for resistance prediction [23]. certain methylated drugs of chemotherapy in vitro [13]. Our results showed that histologic type indicating OCCC The function of MMR is to correct mistakes in DNA or endometrioid carcinoma was not an independent risk replication and play an important role in the sensitivity factor of platinum-based drug resistance (55.77% vs 44.23%, of DNA damage factors. MMR deficiency might result P = 0.435), which was not consistent with previous studies, from germline mutations of two major MMR genes, such suggesting that the platinum-based drug resistance in as hMLH1 and hMSH2, as well as epigenetic silencing these two types of tumors might have similarities. More due to the methylation of the hMLH1 promoter, leading molecular biological researches were expected to explore to inactivation of the gene system. Cai et al. reported that the molecular mechanism of chemoresistance in EAOC. the high expression of mutations in hMLH1 and hMSH2 existed in OCCC and was associated with its development [14]. In addition, Niimi K et al. also reported that the Conclusion expression of DNA damage repair related protein REV7 in This study regarded endometriosis-related OCCC and OCCC was significantly higher than that in other types of endometrioid carcinoma as a whole of EAOC for the EOCs (73.5% vs 53.4%), and the knockdown of REV gene first time and analyzed the clinicopathological risk could induce apoptosis and DNA damage in tumor cells, factors of platinum-based chemoresistance. Multivariate leading to a significant improvement of chemoresistance analysis showed that FIGO stage, positive LNs, lack of to cisplatin in OCCC [15]. On the other hand, Itamochi H lymphadenectomy and history of breast cancer were et al. reported that the use of CHK inhibitors could independent risk factors of drug resistance in patients with improve the drug resistance of OCCC to cisplatin [16], EAOC. This finding is of certain value for predicting while the main function of cell cycle checkpoint kinase platinum-based drug resistance in the treatment of EAOC, (CHK) was to regulate the synthesis of DNA in tumor which may give some instructions for designing individual- cells. ized chemotherapy regimens. In the future, it is expected to Ren et al. Journal of Ovarian Research (2018) 11:40 Page 6 of 7 carry out more accurate molecular typing for such patients Abbreviations Ca125: Cancer antigen 125; DFS: Disease-free survival; EAOC: Endometriosis- through molecular biological study, which can be used to associated ovarian cancer; EAOCCC: Endometriosis-associated ovarian clear guide precise medication of chemotherapy drugs for patients cell carcinoma; EAOEC: Endometriosis-associated ovarian endometrioid with ovarian cancers. carcinoma; OS: Overall survival Acknowledgements We appreciate the gynecologists at Peking Union Medical College Hospital Methods for their diligent clinical work and precise data recording about the cases we reported in this article. This is a retrospective study conducted at Department of Obsterics and Gynecology, Peking Union Medical College Funding Hospital(PUMCH). We identified all the 304 patients This study was funded by National Key R&D Program of China (No.SQ2017YFSF080001) and National Natural Science Foundation of China who received surgical treatments and postoperative (No. 81501236). chemotherapy from January 2000 to December 2012, including 118 cases of OCCCs and 186 cases of endome- Availability of data and materials The dataset supporting the conclusions of this article is included within the trioid carcinomas confirmed by postoperative histo- article and its additional files. pathology. All patients with EAOC of early stage (stage I and II) have received completed staging surgery; and those Authors’ contributions TR and TS make substantial contributions to conception and design, analysis of advanced stage (stage III and IV) have undergone and interpretation of data, and drafting the article. JS has reviewed the optimal CRS, except for those with unresectable tumors pathological slides. WS, YX and JL have designed the study and participate who received suboptimal CRS. They all received adjuvant in