ObjectivesGastric-type endocervical adenocarcinoma (GEA) is a rare malignant tumor that is not associated with high-risk HPV infection, known for its high invasiveness and resistance to current treatments. This study assessed the effectiveness of anti-angiogenic regimens in real-world GEA patients.MethodsPatients with GEA were enrolled between February 2012 and March 2023, and their clinicopathological characteristics were collected from their medical records. The patients were categorized into groups based on whether they received anti-angiogenic treatments or not. Survival analysis was conducted using the Kaplan-Meier method.ResultsA total of 43 GEA patients were enrolled in this study, with 23 cases who received anti-angiogenic drugs (nine received them as the primary treatment, 12 as first-line therapy after recurrence/metastasis, and two as second-line therapy) as the observation group. The other 20 patients who received similar treatments without the anti-angiogenic regimens serve as the control group. Compared to the control group, the addition of anti-angiogenic drugs as the primary treatment mildly extended progression-free survival (PFS) while not being statistically significant (16 months vs 11 months, p = 0.744). The negative results were also observed in 12 patients who started anti-angiogenic therapy as first-line therapy after recurrence/metastasis (8.5 months vs 9 months, p = 0.518). As for the overall survival (OS), no benefits were detected in either patients who started the anti-angiogenic therapy as primary or subsequent treatments (p = 0.499 and 0.450, respectively).ConclusionWe firstly evaluated the efficacy of anti-angiogenic drugs in treating patients with GEA. Although with a small sample size, our preliminary results clearly proposed that the anti-angiogenic therapy failed in suppressing tumors and should not be a preferred choice for GEA. As a much rarer tumor without standard treatments, we herein warned of a pitfall for gynecologic oncologists when facing this malignancy.

A rare coexistence of high-grade serous ovarian cancer and an obturator nerve schwannoma presented as a node-like pelvic sidewall mass. A 50-year-old woman had progressive abdominal distension, CA-125 1534 U/mL (reference range 0-35 U/mL), and computed tomography (CT) showing ovarian cancer with a left sidewall mass interpreted as nodal disease. After three cycles of paclitaxel-carboplatin, the ovarian disease regressed while the sidewall mass was unchanged. Because a percutaneous route was likely to traverse major vessels and open cytoreduction was planned, biopsy was deferred. At laparotomy, a well-circumscribed lesion centered on the obturator canal was dissected along the epineurial plane and intracapsularly enucleated, preserving the obturator nerve and its fascicles. Pathology showed schwannoma (spindle-cell fascicles with Verocay bodies; diffuse S-100 positivity; no epithelial markers). Posttreatment CT met the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for complete response; the patient received maintenance olaparib plus bevacizumab and, at 32-month follow-up, had no evidence of recurrence with intact adductor function. This case suggests that, during ovarian cancer cytoreduction, a stable, well-circumscribed sidewall mass on CT-particularly along the obturator canal-should raise suspicion for a neurogenic tumor; when biopsy access is unsafe and open surgery is planned, nerve-sparing enucleation is an appropriate management option.

Gastric-type endocervical adenocarcinoma (GEA) usually exhibits notable aggressiveness and resistance to current therapies. A high expression of programmed death-ligand 1 (PD-L1) was previous reported in GEA and indicated it might benefit from immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. In the present study, the efficacy of immunotherapy in a panel of patients with GEA was explored, aiming to provide the first-hand evidence on this topic. A total of 44 pathologically diagnosed patients with GEA were recruited from the First Affiliated Hospital of Zhengzhou University and the Cancer Hospital of Zhengzhou University. The clinical and pathological information including age, tumor stage, treatments and prognosis were retrieved from our medical records system. Kaplan-Meier analysis was conducted to evaluate the role of immunotherapy on patients' overall survival (OS) and progression-free survival (PFS). According to the treatments, patients with GEA were divided into two groups: The immunotherapy group (n=19) and the non-immunotherapy group (n=25, the control group). In the immunotherapy group, 9 patients received PD-1/PD-L1 inhibitors as part of their primary treatment, while the remaining 10 received it after tumor recurrence/metastasis. Compared with the control group, the use of immunotherapy during primary treatment significantly extended PFS (median PFS: 14 vs. 6 months, P=0.004) and OS (median OS: 24 vs. 16 months, P=0.019). However, in the 10 patients who initiated immunotherapy after tumor recurrence/metastasis, the survival benefits were only observed for OS (median OS: 33.5 vs. 16 months, P=0.013) but not PFS. Furthermore, the efficacy of immunotherapy was more significant in patients with PD-L1-positive GEA than those PD-L1-negative cases, which improved both the PFS (median PFS: 17 vs. 7 months, P=0.002) and OS (median OS: 36 vs. 16 months, P<0.001). This is the first study, to the best of our knowledge, reporting the efficacy of immunotherapy for GEA. It was demonstrated that the earlier use of PD-1/PD-L1 inhibitors was significantly associated with an improved prognosis, and PD-L1 status could predict the response of immunotherapy. These preliminary findings warrant further validations in the future.

