Metastatic Cervical Carcinoma Research Articles

A phase 1/2, open-label, multicenter, dose escalation and cohort expansion study of the safety and efficacy of anti-CD70 allogeneic CRISPR-Cas9–engineered T cells (CTX131) in adult patients with relapsed or refractory solid tumors.

TPS2676 Background: CD70, a type II transmembrane protein and member of the tumor necrosis factor (TNF) receptor family, demonstrates high expression across multiple malignancies making it an attractive target for chimeric antigen receptor (CAR) T cell therapy. CD70 is expressed in 80% of clear cell renal cell carcinoma (ccRCC) and in 40-60% of cervical carcinoma (CC), esophageal carcinoma (EC), pancreatic adenocarcinoma (PAC), and pleural mesothelioma (PM) (1). CTX131 is a CD70-directed allogeneic CAR T cell investigational product manufactured ex vivo from healthy donor T cells using CRISPR/Cas9 technology. Genetic modifications in CTX131 include targeted insertion of a CD70-directed CAR construct, and targeted disruption of 5 loci: TRAC (to reduce risk of GvHD), B2M (to improve persistence in the allogeneic setting), CD70 (to reduce fratricide and improve anti-tumor function), TGFBR2 (to reduce immunosuppressive effect of TGFB in the tumor microenvironment), and Regnase-1 (to improve functional persistence) (2). Preclinical studies show the combination of TGFBR2 and Regnase-1 disruption in CTX131 works synergistically to enhance anti-tumor activity, inhibit tumor growth in xenograft mouse models, prolong survival, and increase central memory T cell populations (3). Methods: We are conducting a phase 1/2 study in patients (pts) with unresectable or metastatic ccRCC, CC, EC, PAC, and PM. Part 1 is a dose escalation with two separate cohorts, one for ccRCC pts and another for CC, EC, PAC, and PM pts. Part 1 ccRCC cohort began recruiting in 2023. Part 2 is a single-arm expansion of disease-specific cohorts. Key eligibility criteria include at least one prior line of standard treatment, ECOG status 0-1, evaluable disease per RECIST v1.1 (or modified RECIST1.1 for PM), adequate hematologic and organ function, and availability of tumor tissue for CD70 IHC. Key exclusion criteria include prior treatment with CD70-targeting agents and active CNS metastasis. Pts will receive standard lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 daily x 3 days followed by CTX131 IV infusion at doses ranging from 30-900 million cells in 4 dose level cohorts. Redosing with CTX131 is permitted. For Part 1, the primary endpoint is DLTs with secondary endpoints including ORR, DOR, PFS, and OS. For Phase 2 the primary endpoint is ORR by IRC assessment. The trial is currently open with enrollment ongoing. 1. Flieswasser et. al. 2019. 2. Mai et. al. 2023. 3. Terrett 2023. Clinical trial information: NCT05795595 .

Survival outcomes in head and neck squamous cell carcinoma of unknown primary: A national cohort study.

To investigate factors influencing survival in head and neck squamous cell carcinoma of unknown primary (HNSCCUP). A retrospective observational cohort study was conducted, over 5 years from January 2015, in UK Head and Neck centres, of consecutive adults undergoing 18F-Fluorodeoxyglucose-PET-CT within 3 months of diagnosis with metastatic cervical squamous cell carcinoma. Patients treated as HNSCCUP underwent survival analysis, stratified by neck dissection and/or radiotherapy to the ipsilateral neck, and by HPV status. Data were received from 57 centres for 965 patients, of whom 482 started treatment for HNSCCUP (65.7% HPV-positive, n = 282/429). Five-year overall survival (OS) for HPV-positive patients was 85.0% (95% CI 78.4-92.3) and 43.5% (95% CI 32.9-57.5) for HPV-negative. HPV-negative status was associated with worse OS, disease-free (DFS), and disease-specific (DSS) survival (all p < .0001 on log-rank test) but not local control (LC) (p = .16). Unilateral HPV-positive disease treated with surgery alone was associated with significantly worse DFS (p < .0001) and LC (p < .0001) compared to radiotherapy alone or combined modalities (5-year DFS: 24.9%, 82.3% and 94.3%; 5-year LC: 41.8%, 98.8% and 98.6%). OS was not significantly different (p = .16). Unilateral HPV-negative disease treated with surgery alone was associated with significantly worse LC (p = .017) (5-year LC: estimate unavailable, 93.3% and 96.6%, respectively). Small numbers with bilateral disease precluded meaningful sub-group analysis. HPV status is associated with variable management and outcomes in HNSCCUP. Unilateral neck disease is treated variably and associated with poorer outcomes when managed with surgery alone. The impact of diagnostic oropharyngeal surgery on primary site emergence, survival and functional outcomes is unestablished.

