Case report: Response with chemotherapy and Olaparib in a patient with advanced cervical adenocarcinoma

Case report: Response with chemotherapy and Olaparib in a patient with advanced cervical adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Case report: Response with chemotherapy and Olaparib in a patient with advanced cervical adenocarcinoma Jing Zhuang, Baoning Qin, Yang Yu, Zixing Kou, Chunjie Sun, Fanfan Meng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2731213/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Cervical adenocarcinomas are a heterogeneous group of tumors, accounting for approximately 20% of all cervical cancers. Many clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway. At present, there are few data available on the activity of PARPi in endometrial and cervical cancers. And poly-(ADP)-ribose polymerase inhibitors (PARPi) are changing clinical practice in the BRCA mutant patients with cervical cancer. Case Description: Here, we report the case of a 66-year-old female patient admitted to the hospital due to abnormal vaginal bleeding. She was diagnosed with advanced cervical adenocarcinomas, and received chemotherapy followed by Paclitaxe and Cisplatin in the first-line. However, after one cycle of treatment, the patient's disease progressed. To identify more opportunities for treatment, the biopsy tissue was genetic tested and found BRCA1 exon 23 mutation and PD-L1 positive score, which motivated chemotherapy combined with immune checkpoint inhibitors, and the tumor size decreased. However, because of the side effects of from long-term chemotherapy, the patient chosen Olaparib treatment in the later stage. The patient benefited long-term disease control for about 24 months. Conclusions: This case might support the strategy that PARPi could be an alternative treatment for cervical adenocarcinoma patients with BRCA1 mutation in the future. cervical adenocarcinoma BRCA1 chemotherapy Olaparib Sindilimab Figures Figure 1 Figure 2 Figure 3 1. Introduction Cervical cancer is the fourth most cancer in female cancer patients. It includes different histological subtypes: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma [1]. In cervical cancer, the most common type is squamous cell carcinoma (73,2%), cervical adenocarcinoma secondly (18,4%), and then cervical adenosquamous carcinoma (8,4%) [2]. For decades, the incidence rate of cervical squamous cell carcinoma has been declining continuously. However, the incidence rate of cervical adenocarcinoma seems to be increasing [3]. At present, studies have shown that compared with adenocarcinoma, squamous cell subtypes have significant response to adjuvant therapy, and there are also differences in immune microenvironments and tumor escape mechanisms [4]. Overall, the therapeutic effect of cervical adenocarcinoma is not as good as cervical squamous cell carcinoma. Chemotherapy or combining chemotherapy and Bevacizumab are the first-line therapy for recurrent and metastatic cervical cancer in NCCN Guidelines. The treatment of cervical adenocarcinoma is more complicated than squamous cell carcinoma, and it is easy to develop resistance to chemotherapy [5]. Therefore, it is increasingly necessary to search for targeted and new therapies as monotherapy or adjuvant therapy [6]. The retrospective review of patients with cervical cancer, treated at the Royal Marsden Hospital showed that 70% of women treated with systemic therapy for recurrent or metastatic cervical cancer subsequently received second-line therapy with an ORR of 13.2%, a median PFS of 3.2 months and a median overall survival of 9.3 months [7]. In this report, we described the benefits of Olaparib in a patient with cervical adenocarcinomas who have metastasized to the posterior bladder wall and left side of uterus. 2. Case Description A 66-year-old female patient who was admitted to the hospital on March 23, 2020, suffered from abnormal vaginal bleeding and low back pain. Computed tomography scans revealed solid cystic tumors in the left adnexal area, and the tumors metastasized to the posterior bladder wall and left side of the uterus (Fig. 1). Based on the histological features of hematoxylin and eosin (HE) stained specimens and immunohistochemistry of the biopsy tissue, this case was diagnosed as cervical adenocarcinoma (Fig. 2). Considering her physical condition and the large tumor, the patient did not choose surgical treatment and selected TP chemotherapy (Paclitaxe and Cisplatin). After a cycle of chemotherapy, the