BRCA1 Expression and Its Combined Low Expression with PARP1 and ERCC1 Predict Chemotherapeutic Response in Ovarian Cancer
DOI:
https://doi.org/10.31584/jhsmr.20231000Keywords:
BRCA1, chemotherapy, DNA repair, prognosis ovarian cancerAbstract
Objective: This study aimed to evaluate the associations of immunohistochemical expressions of various deoxyribonucleic acid repair proteins, either individually or combined, with the response to platinum-based chemotherapy and overall survival in epithelial ovarian cancer.
Material and Methods: This retrospective cohort study included patients with epithelial ovarian cancer who were treated by primary cytoreductive surgery with adjuvant platinum-based chemotherapy at Songklanagarind Hospital between January 2008 and December 2019. Immunohistochemistry analysis of breast cancer type 1 (BRCA1), poly (ADP-ribose) polymerase 1 (PARP1), X-ray repair cross-complementing 1 (XRCC1), and excision repair cross-complementation group 1 (ERCC1) expression was performed. Logistic regression was used to evaluate factors associated with chemotherapeutic response and Cox regression was applied for survival analysis.
Results: Chemotherapeutic response was achieved in 205 of 249 patients (82.3%). Low BRCA1 expression was associated with good response (odds ratio [OR] 5.01, 95% confidence interval [CI] 1.78–14.1) and favorable overall survival (hazard ratio 0.61, 95% CI 0.38–0.98). PARP1, XRCC1, and ERCC1 showed no significant predictive or prognostic roles; however, combined low expression of PARP1/BRCA1 (OR 7.62, 95% CI 1.69–34.31) and ERCC1/BRCA1 (OR 6.98, 95% CI 1.5–32.52) additively enhanced response compared to high/high expressions.
Conclusion: This study provides evidence that epithelial ovarian cancer (EOC) with low BRCA1 expression is more likely to be responsive to platinum-based therapy and is associated with favorable overall survival compared to tumors with high BRCA1 expression. The study supports a potential therapeutic strategy involving co-depletion of PARP1/BRCA and ERCC1/BRCA1 expression, although additional studies are needed.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
Arnold M, Rutherford M, Lam F, Bray F, Ervik M, Soerjomataram I. ICBP SURVMARK-2 online tool: International Cancer Survival Benchmarking [monograph on the Internet]. Lyon: International Agency for Research on Cancer [cited 2021 Dec 03]. Available from: http://gco.iarc.fr/survival/survmark
Pokhriyal R, Hariprasad R, Kumar L, Hariprasad G. Chemotherapy resistance in advanced ovarian cancer patients. Biomark Cancer 2019;1179299X19860815.
Damia G, Broggini M. Platinum resistance in ovarian cancer: role of DNA repair. Cancers (Basel) 2019;11:119.
Lord CJ, Tutt ANJ, Ashworth A. Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors. Annu Rev Med 2015;66:455–70.
Rose M, Burgess JT, O’Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol 2020;9;8:564601.
Jiang X, Li X, Li W, Bai H, Zhang Z. PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 2019;23:2303–13.
Gan A, Green AR, Nolan CC, Martin S, Deen S. Poly (adenosine diphosphate-ribose) polymerase expression in BRCA-proficient ovarian high-grade serous carcinoma; association with patient survival. Hum Pathol 2013;44:1638–47.
Marques M, Beauchamp MC, Fleury H, Laskov I, Qiang S, Pelmus M, et al. Chemotherapy reduces PARP1 in cancers of the ovary: implications for future clinical trials involving PARP inhibitors. BMC Med 2015;13:217.
Nomura H, Kataoka F, Aoki D, Jinno H, Kitagawa Y, Sato Y, et al. Expression of potential biomarkers associated with homologous recombination repair in patients with ovarian or triple-negative breast cancer. Cancer Biomark 2016;16:145-52.
Abdel-Fatah T, Sultana R, Abbotts R, Hawkes C, Seedhouse C, Chan S, et al. Clinicopathological and functional significance of XRCC1 expression in ovarian cancer. Int J Cancer 2013; 132:2778–86.
Mesquita KA, Alabdullah M, Griffin M, Toss MS, Fatah TMAA, Alblihy A, et al. ERCC1-XPF deficiency is a predictor of Olaparib induced synthetic lethality and platinum sensitivity in epithelial ovarian cancers. Gynecol Oncol 2019;153:416–24.
