YANG Jie,XIANG Yang (Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China)
Funds: Clinical Research Funds of the Central High-level Hospital(2022-PUMCH-B-083)
通信作者：向阳，E-mail：[email protected]
Prof. Yang Xiang
Director of the Gynecologic Cancer Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Peking Union Medical College, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Doctoral Supervisor, and the first batch of Peking Union Scholars Distinguished Professor, enjoy special government allowances
The 9th National Health Outstanding Contribution Young and Middle-aged Experts
Executive Member of the International Society of Trophoblastic Oncology and 18th Executive Chairman
Chairman-elect of the Gynecologic Oncology Branch of the Chinese Medical Association
Chairman of the Endoscopy (Gynecology) Professional Committee of the "Belt and Road" Medical Talent Training Alliance of the National Health Commission
President of the Minimally Non-Invasive Medicine Branch of the Chinese Medical Doctor Association
Chairman of the Gynecologic Oncology Professional Committee of the Obstetrics and Gynecology Branch of the Chinese Medical Doctor Association
Vice Chairman of the Tumor Endocrinology Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Uterine Oncology Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Colposcopy and Cervical Pathology Branch (CSCCP) of the Chinese Eugenics Science Association
Chairman of the Gynecologic Oncology Committee of the China Primary Health Care Foundation
Chairman of the Gynecologic Oncology Branch of Beijing Medical Association
Vice Chairman of the Obstetrics and Gynecology Branch of Beijing Medical Association
Vice President of the Obstetrics and Gynecology Branch of Beijing Medical Doctor Association
He is mainly committed to the clinical and basic research of gynecologic tumors
Ovarian cancer is a common tumor with a high degree of malignancy in the female reproductive system, which seriously endangers women's health. With the deepening of the understanding of the molecular level of ovarian cancer genes, as well as the gradual application of targeted drugs, antibody drug conjugates, immunotherapy, and thermal perfusion chemotherapy to clinical practice, the precision treatment methods for ovarian cancer are becoming more and more abundant, and great progress has been made for refractory, relapsed and drug-resistant ovarian cancer. Ovarian epithelial carcinoma is the most common type of ovarian malignancy, and this article reviews and summarizes the progress of ovarian cancer research in the 2023 International Oncology Conference, and reviews the research results of ovarian epithelial cancer this year, in order to serve clinical diagnosis and practice.
【Keywords】ovarian cancer, ovarian epithelial carcinoma, precision therapy, targeted therapy, antibody drug conjugate, immunotherapy, thermal perfusion chemotherapy
As the most intractable malignant tumor of the female reproductive system, ovarian cancer ranks third in the annual incidence rate of female reproductive system tumors, and the mortality rate ranks first among gynecological malignant tumors [1]. Ovarian cancer is generally divided into epithelial cancer, germ cell malignancy, and sex cord stromal cell tumor according to different tissue sources, among which epithelial cancer is the most common type of ovarian malignancy, accounting for about 90%. Because the ovaries are located deep in the pelvis, there are no specific symptoms in the early stage of the tumor, and most of the patients are already at an advanced stage when they visit the hospital, and the prognosis is poor, which seriously threatens the life safety of patients. 2023 is a year of harvest in the field of gynecologic oncology, in which the Society of Gynecologic Oncology (SGO), the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology, the European Society of Gynecologic Oncology and the International Society of Gynecologic Oncology have all presented major academic achievements that have changed clinical diagnosis and treatment. Surgery and chemotherapy have long been important cornerstones for the treatment of ovarian cancer [2]. However, even with surgery to achieve complete resection and standardized chemotherapy, recurrence of ovarian cancer is still inevitable. Therefore, prolonging the recurrence-free survival of patients is the unanimous pursuit of gynecologic oncologists and researchers. With the deepening of the research on maintenance therapy, researchers have paid more and more attention to the effectiveness of drug therapy and the reduction of toxicity and side effects, and with the deepening of the understanding of the molecular level of ovarian cancer genes and the gradual application of targeted drugs to clinical practice, the precision treatment methods of ovarian cancer have become more and more abundant, and targeted therapy and immunotherapy have also been gradually applied to maintenance therapy after surgery or chemotherapy [3]. Recurrence and drug resistance have always been difficult points in the treatment of ovarian cancer, and it is difficult to achieve a satisfactory effective rate of drug efficacy. This year, a breakthrough has been made in this issue, and the use of antibody drug conjugates (ADCs) has significantly improved the effective rate of treatment of this refractory tumor [4], making long-term survival possible for patients with relapse and drug resistance.