patient had disease progression. To identify more opportunities for treatment, biopsy tissue was collected and subjected to genetic testing of 600 cancer-related genes using next-generation sequencing (NGS). The results revealed that BRCA1 (p. S1841fs) mutations were identified. Meanwhile, the patient had PD-L1 positive score, Combined Proportion Score (CPS 4) (Fig. 3). PD-L1 expression was assessed by using the 22C3 anti-PD-L1 antibody (Dako 22C3). The anti-PD1 antibody pembrolizumab was approved by the Food and Drug Administration (FDA) for the treatment of recurrent or metastatic cervical cancer progressing after one or more lines of chemotherapy with PD-L1 expression in 2018. The patient changed the original chemotherapy regimen and received FAC chemotherapy (Fluorouracil, Epirubicin and Hydrochlorid) combined with a PD-1 inhibitor (Sindilimab, Suzhou Xinda Medicine Co., Ltd). After one month treatment, the tumor was reevaluated using CT scans on May 30, 2020, and revealed a decreased tumor size in the left adnexal. Two months later, CT scans revealed the tumor size of the left adnexal more obviously decreased, and the multiple enlarged lymph nodes disappeared in retroperitoneal. However, the patient suspended immunotherapy (Sintilimab) for personal reasons and continued the FAC chemotherapy regimen. The following CT scans revealed the tumor in the left adnexal area continues shrunk from November 2020 to February 2021. Unfortunately, because of long-term chemotherapy, the patient developed myelosuppression seriously. Considering BRCA1 exon 23 mutation, the patient changed Olaparib treatment. Color doppler ultrasonography revealed that the patient's condition was currently stable until July 2021. Fortunately, the following CT scans examinations did not show any recurrence in March 2022, and the patient is still receiving Olaparib treatment (Fig. 1). 3. Discussion In the case report, the patient diagnosed with cervical adenocarcinoma with multiple metastases. Considering the lower response to chemotherapy, the patient underwent biopsy tissue DNA sequencing to search for targeted therapy opportunities. In addition, technologies of proteomics have advanced the dissection of the underlying molecular signaling events in cancer. As such, proteomics analysis may uncover new therapeutic choices in ovarian and cervical cancers, which can reduce the emergence of drug resistance [8]. The results of the NGS showed the BRCA1 exon 23 mutation and PD-L1 positive score. This suggests that anti-PD-1/PD-L1 immunotherapy may promise a PD-L1-positive advanced solid tumor. Sintilimab is a humanized and selective anti-PD-1 monoclonal antibody, which can block the interaction between PD-1 and its ligand and bind to the PD-1 receptor. This drug has been approved to treat relapsed or refractory classical Hodgkin's lymphoma in China, and clinical trials were conducted on several advanced solid tumors. Further, the therapy of Sintilimab plus Anlotinib has shown efficacy and acceptable safety for advanced cervical cancer patients failed prior chemotherapy [9,10]. Therefore, the patient with PD-L1 positive score achieved partial remission after three months Sintilimab combined with chemotherapy, and CT showed a perfect clinical effect. BRCA1 and BRCA2 are two significant genes, which play essential roles in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) break [11]. Much researches confirmed that there is a "synthetic lethal" interaction between PARPi and BRCA1 or BRCA2 mutations tumors. PARPi combined with DNA-damaging agents can lead to DNA repair defects and display potent anti-tumor activity. Therefore, PARPi can lead to the inactivation of BRCA and may be sensitive to the patients carrying germline mutations or somatic mutations with BRCA [12]. Combinations of PARP inhibitors with drugs that inhibit homologous recombination may sensitise cancers with a primary or secondary homologous recombination proficiency to PARP inhibitors and potentially expand their use beyond homologous recombination-deficient cancers. Regarding this, PARP inhibitors may be combined separately with anti-angiogenics and immune checkpoint inhibitors as well as with PI3K, AKT, mTOR, WEE1, MEK, and CDK4/6 inhibitors, or even with standard chemotherapy [13]. The FDA has approved Olaparib for treating recurrent platinum-sensitive ovarian cancer in the germline or somatic BRCA1/2 mutations. Furthermore, PARPi in treating cervical and uterine cancer are under clinical evaluation [14,15]. Rucaparib has been