revising it critically for important intellectual content. KS have contributed to some valuable advice during preparing this paper. All authors read and chemotherapy of platinum-based regimens after primary approved the final manuscript. surgery. The clinicopathologic data of patients with EAOC were Ethics approval and consent to participate Obstetrics and Gynecology Peking Union Medical College Hospital Human collected, including age, initial symptoms, menopause Research Ethics Committee Approval was obtained for the use of all samples. status, number of pregnancies and labors, previous medical complications, preoperative CA125 level, FIGO Competing interests The authors declare that they have no competing interests. stage, tumor size, laterality, histologic type, grade, coexisting endometriosis, lymph nodes(LNs) metastasis, lymphadenec- Publisher’sNote tomy (the resection of pelvic LNs with or without Springer Nature remains neutral with regard to jurisdictional claims in para-aortic LNs), residual tumor, history of hysterectomy published maps and institutional affiliations. and tubal ligation, coexisting endometrial lesions (including Author details endometrial polyps, atypical hyperplasia and endometrial Department of Obstetrics and Gynecology, Peking Union Medical College cancer), history of breast cancer, history of hypertension Hospital, Chinese Academy of Medical Science and Peking Union Medical and diabetes. Platinum-based drug resistance in ovarian College, 1 ShuaiFuYuan, DongCheng District, Beijing 100730, China. Department of Pathology, Peking Union Medical College Hospital, Chinese cancer was defined as a definite progression or recurrence Academy of Medical Science and Peking Union Medical College, Beijing, of disease within 6 months after completing the last cycle People’s Republic of China. of chemotherapy for initial treatments. In this study, we Received: 12 February 2018 Accepted: 20 May 2018 defined ovarian cancer concurrent with endometriosis as the presence of ovarian cancer and endometriosis identified histologically in the same ovary, the presence of endometri- References 1. Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS. 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Rowinsky EK, Donehower RC, Jones RJ, Tucker RW. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res. 1988; 48:4093–100. 22. Rolitsky CD, Theil KS, McGaughy VR, Copeland LJ, Niemann TH. HER-2/neu amplification and overexpression in endometrial carcinoma. Int J Gynecol Pathol. 1999;18:138–43. 23. M P-E, P K, U P. Preoperative serum 8-hydroxydeoxyguanosine is associated with chemoresistance and is a powerful prognostic factor in endometrioid- type epithelial ovarian cancer. BMC Cancer. 2015;15:493. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Ovarian Research Springer Journals

Clinical analysis of chemo-resistance risk factors in endometriosis associated ovarian cancer

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Abstract

Background: To analyze the clinical characteristics and chemo-resistance related factors of patients with resistant and non-resistant endometriosis-associated ovarian cancer (ovarian clear cell carcinoma and endometrioid carcinoma) by reviewing the data of epithelial ovarian cancer patients who received initial treatment in our hospital over a 12-year period. Results: Among the 304 patients, 17.1% were seen with platinum-based drug resistance. The ROC curve of continuous variables was drawn according to resistance situation, then they were grouped by age (< 48 or ≥ 48 years), tumor size (< 7 cm or ≥ 7 cm) and Ca125 (< 90 and ≥ 90 U/ml). In univariate analysis, age ≥ 48 years, initial symptom of abdominal distension or weight loss, abnormal preoperative serum Ca125, Ca125 < 90 U/ml, advanced FIGO stage, absence of endometriosis, bilateral tumors, lack of lymphadenectomy, positive lymph nodes, unsatisfactory initial cytoreduction surgery and history of breast cancer were all related to drug resistance in ovarian cancer. In multivariate analysis, advanced stage, lack of lymphadenectomy, positive lymph nodes and history of breast cancer were independent risk factors related to