Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer Shoko Kitazawa, Tatsuyuki Chiyoda, Kohei Nakamura, Kensuke Sakai, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2847818/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Aug, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Japan’s health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. Methods We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. Results Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with others). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Conclusion Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients’ prognosis and performance status should be considered before performing the test. cancer genomic profiling ovarian cancer cervical cancer endometrial cancer molecular tumor board Introduction The incidence of gynecological malignancies in Japan is approximately 42,500, with 11,684 deaths, per year [ 1 ]. The standard treatment for advanced gynecologic cancer with distant metastasis or recurrence is systemic chemotherapy. However, standard chemotherapy has many refractory cases. Although the prognosis varies greatly depending on histological type, progression stage, and patient background, personalized medicine is currently being recommended. In June 2019, the Pharmaceuticals and Medical Devices Agency launched comprehensive genome profiling (CGP), a multigene panel testing method, for "patients with solid tumors for which no standard treatment is available, or patients with locally advanced or metastatic solid tumors for which standard therapy has been completed (including those expected to complete standard therapy)" in Japan [ 2 ]. At the same time, FoundationOne® CDx (Foundation Medicine, Inc.; Cambridge, MA, US; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) and OncoGuide™ NCC Oncopanel (Sysmex Corp., Kobe, Japan) were approved to be covered by Japan’s health insurance for all solid tumors. Concurrently, the cancer genome medical system was innovated with the establishment of the Designated Core Hospital for Cancer Genomic Medicine, Designated Cancer Care Hospital, and Center for Cancer Genomics and Advanced Therapeutics. OncoGuide™ NCC Oncopanel has been conducted in Japan, and 124 genes (including 13 fusion genes) have been analyzed, with tumor tissue (formalin-fixed paraffin-embedded [FFPE]) DNA and nontumor tissue (whole blood) DNA as target samples. FoundationOne® CDx analyzes 324 genes (including 36 fusion genes) with tumor tissue (FFPE) DNA as the target sample. FoundationOne® cannot distinguish whether the detected variants are somatic or germline in origin. In both tests, the biomarkers for immune checkpoint inhibitors (ICIs) are microsatellite instability (MSI) and tumor mutation burden (TMB) (Table 1 ). OncoGuide™ NCC Oncopanel FoundationOne®CDx Table 1 Tissue gene panel testing approved in Japan Country of origin Japan US Number of genes 123 324 Required sample FFPE, blood FFPE Proportion of tumor cells needed for analysis > 20% > 20% Biomarkers for immune checkpoint inhibitor MSI, TMB MSI, TMB FFPE, formalin-fixed paraffin-embedded; MSI, microsatellite instability; TMB, tumor mutation burden; US, United States Since the health insurance approved to cover CGP, the number of CGP exams performed has been increasing [ 2 – 6 ]; however, the status of multigene panel testing in gynecological malignancies and the clinicopathological characteristics of the patients remain insufficiently reported [ 7 , 8 ]. Thus, this study aimed to summarize the results of the CGP examination at our hospital (Designated Core Hospital for Cancer Genomic Medicine) to investigate its usefulness as a potential treatment option for advanced and recurrent gynecologic cancers. Patients and Methods Study design and patients We enrolled patients who underwent CGP for gynecologic malignancies at our hospital between November 2019 and October 2022 and identified those who received CGP via FoundationOne® CDx and those via OncoGuide™ NCC Oncopanel. The indication and timing of CGP were determined by the attending physician, but as a principle of health insurance coverage, this study included patients who were refractory to the standard therapy or the current therapy. No restrictions were made in terms of carcinoma or histological type among gynecological malignancies, as well as pre-examination treatment. Tumor samples were obtained from surgical or biopsy specimens. We did not use cell blocks taken from pleural or ascites fluid. The clinicopathological characteristics of the 102 patients who underwent CGP were extracted from medical records and characterized after the study protocol was approved by the ethics committee of the hospital (approval No.: 20120243, 20070081, and 20150197). Results Patients and characteristics This study included 102 patients with advanced gynecologic cancer who underwent CGP between November 2019 and October 2022 (Table 2 ). Among them, 9 underwent OncoGuide™ NCC Oncopanel, whereas 93 underwent FoundationOne® CDx. Table 2 summarizes patients’ characteristics, test results, and post-test follow-up. All patients were treated at the hospital, and they gave informed consent before multigene panel testing. The median age was 55.5 years. None of them had unsuitable specimens; thus, all could be examined. Cervical cancer Endometrial cancer** Ovarian cancer*** Sarcoma Vaginal cancer Total % Table 2 Patients’ characteristics and results n = 32 n = 18 n = 43 n = 8 n = 1 102 100 FIGO stage, n Stage 0 1* Stage I 14 2 5 4 0 25 24.5 Stage II 9 3 0 4 0 16 15.6 Stage III 5 3 27 0 0 35 34.3 Stage IV 3 10 11 0 1 25 24.5 Gene results Actionable gene (+) 30 18 42 7 1 98 96 (-) 2 0 1 1 0 4 3.9 Druggable gene (+) 21 15 28 5 1 70 68.6 (-) 11 3 15 3 0 32 31.3 Common gene alterations BRCA1 2 0 0 0 0 2 PIK3CA 9 5 6 0 1 21 TMB-H 5 5 0 1 0 11 LOH-high 0 0 9 0 0 9 ERBB2 4 2 2 0 0 8 ATM 1 1 1 0 0 3 PTEN 2 5 3 1 1 12 CDKN2A 5 1 1 1 0 8 CCND1 2 1 0 0 0 3 FGF3 2 1 0 0 0 3 MSI-H 0 1 0 0 0 1 Timing of tests After the 1st-line 9 2 5 4 1 21 20.5 After 2nd -line 17 11 13 4 0 45 44.1 After 3rd-line 3 3 12 0 0 18 17.6 After the 4th-line 3 2 11 0 0 16 15.6 More 0 0 2 0 0 2 1.9 After the results were provided Died before the results were provided 0 0 1 0 1 2 1.9 Could not be treated because of worsened performance status (PS > 2) 5 4**** 4 0 0 13 12.7 Denied treatment 2 1 2 1 0 6 5.8 Did not have the recommended treatment 17 8 29 6 0 60 58.8 Not yet administered 3 3 3 1 0 10 9.8 Received molecularly targeted therapy 5 2 4 0 0 11 10.7 *includes a patient with remote metastasis after an initial diagnosis of adenocarcinoma in situ **includes two patients with carcinosarcoma of the uterus ***includes 6 patients with peritoneal cancers and 1 patient with granular-cell carcinoma ****include a patient who could not be treated because of severe medical histories LOH, loss of heterozygosity; MSI-H, high microsatellite instability; TMB-H, high tumor mutation burden The majority of these patients had ovarian cancer (including peritoneal cancer and granulosa cell tumor) (n = 43), followed by cervical cancer, endometrial cancer (including 2 carcinosarcomas), sarcoma, and vaginal cancer (n = 32, 18, 8, and 1, respectively). One patient with stage 0 cervical cancer was initially diagnosed with adenocarcinoma in situ pathologically before metastasis. Table 3 shows the histological types. Of the patients with ovarian cancer, 25 had high-grade serous carcinoma (HGSC) and 1 had a low grade. n Table 3 Histological subtypes of gynecologic cancers included in the study Cervical cancer 32 squamous cell carcinoma 12 adenocarcinoma 