approved by the FDA for the treatment of mCRPC patients with somatic and/or germline DDR alterations who have progressed through enzalutamide or abiraterone treatment. Upon the observed synergy between the androgen and DNA damage repair pathways, there is a plausible rationale to use the combination of androgen receptor signaling inhibitors with PARP inhibitors in patients even unselected for DNA damage repair alterations [16]. A 49 years old advanced cervical cancer patient with BRCA1 mutation who treated with Olaparib and Bevacizumab maintenance therapy obtained a complete pathological response. Pelvic MRI showed a decrease of 50% in the tumor. After a one-year follow-up, clinical and radiological examination, no recurrence was found [17]. Another case report showed that a uterine serous carcinoma patient with BRCA2 mutation was treated with Olaparib. The patient got a progression-free survival for 11 months [18]. Currently, there is barely available data on the effectiveness of PARPi treated with cervical adenocarcinomas. However, some researching results tend to be prospective. In summary, we report that cervical adenocarcinoma may be cancer associated with BRCA mutations. It seems beneficial for the DNA testing for BRCA1 mutation in cervical adenocarcinomas patients, and PARPi may be a feasible option. In conclusion, this study reported a cervical adenocarcinoma patient with the severe left side uterus metastasis, who harboured BRCA1 mutation. The combination of chemotherapy and Olaparib is effective in this case, which provides a feasible and novel treatment option for advanced cervical adenocarcinoma patients with BRCA mutation in the future. Declarations Acknowledgements This work of partial data and collection was supported by Clinical Oncology Research Alliance (CORA). Author Contributions JZ and BQ collected and organized the data. YY and CS wrote the manuscript. ZK, FM and YZ prepared the figures. LL critically revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version. Funding None. Availability of data and materials Not applicable. Ethics approval and consent to participate The study was approved by the ethics committee of Weifang Traditional Chinese Hospital. Written informed consent was obtained from the participants for publication of the details of their medical case and any accompanying images. Consent for publication Informed consent has been obtained from the patient included in this study. Competing interests The authors declare no competing interests. References Bray F, Ferlay J, Soerjomataram I, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492. Kajimina Katumbayi JC, Muyulu NP, Zakayi PK, et al. Epidemiologic and histopathologic characteristics of 1280 uterine cervical cancers in Kinshasa. Gynecol Obstet Fertil Senol. 2022;50(1):53-61. doi: 10.1016/j.gofs.2021.07.001. Chung TK, Van Hummelen P, Chan PK, et al. Genomic aberrations in cervical adenocarcinomas in Hong Kong Chinese women. Int J Cancer. 2015;137(4):776-83. doi: 10.1002/ijc.29456. Boussios S, Seraj E, Zarkavelis G, et al. Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review. Crit Rev Oncol Hematol. 2016; 108:164-174. doi: 10.1016/j.critrevonc.2016.11.006. Mabuchi S, Okazawa M, Matsuo K, et al. Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell carcinoma. Gynecol Oncol. 2012;127(1):114-20. doi: 10.1016/j.ygyno.2012.06.021. Fortman D, Issa R, Stanbery L, et al. HER2-positive metastatic cervical cancer responsive to first and second-line treatment: A case report. Gynecol Oncol Rep. 2019; 31:100520. doi: 10.1016/j.gore.2019.100520. McLachlan J, Boussios S, Okines A, et al.The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer. Clin Oncol (R Coll Radiol). 2017 Mar;29(3):153-160. doi: 10.1016/j.clon.2016.10.002. Ghose A, Gullapalli SVN, Chohan N, et al. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes. 2022 May 9;10(2):16. doi: 10.3390/proteomes10020016. Xu Q, Chen C, Sun Y, et al. 865P A phase II study of sintilimab plus anlotinib for Chinese patients (pts) with persistent, recurrent, or metastatic cervical cancer (CC). Annals of Oncology, 2020, 31: S640. doi: 10.1016/j.annonc.2020.08.1004. Xu Q, Wang J, Sun Y, et al. Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1-Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial. J Clin Oncol. 2022;40(16):1795-1805. doi:10.1200/JCO.21.02091. Gorodetska I, Kozeretska I, Dubrovska A. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer. 2019;10(9):2109-2127. doi: 10.7150/jca.30410. Faraoni I, Graziani G. Role of BRCA Mutations in Cancer Treatment with Poly (ADP-ribose) Polymerase (PARP) Inhibitors. Cancers (Basel). 