The KEYNOTE-A18 trial recently demonstrated the benefits of first-line treatment with programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors for advanced cervical cancer. Herein, we investigated this using real-world data from a large Chinese cohort. From January 2020 to June 2023, 91 patients diagnosed with advanced cervical cancer receiving first-line systemic therapy incorporating PD-1/PD-L1 inhibitors were recruited as the treatment group, while 101 patients who did not receive PD-1/PD-L1 inhibitors were included as the control group. Baseline characteristics, including patient age, the International Federation of Gynecology and Obstetrics (FIGO) stage, histological subtypes, tumor diameter, PD-L1 expression, overall survival (OS), and progression-free survival (PFS), were extracted from the medical records. Survival analysis was performed utilizing the Kaplan-Meier curve and Cox regression analysis was used to compare the effects of different factors on patients’ survival. The addition of PD-1/PD-L1 inhibitors significantly prolonged PFS compared to the control group (median PFS: 19 vs. 11 months, p=0.000). Stratified analysis showed that higher expression of PD-L1 (median PFS: 14 vs. 14 months, p=0.031), earlier FIGO stage (median PFS: 20 vs. 11 months, p=0.000), and tumor diameter ≤4 cm (median PFS: 47 vs. 12 months, p=0.000) were associated with a better PFS. No statistical difference was detected in OS between the two groups. In the stage IVB subgroup, PD-1/PD-L1 inhibitors showed no benefits in either OS or PFS. Moreover, Cox regression analysis showed that only the use of PD-1/PD-L1 inhibitors was associated with prolonged PFS (hazard ratio = 0.43, 95% confidence interval 0.30 – 0.61, p=0.000). The first-line treatment containing PD-1/PD-L1 inhibitors significantly delayed tumor recurrence, especially for those with positive expression of PD-L1 and relatively small tumors.

BACKGROUND:We herein retrospectively analyzed the clinicopathologic features from a large cohort of GAS patients to provide real-world evidence for optimizing the diagnosis and treatment. RESEARCH DESIGN AND METHODS:One hundred and fifty-seven GAS patients from three hospitals were recruited for analysis. We extracted clinical and pathologic information from patient medical records and performed regular follow-up. Logistic regression and Kaplan - Meier analyses were conducted to identify the prognostic factors. RESULTS:31.2% exhibited stage I tumor, and 11.5%, 33.1%, and 24.2% manifested tumors at stages II, III, and IV, respectively. For the entire group, the median progression-free survival (PFS) and overall survival (OS) were 22 and 33 months, respectively. Multivariate analysis showed tumor stage and ovarian metastasis were predictors for PFS; and that ovarian metastasis and small tumor diameter were independent prognostic factors for OS. We determined an abnormal elevation of tumor abnormal protein (TAP) in 76% GAS patients, which could serve as a sensitive marker for tumor recurrence/metastasis. CONCLUSIONS:We demonstrated that ovarian metastasis and FIGO stage (including tumor diameter) were independent prognostic predictors for GAS patients. Moreover, we were the first to report that TAP constituted a potent marker for GAS surveillance, thus warranting further investigation.