Effect of hypoxia-inducible factor-1 alpha expression on survival in patients with metastatic cervical squamous cell carcinoma treated with first-line chemotherapy and bevacizumab.

This study addresses the gap in understanding the prognostic relevance of hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression in metastatic cervical squamous cell carcinoma (SCC) patients undergoing anti-vascular endothelial growth factor (VEGF)-based therapy. A retrospective multicenter study (n = 34) explored HIF-1 alpha expression via immunohistochemistry in patients treated with platinum chemotherapy and bevacizumab. Median progression-free survival (PFS) was significantly lower in the HIF-1 alpha low score group compared to the high score group (4.9 vs 12.9 months, P = 0.014). Similarly, the median overall survival (OS) was significantly reduced in the HIF-1 alpha low score group (8.3 vs 20.4 months, P = 0.006). This study, the first of its kind, highlights the prognostic significance of HIF-1 alpha expression in metastatic cervical SCC patients treated with bevacizumab-based therapy.

Prognostic models for predicting overall and cancer-specific survival of patients with initially diagnosed metastatic cervical squamous cell carcinoma: A study based on SEER database.

Cervical squamous cell carcinoma (CSCC) is the most common histological type of cervical cancer (CC). And mCSCC is the end stage of CSCC. The aim of this study was to develop prognostic nomograms that provide better predictions for overall survival (OS) and cancer-specific survival (CSS) in mCSCC patients. Data from patients with initially diagnosed mCSCC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The nomograms for OS and CSS were constructed based on Cox regression analysis. The validation of the newly established nomograms was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). A total of 2198 patients with mCSCC were included and randomly split into training (n = 1539) and validation (n = 659) cohorts in a 7:3 ratio. Multivariate analyses revealed that the prognostic variables significantly related to the OS and CSS were marital status, T stage, brain metastasis, lung metastasis, tumor size, number of positive lymph nodes, chemotherapy, and radiotherapy. The nomograms were constructed based on these factors. The C-index value of the nomograms for predicting OS and CSS was 0.714 and 0.683, respectively. The calibration curves of the nomograms showed good consistency between nomogram prediction and actual survival for both OS and CSS, and the DCAs showed great clinical usefulness of the nomograms. The mCSCC patients were classified into low- and high-risk groups based on the scores from the nomograms. In the validation cohort, mCSCC patients with low-risk had much higher OS and CSS than those with high-risk. We constructed nomograms for predicting the OS and CSS of patients with initially diagnosed mCSCC. Our models had satisfactory predictive performance and could be useful in survival prediction for mCSCC.

Final analysis of a randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311)

ObjectiveTo assess the efficacy of dose-dense weekly paclitaxel plus carboplatin in metastatic or recurrent cervical carcinoma, we conducted a phase II/III randomized controlled study comparing dose-dense paclitaxel and carboplatin with...

Resveratrol and Cervical Cancer: A New Therapeutic Option.

Globally, cervical cancer is the second most common cancer and the third main cause of death related to cancer in women. The cervical cancer mortality rate is higher in underdeveloped and developing vs. developed countries. Chronic infection with human papilloma virus (HPV) can trigger cervical cancer by an interplay of a variety of pathways and molecules (i.e., inflammatory mediators, oxidative stress and apoptosis), leading to carcinogenesis and cancer progression. Cervical carcinoma is treatable in the early stages, while it progresses to metastasis at advanced stages; however, generally, it is poorly manageable with current treatment options. For future advances in the treatment of metastatic or recurrent cervical cancer carcinoma, the identification of new therapeutic platforms is necessary. A new generation of drugs, herbs and spices may provide novel opportunities for cancer therapy. Among the herb-based components, resveratrol has several beneficial effects given its anticancer activities (e.g., anti-angiogenesis, anti-proliferation, anti-metastatic and pro-apoptotic). Hence, this therapeutic agent may prove to have promising potential if clinically corroborated to possess anticancer efficacy. Here, we summarize the chemopreventive and treatment actions of resveratrol for cervical cancer as well as its mechanism of action.