2018;10(12):487. doi: 10.3390/cancers10120487. Shah S, Cheung A, Kutka M, et al. Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes. Int J Environ Res Public Health. 2022 Jul 1;19(13):8113. doi: 10.3390/ijerph19138113. Lheureux S, Mirza M, Coleman R. The DNA Repair Pathway as a Target for Novel Drugs in Gynecologic Cancers. J Clin Oncol. 2019;37(27):2449-2459. doi: 10.1200/JCO.19.00347. Le Gac M, Koual M, Delanoy N, et al. Place of PARP inhibitors in the treatment of endometrial and cervical cancers. Bull Cancer. 2022;109(1):65-75. doi: 10.1016/j.bulcan. Boussios S, Rassy E, Shah S, et al. Aberrations of DNA repair pathways in prostate cancer: a cornerstone of precision oncology. Expert Opin Ther Targets. 2021 May;25(5):329-333. doi: 10.1080/14728222.2021.1951226. Montero-Macias R, Koual M, Crespel C, et al. Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report. J Med Case Rep. 2021;15(1):210. doi: 10.1186/s13256-021-02767-9. Inoue K, Tsubamoto H, Ueda T, et al. Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report. Gynecol Oncol Rep. 2020; 32:100563. doi: 10.1016/j.gore.2020.100563. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2731213","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":186628096,"identity":"04af2827-d214-4121-af1b-e8ca59eadd9f","order_by":0,"name":"Jing Zhuang","email":"","orcid":"","institution":"Department of Oncology, Weifang Traditional Chinese Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Zhuang","suffix":""},{"id":186628097,"identity":"7cd8102b-8bb3-4204-b961-9c0f99129d55","order_by":1,"name":"Baoning Qin","email":"","orcid":"","institution":"Department of Oncology, Weifang Traditional Chinese Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Baoning","middleName":"","lastName":"Qin","suffix":""},{"id":186628098,"identity":"f7e74a8b-5493-4416-881f-6f4c8a2f9356","order_by":2,"name":"Yang Yu","email":"","orcid":"","institution":"College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Yu","suffix":""},{"id":186628099,"identity":"71c22f30-bc25-4264-a7be-ebd7534e147b","order_by":3,"name":"Zixing Kou","email":"","orcid":"","institution":"College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zixing","middleName":"","lastName":"Kou","suffix":""},{"id":186628100,"identity":"3351ee1a-ea1e-45cb-8bf3-b931fc5c7b4d","order_by":4,"name":"Chunjie Sun","email":"","orcid":"","institution":"College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chunjie","middleName":"","lastName":"Sun","suffix":""},{"id":186628101,"identity":"77bd6c23-b7ad-4532-a279-f3f1d1e649c3","order_by":5,"name":"Fanfan Meng","email":"","orcid":"","institution":"Department of Medicine, Yinfeng Gene Technology Co Ltd","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fanfan","middleName":"","lastName":"Meng","suffix":""},{"id":186628102,"identity":"bcf84e9c-4bbf-4edb-ab71-2827a63ab6ac","order_by":6,"name":"Yaxuan Zhang","email":"","orcid":"","institution":"Department of Medicine, Yinfeng Gene Technology Co Ltd","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yaxuan","middleName":"","lastName":"Zhang","suffix":""},{"id":186628103,"identity":"a741ab8a-1c7a-44ea-aa0d-e902e164c8b8","order_by":7,"name":"Ling Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACPmbmhgMMDP/k7Oc/PnDgQwURWtiYGUFaDhgbMKQlHpxxhhgtDIwNQOpA4gaGHOPDvC3EaGFnbDxc8OsO43aGMx8O8DYwyPOLHSDssMMz+54xWzb2bjgguYPBcObsBCK08PYwszEc5t1wwPAMQ4LBbSK18DAc43lwILGNWC08Pw5LGJzhYThwkGgtvA1pBpIz2AwONpyRIOwXfv7Dhz/z/LGp75dgfvz5T4WNPL80AS1gwNgGZ0oQoRwM/hCrcBSMglEwCkYkAACZ50nqEpx7+AAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Medicine, Yinfeng Gene Technology Co Ltd","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2023-03-24 09:29:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2731213/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2731213/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34939846,"identity":"1f2c7e41-b46c-46b9-9b18-42ee9405f80b","added_by":"auto","created_at":"2023-03-28 19:57:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":466682,"visible":true,"origin":"","legend":"\u003cp\u003eThe treatment timeline received and equivalent CT scans imaging and Color doppler ultrasonography. da., days; mo., month(s); SD, stable disease; PD, progressive disease; TP, Paclitaxe and Cisplatin; FAC, Fluorouracil, Epirubicin and Hydrochlorid\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2731213/v1/b0016366cd6e47457fa0646b.jpg"},{"id":34939847,"identity":"3d2585e2-4ede-4bee-a874-e735862390bd","added_by":"auto","created_at":"2023-03-28 19:57:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":374827,"visible":true,"origin":"","legend":"\u003cp\u003eA. Hematoxylin and eosin (HE) staining image (×200). B. Immunohistochemical stained in the tumor cells (×200).