Molnár S, Beke L, Méhes G, Póka R. The prognostic value of PARP expression in high-grade epithelial ovarian cancer. Pathol Oncol Res 2020;26:2549–55.
Ali R, Alabdullah M, Alblihy A, Miligy I, Mesquita KA, Chan SY, et al. PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers. Cancer Lett 2020;469:124–33.
Hjortkjær M, Waldstrøm M, Jakobsen A, Kanstrup H, Søgaard-Andersen E, Dahl Steffensen K. The prognostic value of BRCA1 and PARP expression in epithelial ovarian carcinoma: immunohistochemical detection. Int J Gynecol Pathol 2017;36:180–9.
Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011;21:771–5.
Javadi S, Ganeshan DM, Qayyum A, Iyer RB, Bhosale P. Ovarian cancer, the revised FIGO staging system, and the role of imaging. AJR Am J Roentgenol 2016; 206:1351–60.
Carser JE, Quinn JE, Michie CO, O’Brien EJ, McCluggage WG, Maxwell P, et al. BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer. Gynecol Oncol 2011;123:492–8.
Meisel JL, Hyman DM, Garg K, Zhou Q, Dao F, Bisogna M, et al. The performance of BRCA1 immunohistochemistry for detecting germline, somatic, and epigenetic BRCA1 loss in high-grade serous ovarian cancer. Ann Oncol 2014;25:2372–8.
Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature 2012;481:287–94.
Sun C, Li N, Ding D, Weng D, Meng L, Chen G, et al. The role of BRCA status on the prognosis of patients with epithelial ovarian cancer: a systematic review of the literature with a meta-analysis. PLoS One 2014;9:e95285.
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;307:382-90.
Vencken PMLH, Kriege M, Hoogwerf D, Beugelink S, van der Burg MEL, Hooning MJ, et al. Chemosensitivity and outcome of BRCA1-and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 2011;22:1346–52.
Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, et al. Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas. Mol Cancer 2009;8:48.
Ganzinelli M, Mariani P, Cattaneo D, Fossati R, Fruscio R, Corso S, et al. Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations. Eur J Cancer 2011;47:1086-94.
Veskimäe K, Staff S, Grönholm A, Pesu M, Laaksonen M, Nykter M, et al. Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry. Tumour Biol 2016;37:11991–9.
Steffensen KD, Waldstrøm M, Jakobsen A. The relationship of platinum resistance and ERCC1 protein expression in epithelial ovarian cancer. Int J Gynecol Cancer 2009;19:820-5.
Rubatt JM, Darcy KM, Tian C, Muggia F, Dhir R, Armstrong DK, et al. Pre-treatment tumor expression of ERCC1 in women with advanced stage epithelial ovarian cancer is not predictive of clinical outcomes: a gynecologic oncology group study. Gynecol Oncol 2012;125:421-6.
Rimm DL, Camp RL, Charette LA, Olsen DA, Provost E. Amplification of tissue by construction of tissue microarrays. Exp Mol Pathol 2001;70:255-64.
Rosen DG, Huang X, Deavers MT, Malpica A, Silva EG, Liu J. Validation of tissue microarray technology in ovarian carcinoma. Mod Pathol 2004;17:790-7.
Hecht JL, Kotsopoulos J, Gates MA, Hankinson SE, Tworoger SS. Validation of tissue microarray technology in ovarian cancer: results from the nurses’ health study. Cancer Epidemiol Biomarkers Prev 2008;17:3043-50.
Muñoz-Repeto I, García MJ, Kamieniak M, Ramón Y, Cajal T, Domingo S, et al. Phenotypic characterization of hereditary epithelial ovarian cancer based on a tissue microarray study. Histol Histopathol 2013;28:133-44.
Byrne T, Nelson L, Beirne JP, Sharpe D, Quinn JE, McCluggage WG, et al. BRCA1 and MAD2 are coexpressed and are prognostic indicators in tubo-ovarian high-grade serous carcinoma. Int J Gynecol Cancer 2018;28:472-8.
Beirne JP, Quinn JE, Maxwell P, Kalloger SE, McAlpine J, Gilks CB, et al. BRCA1 immunohistochemical staining as a prognostic indicator in uterine serous carcinoma. Int J Gynecol Cancer 2013;23:113-8.
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