RF30 | PSAT135 Rare Case of Hypercalcemia Mediated by an Ectopic Parathyroid Hormone (PTH), and Parathyroid Hormone-Related Peptide (PTHrP) Co-Secretion Secondary to Metastatic Cervical Carcinoma

Abstract Introduction Hypercalcemia of malignancy occurs in ∼20-30% of cancer patients. This mostly occurs by three mechanisms: humoral mediated from excess production of PTHrP, osteoclast mediated bone resorption from osteolytic metastasis and calcitriol mediated in granulomatous diseases such as lymphoma. Very rarely, PTH mediated hypercalcemia can occur in the setting of ectopic PTH production from tumor cells. Case presentation A 57 year- old woman with a medical history of hypertension and hyperthyroidism presented to the emergency department with several days of fatigue, nausea, vomiting, constipation and abdominal pain. Exam was remarkable for a heart rate (HR) of 140, lethargy, dry mucous membranes and chronic bilateral proptosis. Labs were remarkable for corrected calcium level of 18.38 mg/dl, Phosphorous of 3.2 mg/dL, Mg level of 1.2 mEq/L, blood urea nitrogen (BUN) of 20 mg/dL, creatinine of 1.6 mg/dL alkaline phosphatase of 170 units/L, and Lactic acid was 3.0 mmol/L. TSH 0.291 (0.40-4.7), FT4 1.51 ng/dl (0.70-1.80), FT3 3.2 pg/ml (2.8-5.3). Patient was treated with IV fluids, calcitonin 4u/kg bid, zoledronic acid 4 mg and started on cinacalcet. Further workup revealed elevated PTH of 1351 pg/ml (16-80), PTH-rP of 28 (&amp;lt;2), 25-hydroxyvitamin D of 25.5 ng/ml (30-100), 1,25-dihydroxy vitamin D level of 59.8 pg/ml (19.9-79.3). Patient couldn't tolerate sestamibi scan. 4DCT couldn't be performed due to creatinine elevation Bedside US performed did not show any evidence of parathyroid adenoma. CT, abdomen and pelvis a large mass in the cervix and cecum. Cervical biopsy revealed necrotic tumor with vary rare nests of viable atypical cells. Given persistent hypercalcemia, despite additional treatment, CRRT was initiated on hospital day 15 with rapid normalization of calcium level. However, patient continued to rapidly deteriorate with multi-organ failure and was transitioned to comfort care before expiring. Autopsy revealed poorly differentiated necrotic cervical carcinoma measuring 12×6×8 cm with metastasis to the left ovary as well as multiple tumor lesions in the liver. Parathyroid glands were normal on gross exam. PTH staining could not be performed given degree of tumor necrosis Discussion Hypercalcemia with elevated PTH and negative localization studies, should raise suspicion for ectopic PTH production from underlying malignancy. In PTHrP mediated hypercalcemia, PTH as well as 1,25 (OH) D are expected to be suppressed. This patient had an elevated PTHrP but not enough to suppress PTH or 1,25 (OH) D level. Given that parathyroid glands were normal on gross exam; this is consistent with ectopic PTH mediated hypercalcemia with component of PTHrP co-secretion. Hypercalcemia of malignancy presents late and portends a poor prognosis and therefore appropriate diagnosis and management is critical. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:42 p.m. - 12:47 p.m.