\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2731213/v1/07c2ccf22276c492108d951d.jpg"},{"id":34939848,"identity":"3cb18148-c8e3-4f83-9ede-f14114dfbe66","added_by":"auto","created_at":"2023-03-28 19:57:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":922565,"visible":true,"origin":"","legend":"\u003cp\u003eThe BRCA1 p. S1841fs mutation was visualized by IGV software.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2731213/v1/6fc783fee8c23edb0c4fbcf0.jpg"},{"id":35018013,"identity":"73d14fea-5805-4cc7-96a4-734002ab4154","added_by":"auto","created_at":"2023-03-30 04:44:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":470958,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2731213/v1/4e203f3b-1334-49ef-b611-097360e2091e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case report: Response with chemotherapy and Olaparib in a patient with advanced cervical adenocarcinoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCervical cancer is the fourth most cancer in female cancer patients. It includes different histological subtypes: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma\u0026nbsp;[1]. In cervical cancer, the most common type is squamous cell carcinoma (73,2%), cervical adenocarcinoma secondly (18,4%), and then cervical adenosquamous carcinoma (8,4%)\u0026nbsp;[2]. For decades, the incidence rate of cervical squamous cell carcinoma has been declining continuously. However, the incidence rate of cervical adenocarcinoma seems to be increasing\u0026nbsp;[3].\u0026nbsp;At present, studies have shown that compared with adenocarcinoma, squamous cell subtypes have significant response to adjuvant therapy, and there are also differences in immune microenvironments and tumor escape mechanisms\u0026nbsp;[4]. Overall, the therapeutic effect of cervical adenocarcinoma is not as good as cervical squamous cell carcinoma. Chemotherapy or combining chemotherapy and Bevacizumab are the first-line\u0026nbsp;therapy\u0026nbsp;for recurrent and metastatic cervical cancer in NCCN Guidelines. The treatment of cervical adenocarcinoma is more complicated than squamous cell carcinoma, and it is easy to develop resistance to chemotherapy\u0026nbsp;[5]. Therefore, it is increasingly necessary to search for targeted and new therapies as monotherapy or adjuvant therapy\u0026nbsp;[6].\u0026nbsp;The retrospective review of patients with cervical cancer, treated at the Royal Marsden Hospital showed that 70% of women treated with systemic therapy for recurrent or metastatic cervical cancer subsequently received second-line therapy with an ORR of 13.2%, a median PFS of 3.2 months and a median overall survival of 9.3 months [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this report, we described the benefits of Olaparib in a patient with cervical adenocarcinomas who have metastasized to the posterior bladder wall and left side of uterus.\u003c/p\u003e"},{"header":"2. Case Description","content":"\u003cp\u003eA 66-year-old female patient who was admitted to the hospital on March 23, 2020, suffered from abnormal vaginal bleeding and low back pain. Computed tomography scans revealed solid cystic tumors in the left adnexal area, and the tumors metastasized to the posterior bladder wall and left side of the uterus\u0026nbsp;(Fig.\u0026nbsp;1). Based on the histological features of hematoxylin and eosin (HE) stained specimens and immunohistochemistry of the biopsy tissue, this case was diagnosed as cervical adenocarcinoma\u0026nbsp;(Fig. 2). Considering her physical condition and the large tumor, the patient did not choose surgical treatment and selected TP chemotherapy (Paclitaxe and Cisplatin). After a cycle of chemotherapy, the patient had disease progression. To identify more opportunities for treatment, biopsy tissue was collected and subjected to genetic testing of 600 cancer-related genes using next-generation sequencing (NGS). The results revealed that \u003cem\u003eBRCA1\u003c/em\u003e (p. S1841fs) mutations were identified. Meanwhile, the patient had PD-L1 positive score, Combined Proportion Score (CPS 4)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(Fig. 3). PD-L1 expression was assessed by using the 22C3 anti-PD-L1 antibody (Dako 22C3). The anti-PD1 antibody pembrolizumab was approved by the Food and Drug Administration (FDA) for the treatment of recurrent or metastatic cervical cancer progressing after one or more lines of chemotherapy with PD-L1 expression in 2018.