platinum-based drug resistance (P <0.05). Conclusion: For patients of endometriosis-related ovarian cancer, platinum-based drug resistance were associated with advanced FIGO stage, lack of lymphadenectomy, positive lymph nodes and history of breast cancer. Keywords: Chemo-resistance, Risk factors, Endometriosis associated ovarian cancer Background of OCCC were with unilateral pelvic mass of early stage, At present, many scholars regard endometriosis-associated their prognosis was better than other types of EOC. The ovarian cancer(EAOC) as a special pathological type of 5-year survival rate of OCCC patients with early stage was epithelial ovarian cancer(EOC), including ovarian clear cell higher than 80% [3]. However, the prognosis of those with carcinoma (OCCC) and endometrioid carcinoma. Studies advanced stage was poorer than that of other EOCs with have reported that the clinical features and prognosis of the 5-year survival rate about 20%, which might be related patients with EAOC were different from those with other to the resistance to platinum-based chemotherapy [4]. The EOCs. Compared with ovarian serous carcinoma, the onset clinical risk factors of chemo-resistance in patients with age of OCCC was younger (55 vs 64 years; median age) [1]. EAOC have not been reported. By retrospectively analyzing A study comparing early ovarian cancer and advanced ovar- the data of EOC patients who received initial treatment in ian cancer (I/II vs. III/IV) reported that 57–81% of OCCC our hospital over a 12-year period, this study intended to were diagnosed in early stage (I/II) [2]. Since most patients analyze the clinical features and chemo-resistance related factors of patients with resistant and non-resistant EAOC (OCCC and endometrioid carcinoma), expecting to provide * Correspondence: wangshu219@hotmail.com; XiangY@pumch.cn; references for the guidance of clinical treatments and the langjh@hotmail.com prediction of survival outcomes. Tong Ren and Ting-Ting Sun contributed equally to this work. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 ShuaiFuYuan, DongCheng District, Beijing 100730, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ren et al. Journal of Ovarian Research (2018) 11:40 Page 2 of 7 Table 1 Clinical and morphological characteristics of patients with or without chemo-resistance Variable Category Number(%) Chemo-sensitive(%) Chemoresistance(%) P 304 252(82.9%) 52(17.1%) Age < 48 129(42.43) 114(45.24) 15(28.85) 0.0294* ≥48 175(57.57) 138(54.76) 37(71.15) Menopausal status Pre 161(52.96) 139(55.16) 22(42.31) 0.0909 Post 143(47.04) 113(44.84) 30(57.69) Gravidity < 1 35(11.51) 31(12.3) 4(7.69) 0.3431 > = 1 269(88.49) 221(87.7) 48(92.31) Parity < 1 51(16.78) 46(18.25) 5(9.62) 0.1290 > = 1 253(83.22) 206(81.75) 47(90.38) Abdominal pain No 210(69.08) 174(69.05) 36(69.23) 0.9016 Yes 93(30.59) 77(30.56) 16(30.77) Bloating No 243(79.93) 208(82.54) 35(67.31) 0.0125* Yes 61(20.07) 44(17.46) 17(32.69) Palpable mass No 223(73.36) 182(72.22) 41(78.85) 0.3253 Yes 81(26.64) 70(27.78) 11(21.15) Incidental finding No 256(84.21) 208(82.54) 48(92.31) 0.0786 Yes 48(15.79) 44(17.46) 4(7.69) Irregular menstruation No 275(90.46) 226(89.68) 49(94.23) 0.3094 Yes 29(9.54) 26(10.32) 3(5.77) Postmenopausal bleeding No 285(93.75) 235(93.25) 50(96.15) 0.4316 Yes 19(6.25) 17(6.75) 2(3.85) Emaciation No 294(96.71) 248(98.41) 46(88.46) 0.0002* Yes 10(3.29) 4(1.59) 6(11.54) Abnormal vaginal discharge No 302(99.34) 250(99.21) 52(100) 0.5192 Yes 2(0.66) 2(0.79) 0(0) Ca125 in normal range(< 35 U/L) No 249(81.91) 199(78.97) 50(96.15) 0.0034* Yes 55(18.09) 53(21.03) 2(3.85) CA125group < 90 112(36.84) 104(41.27) 8(15.38) 0.0004* ≥90 192(63.16) 148(58.73) 44(84.62) Early or late Stage FIGO I + II 185(60.86) 175(69.44) 10(19.23) <.0001* FIGO III + IV 119(39.14) 77(30.56) 42(80.77) FIGO stage I 141(46.38) 136(53.97) 5(9.62) <.0001* II 44(14.47) 39(15.48) 5(9.62) III 104(34.21) 69(27.38) 35(67.31) IV 15(4.93) 8(3.17) 7(13.46) Tumor size group < 7 80(26.32) 66(26.19) 14(26.92) 0.9130 ≥7 224(73.68) 186(73.81) 38(73.08) Pathology Grade G1 45(24.19) 44(28.03) 1(3.45) 0.0128* G2 59(31.72) 49(31.21) 10(34.48) G3 82(44.09) 64(40.76) 18(62.07) Pathology