S1760 Metastatic Cervical Squamous Cell Carcinoma of the Distal Bile Duct

Introduction: Squamous cell carcinoma (SCC) of the bile duct is sporadic. Most cases are primary. Only 2 cases of cervical SCC metastatic to the bile ducts have been reported. Consideration of this diagnosis is essential in patients who have a history of malignancy and present with symptoms of biliary obstruction. Case Description/Methods: A 63-year-old female presented with persistent abdominal pain, nausea, and vomiting. Mild abdominal tenderness and scleral icterus were noted on physical examination. Bilirubin, AST, and ALT were elevated. Magnetic resonance cholangiopancreatography (MRCP) revealed dilated intra- and extra-hepatic bile ducts; however, there was no evidence of an apparent mass or gallstones. A lesion was observed at the ampullary level measuring around 1 cm that was brushed and biopsied on endoscopic cholangiopancreatography (ERCP). A metal stent was placed for decompression in the common bile duct. Pathology revealed poorly differentiated SCC with an immune profile favoring metastasis from the gynecologic tract. The patient was diagnosed with SCC of the cervix 15 months prior to presentation. A biopsy of the cervical tissue showed poorly differentiated cervical SCC with positivity in CK7 and HMWK, scattered positive staining of vimentin. Chemo-radiation was initiated with Cisplatin, Paclitaxel, and Bevacizumab. Next-generation sequencing (NGS) showed an immunohistochemical profile consistent with gynecological cancers, namely, MLH1, PMS2, MSH2, and MSH6. Pembrolizumab was also started due to positive PDL-1 expression and mutations in ATM and KMT2D. These agents were continued after she underwent the biliary decompression. Discussion: Metastatic SCC of the biliary tract is rare. Due to its low incidence, there is no standardized treatment strategy; however, there are reported cases of surgical resection in addition to chemoradiotherapy. Very few cases of cervical SCC have been reported to spread to gastrointestinal organs. NGS is a modality that has been widely implemented. The combination of immunohistology staining and NGS can aid in the diagnosis and help guide chemotherapy. The genetic variations present a valuable tool to aim the treatment of cervical cancer. While survival rates for patients with cervical carcinoma have improved, treatment remains difficult as not enough cases exist to compare treatment modalities. Limited knowledge is present regarding managing extra-hepatic duct squamous cell carcinoma since it is rare.

RIGHT-SIDED CHYLOTHORAX DUE TO RECURRENT CERVICAL CANCER WITH PLEURAL METASTASIS

RIGHT-SIDED CHYLOTHORAX DUE TO RECURRENT CERVICAL CANCER WITH PLEURAL METASTASIS

Pembrolizumab, radiotherapy, and an immunomodulatory five-drug cocktail in pretreated patients with persistent, recurrent, or metastatic cervical or endometrial carcinoma: Results of the phase II PRIMMO study

A phase II study (PRIMMO) of patients with pretreated persistent/recurrent/metastatic cervical or endometrial cancer is presented. Patients received an immunomodulatory five-drug cocktail (IDC) consisting of low-dose cyclophosphamide, aspirin, lansoprazole, vitamin D, and curcumin starting 2 weeks before radioimmunotherapy. Pembrolizumab was administered three-weekly from day 15 onwards; one of the tumor lesions was irradiated (8Gyx3) on days 15, 17, and 19. The primary endpoint was the objective response rate per immune-related response criteria (irORR) at week 26 (a lower bound of the 90% confidence interval [CI] of > 10% was considered efficacious). The prespecified 43 patients (cervical, n = 18; endometrial, n = 25) were enrolled. The irORR was 11.1% (90% CI 2.0–31.0) in cervical cancer and 12.0% (90% CI 3.4–28.2) in endometrial cancer. Median duration of response was not reached in both cohorts. Median interval-censored progression-free survival was 4.1 weeks (95% CI 4.1–25.7) in cervical cancer and 3.6 weeks (95% CI 3.6–15.4) in endometrial cancer; median overall survival was 39.6 weeks (95% CI 15.0–67.0) and 37.4 weeks (95% CI 19.0–50.3), respectively. Grade ≥ 3 treatment-related adverse events were reported in 10 (55.6%) cervical cancer patients and 9 (36.0%) endometrial cancer patients. Health-related quality of life was generally stable over time. Responders had a significantly higher proportion of peripheral T cells when compared to nonresponders (p = 0.013). In conclusion, PRIMMO did not meet its primary objective in both cohorts; pembrolizumab, radiotherapy, and an IDC had modest but durable antitumor activity with acceptable but not negligible toxicity.Trial registration ClinicalTrials.gov (identifier NCT03192059) and EudraCT Registry (number 2016-001569-97).