\u0026nbsp;The\u0026nbsp;patient changed the original chemotherapy regimen and received FAC chemotherapy (Fluorouracil, Epirubicin and Hydrochlorid) combined with a PD-1 inhibitor (Sindilimab, Suzhou Xinda Medicine Co., Ltd). After one month treatment, the tumor was reevaluated using CT scans on May 30, 2020, and revealed a decreased tumor size in the left adnexal. Two months later, CT scans revealed the tumor size of the left adnexal more obviously decreased, and the multiple enlarged lymph nodes disappeared in retroperitoneal. However, the patient suspended immunotherapy (Sintilimab) for personal reasons and continued the FAC chemotherapy regimen. The following CT scans revealed the tumor in the left adnexal area continues shrunk from November 2020 to February 2021. Unfortunately, because of long-term chemotherapy, the patient developed myelosuppression seriously. Considering \u003cem\u003eBRCA1\u003c/em\u003e exon 23 mutation, the patient changed Olaparib treatment. Color doppler ultrasonography revealed that the patient\u0026apos;s condition was currently stable until July 2021. Fortunately, the following CT scans examinations did not show any recurrence in March 2022, and the patient is still receiving Olaparib treatment (Fig. 1).\u0026nbsp;\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eIn the case report, the patient diagnosed with cervical adenocarcinoma with multiple metastases. Considering the lower response to chemotherapy, the patient underwent biopsy tissue DNA sequencing to search for targeted therapy opportunities. In addition, technologies of proteomics have advanced the dissection of the underlying molecular signaling events in cancer. As such, proteomics analysis may uncover new therapeutic choices in ovarian and cervical cancers, which can reduce the emergence of drug resistance\u0026nbsp;[8].\u0026nbsp;The results of the NGS showed the \u003cem\u003eBRCA1\u003c/em\u003e exon 23 mutation and PD-L1 positive score. This suggests that\u0026nbsp;anti-PD-1/PD-L1 immunotherapy\u0026nbsp;may promise a PD-L1-positive advanced solid tumor.\u0026nbsp;Sintilimab is a humanized and selective anti-PD-1 monoclonal antibody, which can block the interaction between PD-1 and its ligand and bind to the PD-1 receptor. This drug has been approved to treat relapsed or refractory classical Hodgkin\u0026apos;s lymphoma in China, and clinical trials were conducted on several advanced solid tumors. Further, the therapy of Sintilimab plus Anlotinib has shown efficacy and acceptable safety for advanced cervical cancer patients failed prior chemotherapy\u0026nbsp;[9,10]. Therefore, the patient with PD-L1\u0026nbsp;positive score achieved partial remission after three months\u0026nbsp;Sintilimab combined with chemotherapy, and CT showed a perfect clinical effect.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e are two significant genes, which play essential roles in homologous recombination repair of double-strand deoxyribonucleic acid (DNA) break\u0026nbsp;[11]. Much researches confirmed that there is a \u0026quot;synthetic lethal\u0026quot; interaction between PARPi and \u003cem\u003eBRCA1\u003c/em\u003e or \u003cem\u003eBRCA2\u003c/em\u003e mutations tumors. PARPi combined with DNA-damaging agents can lead to DNA repair defects and display potent anti-tumor activity.\u0026nbsp;Therefore, PARPi can lead to the inactivation of BRCA and may be sensitive to the patients carrying germline mutations or somatic mutations with \u003cem\u003eBRCA\u003c/em\u003e [12].\u0026nbsp;Combinations of PARP inhibitors with drugs that inhibit homologous recombination may sensitise cancers with a primary or secondary homologous recombination proficiency to PARP inhibitors and potentially expand their use beyond homologous recombination-deficient cancers. Regarding this, PARP inhibitors may be combined separately with anti-angiogenics and immune checkpoint inhibitors as well as with PI3K, AKT, mTOR, WEE1, MEK, and CDK4/6 inhibitors, or even with standard chemotherapy [13].\u0026nbsp;The FDA has approved Olaparib for treating recurrent platinum-sensitive ovarian cancer in the germline or somatic \u003cem\u003eBRCA1/2\u003c/em\u003e mutations.