This article summarizes and reviews the progress related to ovarian cancer research at the 2023 International Oncology Conference, and selects several important revolutionary clinical trials this year for analysis and inventory in view of the key issues in the process of clinical diagnosis and treatment, so as to facilitate clinicians to understand the latest progress in ovarian cancer research, provide reference for clinical work, and serve the clinical diagnosis and treatment of ovarian cancer.
1、ADC
Ovarian cancer has always been a difficult point in the treatment of gynecologic cancers, with 70% of patients relapsing in about three years, and most patients with advanced or recurrent ovarian epithelial cancer will develop platinum resistance [5]. The prognosis of platinum-resistant patients is poor, with a response rate of about 20% to chemotherapy drugs, and a low response rate to conventional chemotherapy even when used in combination with bevacizumab. Therefore, there is a clinical need for new therapies for the treatment of recurrent ovarian cancer that can prolong the survival time of patients while reducing the toxicity of chemotherapy drugs [6].
The development of molecularly targeted therapies for ovarian cancer has been challenging. In recent years, the treatment of ovarian cancer has made great progress with the use of polyadenosine diphosphate ribose polymerase (PARP) inhibitors. However, there is still a lack of relatively effective treatment for relapsed and resistant ovarian cancer, especially in patients without BRCA mutations or homologous remodeling with normal repair. In this context, researchers have high hopes for ADCs in the treatment of platinum-resistant ovarian epithelial cancer. ADCs consist of three components: (1) monoclonal antibodies that bind to tumor cell surface antigens, (2) cytotoxic drug payloads, and (3) linkers, which deliver high doses of cytotoxic agents to tumor-associated antigens and directly target tumor cells without excessive systemic toxicity. This mode of administration facilitates the direct delivery of high doses of drugs to tumors, which is why ADCs are also referred to as biomissiles [7].
1.1 叶酸受体(Foliac Receptor,FR)类的ADC
FR is a high-affinity receptor that mediates cellular internalization and uptake of folic acid into the cytoplasm of eukaryotic cells, where FRα is a transmembrane glycoprotein that promotes one-way transport of folic acid into cells through receptor-mediated endocytosis. About 80% of ovarian epithelial carcinomas (especially high-grade serous carcinomas) and serous endometrial carcinoma express FRα, and FRα is also expressed in large amounts in recurrent or metastatic tumors without significant changes with chemotherapy, whereas FRα expression is not high in normal adult tissues. Therefore, this target is very desirable for epithelial ovarian cancer. At present, the ADC drug with a small effect on FRα-related treatment of ovarian cancer is mirvetuximab soravtansine (MIRV). MIRV consists of FRα-binding antibodies, cleavable junctions, and microtubule inhibitors, and cleavable junctions are designed so that cytotoxic metabolites can diffuse into neighboring cells for a bystander effect.
Results from the 2022 Phase II SORAYA trial of MIRV were published at SGO, with an objective response rate (ORR) of 32.4 percent in platinum-resistant patients [8]. On November 14, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval for the use of MIRV in patients with platinum-resistant ovarian cancer with high FRα expression.