Pembrolizumab in pretreated advanced, metastatic cervical, vulvar, vaginal carcinoma (325)

<b>Objectives:</b> Recurrent, pretreated cervical carcinoma is a notoriously difficult-to-treat disease with a poor prognosis. Pembrolizumab was granted accelerated approval by the FDA in June 2018 in the setting of pretreated, recurrent, or metastatic cervical cancer based on preliminary results of the phase II basket trial KEYNOTE-158. While the reported objective response rate was only 12%, many patients exhibited a durable response, with some remaining on treatment for >12 months. We sought to examine the real-world incorporation and utilization of this treatment option and evaluate patient outcomes in an academic and safety-net county hospital system. <b>Methods:</b> Based upon timing of accelerated FDA approval and to allow for lead-in, review of institutional data identified women with pretreated recurrent, persistent, or metastatic cervical, vaginal, or vulvar carcinoma who were planned to receive pembrolizumab from 2017 to 2021. Demographics and clinical-pathologic data were collected. Duration of treatment, treatment-related adverse events, and clinical outcomes were analyzed. Patients with uterine and ovarian primary tumors, PD-L1 negative status, and those who did not receive a single cycle of treatment were excluded. <b>Results:</b> Fifty-two patients were identified, of whom 20 were included in the analysis. The median number of prior systemic lines of treatment was 1 (max 4). The objective response rate was 11.7%, with a clinical benefit rate of 47%. Overall, the median duration of treatment (mDOT) was 2.1 months (two cycles, IQR: 1-8). Among patients with progression of disease or death, mDOT was 2.1 months (two cycles, IQR: 2-3). Twenty-five percent of patients received at least ten cycles, all of whom presently remain on treatment (mDOT 13 months). Treatment was generally well-tolerated, with 25% experiencing any toxicity (majority G2 hypothyroidism). One patient suffered grade 3+ toxicity - immune-mediated colitis, which resulted in cessation of treatment after one cycle. The most common reasons for non-initiation of treatment with pembrolizumab included a loss to follow-up, PD-L1 negative tumors, or enrollment in clinical trials. <b>Conclusions:</b> Pembrolizumab is generally well-tolerated in the treatment of recurrent cervical cancer, and real-world experience is compared favorably with published clinical trial outcomes data. One- quarter of patients experienced a durable response of > 10 months with minimal toxicity.

Whole-Exome Sequencing Could Distinguish Primary Pulmonary Squamous Cell Carcinoma From Lung Metastases in Individuals With Cervical Squamous Cell Carcinoma.

Aims: Metastatic cervical carcinoma is hard to cure using traditional treatment and new therapeutic approaches are needed. However, the process of clonal evolution and the molecular alterations that contribute to tumor progression from primary to metastatic carcinoma remain unclear. It is currently difficult to distinguish between the primary pulmonary squamous cell carcinoma (PPSCC) and metastatic cervical squamous cell carcinoma (CSCC). Methods: Paired primary CSCC and lung/lymph nodes metastatic lesions from eight patients were analyzed by whole-exome sequencing (WES). WES data of matched specimens and normal samples were aligned to the human reference genome and analyzed to identify somatic mutations in primary and metastatic lesions. Results: A total of 1,254 somatic variants were identified. All the primary lesions and metastatic lesions shared mutations, the percentage of shared mutations between primary lesions and corresponding metastatic lesions varied significantly, ranging from 6% to 70%. In other words, all the metastatic lesions are clonally related to primary lesions, confirming WES could prove they are metastatic from the cervix but not PPSCC. We tried to apply a gene panel to help distinguish PPSCC and metastatic CSCC but failed because the mutations were widely distributed in CSCC. Interestingly, lymph nodes metastasis (LNM) harbored fewer cancer driver mutations than primary CSCC specimens with a significant difference. Besides this, there was no significant difference in somatic mutations and copy number variation (CNV) between primary and metastatic CSCC. Conclusion: Our data demonstrate that WES is an additional helpful tool in distinguishing PPSCC and metastatic CSCC, especially for certain difficult cases.