Although high-grade neuroendocrine carcinoma of the cervix (HGNECC) accounts for less than 1% of all cervical cancers, it exhibits marked aggressiveness and resistance to radiation and chemotherapy. We retrospectively investigated the efficacy of immunotherapy for recurrent/metastatic HGNECC in a real-world setting. From September 2016 to December 2022, a total of 29 patients with HGNECC accepted PD-1/PD-L1 inhibitors; of these, six cases (20.7%) were PD-L1 positive (combined positive score ≥ 1). According to their primary treatment, the patients were assigned to either a surgery group (n = 14) or a non-surgery group (n = 15). In the surgery group, four patients received anti-PD-1 therapy immediately after surgery, while six, two, one, and one patients started immunotherapy after the first, second, third, and forth recurrence, respectively. In the non-surgery group, seven patients started immunotherapy as part of their primary treatment, while the other four, two, and two patients received anti-PD-1 drugs as the second, third, and forth lines of treatment, respectively. The seven-patient group showed longer progression-free survival after immunotherapy (PFSi) and overall survival than those of their counterparts (P = 0.085 and 0.08, respectively), while this benefit was not observed in other subgroups. No significant correlation was observed between PD-L1 and PFSi expression. Interestingly, one patient with a high tumor mutation burden (TMB-H) had a long PFSi of 26 months and experienced no recurrence until the last follow-up. Based on these findings, we propose that PD-1/PD-L1 inhibitors may prolong the survival of patients with HGNECC who start immunotherapy as the first-line of treatment. This indicates that early immunotherapy may be a better choice for this challenging malignancy. Moreover, the predictive role of TMB-H in immunotherapeutic outcomes requires further investigation.

IN10018 is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK). Our previous work showed promising objective response rate (ORR) and progression-free survival (PFS) of IN10018 in combination with PLD in PROC patients (Wu et al, ASCO2022). Here we present the fully enrolled study data, especially the overall survival (OS).

BACKGROUND:As a rare pathologic subtype, small cell carcinoma of the cervix (SCCC) is characterized by extensive aggressiveness and resistance to current therapies. To date, our knowledge of SCCC origin and progression is limited and sometimes even controversial. Herein, we explored the whole-protein expression profiles in a panel of SCCC cases, aiming to provide more evidence for the precise diagnosis and targeting therapy.METHODS:Eighteen SCCC samples and six matched normal cervix tissues were collected from January 2013 to December 2017. Data independent acquisition mass spectrometry (DIA) was performed to discriminate the different proteins (DEPs) associated with SCCC. The expression of CDN2A and SYP in corresponding SCCC tissues was verified using immunohistochemistry. GO and KEGG enrichment analyses were used to identify the key DEPs related to SCCC development and tumor recurrence.RESULTS:As a result, 1311 DEPs were identified in SCCC tissues (780 up-regulated and 531 down-regulated). In up-regulated DEPs, both GO analysis and KEGG analysis showed the most enriched were related to DNA replication (including nuclear DNA replication, DNA-dependent DNA replication, and cell cycle DNA replication), indicating the prosperous proliferation in SCCC. As for the down-regulated DEPs, GO analysis showed that the most enriched functions were associated with extracellular matrix collagen-containing extracellular matrix. KEGG analysis revealed that the DEPs were enriched in Complement and coagulation cascades, proteoglycans in cancer, and focal adhesion-related pathways. Down-regulation of these proteins could enhance the mobility of cancer cells and establish a favorable microenvironment for tumor metastasis, which might be accounted for the frequent local and distant metastasis in SCCC. Surprisingly, the blood vessels and circulatory system exhibit a down-regulation in SCCC, which might be partly responsible for its resistance to anti-angiogenic regimens. In the stratification analysis of early-stage tumors, a group of enzymes involved in the cancer metabolism was discriminated in these recurrence cases.CONCLUSIONS:Using quantitative proteomics analysis, we first reported the whole-protein expression profiles in SCCC. Significant alterations were found in proteins associated with the enhancement of DNA replication and cellular motility. Besides the association with mitosis, a unique metabolic feature was detected in cases with tumor recurrence. These findings provided novel targets for disease surveillance and treatments, which warranted further validation in the future.