type Endometrioid 186(61.18) 157(62.30) 29(55.77) 0.435 Clear cell 118(38.82) 95(37.70) 23(44.23) Endometriosis No 235(77.30) 188(74.6) 47(90.38) 0.0134* Yes 69(22.70) 64(25.4) 5(9.62) Ren et al. Journal of Ovarian Research (2018) 11:40 Page 3 of 7 Table 1 Clinical and morphological characteristics of patients with or without chemo-resistance (Continued) Variable Category Number(%) Chemo-sensitive(%) Chemoresistance(%) P Side of tumor Unilateral 212(69.74) 183(72.62) 29(55.77) 0.0160* Bilateral 92(30.26) 69(27.38) 23(44.23) LN metastasis No 213(70.07) 195(77.38) 18(34.62) <.0001* Yes 40(13.16) 24(9.52) 16(30.77) unclear 51(16.78) 33(13.1) 18(34.62) LN dissection No 51(16.78) 33(13.1) 18(34.62) 0.0002* Yes 253(83.22) 219(86.9) 34(65.38) Residual disease No 231(75.99) 207(82.14) 24(46.15) <.0001* Yes 73(24.01) 45(17.86) 28(53.85) TH No 297(97.7) 246(97.62) 51(98.08) 0.8411 Yes 7(2.3) 6(2.38) 1(1.92) Tubal ligation No 290(95.39) 243(96.43) 47(90.38) 0.0583 Yes 14(4.61) 9(3.57) 5(9.62) Sterilization surgery No 283(93.09) 237(94.05) 46(88.46) 0.1481 Yes 21(6.91) 15(5.95) 6(11.54) Endometrial disorder No 252(82.89) 208(82.54) 44(84.62) 0.7174 Yes 52(17.11) 44(17.46) 8(15.38) Variable endometrial disorder No 252(82.89) 207(82.14) 45(86.54) 0.7998 EP 27(8.88) 23(9.13) 4(7.69) EIN 22(7.24) 19(7.54) 3(5.77) EC 3(0.99) 3(1.19) 0(0) Breast cancer No 296(97.37) 248(98.41) 48(92.31) 0.0123* Yes 8(2.63) 4(1.59) 4(7.69) HT No 250(82.24) 208(82.54) 42(80.77) 0.7610 Yes 54(17.76) 44(17.46) 10(19.23) DM No 286(94.08) 236(93.65) 50(96.15) 0.4862 Yes 18(5.92) 16(6.35) 2(3.85) According to the classification system of FIGO staging (2013 version) Abbreviation: Ca125 cancer antigen 125, EM endometriosis, LN lymph node, TH total hysterectomy, EP endometrial polyps, EIN endometrial intraepithelial neoplasm, EC endometrial cancer, HT hypertension, DM diabetic mellitus *P < 0.05 Results Ca125 < 90 U/L (84.62% vs 58.73%, P = 0.0004), more ad- A total of 304 patients diagnosed with EAOC and treated vanced FIGO stage(III + IV) (80.77% vs 30.56%, P < 0.001), in PUMCH were identified, 52(17.1%) of which were seen more high-grade tumor(62.07% vs 40.76%; P = 0.0128), with platinum-based drug resistance and the rest fewer coexisting endometriosis (9.62% vs 25.4%, P = 252(82.9%) were in the non-resistant group. Table 1 0.0134), more bilateral tumors (44.23% vs 27.38%, P = showed the demographic and clinical characteristics of all 0.0160), more positive LNs (30.77% vs 9.52%, P <0.001), the patients. In this study, based on the ROC curve of fewer lymphadenectomy (34.62% vs 13.1%, P = 0.0002), chemo-resistance, the above continuous variables were more residual tumor > 1 cm and more history of breast grouped by age, tumor size and Ca125 level[age: < 48 or ≥ cancer (7.69% vs 1.59%, P = 0.0123). Meanwhile, there was 48 years; tumor size: < 7 cm or ≥ 7 cm; Ca125: < 90 U/L no statistically significant difference seen in menopause sta- or ≥90 U/L],as seeninFig. 1.Univariateanalysisshowed tus, number of pregnancies and labors, tumor size, histo- that compared with the non-resistant group, there were logic type, coexisting endometrial lesions, history of more patients with age ≥ 48 years in the chemo-resistant hysterectomy or tubal sterilization and history of diabetes group (71.15% vs 54.76%, P = 0.0294), more with symptoms mellitus or hypertension, as showed in Table 1 (P >0.05). of abdominal distension (32.69% vs 17.46%, P = 0.0125) and In multivariate analysis however, only FIGO stage (P = emaciation (11.54% vs 1.59%, P = 0.0002), fewer with nor- 0.004), positive LNs (P = 0.040), lymph nodes resection mal level of Ca125 (3.85% vs 21.03%, P = 0.0034) but more (P = 0.016) and history of breast cancer (P = 0.044) were Ren et al. Journal of Ovarian Research (2018) 11:40 Page 4 of 7 Fig. 1 ROC curve for age of disease onset, tumor size, pre-surgery Ca125 in the occurrence of chemo-resistance independent risk factors of platinum-based drug investigated the clinicopathological risk factors of resistance, while onset age, initial symptoms, Ca125 platinum-based chemoresistance. Univariate analysis showed level, coexisting endometriosis and residual tumors were that