Pemetrexed-cisplatin combined with antiangiogenesis drug in recurrent and metastatic cervical carcinoma: A case report and literature review

Pemetrexed is an antifolate agent which has shown activity on various tumors. But no result has been reported on the clinical efficacy and toxicity of pemetrexed combined with antiangiogenesis drug in patients with cervical cancer. Apatinib is an oral antiangiogenesis drug in cervical cancer, which has been reported efficacy and safety in cervical cancer. Here, we present a 50-year-old woman who was diagnosed with recurrent and metastatic cervical adenocarcinoma two years after postoperative adjuvant radiotherapy. After pathology and magnetic resonance imaging confirmed the recurrence and metastasis, the patient was administered pemetrexed 500 mg/m2 and cisplatin 50 mg/m2 on day 1, cycled every three weeks for four cycles. Then add apatinib 500 mg/d from day 1 to day 21 combined with pemetrexed and cisplatin for two cycles, followed by pemetrexed 500 mg/m2 on day 1 combined with apatinib every 21 days per cycle for two cycles. Finally, a single dose of apatinib is a maintenance therapy. According to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 standard, she was confirmed as Partial Response (PR). Now, the Progression-Free Survival (PFS) of the patient has been 21 months. No grade III-IV adverse effects have been found. In conclusion, pemetrexed-cisplatin combined with antiangiogenesis drug might be an effective and mild toxic treatment for patients with recurrent or metastatic cervical carcinoma. Further prospective clinical trials are needed to verify this conclusion.

CABOCOL-01 trial: a single-arm phase II study assessing safety and efficacy of Cabozantinib for advanced or metastatic cervical carcinoma after platinum treatment failure

BackgroundCervical cancer is the tenth diagnosed cancer in the world. Early-stage and locally recurrent disease may be cured with radical surgery or chemo-radiotherapy. However, if disease persists or recurs, options are limited and the prognosis is poor. In addition to chemotherapy, bevacizumab, an antiangiogenic agent, has recently demonstrated its efficacy in this setting. Cabozantinib is an oral small molecule tyrosine kinase inhibitor that exhibits potent inhibitory activity against several receptor tyrosine kinases that are known to influence tumor growth, metastasis, and angiogenesis. The main targets of Cabozantinib are VEGFR2, MET and AXL. It is currently approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma and medullary thyroid carcinoma. Given its angiogenic properties associated with growth factor receptors inhibition, Cabozantinib represents a potential active treatment in cervical carcinoma. In this context, we propose to assess the efficacy and safety of cabozantinib monotherapy in advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment.MethodsThis study is a single-arm two-stage multicenter phase II aiming to simultaneously assess efficacy and safety of Cabozantinib among advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. The main criterion will be based on both safety and clinical efficacy by conducting a Bryant-and-Day design. Safety endpoint is the proportion of patients with clinical gastro-intestinal (GI) perforation/fistula, GI-vaginal fistula and genito-urinary (GU) fistula events grade ≥ 2 (NCI CTCAE V.5.0) occurring up to one month after the end of treatment. Efficacy endpoint is the proportion of patients with disease control rate 3 months after Cabozantinib initiation. A patients’ self-reported quality of life evaluation is also planned, as well as the investigation of nutritional outcomes. Cabozantinib will be administered at the daily dose of 60 mg given orally, without interruption until disease progression or discontinuation for any cause.DiscussionCabozantinib is a promising drug for patients with advanced/metastatic cervical cancer where few therapeutics options are available after failure to platinum-based regimen metastatic CC. It appears challenging to assess the interest of Cabozantinib in this indication, taking into account the potential toxicity of the drug.Trial registrationNCT04205799, registered “2019 12 19”.Protocol versionVersion 3.1 dated from 2020 08 31.

PD-L1 expression and immune stromal features in HPV-independent cervical adenocarcinoma.

Human papilloma virus (HPV)-independent cervical adenocarcinoma (CA) is usually diagnosed at an advanced stage, while the therapeutic options are limited. Therefore, effective treatment options are required. The programmed cell death 1 (PD-1) inhibitor pembrolizumab has been approved for the treatment of patients with recurrent or metastatic cervical squamous cell carcinoma expressing PD-ligand 1 (PD-L1). However, no data regarding PD-L1 expression in HPV-independent CA are available. Thus, we evaluated the association between PD-L1 expression and the clinicopathological characteristics and survival of patients with HPV-independent CA. We evaluated PD-L1, mismatch repair (MMR) protein expression and the immune stromal features of 44 patients with HPV-independent CA. PD-L1 expression was defined as a combined positive score (CPS) ≥1 and a tumour proportion score (TPS) ≥1%. PD-L1 expression was observed in 14 cases (31.8%) with CPS ≥1 and 12 cases (27.3%) with TPS ≥1%. PD-L1 expression, based on either the CPS or the TPS, was associated with a high tumour-infiltrating lymphocyte percentage (CPS=P<0.001; TPS=P<0.001). Patients with a PD-L1 CPS ≥1 showed worse progression-free survival and overall survival than PD-L1-negative patients (P=0.004 and P=0.023, respectively). Forty-two cases demonstrated intact MMR expression and two cases demonstrated loss of MSH2/MSH6. Our data demonstrated that PD-L1 was expressed in HPV-independent CA, especially in clear cell carcinoma, and that PD-L1 expression is a negative prognostic marker. Our data support the role of PD-L1 in HPV-independent CA and its potential as an immunotherapeutic target.