At the 2023 ASCO Annual Meeting, Professor Moore presented the preliminary results of the Phase III MYRASOL study, which were encouraging [4]. The study included 453 patients with platinum-resistant recurrent ovarian cancer with high FRα expression, and 14%, 39%, and 47% of patients with first-, second, and third-line chemotherapy accounted for them, respectively. Sixty-two percent had been treated with bevacizumab and 55 percent had been treated with a PARP inhibitor. In the study, 453 patients were randomized 1:1 to MIRV (3 weeks of treatment with MIRV 6 mg/kg) and chemotherapy (including single-agent paclitaxel, pegylated liposomal doxorubicin, or topotecan) (IC group), with 227 patients randomized to MIRV and 226 patients randomized to I.C. The main endpoint of the study was progression-free survival (PFS) time, and the secondary endpoints were ORR and overall survival (OS) time, with a median follow-up time of 13.1 months, a median PFS time of 5.62 months in the MIRV group and 3.98 months in the IC group (HR=0.65, 95%CI 0.52~0.81); and ORR The MIRV group was 42.3% and the IC group was 15.9% (HR=0.72, 95%CI 0.56~0.92), of which 12 patients in the MIRV group had a complete response (5.3%), the median OS time was 16.46 months in the MIRV group and 12.75 months in the IC group (HR=0.67, 95%CI 0.50~0.88)), and the adverse events were mainly low-grade ocular complications (all grades: MIRV group: IC group=56%∶9%) ≥grade 3: 14%vs. 0%), and gastrointestinal events (all grades: 70%vs. 66% in the IC group; grade ≥3: 13%vs. 15% in the MIRV group: 13%vs. 15% in the IC group), and the incidence ≥of total grade 3 adverse events (42%vs. 54%), serious adverse events (24%vs. 33%), and discontinuation due to adverse drug reactions (9%vs. 16%) was lower in the MIRV group compared with the IC group. It can be seen that the ORR of patients with platinum-resistant ovarian cancer reaches >40% after treatment, which can be considered a big leap in the treatment effect of ovarian cancer.
In the future, the direction of research is the effect of MIRV combined with other drugs, and whether MIRV can be used as a first-line treatment instead of paclitaxel. Although the MYRASOL study was effective, the limitations of ADCs need to be recognized, and only 36% of patients in the SORAYA study had high FRα expression at initial screening. Therapeutic exploration for patients with relapsed resistance continues, and ADCs targeting other targets and cytotoxic drugs with different payloads are also being developed.
1.2 人表皮生长因子受体-2（human epidermal growth factor receptor-2，HER-2）相关的ADC
Ovarian cancer tumors are highly heterogeneous, and for some ovarian cancers expressing HER-2, it may be a targeted target and related targeted therapy can be carried out. The DESTINEY-PanTumor02 study of HER-2-related ADC agents in drug-resistant patients was reported at the 2023 ASCO Congress[9]. Trastuzumab deruxtecan (T-DXd) is an HER-2-directed antibody-drug conjugate approved for HER-2-expressing breast and gastric cancers and HER-2-mutated non-small cell lung cancers. The study is a phase II clinical trial evaluating the efficacy of T-DXd (5.4 mg/kg, 1 time/3 weeks) for HER-2 expression [immunohistochemistry (IHC) 3+ or 2+] in 267 patients with endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, biliary tract cancer, pancreatic cancer, and other types of tumors of locally advanced or metastatic tumors (≥ first-line systemic therapy), with ORR as the primary endpoint and secondary endpoints including safety, duration of response (DOR), PFS, and OS. The median follow-up time was 12.75 months, the ORR was 37.1% (95%CI 31.3%~43.2%) (all 7 tumor types were in remission, including 45% for ovarian cancer), the median DOR time was 11.3 months (95%CI 9.6~17.8 months), the median PFS time was 6.9 months (95%CI 5.6~8.0 months), and the median OS time was 13.4 months (95% The CI was 11.9~15.5 months). In this study, the ORR of patients with HER-2 IHC 3+ expression (n=75) was 61.3% (95%CI 49.4%~72.4%), the median DOR time was 22.1 months (95%CI 9.6 months ~ not reached), the median PFS time was 11.9 months (95%CI 8.2~13.0 months), and the median OS time was 21.1 months (95%CI 15.3~29.6 months). ≥Grade 3 drug-related adverse events were observed in 40.8% of patients in the study, 10.5% had drug-related interstitial lung disease, and 3 of them died.