age, higher level of Ca125, advanced FIGO stage, not, as seen in Table 2. high-grade tumor, absence of endometriosis, bilateral tumors, lack of lymphadenectomy, positive LNs, residual Discussion lesion > 1 cm and history of breast cancer were related to This study regarded OCCC and ovarian endometrioid chemoresistance. However, multivariate analysis showed carcinoma as a whole of EAOC for the first time and that FIGO stage, lack of lymphadenectomy, positive LNs and history of breast cancer were independent risk factors associated with drug resistance to platinum in patients Table 2 Multivariate analysis of risk factors of chemo-resistance with such type of EOC. among endometriosis related ovarian cancer patients A large number of previous studies focused on the B S.E. P OR(95%CI) drug resistance in OCCC. Some retrospective studies Age .337 .395 .393 1.4(0.65~ 3.04) have shown that OCCC was resistant to traditional plati- Bloating −.057 .401 .886 0.94(0.43~ 2.07) num-based chemotherapy regimens with an objective ef- Emaciation 1.447 .791 .067 4.25(0.9~ 20.02) fective rate of 11–27%, while the response rate of serous Ca125 in normal range .728 .797 .361 2.07(0.43~ 9.87) adenocarcinoma (SAC) was 73–81%, significantly higher than that of OCCC [5–7]. Utsunomiya et al. found that EM −.016 .573 .978 0.98(0.32~ 3.03) the effective rate of paclitaxel plus carboplatin (TC) FIGO stage 1.422 .497 .004* 4.15(1.57~ 10.97) regimen in patients with OCCC was not high either [8]. LN metastasis .980 .477 .040* 2.66(1.05~ 6.78) Rauh-Hain et al. reported that the response rate of 121 LN dissection 1.059 .440 .016* 2.88(1.22~ 6.82) OCCC patients treated with first-line platinum-based Residual disease .396 .405 .328* 1.49(0.67~ 3.29) chemotherapy regimens was 79 and 24% of the patients Breast cancer 1.851 .918 .044* 6.37(1.05~ 38.49) relapsed within 6 months after the last cycle of chemo- therapy of initial treatments [9]. Moreover, their results Constant −5.388 1.018 .000 showed that unsatisfactory cytoreductive surgery and *The difference reached statistical significance. P values were cultivated by Cox regression analysis. The overall test of the above model showed the wide dissemination of tumors were significantly associ- model was significance, p < 0.0001 a ated with platinum resistance by multivariate logistic According to the classification system of FIGO staging (2013 version) Abbreviation: Ca125 cancer antigen 125, EM endometriosis, LN lymph node regression analysis. On the other hand, Liang et al. have Ren et al. Journal of Ovarian Research (2018) 11:40 Page 5 of 7 reported that advanced stage, poor differentiation, LN In addition, the up-regulation of growth factor signaling positivity, CA125 level > 1000 U/mL and suboptimal pathway is related to drug resistance in tumor. As cell sur- cytoreductive surgery would lead to drug resistance or face receptor tyrosine kinase, epidermal growth-factor re- partial sensitivity to chemotherapy during the treatment ceptor (EGFR) can activate the mitogen-activated protein of OCCC. These results were not in full accord with kinase pathway, thus inhibiting the apoptosis induced by the findings of this study [10]. chemotherapy drugs [17]. An immunohistochemical study The mechanism of drug resistance to chemotherapy in showed that EGFR could be found in 61% of CCC, and OCCC was complex, which might be related to the low the overexpression of EGFR might be related to chemo- proliferation rate of the tumors, the increase of damage therapy resistance and poor prognosis of ovarian cancer to DNA repair activity, the up-regulation of growth [18]. Siddiqui GK et al. reported that in factor signaling pathway and the abnormal expression of platinum-resistant group, the proportion of patients microtubule-disaggregated protein, etc. Studies have shown with high expression of VEGF in tumor tissues was that the high resistance of OCCC to chemotherapy might significantly higher than it in the platinum-sensitive group be related to its low cell proliferation rate [4]. Itamochi et (86% vs 2%), suggesting that the resistance of EOC to al. reported that the doubling time for tumor cells of platinum-based