5567 Background: IN10018 is a highly potent and selective oral inhibitor of focal adhesion kinase (FAK). IN10018 is synergistic with PLD against ovarian cancer in PDX models. This study evaluated the safety, tolerability, and antitumor activities of IN10018 in combination with PLD in patients with platinum-resistant ovarian cancer (PROC). Methods: This is an open-label phase Ib trial in patients with PROC (high-grade serous carcinoma only). Patient were treated with IN10018 in combination with PLD. This study has a dose-confirmation part and a dose-expansion part. Dose-expansion part was conducted at RP2D dose level to evaluate the primary endpoint of objective response rate (ORR). Secondary endpoints included disease control rate (DCR, CR + PR + SD ≥ 6 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of December 31, 2021 (cutoff date for all assessments), a total of 42 PROC patients were enrolled. 92.9% (39/42) patients had 1-3 prior lines of therapy and 14.3% (6/42) had prior bevacizumab use. The RP2D of the combination was determined as IN10018 100 mg QD in combination with PLD 40 mg/m2 Q4W in the dose-confirmation part since no DLTs were observed in 6 patients treated. The safety profile of the combination is comparable to these single agents alone without additive toxicities. No IN10018 related death was observed, and 9.5% (4/42) patients reported IN10018 related SAEs which were also PLD related. The most frequently reported IN10018 related AEs were proteinuria, decreased appetite, fatigue and AEs of gastrointestinal origin such as nausea, diarrhea, vomiting. Majority of these IN10018 related AEs were CTCAE grade 1 and 2, and 14.3% (6/42) had grade 3 AEs. No IN10018 related grade 4 or 5 AEs were reported. Proteinuria was noted asymptomatic, reversible, could be managed with appropriate dose interruption/reduction and only one proteinuria event resulted in IN10018 dose reduction. Antitumor response (as assessed by investigator) was evaluable in 30 patients. 17 patients had best overall response of PR including 13 confirmed PRs and 4 unconfirmed (2 in follow-up to be confirmed). No patient had CR and 9 patients had SD. The ORR is 56.7% (95% CI: 37.4%, 74.5%), the DCR is 86.7% (95% CI: 69.3%, 96.2%), and the median DOR was 4.5 months (95% CI: 2.7 months – NA) and is continuing to mature. Among the 20 efficacy evaluable patients who had at least 6 months of follow up, the ORR is 65.0% (13/20, 95% CI: 40.8%, 84.6%) and the DCR is 90.0% (18/20, 95% CI: 68.3%, 98.8%). In all 42 enrolled patients, the observed median PFS is 6.2 months (95% CI: 6.2 months - NA) and maturing. Conclusions: The combination of IN10018 with PLD showed promising antitumor activities and manageable safety profile in PROC patients. This combination warrants further confirmation in a randomized controlled trial.

ObjectiveSmall cell carcinoma of the cervix (SCCC) is rare but extremely aggressive and resistant to current therapies. We herein evaluate the efficacy of bevacizumab, apatinib, and anlotinib in recurrent/metastatic SCCC patients in a real-world setting. MethodsRecurrent/metastatic SCCC patients were recruited between January 2013 and July 2020. Baseline characteristics were extracted from medical records, and patients were divided into an anti-angiogenic group and non-anti-angiogenic group. The efficacy of treatments was determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Kaplan-Meier analysis was performed for survival analysis. ResultsSixteen patients received anti-angiogenic drugs after tumor recurrence/metastasis; of them, 10 cases received them as first-line treatment, 5 cases as second-line treatment, and 1 case as fourth-line treatment. Another 23 patients received traditional therapies, including surgery, chemotherapy, and radiotherapy. The use of anti-angiogenic drugs in first-line treatment significantly prolonged progression-free survival (PFS) compared to the controls, with a median PFS of 8 months (2-20 months) and 3 months (1-10 months), respectively (P = .025). This trend was also notable in patients who started anti-angiogenic treatment after the second-line recurrence/metastasis. However, there was no benefits for overall survival (OS) in either the 10 first-line cases or all 16 cases (P = .499 and .31, respectively). Both bevacizumab and small molecule drugs (apatinib and anlotinib) presented similar efficacy in SCCC patients. ConclusionsAt present, this is the largest cohort study that provides real-world data, showing that anti-angiogenic regimens could significantly prolong PFS in recurrent/metastatic SCCC. Aside from bevacizumab, the novel oral small molecule drugs provide more choices with similar efficacy. These findings warrant further validation in well-designed future studies.

Overexpression of HOTAIR (HOX antisense intergenic RNA) is significantly correlated with tumor progression and poor prognosis in human ovarian cancer. However, the underlying mechanisms are largely unknown. In the present study, we investigated the roles of HOTAIR in the initiation and chemoresistance of ovarian cancer. As our data show, HOTAIR overexpression promoted cell cycle progression (and thus cell proliferation) by activating the wnt/β-catenin signaling pathway. Likewise, knockdown of HOTAIR suppressed cell proliferation and arrested cell cycle at G1 phase via inhibition of wnt/β-catenin signaling. Moreover, the results of primary culture demonstrated that elevated HOTAIR expression correlated positively with chemoresistance in ovarian cancer. In vitro and in vivo, HOTAIR induced cellular resistance to cisplatin by activating the wnt/β-catenin pathway, which could be reversed by pre-treatment with the wnt/β-catenin inhibitor, XAV939. In conclusion, HOTAIR promotes the initiation and chemoresistance of ovarian cancer by activating wnt/β-catenin signaling, suggesting that HOTAIR might be a potent therapeutic target for ovarian cancer treatment.