The above studies suggest that HER-2-expressing tumors may be more sensitive to T-DXd, and IHC 3+ people may benefit the most, and T-DXd may have potential value in the treatment of refractory or advanced HER-2-expressing solid tumors, but the mechanism of drug-related pulmonary interstitization still needs to be further explored to reduce adverse reactions.
2. PARP inhibitors and immune checkpoint inhibitors
Combined maintenance therapy
Due to the high risk of recurrence of ovarian cancer, maintenance therapy has long been one of the means used by gynecologic oncologists to try to delay tumor recurrence. Although PARP inhibitors and bevacizumab maintenance therapy have greatly improved the prognosis of some patients with ovarian cancer, the overall prognosis is still limited, and researchers continue to explore maintenance therapy methods. In 2023, ASCO released the results of the Phase III NCT03737643 study [10]. The study evaluated the effect of first-line treatment with paclitaxel carboplatin chemotherapy, bevacizumab, durvalumab, and durvalumab maintenance therapy after maintenance therapy with bevacizumab, durvalumab, and olaparib in non-BRCA-mutated advanced ovarian cancer, and included 1 130 patients who were treated by the Inter-national Federation of Gynecology and Obstetrics, FIGO) stage III or IV high-grade epithelial carcinoma of the ovary without systemic BRCA mutation, and has completed tumor cytoreductive surgery and 1 cycle of paclitaxel carboplatin chemotherapy. In the second cycle of the study, patients were randomly divided into three groups on a 1:1:1 basis: the first group was paclitaxel carboplatin chemotherapy + bevacizumab (15 mg/kg, once a time/3 weeks) + durvalumab placebo for up to 6 cycles, followed by bevacizumab (15 mg/kg, once a week, a total of 15 months) + durvalumab placebo (a total of 24 months) + olaparib placebo (a total of 24 months), and the second group was paclitaxel carboplatin chemotherapy + bevacizumab + durvalumab (1 120 mg, once / 3 weeks), followed by bevacizumab + durvalumab + olaparib placebo, and paclitaxel carboplatin chemotherapy + bevacizumab + durvalumab in the third group, followed by bevacizumab + durvalumab + olaparib (300 mg, 2 times/day). The endpoint of the study was PFS in group 3 and group 1, and the PFS in group 3 was significantly improved compared with group 1 in the interim analysis [homologous recombination deficiency (HRD) + HR=0.49, 95%CI 0.34~0.69, P<0.0001) in the subgroup; overall HR=0.63, 95%CI 0.52~0.76, P]. <0.0001];PFS appeared to improve in group 2 compared with group 1, but not to be statistically significant. The serious adverse events in group 1, group 2 and group 3 of the study were 34%, 43% and 39%, respectively, and the combination treatment did not significantly increase the serious adverse events, and the treatment effectiveness was good, but the long-term survival still needs further results to support.
3. Post-line maintenance therapy with PARP inhibitors
and indication changes
With the full application of PARP inhibitors to first-line and late-line maintenance therapy, the accumulation of PFS and OS data has also raised concerns. As a result, in November 2022, the FDA issued several letters of recommendation to clinicians, and modified some indications in the post-line maintenance therapy of PARP inhibitors, withdrawing some previously approved indications. The FDA withdrew the indication for maintenance therapy with niraparib and rucaparib for the treatment of platinum-sensitive ovarian cancer patients with non-germline BRCA1/2 mutations due to the lack of benefit from the use of PARP inhibitors from the NOVA and ARIEL3 studies [11-13]. Similarly, the FDA withdrew these three drugs as monotherapy indications for patients with recurrent ovarian cancer because the ARIEL4, SOLO3, and QUADRA trials showed no difference in OS outcomes in the rucaparib, olaparib, and niraparib arms compared with the placebo group. Therefore, researchers need to weigh and consider various factors such as the biological characteristics of the tumor, treatment results, and long-term survival, and formulate a more suitable treatment plan and conduct research verification. These revisions emphasize the importance of reviewing the risk-benefit relationship in the context of the patient's disease. The potential to provide a shorter duration of maintenance therapy early has led to a shift in first-line therapy to PARP inhibitors in most patients. For those who did not receive this maintenance therapy beforehand, if PARP inhibitor therapy is being considered after relapse, platinum-sensitive disease and BRCA1/2 mutations and/or HRD-positive should predominate.