chemotherapy was related to VEGR OCCC was significantly longer than that of SAC (61.4 vs expression [19]. Mabuchi S et al. confirmed in vitro that 29.8 h) [11]. Ki-67 protein was expressed at various stages the expression of VEGF in cisplatin-resistant OCCC cell of the cell cycle, representing the proliferative activity of lines was significantly higher than that in cisplatin-sensitive the cells, and its expression in OCCC was significantly OCCC cell lines, suggesting that the generation of drug lower than that in SAC. In addition, the Ki-67 labelling resistance might be related to the angiogenesis in the index (LI) in patients that are resistant to platinum-based tumors [20]. According to previous literatures, the chemotherapy was significantly lower than it in those sensi- expression of HER2 in OCCC was much higher than it tive (15.3% vs 30.2%) [4]. As known, platinum-based drugs in other major histological types of EOCs, and tumors inhibited the proliferation of tumor cells mainly by with overexpression of HER2 showed low sensitivity to hindering the replication of DNA. Therefore, the low traditional anti-tumor drugs, leading to the poor progno- proliferation rate of OCCC cells enabled them to some sis of these patients [21, 22]. extent to be tolerant to platinum-based drugs targeting Studies about the drug resistance in ovarian endometrioid on DNA, which suggested that the chemoresistance of carcinoma was limited. Pylväs-Eerola et al. have reported OCCC might be associated with its low proliferation that the preoperative level of 8-hydroxy-2-deoxyguanosine rate [12]. in patients were significantly associated with chemoresis- Previous studies have showed tumors lack of DNA tance of ovarian endometrioid carcinoma, which could be mismatch repair (MMR) system were highly resistant to used as a factor for resistance prediction [23]. certain methylated drugs of chemotherapy in vitro [13]. Our results showed that histologic type indicating OCCC The function of MMR is to correct mistakes in DNA or endometrioid carcinoma was not an independent risk replication and play an important role in the sensitivity factor of platinum-based drug resistance (55.77% vs 44.23%, of DNA damage factors. MMR deficiency might result P = 0.435), which was not consistent with previous studies, from germline mutations of two major MMR genes, such suggesting that the platinum-based drug resistance in as hMLH1 and hMSH2, as well as epigenetic silencing these two types of tumors might have similarities. More due to the methylation of the hMLH1 promoter, leading molecular biological researches were expected to explore to inactivation of the gene system. Cai et al. reported that the molecular mechanism of chemoresistance in EAOC. the high expression of mutations in hMLH1 and hMSH2 existed in OCCC and was associated with its development [14]. In addition, Niimi K et al. also reported that the Conclusion expression of DNA damage repair related protein REV7 in This study regarded endometriosis-related OCCC and OCCC was significantly higher than that in other types of endometrioid carcinoma as a whole of EAOC for the EOCs (73.5% vs 53.4%), and the knockdown of REV gene first time and analyzed the clinicopathological risk could induce apoptosis and DNA damage in tumor cells, factors of platinum-based chemoresistance. Multivariate leading to a significant improvement of chemoresistance analysis showed that FIGO stage, positive LNs, lack of to cisplatin in OCCC [15]. On the other hand, Itamochi H lymphadenectomy and history of breast cancer were et al. reported that the use of CHK inhibitors could independent risk factors of drug resistance in patients with improve the drug resistance of OCCC to cisplatin [16], EAOC. This finding is of certain value for predicting while the main function of cell cycle checkpoint kinase platinum-based drug resistance in the treatment of EAOC, (CHK) was to regulate the synthesis of DNA in tumor which may give some instructions for designing individual- cells. ized chemotherapy regimens. In the future, it is expected to Ren et al. Journal of Ovarian Research (2018) 11:40 Page 6 of 7 carry out more accurate molecular typing for