\u0026nbsp;Furthermore, PARPi in treating cervical and uterine cancer are under clinical evaluation\u0026nbsp;[14,15]. Rucaparib has been approved by the FDA for the treatment of mCRPC patients with somatic and/or germline DDR alterations who have progressed through enzalutamide or abiraterone treatment. Upon the observed synergy between the androgen and DNA damage repair pathways, there is a plausible rationale to use the combination of androgen receptor signaling inhibitors with PARP inhibitors in patients even unselected for DNA damage repair alterations\u0026nbsp;[16].\u0026nbsp;A\u0026nbsp;49 years old advanced cervical cancer patient with \u003cem\u003eBRCA1\u003c/em\u003e mutation who treated with\u0026nbsp;Olaparib and\u0026nbsp;Bevacizumab maintenance therapy obtained a complete pathological response. Pelvic MRI showed a decrease of 50% in the tumor. After a one-year follow-up, clinical and radiological examination,\u0026nbsp;no recurrence was found\u0026nbsp;[17]. Another case report showed that a uterine serous carcinoma patient with \u003cem\u003eBRCA2\u003c/em\u003e mutation was treated with Olaparib. The patient got a progression-free survival for 11 months\u0026nbsp;[18]. Currently, there is barely available data on the effectiveness of PARPi treated with cervical adenocarcinomas. However, some researching results tend to be prospective. In summary, we report that cervical adenocarcinoma may be cancer associated with \u003cem\u003eBRCA\u003c/em\u003e mutations. It seems beneficial for the DNA testing for \u003cem\u003eBRCA1\u003c/em\u003e mutation in cervical adenocarcinomas patients, and PARPi may be a feasible option.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study reported a cervical adenocarcinoma patient with the severe left side uterus metastasis, who harboured \u003cem\u003eBRCA1\u003c/em\u003e mutation. The combination of chemotherapy and Olaparib is effective in this case, which provides a feasible and novel treatment option for advanced cervical adenocarcinoma patients with BRCA mutation in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work of partial data and collection was supported by Clinical Oncology Research Alliance (CORA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJZ and BQ collected and organized the data. YY and CS wrote the manuscript. ZK, FM and YZ prepared the figures. LL critically revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the ethics committee of Weifang Traditional Chinese Hospital. Written informed consent was obtained from the participants for publication of the details of their medical case and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent has been obtained from the patient included in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Ferlay J, Soerjomataram I, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492.\u003c/li\u003e\n\u003cli\u003eKajimina Katumbayi JC, Muyulu NP, Zakayi PK, et al. Epidemiologic and histopathologic characteristics of 1280 uterine cervical cancers in Kinshasa. Gynecol Obstet Fertil Senol. 2022;50(1):53-61. doi: 10.1016/j.gofs.2021.07.001.\u003c/li\u003e\n\u003cli\u003eChung TK, Van Hummelen P, Chan PK, et al. Genomic aberrations in cervical adenocarcinomas in Hong Kong Chinese women. Int J Cancer. 2015;137(4):776-83. doi: 10.1002/ijc.29456. \u003c/li\u003e\n\u003cli\u003eBoussios S, Seraj E, Zarkavelis G, et al. Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review. Crit Rev Oncol Hematol. 2016; 108:164-174. doi: 10.1016/j.critrevonc.2016.11.006. \u003c/li\u003e\n\u003cli\u003eMabuchi S, Okazawa M, Matsuo K, et al. Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell carcinoma. Gynecol Oncol. 2012;127(1):114-20. doi: 10.1016/j.ygyno.2012.06.021. \u003c/li\u003e\n\u003cli\u003eFortman D, Issa R, Stanbery L, et al. HER2-positive metastatic cervical cancer responsive to first and second-line treatment: A case report. Gynecol Oncol Rep. 2019; 31:100520. doi: 10.1016/j.gore.2019.100520. \u003c/li\u003e\n\u003cli\u003eMcLachlan J, Boussios S, Okines A, et al.The Impact of Systemic Therapy Beyond First-line Treatment for Advanced Cervical Cancer. Clin Oncol (R Coll Radiol). 2017 Mar;29(3):153-160. doi: 10.1016/j.clon.2016.10.002.\u003c/li\u003e\n\u003cli\u003eGhose A, Gullapalli SVN, Chohan N, et al. Applications of Proteomics in Ovarian Cancer: Dawn of a New Era. Proteomes. 2022 May 9;10(2):16. doi: 10.3390/proteomes10020016. \u003c/li\u003e\n\u003cli\u003eXu Q, Chen C, Sun Y, et al. 865P A phase II study of sintilimab plus anlotinib for Chinese patients (pts) with persistent, recurrent, or metastatic cervical cancer (CC). Annals of Oncology, 2020, 31: S640. doi: 10.1016/j.annonc.2020.08.1004.