12 endocervical adenocarcinoma, usual type 8 mucinous adenocarcinoma 3 adenocarcinoma admixed with neuroendocrine carcinoma 1 adenosquamous carcinoma 5 neuroendocrine tumors 3 Endometrial cancer 18 EMG1/G2 5 EMG3 2 serous carcinoma 6 clear cell carcinoma 2 carcinosarcoma 2 others 1 Ovarian cancer 43 Serous carcinoma 26 HGSC 25 LGSC 1 clear cell carcinoma 8 EM 5 small cell carcinoma 1 carcinosarcoma 1 mixed carcinoma (serous + clear) 1 granulosa cell tumor 1 Sarcoma 8 leiomyosarcoma 6 endometrial stromal sarcoma 2 Vaginal cancer 1 large cell neuroendocrine carcinoma 1 EM, endometrioid carcinoma; G, grade; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma Common druggable gene alterations Gene results revealed 98 patients with actionable gene alterations and 70 patients with druggable gene alterations. The most common druggable gene alteration was PIK3CA mutation, followed by PTEN mutation and high TMB (TMB-H) (n = 21, 12, and 11, respectively). Patients with cervical cancer, endometrial cancer, and endometrial stromal sarcoma exhibited TMB-H. The histological types of cervical cancer were squamous cell carcinoma in 4 patients and adenosquamous carcinoma in 1 patient. Three of them received the recommended therapy, one was still on current therapy but was being offered pembrolizumab as a treatment option, and one did not receive pembrolizumab at the patient’s request. Furthermore, the histological types found in patients with TMB-H endometrial cancer were endometrioid carcinoma (EM) grade (G) 2, EMG3, serous carcinoma, clear cell carcinoma, and adenocarcinoma individually. Only one of them was eligible for the recommended treatment; the others could not receive the recommended treatment because of deterioration of the general condition, regardless of the test results. Among all the patients, only one had high MSI (MSI-H). This patient had stage IIIC1 endometrial cancer with an MSH2 pathogenic variant. Genetic counseling was recommended, but when the result was obtained, the patient could not receive treatment because of an aggravated general condition. This patient died shortly afterward. Results and course of CGP The attending physician conducted CGP when the patient was diagnosed with the progression of disease during or after the first-line treatment (n = 21), during or after the second-line (n = 45), during or after the third-line (n = 18), during or after the fourth-line (n = 16), and after more than the fourth-line (n = 2). Unfortunately, two patients (1.9%) died before the test results were available. In addition, 13 (12.7%) could not be treated with chemotherapy because of a very poor general condition when the test results were provided (performance status ≥ 2). One of these patients was ineligible for chemotherapy because of medical history, even though the recommended therapy was offered. Although 70 patients had druggable gene alteration, 10 patients for whom PARP inhibitor was recommended and had already been treated with a PARP inhibitor were classified as having no recommended treatment. In addition, 18 patients who had recommended treatment for which there were no off-label clinical trials were also categorized as “patients who did not have recommended treatment group”. As a result, 60 patients (58.8%) had no recommended treatment. Meanwhile, 10 patients (9.8%) had a recommended treatment but did not pursue it because they were responding to their current treatment. They were supposed to receive the recommended treatment if the current treatment would not effective. A total of 11 patients (5 with cervical cancer, 2 with endometrial cancer, and 4 with ovarian cancer) (10.8%) received the recommended treatment (Table 4 ). Among them, 3 were tested after the initial treatment, 5 after the second-line, 2 after the third-line, and 1 in the fourth-line. Nivolumab was the most commonly administered drug as a recommended therapy. Age Diagnosis Histology Stage Lines of Chemotherapy Druggable Gene Alteration Medicine Table 4 Summary of the 11 patients who received molecularly targeted therapy 1 40 Cervical cancer Squamous cell carcinoma IIIB 2 TMB-H BRCA1 Pembrolizumab 2 55 Cervical cancer Endocervical adenocarcinoma, usual type IA 2 PTEN BRCA1 Olaparib 3 56 Cervical cancer Squamous cell carcinoma IB1 1 TMB-H Nivolumab 4 57 Cervical cancer Squamous cell carcinoma IIIB 2 PIK3CA Everolimus 5 78 Cervical cancer Squamous cell carcinoma IIIB 3 TMB-H Nivolumab 6 59 Ovarian cancer EMG2 IC1 3 PIK3CA Everolimus 7 66 Ovarian cancer HGSC IIIA1 2 LOH-high, CD274, PDCD1LG2 Nivolumab 8 66 Ovarian cancer HGSC IVB 4 TSC1 BRIP1 Platinum drugs 9 79 Ovarian cancer EMG2 IA 1 PIK3CA and ERBB2 amplification Trastuzumab 10 64 Endometrial cancer Serous carcinoma IVB 1 TMB-H, PIK3CA , and BRCA1 Nivolumab 11 63 Endometrial cancer EMG2 II 2 PTEN Everolimus EM, endometrioid carcinoma grade; G, grade; HGSC, high-grade serous carcinoma; LOH, loss of heterozygosity; TMB-H, high tumor mutation burden Patients with cervical cancer received the most frequently recommended treatment among gynecological cancers, with 5 (15.6%) being eligible for the recommended treatment. Among these 5 patients, 4 had squamous cell carcinoma and 1 had endocervical adenocarcinoma, usual type. Conversely, 17 had no recommended treatment. Most of the patients were examined after the second-line, and their conditions mainly had progressed or relapsed after systemic chemotherapy for recurrence after concurrent chemoradiation therapy (CCRT). Regarding endometrial carcinoma, two patients (10.5%) could receive the recommended treatment. The patient with EMG2 had a PTEN mutation and received everolimus. The other patient, who was diagnosed with serous carcinoma, had TMB-H and received nivolumab. In ovarian cancer, four patients (9.3%) were eligible for the recommended treatment (2 with HGSC and 2 with EMG2). One of the patients had PIK3CA mutation and ERBB2 amplification and received trastuzumab, a HER2 inhibitor. While most of the patients who could receive the recommended treatment had been tested after second-line chemotherapy, one was tested after four times of recurrence before receiving the recommended treatment. Discussion In Japan, approximately 22.3% of patients who underwent CGP in all solid tumors were treated with molecularly targeted therapy as the recommended treatment [ 4 ], but few were reported with regard to gynecological malignancies [ 7 ]. Of all 102 included patients, 32 had no druggable gene alterations, suggesting that these 32 patients did not receive the recommended treatment. In contrast, 11 (10.7%) out of 70 patients who had druggable gene alterations received the recommended treatment, with cervical cancer as the most common case (5 cases). The druggable gene alterations were TMB-H in 4 patients and PIK3CA and BRCA1 in 3 patients each, and nivolumab was the most common drug administered as the recommended treatment. According to KEYNOTE-158 [ 9 ], which reported that ICIs are effective for solid tumors with MSI-H, most of the MSI-H tumors have TMB-H (> 20 mut/Mb) [ 10 , 11 ]. Only one patient was diagnosed with MSI-H by CGP in this study. This might be because the MSI test had been performed before the CGP test, and patients with MSI-H were already undergoing treatment. The fact that MSI-H patients have a higher ICI response rate and a lower relapse rate may also have contributed to the result that only one patient was diagnosed with MSI-H. Considering the fact that only one patient had MSI-H in the present study and roughly 4% of cancers have MSI-H [ 10 ], MSI-H alone could not be a helpful biomarker for ICI