such patients Abbreviations Ca125: Cancer antigen 125; DFS: Disease-free survival; EAOC: Endometriosis- through molecular biological study, which can be used to associated ovarian cancer; EAOCCC: Endometriosis-associated ovarian clear guide precise medication of chemotherapy drugs for patients cell carcinoma; EAOEC: Endometriosis-associated ovarian endometrioid with ovarian cancers. carcinoma; OS: Overall survival Acknowledgements We appreciate the gynecologists at Peking Union Medical College Hospital Methods for their diligent clinical work and precise data recording about the cases we reported in this article. This is a retrospective study conducted at Department of Obsterics and Gynecology, Peking Union Medical College Funding Hospital(PUMCH). We identified all the 304 patients This study was funded by National Key R&D Program of China (No.SQ2017YFSF080001) and National Natural Science Foundation of China who received surgical treatments and postoperative (No. 81501236). chemotherapy from January 2000 to December 2012, including 118 cases of OCCCs and 186 cases of endome- Availability of data and materials The dataset supporting the conclusions of this article is included within the trioid carcinomas confirmed by postoperative histo- article and its additional files. pathology. All patients with EAOC of early stage (stage I and II) have received completed staging surgery; and those Authors’ contributions TR and TS make substantial contributions to conception and design, analysis of advanced stage (stage III and IV) have undergone and interpretation of data, and drafting the article. JS has reviewed the optimal CRS, except for those with unresectable tumors pathological slides. WS, YX and JL have designed the study and participate who received suboptimal CRS. They all received adjuvant in revising it critically for important intellectual content. KS have contributed to some valuable advice during preparing this paper. All authors read and chemotherapy of platinum-based regimens after primary approved the final manuscript. surgery. The clinicopathologic data of patients with EAOC were Ethics approval and consent to participate Obstetrics and Gynecology Peking Union Medical College Hospital Human collected, including age, initial symptoms, menopause Research Ethics Committee Approval was obtained for the use of all samples. status, number of pregnancies and labors, previous medical complications, preoperative CA125 level, FIGO Competing interests The authors declare that they have no competing interests. stage, tumor size, laterality, histologic type, grade, coexisting endometriosis, lymph nodes(LNs) metastasis, lymphadenec- Publisher’sNote tomy (the resection of pelvic LNs with or without Springer Nature remains neutral with regard to jurisdictional claims in para-aortic LNs), residual tumor, history of hysterectomy published maps and institutional affiliations. and tubal ligation, coexisting endometrial lesions (including Author details endometrial polyps, atypical hyperplasia and endometrial Department of Obstetrics and Gynecology, Peking Union Medical College cancer), history of breast cancer, history of hypertension Hospital, Chinese Academy of Medical Science and Peking Union Medical and diabetes. Platinum-based drug resistance in ovarian College, 1 ShuaiFuYuan, DongCheng District, Beijing 100730, China. Department of Pathology, Peking Union Medical College Hospital, Chinese cancer was defined as a definite progression or recurrence Academy of Medical Science and Peking Union Medical College, Beijing, of disease within 6 months after completing the last cycle People’s Republic of China. of chemotherapy for initial treatments. In this study, we Received: 12 February 2018 Accepted: 20 May 2018 defined ovarian cancer concurrent with endometriosis as the presence of ovarian cancer and endometriosis identified histologically in the same ovary, the presence of endometri- References 1. Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS. 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Journal of Ovarian ResearchSpringer Journals

Published: May 29, 2018

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