4、热灌注化学药物疗法（hyperthermic intraperitoneal chemotherapy，HIPEC）在卵巢癌手术中的应用
Advanced ovarian cancer is difficult to achieve complete resection by surgery, and researchers have long hoped to improve outcomes with perioperative intraperitoneal HIPEC, but there are currently no guidelines that explicitly recommend the routine use of HIPEC in the perioperative period. At this year's ASCO meeting, researchers reported NCT00426257 findings [14]. In this study of 245 patients, patients with FIGO stage III ovarian cancer were randomly assigned to HIPEC and no HIPEC at the time of intermittent cytoreductive surgery, with a mean follow-up of 10.1 years, and median PFS was 14.2 months versus 10.7 months in the HIPEC and no HIPEC groups (HR=0.66, 95% The CI was 0.50~0.87, P=0.003), and the median OS time was 45.7 months and 33.9 months, respectively (HR=0.67, 95%CI 0.48~0.94, P=0.02). However, in recent years, it has been reported that HIPEC does not significantly improve the prognosis of patients with ovarian cancer [15-16], so the therapeutic significance of HIPEC remains controversial. In addition, due to the limitations of various factors such as equipment and operation duration, it is difficult for HIPEC to be widely used in clinical practice.
5. Targeted therapy for low-grade ovarian serous carcinoma
Although low-grade ovarian serous carcinoma is not highly malignant, it lacks sensitive chemotherapy drugs. In patients with advanced and recurrent disease, the prognosis remains suboptimal if surgical resection is not possible. This type of tumor usually occurs in young patients, and even though the OS is better than that of high-grade ovarian cancer, the physical and psychological burden on the patient is heavier. For a long time, there has been no breakthrough in the treatment of low-grade serous carcinoma. This type of ovarian cancer is different from high-grade serous carcinoma in that there are almost no mutations in TP53, but there are usually mutations in the RAS pathway and PIK pathway, so targeted therapy may be a breakthrough point. At the 2023 GO meeting, the investigators reported the results of the Phase II NCT03673124 study [17]. The study included 48 patients with recurrent low-grade serous ovarian cancer who had not previously been treated with a CDK4/6 inhibitor or letrozole, and prior therapy consisted of 73% chemotherapy, 27% hormonal therapy, and 13% immunotherapy (600 mg/day with ribociclib for 3 weeks, 1 week off, plus 2.5 mg/day letrozole for 28 days until disease progression). The primary endpoint of the study was 23%, all of which were partial responses, with a clinical response rate of 79%, a median DOR time of 19.1 months (95%CI of 4.8~35.8 months), a median PFS time of 19.1 months, a median OS time not reached, and the most common grade 3 adverse events were neutrophil (44%) and leukocyte (8%) decreases. Overall, the combination treatments in the study were very well tolerated, and while nearly 40% of patients are still in the study, the results are encouraging enough.
6. Summary and outlook
In 2023, the results of ovarian cancer have been fruitful, in addition to the demonstration of the results of in-depth studies of PARP inhibitors and the changes in indications, the effect of ADC in the treatment of ovarian cancer is also gratifying, the exploration of immunosuppressants is also being further carried out, and other rare types of ovarian epithelial carcinoma such as low-grade serous carcinoma and clear cell carcinoma have also made great progress. With the development of targeted therapy drugs and immunotherapy drug research, it will become possible for ovarian cancer to become a chronic disease. In the future, it is necessary to deepen the understanding of the molecular biological characteristics of tumors and the in-depth understanding of tumor heterogeneity, so as to help achieve precise clinical management and ultimately improve the prognosis of patients.