treatments in a broad spectrum. Nevertheless, microsatellite-stable tumors with TMB-H benefit from ICIs [ 11 ]. Treatment options for recurrent gynecologic malignancies have widened these days. However, while the views on the treatment of recurrent tumors have been generalized to some extent, defining a standard treatment remains difficult. Although treatment options that may offer a longer prognosis are increasing in number, prognosis may still be poor because of the severity of diseases. Nonetheless, CGP may help expand treatment options for these patients. In this study, the most common time for CGP testing in patients with cervical cancer was around the second-line of treatment. Currently, radiotherapy and systemic chemotherapy are the most common treatment options for recurrent cervical cancer [ 13 ]; surgery is sometimes performed [ 14 ], but its effect on prognosis has not been established [ 14 – 16 ]. Given the current situation, many patients are expected to undergo multigene panel testing for recurrence after the standard treatment around the second-line. Recently, following the results of KEYNOTE-826 [ 17 ], treatment with additional ICIs and cytotoxic chemotherapeutic agents for patients with advanced or relapsed cervical cancer has been covered by insurance in Japan. In addition to pembrolizumab, ICIs such as cemiplimab [ 18 – 19 ] and dual checkpoint blockades such as balstilimab plus zalifrelimab [ 20 ] and the human anti-tissue factor antibody of tisotumab vedotin [ 21 ] are gaining attention. Especially cemiplimab has just been covered by insurance and is expected to be effective shortly in Japan. These new drugs for cervical cancer have shown promising therapeutic efficacy, and depending on the response rate to these drugs, the timing of multigene panel testing after the second-line treatment may be acceptable. However, given the risk of mortality or worsening of the general condition at the time when panel test results are already available, panel testing may be conducted after the recurrence of advanced cancer of special histological types. The treatment of recurrent endometrial cancer has been partly surgery and mainly systemic chemotherapy (paclitaxel plus carboplatin, and docetaxel plus cisplatin [DP]). In KEYNOTE-775, lenvatinib plus pembrolizumab enabled prolonged progression-free survival and overall survival in patients with recurrent endometrial cancer, regardless of being mismatch repair proficient or deficient, compared with the conventional therapy of DP [ 22 ]. In Japan, lenvatinib plus pembrolizumab has already been covered by health insurance for the treatment of recurrent advanced endometrial cancer since December 2021. Given that our study period began in November 2019, we were able to include many cases with worsened general conditions after DP therapy. If this therapy will be shown to be effective in the future in Japan, the timing and prognosis of multigene panel testing may change. In January 2018, olaparib was approved as maintenance therapy in platinum-sensitive recurrent ovarian cancer, and in June 2019, it was approved as maintenance therapy after initial chemotherapy in BRCA1/2 mutation–positive ovarian cancer [ 23 ]. The PRIMA trial showed the benefit of niraparib in advanced ovarian cancer with or without homologous recombination deficiency (HRD) [ 24 ]. In addition, the PAOLA-1 trial showed that olaparib plus bevacizumab is effective for advanced ovarian cancer with HRD [ 25 ], and the efficacy of rucaparib also gained attention [ 26 ]. Thus, treatment options with poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer have evolved remarkably over the past few years. However, many challenges are still existing in the treatment of clear cell carcinoma [ 27 ], which is relatively common in the Japanese population and refractory to chemotherapy, and mucinous carcinoma, which does not respond well to chemotherapy. While CGP is promising for patients without treatment options (7 patients in this study), the previously administered treatments are recommended by CGP. For example, PARP inhibitor is recommended for a patient who already received PARP inhibitor before. In such a case, PARP inhibitor may not be given because the patient is already practically refractory to PARP inhibitor. Therefore, the 7 patients were included in the 29 patients for which no treatment was recommended as written in Table 2 . Although the treatment options for recurrent ovarian cancer are diversified and difficult to standardize, CGP should be performed in case the standard therapy will no longer be effective, and then linked to the recommended therapy. Regarding rare gynecologic tumors, we had one patient with vaginal cancer. Generally, vaginal cancer is uncommon and has a poor prognosis. Our patient had a histology of neuroendocrine and had no recommended treatment. Unfortunately, the patient died before the result was obtained. More cases of vaginal cancer should be accumulated in the future. Although chemotherapy widens the range of treatment options, the patient's general condition should be evaluated. However, in this study, 2 patients died and 14 were in poor general condition when the results were obtained. Considering that the test is performed under the assumption that chemotherapy will be administered, the patient's prognosis should be predicted, and the test should be performed at the appropriate time. The range of prognosis and treatment options for recurrence differs depending on the type of cancer; hence, our study results are impossible be generalized. At our hospital, the timing of CGP testing was left to the discretion of the attending physician. The prognosis varies not only by tumor and stage but also by patient background and age; thus, scheduling of tests may be necessary, with the anticipation that the standard treatment may be no longer effective in the future. In addition, six patients did not receive treatment at their request. Although their exact reasons were not fully examined in this study, they expressed difficulty in traveling to the distant medical institution where the clinical trial was being conducted, or they were resistant to the new treatment. We need to emphasize that the panel test is only a test for additional treatment and that the patient's living will should be checked again before the test. In conclusion, by multigene panel testing, 10.8% of patients received the recommended treatment despite druggable gene alterations being found in many cases. TMB-H was observed in various histological subtypes of cervical/endometrial cancer; thus, it can be a therapeutic biomarker of immune therapy. Furthermore, patients’ prognosis and personal status should be considered before ordering the test. Declarations Acknowledgments We are grateful to Ms. Hitomi Nishino, Ms. Atsuko Fukushima and Ms. Tomomi Noda for administrative assistance. This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 21H03079, 21K16822. Conflicts of Interest Tatsuyuki Chiyoda reported grants from Takeda Pharmaceutical Company. Daisuke Aoki reported honoraria from Takeda Pharmaceutical Company, Chugai Pharmaceutical Company, AstraZeneca, MSD and Myriad Genetics. Other authors declare no conflicts of interest regarding this study. References National Cancer Center, Japan. 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Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. doi: 10.1056/NEJMoa2112187. PMID: 35139273. O'Malley DM, Neffa M, Monk BJ, Melkadze T, Huang M, Kryzhanivska A, Bulat I, Meniawy TM, Bagameri A, Wang EW, Doger de Speville Uribe B, Hegg R, Ortuzar Feliu W, Ancukiewicz M, Lugowska I. Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. J Clin Oncol. 2022 Mar 1;40(7):762-771. doi: 10.1200/JCO.21.02067. Epub 2021 Dec 21. PMID: 34932394; PMCID: PMC8887945. Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindeløv SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I; innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 May;22(5):609-619. doi: 10.1016/S1470-2045(21)00056-5. Epub 2021 Apr 9. PMID: 33845034. Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448. doi: 10.1056/NEJMoa2108330. Epub 2022 Jan 19. PMID: 35045221. Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505. doi: 10.1056/NEJMoa1810858. Epub 2018 Oct 21. PMID: 30345884. Kurnit KC, Coleman RL, Westin SN. Using PARP Inhibitors in the Treatment of Patients With Ovarian Cancer. Curr Treat Options Oncol. 2018 Nov 15;19(12):1. doi: 10.1007/s11864-018-0572-7. PMID: 30535808; PMCID: PMC8240125. Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Fujiwara K, Vergote I, Colombo N, Mäenpää J, Selle F, Sehouli J, Lorusso D, Guerra Alía EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marmé F, Combe P, de Gregorio N, Rodrigues M, Buderath P, Dubot C, Burges A, You B, Pujade-Lauraine E, Harter P; PAOLA-1 Investigators. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2416-2428. doi: 10.1056/NEJMoa1911361. PMID: 31851799. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017 Jan;18(1):75-87. doi: 10.1016/S1470-2045(16)30559-9. Epub 2016 Nov 29. PMID: 27908594. Takano M, Sugiyama T, Yaegashi N, Sakuma M, Suzuki M, Saga Y, Kuzuya K, Kigawa J, Shimada M, Tsuda H, Moriya T, Yoshizaki A, Kita T, Kikuchi Y. Low response rate of second-line chemotherapy for recurrent or refractory clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):937-42. doi: 10.1111/j.1525-1438.2007.01158.x. Epub 2007 Dec 13. PMID: 18081792. Cite Share Download PDF Status: Published Journal Publication published 13 Aug, 2023 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 18 May, 2023 Reviewers agreed at journal 29 Apr, 2023 Reviewers invited by journal 28 Apr, 2023 Editor assigned by journal 26 Apr, 2023 First submitted to journal 25 Apr, 2023 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-2847818","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":196118324,"identity":"0374f1ad-79db-4f80-ad14-805b35c12064","order_by":0,"name":"Shoko Kitazawa","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shoko","middleName":"","lastName":"Kitazawa","suffix":""},{"id":196118325,"identity":"55a9bd69-b5db-4f2f-bda7-bd6e17d1c679","order_by":1,"name":"Tatsuyuki Chiyoda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYDACCcYGBgY2BjkJBhCDhwQtxqRoARFsDIkziHYX/+zmNokPZXbpM9ubGx8wyNwhwpI7B9skZ5xLzp3Nc7DZgIHnGWEtBhKJbdK8bcy584AMCQaew0RrqU+Xk39ImpbDCdISjERqkbiR2Gw549xxw5k9ic0GCcT4hX9G+sMbH8qq5SWOH3/44GMPESEGBCwScGZizwGitDB/QLB/EKdlFIyCUTAKRhYAADTROQtyig1dAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8214-2242","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Tatsuyuki","middleName":"","lastName":"Chiyoda","suffix":""},{"id":196118326,"identity":"a95d65cf-9fc7-4565-b08d-cbfa56ec1442","order_by":2,"name":"Kohei Nakamura","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Nakamura","suffix":""},{"id":196118327,"identity":"344bf295-6a1b-4cc8-acc6-df872a762486","order_by":3,"name":"Kensuke Sakai","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kensuke","middleName":"","lastName":"Sakai","suffix":""},{"id":196118328,"identity":"4336605b-8567-42a0-9ac0-063aa358028f","order_by":4,"name":"Tomoko Yoshihama","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Yoshihama","suffix":""},{"id":196118329,"identity":"00d16a76-f97d-4e04-bd6f-0640cdf685e7","order_by":5,"name":"Hiroshi Nishio","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nishio","suffix":""},{"id":196118330,"identity":"e6acc5d7-052d-4fac-aa58-7f4eabbe5cf8","order_by":6,"name":"Yusuke Kobayashi","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Kobayashi","suffix":""},{"id":196118331,"identity":"7ad7dbf1-a85c-41f9-be78-9a585099c178","order_by":7,"name":"Takashi Iwata","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Iwata","suffix":""},{"id":196118332,"identity":"df32fd14-0565-4328-8a76-335f5251e62f","order_by":8,"name":"Kouji Banno","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kouji","middleName":"","lastName":"Banno","suffix":""},{"id":196118333,"identity":"f88561c5-b4a6-4452-8b72-9ebfaae2e0a2","order_by":9,"name":"Wataru Yamagami","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wataru","middleName":"","lastName":"Yamagami","suffix":""},{"id":196118334,"identity":"c4a0df80-47f2-4e5e-98af-6daa33843ebd","order_by":10,"name":"Hiroshi Nishihara","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nishihara","suffix":""},{"id":196118335,"identity":"8ee9c046-f1db-4686-8720-cbbe5e4d933f","order_by":11,"name":"Daisuke Aoki","email":"","orcid":"","institution":"Keio University - Shinanomachi Campus: Keio Gijuku Daigaku - Shinanomachi Campus","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Aoki","suffix":""}],"badges":[],"createdAt":"2023-04-22 08:32:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2847818/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2847818/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-023-02398-8","type":"published","date":"2023-08-13T21:57:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44736651,"identity":"96d202eb-366b-48d8-88ab-f13873c4822e","added_by":"auto","created_at":"2023-10-16 22:31:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":375669,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2847818/v1/fcb4d819-d3fe-445d-b327-7c8dae3a8ab1.pdf"}],"financialInterests":"","formattedTitle":"Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe incidence of gynecological malignancies in Japan is approximately 42,500, with 11,684 deaths, per year [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. The standard treatment for advanced gynecologic cancer with distant metastasis or recurrence is systemic chemotherapy. However, standard chemotherapy has many refractory cases. Although the prognosis varies greatly depending on histological type, progression stage, and patient background, personalized medicine is currently being recommended.\u003c/p\u003e\n\u003cp\u003eIn June 2019, the Pharmaceuticals and Medical Devices Agency launched comprehensive genome profiling (CGP), a multigene panel testing method, for \u0026quot;patients with solid tumors for which no standard treatment is available, or patients with locally advanced or metastatic solid tumors for which standard therapy has been completed (including those expected to complete standard therapy)\u0026quot; in Japan [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. At the same time, FoundationOne\u0026reg; CDx (Foundation Medicine, Inc.; Cambridge, MA, US; Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) and OncoGuide\u0026trade; NCC Oncopanel (Sysmex Corp., Kobe, Japan) were approved to be covered by Japan\u0026rsquo;s health insurance for all solid tumors. Concurrently, the cancer genome medical system was innovated with the establishment of the Designated Core Hospital for Cancer Genomic Medicine, Designated Cancer Care Hospital, and Center for Cancer Genomics and Advanced Therapeutics.