\u003c/li\u003e\n\u003cli\u003eXu Q, Wang J, Sun Y, et al. Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1-Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial. J Clin Oncol. 2022;40(16):1795-1805. doi:10.1200/JCO.21.02091.\u003c/li\u003e\n\u003cli\u003eGorodetska I, Kozeretska I, Dubrovska A. BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. J Cancer. 2019;10(9):2109-2127. doi: 10.7150/jca.30410. \u003c/li\u003e\n\u003cli\u003eFaraoni I, Graziani G. Role of BRCA Mutations in Cancer Treatment with Poly (ADP-ribose) Polymerase (PARP) Inhibitors. Cancers (Basel). 2018;10(12):487. doi: 10.3390/cancers10120487. \u003c/li\u003e\n\u003cli\u003eShah S, Cheung A, Kutka M, et al. Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes. Int J Environ Res Public Health. 2022 Jul 1;19(13):8113. doi: 10.3390/ijerph19138113. \u003c/li\u003e\n\u003cli\u003eLheureux S, Mirza M, Coleman R. The DNA Repair Pathway as a Target for Novel Drugs in Gynecologic Cancers. J Clin Oncol. 2019;37(27):2449-2459. doi: 10.1200/JCO.19.00347.\u003c/li\u003e\n\u003cli\u003eLe Gac M, Koual M, Delanoy N, et al. Place of PARP inhibitors in the treatment of endometrial and cervical cancers. Bull Cancer. 2022;109(1):65-75. doi: 10.1016/j.bulcan. \u003c/li\u003e\n\u003cli\u003eBoussios S, Rassy E, Shah S, et al. Aberrations of DNA repair pathways in prostate cancer: a cornerstone of precision oncology. Expert Opin Ther Targets. 2021 May;25(5):329-333. doi: 10.1080/14728222.2021.1951226. \u003c/li\u003e\n\u003cli\u003eMontero-Macias R, Koual M, Crespel C, et al. Complete pathological response to olaparib and bevacizumab in advanced cervical cancer following chemoradiation in a BRCA1 mutation carrier: a case report. J Med Case Rep. 2021;15(1):210. doi: 10.1186/s13256-021-02767-9. \u003c/li\u003e\n\u003cli\u003eInoue K, Tsubamoto H, Ueda T, et al. Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report. Gynecol Oncol Rep. 2020; 32:100563. doi: 10.1016/j.gore.2020.100563. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cervical adenocarcinoma, BRCA1, chemotherapy, Olaparib, Sindilimab","lastPublishedDoi":"10.21203/rs.3.rs-2731213/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2731213/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCervical adenocarcinomas are a heterogeneous group of tumors, accounting for approximately 20% of all cervical cancers. Many clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway.\u003c/p\u003e\n\u003cp\u003eAt present, there are few data available on the activity of PARPi in endometrial and cervical cancers. And poly-(ADP)-ribose polymerase inhibitors (PARPi) are changing clinical practice in the BRCA mutant patients with cervical cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Description:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHere, we report the case of a 66-year-old female patient admitted to the hospital due to abnormal vaginal bleeding. She was diagnosed with advanced cervical adenocarcinomas, and received chemotherapy followed by Paclitaxe and Cisplatin in the first-line. However, after one cycle of treatment, the patient's disease progressed. To identify more opportunities for treatment, the biopsy tissue was genetic tested and found BRCA1 exon 23 mutation and PD-L1 positive score, which motivated chemotherapy combined with immune checkpoint inhibitors, and the tumor size decreased. However, because of the side effects of from long-term chemotherapy, the patient chosen Olaparib treatment in the later stage. The patient benefited long-term disease control for about 24 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case might support the strategy that PARPi could be an alternative treatment for cervical adenocarcinoma patients with BRCA1 mutation in the future.\u003c/p\u003e","manuscriptTitle":"Case report: Response with chemotherapy and Olaparib in a patient with advanced cervical adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-28 19:57:23","doi":"10.21203/rs.3.rs-2731213/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1240180c-b846-4edc-9919-7bb47a82fa36","owner":[],"postedDate":"March 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-30T04:44:24+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-28 19:57:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2731213","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2731213","identity":"rs-2731213","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}