Bibliography:
[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[2] VENEZIANI A C, GONZALEZ-OCHOA E, ALQAISI H, et al. Heterogeneity and treatment landscape of ovarian carcinoma[J]. Nat Rev Clin Oncol, 2023, 20(12):820-842.
[3] TATTERSALL A, RYAN N, WIGGANS A J, et al. Poly (ADP‐ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer[J/CD]. Cochrane DB Syst Rev, 2022(2):CD007929.
[4] MOORE K N, ANGELERGUES A, KONECNY G E, et al. Phase Ⅲ MIRASOL (GOG 3045/ENGOT-ov55) study: initial report of mirvetuximab soravtansine vs. investigator's choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression[J]. J Clin Oncol, 2023, 41(Suppl 17):LBA5507-LBA07.
[5] VENEZIANI A C, GONZALEZ-OCHOA E, ALQAISI H, et al. Heterogeneity and treatment landscape of ovarian carcinoma[J]. Nat Rev Clin Oncol, 2023, 20(12):820-842.
[6] PUJADE-LAURAINE E, HILPERT F, WEBER B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial[J]. J Clin Oncol, 2014, 32(13):1302-1308.
[7] FU Z, LI S, HAN S, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy[J]. Signal Transduct Target Ther, 2022, 7(1):93.
[8] MATULONIS U A, LORUSSO D, OAKNIN A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: Results from the SORAYA study[J]. J Clin Oncol, 2023, 41(13):2436-2445.
[9] MERIC-BERNSTAM F, MAKKER V, OAKNIN A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial[J]. J Clin Oncol, 2023, 2023:Jco2302005.
[10] HARTER P, TRILLSCH F, OKAMOTO A, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): results from the randomized, placebo (pbo)-controlled phase III DUO-O trial[J]. J Clin Oncol, 2023, 41(Suppl 17):LBA5506-LBA06.
[11] MIRZA M R, MONK B J, HERRSTEDT J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer[J]. N Engl J Med, 2016, 375(22):2154-2164.
[12] CLAMP A R, LORUSSO D, OZA A M, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma: the effects of progression-free interval and prior therapies on efficacy and safety in the randomized phase Ⅲ trial ARIEL3[J]. Int J Gynecol Cancer, 2021, 31(7):949-958.
[13] TATTERSALL A, RYAN N, WIGGANS A J, et al. Poly (ADP‐ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer[J/CD]. Cochrane Database Syst Rev, 2022, 2(2):CD007929
[14] ARONSON S L, LOPEZ-YURDA M, KOOLE S N, et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): Final survival analysis of a randomised, controlled, phase 3 trial[J]. Lancet Oncol, 2023, 24(10):1109-1118.
[15] ZIVANOVIC O, CHI D S, ZHOU Q, et al. Secondary cytoreduction and carboplatin hyperthermic intraperitoneal chemotherapy for platinum-sensitive recurrent ovarian cancer: An MSK team ovary phase Ⅱ study[J]. J Clin Oncol, 2021, 39(23):2594-2604.
[16] LIM P Q, HAN I H, SEOW K M, et al. Hyperthermic intraperitoneal chemotherapy (HIPEC): an overview of the molecular and cellular mechanisms of actions and effects on epithelial ovarian cancers[J]. Int J Mol Sci, 2022, 23(17):10078
[17] SLOMOVITZ B, DENG W, KILLION J, et al. GOG 3 026 A phase Ⅱ trial of letrozole + ribociclib in women with recurrent low-grade serous carcinoma of the ovary, fallopian tube or peritoneum: a GOG foundation study[J]. Gynecol Oncol, 2023, 176(1):S2.