\u003c/p\u003e\n\u003cp\u003eOncoGuide\u0026trade; NCC Oncopanel has been conducted in Japan, and 124 genes (including 13 fusion genes) have been analyzed, with tumor tissue (formalin-fixed paraffin-embedded [FFPE]) DNA and nontumor tissue (whole blood) DNA as target samples. FoundationOne\u0026reg; CDx analyzes 324 genes (including 36 fusion genes) with tumor tissue (FFPE) DNA as the target sample. FoundationOne\u0026reg; cannot distinguish whether the detected variants are somatic or germline in origin. In both tests, the biomarkers for immune checkpoint inhibitors (ICIs) are microsatellite instability (MSI) and tumor mutation burden (TMB) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOncoGuide\u0026trade; NCC Oncopanel\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFoundationOne\u0026reg;CDx\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTissue gene panel testing approved in Japan\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCountry of origin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of genes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e324\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRequired sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFFPE, blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFFPE\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProportion of tumor cells needed for analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;20%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiomarkers for immune checkpoint inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSI, TMB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSI, TMB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFFPE, formalin-fixed paraffin-embedded; MSI, microsatellite instability; TMB, tumor mutation burden; US, United States\u003c/p\u003e\n\u003cp\u003eSince the health insurance approved to cover CGP, the number of CGP exams performed has been increasing [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]; however, the status of multigene panel testing in gynecological malignancies and the clinicopathological characteristics of the patients remain insufficiently reported [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Thus, this study aimed to summarize the results of the CGP examination at our hospital (Designated Core Hospital for Cancer Genomic Medicine) to investigate its usefulness as a potential treatment option for advanced and recurrent gynecologic cancers.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eWe enrolled patients who underwent CGP for gynecologic malignancies at our hospital between November 2019 and October 2022 and identified those who received CGP via FoundationOne\u0026reg; CDx and those via OncoGuide\u0026trade; NCC Oncopanel. The indication and timing of CGP were determined by the attending physician, but as a principle of health insurance coverage, this study included patients who were refractory to the standard therapy or the current therapy. No restrictions were made in terms of carcinoma or histological type among gynecological malignancies, as well as pre-examination treatment.\u003c/p\u003e \u003cp\u003eTumor samples were obtained from surgical or biopsy specimens. We did not use cell blocks taken from pleural or ascites fluid.\u003c/p\u003e \u003cp\u003eThe clinicopathological characteristics of the 102 patients who underwent CGP were extracted from medical records and characterized after the study protocol was approved by the ethics committee of the hospital (approval No.: 20120243, 20070081, and 20150197).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients and characteristics\u003c/h2\u003e\n \u003cp\u003eThis study included 102 patients with advanced gynecologic cancer who underwent CGP between November 2019 and October 2022 (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Among them, 9 underwent OncoGuide\u0026trade; NCC Oncopanel, whereas 93 underwent FoundationOne\u0026reg; CDx. Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003esummarizes patients\u0026rsquo; characteristics, test results, and post-test follow-up. All patients were treated at the hospital, and they gave informed consent before multigene panel testing. The median age was 55.5 years. None of them had unsuitable specimens; thus, all could be examined.\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEndometrial cancer**\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOvarian cancer***\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSarcoma\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVaginal cancer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients\u0026rsquo; characteristics and results\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage, n\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage I\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGene results\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eActionable gene (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDruggable gene (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e(-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCommon gene alterations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMB-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLOH-high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eERBB2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eATM\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eCDKN2A\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eCCND1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eFGF3\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMSI-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTiming of tests\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter the 1st-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter 2nd -line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter 3rd-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAfter the 4th-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMore\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter the results were provided\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDied before the results were provided\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCould not be treated because of worsened performance status (PS\u0026thinsp;\u0026gt;\u0026thinsp;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4****\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDenied treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDid not have the recommended treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot yet administered\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReceived molecularly targeted therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e*includes a patient with remote metastasis after an initial diagnosis of adenocarcinoma in situ\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e**includes two patients with carcinosarcoma of the uterus\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e***includes 6 patients with peritoneal cancers and 1 patient with granular-cell carcinoma\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003e****include a patient who could not be treated because of severe medical histories\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eLOH, loss of heterozygosity; MSI-H, high microsatellite instability; TMB-H, high tumor mutation burden\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003eThe majority of these patients had ovarian cancer (including peritoneal cancer and granulosa cell tumor) (n\u0026thinsp;=\u0026thinsp;43), followed by cervical cancer, endometrial cancer (including 2 carcinosarcomas), sarcoma, and vaginal cancer (n\u0026thinsp;=\u0026thinsp;32, 18, 8, and 1, respectively). One patient with stage 0 cervical cancer was initially diagnosed with adenocarcinoma in situ pathologically before metastasis.\u003c/p\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eshows the histological types. Of the patients with ovarian cancer, 25 had high-grade serous carcinoma (HGSC) and 1 had a low grade.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3 \u0026nbsp;Histological subtypes of gynecologic cancers included in the study\u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervical cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eadenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eendocervical adenocarcinoma, usual type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emucinous adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eadenocarcinoma admixed with neuroendocrine carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eadenosquamous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eneuroendocrine tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometrial cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEMG1/G2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEMG3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eserous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eclear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecarcinosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eothers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOvarian cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHGSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLGSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eclear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esmall cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecarcinosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emixed carcinoma (serous\u0026thinsp;+\u0026thinsp;clear)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egranulosa cell tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSarcoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eleiomyosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eendometrial stromal sarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVaginal cancer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elarge cell neuroendocrine carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eEM, endometrioid carcinoma; G, grade; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eCommon druggable gene alterations\u003c/h2\u003e\n \u003cp\u003eGene results revealed 98 patients with actionable gene alterations and 70 patients with druggable gene alterations. The most common druggable gene alteration was \u003cem\u003ePIK3CA\u003c/em\u003e mutation, followed by \u003cem\u003ePTEN\u003c/em\u003e mutation and high TMB (TMB-H) (n\u0026thinsp;=\u0026thinsp;21, 12, and 11, respectively).\u003c/p\u003e\n \u003cp\u003ePatients with cervical cancer, endometrial cancer, and endometrial stromal sarcoma exhibited TMB-H. The histological types of cervical cancer were squamous cell carcinoma in 4 patients and adenosquamous carcinoma in 1 patient. Three of them received the recommended therapy, one was still on current therapy but was being offered pembrolizumab as a treatment option, and one did not receive pembrolizumab at the patient\u0026rsquo;s request. Furthermore, the histological types found in patients with TMB-H endometrial cancer were endometrioid carcinoma (EM) grade (G) 2, EMG3, serous carcinoma, clear cell carcinoma, and adenocarcinoma individually. Only one of them was eligible for the recommended treatment; the others could not receive the recommended treatment because of deterioration of the general condition, regardless of the test results.\u003c/p\u003e\n \u003cp\u003eAmong all the patients, only one had high MSI (MSI-H). This patient had stage IIIC1 endometrial cancer with an \u003cem\u003eMSH2\u003c/em\u003e pathogenic variant. Genetic counseling was recommended, but when the result was obtained, the patient could not receive treatment because of an aggravated general condition. This patient died shortly afterward.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eResults and course of CGP\u003c/h2\u003e\n \u003cp\u003eThe attending physician conducted CGP when the patient was diagnosed with the progression of disease during or after the first-line treatment (n\u0026thinsp;=\u0026thinsp;21), during or after the second-line (n\u0026thinsp;=\u0026thinsp;45), during or after the third-line (n\u0026thinsp;=\u0026thinsp;18), during or after the fourth-line (n\u0026thinsp;=\u0026thinsp;16), and after more than the fourth-line (n\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e\n \u003cp\u003eUnfortunately, two patients (1.9%) died before the test results were available. In addition, 13 (12.7%) could not be treated with chemotherapy because of a very poor general condition when the test results were provided (performance status\u0026thinsp;\u0026ge;\u0026thinsp;2). One of these patients was ineligible for chemotherapy because of medical history, even though the recommended therapy was offered. Although 70 patients had druggable gene alteration, 10 patients for whom PARP inhibitor was recommended and had already been treated with a PARP inhibitor were classified as having no recommended treatment. In addition, 18 patients who had recommended treatment for which there were no off-label clinical trials were also categorized as \u0026ldquo;patients who did not have recommended treatment group\u0026rdquo;. As a result, 60 patients (58.8%) had no recommended treatment. Meanwhile, 10 patients (9.8%) had a recommended treatment but did not pursue it because they were responding to their current treatment. They were supposed to receive the recommended treatment if the current treatment would not effective.\u003c/p\u003e\n \u003cp\u003eA total of 11 patients (5 with cervical cancer, 2 with endometrial cancer, and 4 with ovarian cancer) (10.8%) received the recommended treatment (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Among them, 3 were tested after the initial treatment, 5 after the second-line, 2 after the third-line, and 1 in the fourth-line. Nivolumab was the most commonly administered drug as a recommended therapy.\u003c/p\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDiagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLines of Chemotherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDruggable Gene Alteration\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMedicine\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of the 11 patients who received molecularly targeted therapy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ctbody\u003e\u003c/tbody\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMB-H \u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndocervical adenocarcinoma, usual type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePTEN BRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOlaparib\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIB1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMB-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEverolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCervical cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMB-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOvarian cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEMG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIC1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEverolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOvarian cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHGSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIA1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLOH-high, \u003cem\u003eCD274, PDCD1LG2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOvarian cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHGSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIVB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eTSC1 BRIP1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatinum drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOvarian cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEMG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePIK3CA\u003c/em\u003e and \u003cem\u003eERBB2\u003c/em\u003e amplification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTrastuzumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometrial cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIVB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMB-H, \u003cem\u003ePIK3CA\u003c/em\u003e, \u003cem\u003eand BRCA1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNivolumab\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndometrial cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEMG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ePTEN\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEverolimus\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eEM, endometrioid carcinoma grade; G, grade; HGSC, high-grade serous carcinoma; LOH, loss of heterozygosity; TMB-H, high tumor mutation burden\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003ePatients with cervical cancer received the most frequently recommended treatment among gynecological cancers, with 5 (15.6%) being eligible for the recommended treatment. Among these 5 patients, 4 had squamous cell carcinoma and 1 had endocervical adenocarcinoma, usual type. Conversely, 17 had no recommended treatment. Most of the patients were examined after the second-line, and their conditions mainly had progressed or relapsed after systemic chemotherapy for recurrence after concurrent chemoradiation therapy (CCRT).\u003c/p\u003e\n \u003cp\u003eRegarding endometrial carcinoma, two patients (10.5%) could receive the recommended treatment. The patient with EMG2 had \u003cem\u003ea PTEN\u003c/em\u003e mutation and received everolimus. The other patient, who was diagnosed with serous carcinoma, had TMB-H and received nivolumab.\u003c/p\u003e\n \u003cp\u003eIn ovarian cancer, four patients (9.3%) were eligible for the recommended treatment (2 with HGSC and 2 with EMG2). One of the patients had \u003cem\u003ePIK3CA\u003c/em\u003e mutation and \u003cem\u003eERBB2\u003c/em\u003e amplification and received trastuzumab, a HER2 inhibitor. While most of the patients who could receive the recommended treatment had been tested after second-line chemotherapy, one was tested after four times of recurrence before receiving the recommended treatment.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn Japan, approximately 22.3% of patients who underwent CGP in all solid tumors were treated with molecularly targeted therapy as the recommended treatment [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], but few were reported with regard to gynecological malignancies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOf all 102 included patients, 32 had no druggable gene alterations, suggesting that these 32 patients did not receive the recommended treatment. In contrast, 11 (10.7%) out of 70 patients who had druggable gene alterations received the recommended treatment, with cervical cancer as the most common case (5 cases). The druggable gene alterations were TMB-H in 4 patients and \u003cem\u003ePIK3CA\u003c/em\u003e and \u003cem\u003eBRCA1\u003c/em\u003e in 3 patients each, and nivolumab was the most common drug administered as the recommended treatment. According to KEYNOTE-158 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which reported that ICIs are effective for solid tumors with MSI-H, most of the MSI-H tumors have TMB-H (\u0026gt;\u0026thinsp;20 mut/Mb) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Only one patient was diagnosed with MSI-H by CGP in this study. This might be because the MSI test had been performed before the CGP test, and patients with MSI-H were already undergoing treatment. The fact that MSI-H patients have a higher ICI response rate and a lower relapse rate may also have contributed to the result that only one patient was diagnosed with MSI-H. Considering the fact that only one patient had MSI-H in the present study and roughly 4% of cancers have MSI-H [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], MSI-H alone could not be a helpful biomarker for ICI treatments in a broad spectrum. Nevertheless, microsatellite-stable tumors with TMB-H benefit from ICIs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTreatment options for recurrent gynecologic malignancies have widened these days. However, while the views on the treatment of recurrent tumors have been generalized to some extent, defining a standard treatment remains difficult. Although treatment options that may offer a longer prognosis are increasing in number, prognosis may still be poor because of the severity of diseases. Nonetheless, CGP may help expand treatment options for these patients.\u003c/p\u003e \u003cp\u003eIn this study, the most common time for CGP testing in patients with cervical cancer was around the second-line of treatment. Currently, radiotherapy and systemic chemotherapy are the most common treatment options for recurrent cervical cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]; surgery is sometimes performed [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], but its effect on prognosis has not been established [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Given the current situation, many patients are expected to undergo multigene panel testing for recurrence after the standard treatment around the second-line. Recently, following the results of KEYNOTE-826 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], treatment with additional ICIs and cytotoxic chemotherapeutic agents for patients with advanced or relapsed cervical cancer has been covered by insurance in Japan. In addition to pembrolizumab, ICIs such as cemiplimab [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and dual checkpoint blockades such as balstilimab plus zalifrelimab [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and the human anti-tissue factor antibody of tisotumab vedotin [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] are gaining attention. Especially cemiplimab has just been covered by insurance and is expected to be effective shortly in Japan. These new drugs for cervical cancer have shown promising therapeutic efficacy, and depending on the response rate to these drugs, the timing of multigene panel testing after the second-line treatment may be acceptable. However, given the risk of mortality or worsening of the general condition at the time when panel test results are already available, panel testing may be conducted after the recurrence of advanced cancer of special histological types.\u003c/p\u003e \u003cp\u003eThe treatment of recurrent endometrial cancer has been partly surgery and mainly systemic chemotherapy (paclitaxel plus carboplatin, and docetaxel plus cisplatin [DP]). In KEYNOTE-775, lenvatinib plus pembrolizumab enabled prolonged progression-free survival and overall survival in patients with recurrent endometrial cancer, regardless of being mismatch repair proficient or deficient, compared with the conventional therapy of DP [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In Japan, lenvatinib plus pembrolizumab has already been covered by health insurance for the treatment of recurrent advanced endometrial cancer since December 2021. Given that our study period began in November 2019, we were able to include many cases with worsened general conditions after DP therapy. If this therapy will be shown to be effective in the future in Japan, the timing and prognosis of multigene panel testing may change.\u003c/p\u003e \u003cp\u003eIn January 2018, olaparib was approved as maintenance therapy in platinum-sensitive recurrent ovarian cancer, and in June 2019, it was approved as maintenance therapy after initial chemotherapy in \u003cem\u003eBRCA1/2\u003c/em\u003e mutation\u0026ndash;positive ovarian cancer [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The PRIMA trial showed the benefit of niraparib in advanced ovarian cancer with or without homologous recombination deficiency (HRD) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In addition, the PAOLA-1 trial showed that olaparib plus bevacizumab is effective for advanced ovarian cancer with HRD [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and the efficacy of rucaparib also gained attention [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Thus, treatment options with poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer have evolved remarkably over the past few years. However, many challenges are still existing in the treatment of clear cell carcinoma [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], which is relatively common in the Japanese population and refractory to chemotherapy, and mucinous carcinoma, which does not respond well to chemotherapy. While CGP is promising for patients without treatment options (7 patients in this study), the previously administered treatments are recommended by CGP. For example, PARP inhibitor is recommended for a patient who already received PARP inhibitor before. In such a case, PARP inhibitor may not be given because the patient is already practically refractory to PARP inhibitor. Therefore, the 7 patients were included in the 29 patients for which no treatment was recommended as written in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Although the treatment options for recurrent ovarian cancer are diversified and difficult to standardize, CGP should be performed in case the standard therapy will no longer be effective, and then linked to the recommended therapy.\u003c/p\u003e \u003cp\u003eRegarding rare gynecologic tumors, we had one patient with vaginal cancer. Generally, vaginal cancer is uncommon and has a poor prognosis. Our patient had a histology of neuroendocrine and had no recommended treatment. Unfortunately, the patient died before the result was obtained. More cases of vaginal cancer should be accumulated in the future.\u003c/p\u003e \u003cp\u003eAlthough chemotherapy widens the range of treatment options, the patient's general condition should be evaluated. However, in this study, 2 patients died and 14 were in poor general condition when the results were obtained. Considering that the test is performed under the assumption that chemotherapy will be administered, the patient's prognosis should be predicted, and the test should be performed at the appropriate time. The range of prognosis and treatment options for recurrence differs depending on the type of cancer; hence, our study results are impossible be generalized. At our hospital, the timing of CGP testing was left to the discretion of the attending physician. The prognosis varies not only by tumor and stage but also by patient background and age; thus, scheduling of tests may be necessary, with the anticipation that the standard treatment may be no longer effective in the future. In addition, six patients did not receive treatment at their request. Although their exact reasons were not fully examined in this study, they expressed difficulty in traveling to the distant medical institution where the clinical trial was being conducted, or they were resistant to the new treatment. We need to emphasize that the panel test is only a test for additional treatment and that the patient's living will should be checked again before the test.\u003c/p\u003e \u003cp\u003eIn conclusion, by multigene panel testing, 10.8% of patients received the recommended treatment despite druggable gene alterations being found in many cases. TMB-H was observed in various histological subtypes of cervical/endometrial cancer; thus, it can be a therapeutic biomarker of immune therapy. Furthermore, patients\u0026rsquo; prognosis and personal status should be considered before ordering the test.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to Ms. Hitomi Nishino, Ms. Atsuko Fukushima and Ms. Tomomi Noda for administrative assistance. This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 21H03079, 21K16822.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTatsuyuki Chiyoda reported grants from Takeda Pharmaceutical Company. Daisuke Aoki reported honoraria from Takeda Pharmaceutical Company, Chugai Pharmaceutical Company, AstraZeneca, MSD and Myriad Genetics. Other authors declare no conflicts of interest regarding this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNational Cancer Center, Japan. 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PMID: 18081792.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"cancer genomic profiling, ovarian cancer, cervical cancer, endometrial cancer, molecular tumor board ","lastPublishedDoi":"10.21203/rs.3.rs-2847818/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2847818/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eJapan\u0026rsquo;s health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne\u0026reg; CDx or OncoGuide\u0026trade; NCC Oncopanel between November 2019 and October 2022.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOut of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with others). The most common druggable gene alteration was \u003cem\u003ePIK3CA\u003c/em\u003e mutation (n\u0026thinsp;=\u0026thinsp;21), followed by \u003cem\u003ePTEN\u003c/em\u003e mutation (n\u0026thinsp;=\u0026thinsp;12) and high tumor mutation burden (TMB-H) (n\u0026thinsp;=\u0026thinsp;11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThrough multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients\u0026rsquo; prognosis and performance status should be considered before performing the test.\u003c/p\u003e","manuscriptTitle":"Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-03 22:26:08","doi":"10.21203/rs.3.rs-2847818/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2023-05-18T22:19:53+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-04-29T05:01:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-04-28T23:41:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-04-27T03:23:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2023-04-26T00:46:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"2b134f59-3dcd-41a1-9093-3daa97320d80","owner":[],"postedDate":"May 3rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T22:24:38+00:00","versionOfRecord":{"articleIdentity":"rs-2847818","link":"https://doi.org/10.1007/s10147-023-02398-8","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2023-08-13 21:57:47","publishedOnDateReadable":"August 13th, 2023"},"versionCreatedAt":"2023-05-03 22:26:08","video":"","vorDoi":"10.1007/s10147-023-02398-8","vorDoiUrl":"https://doi.org/10.1007/s10147-023-02398-8","workflowStages":[]},"version":"v1","identity":"rs-2847818","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2847818","identity":"rs-2847818","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}