Metastatic Cervical Carcinoma of Unknown Primary

Metastatic Cervical Carcinoma of Unknown Primary

Clinical activity and safety of simlukafusp alfa, an engineered interleukin-2 variant targeted to fibroblast activation protein-α, combined with atezolizumab in patients with recurrent or metastatic cervical cancer.

5510 Background: Simlukafusp alfa (SIM; FAP-IL2v) comprises an interleukin-2 variant (IL-2v) moiety and an antibody against fibroblast activation protein-α (FAP). The binding of SIM to FAP, expressed on cancer-associated fibroblasts, accounts for retention and accumulation in malignant lesions. The engineered IL-2v moiety has an abolished binding to IL-2Rα while the affinity to IL-2Rβγ is retained, resulting in activation of immune effector CD8 T and NK cells, but not of regulatory T cells, and therefore may augment activity of PD-(L)1 inhibitors. Methods: The clinical activity and safety of the SIM and atezolizumab (ATZ) combination in patients with recurrent or metastatic (R/M) cervical squamous cell carcinoma (SCC) were evaluated in a phase 2 basket study (NCT03386721). Patients (pts) were treated with SIM 10 mg IV and ATZ 1200 mg IV once every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1 assessed by investigators. Secondary endpoints were: disease control rate (DCR), duration of response (DoR), progression free survival (PFS). Results: 47 Pts with ECOG ≥1 and median age of 53 years (range: 25-69) were enrolled. All pts were checkpoint inhibitor naïve and 40 (85%) had ≥ 1 previous lines of therapy in the metastatic setting. The median number of cycles was 6 (range: 1-29). The ORR was 27% (90% CI: 18, 39) and DCR was 71% (90% CI: 58, 80) in 44 response-evaluable patients: 2 (5%) had complete response, 10 (23%) partial response, and 19 (43%) stable disease. Responses were observed across PD-L1 subgroups (SP142 assay, IC/TC cut-off ≥ 1%) with 8/22 and 4/18 responders in PD-L1+ and PD-L1- patients, respectively. Responses were durable, the median DoR was 13.3 months (95% CI: 7.6, 14.7). PFS probability at 6 months was 0.4 (95% CI: 0.27, 0.59). The most common adverse events (AE) (reported in &gt; 30% patients), irrespective of relatedness to treatment and severity, were pyrexia (74.5%), anemia (48.9%), asthenia (48.9%), AST increased (44.7%), nausea (42.6%), ALT increased (42.6%), vomiting (36.2%) and diarrhea (31.9%). Grade 3 and 4 AEs related to SIM were observed in 63.8 % and 29.8 % of pts, respectively, while serious AEs (SAE) related to SIM were reported in 40.4%. The most common SAEs (reported in &gt; 5% pts) irrespective of relatedness to treatment were infusion related reaction (14.9%), pyrexia (6.4%) and hydronephrosis (6.4%). One Grade 5 event occurred, which was unrelated to treatment. Conclusions: SIM in combination with ATZ demonstrated an acceptable safety profile in pts with R/M cervical SCC. The anti-tumor activity compares favorably to the approved PD-1 inhibitors in this setting and supports further exploration of IL-2v and checkpoint inhibition in this patient population of high unmet medical need. Clinical trial information: NCT03386721.

A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis

ObjectiveTo assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. MethodsPatients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. Clinical trial information: jRCTs031180007. ResultsIn total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. ConclusionsThe study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

Machine Learning Models to Predict Primary Sites of Metastatic Cervical Carcinoma From Unknown Primary.

Metastatic cervical carcinoma from unknown primary (MCCUP) accounts for 1–4% of all head and neck tumors, and identifying the primary site in MCCUP is challenging. The most common histopathological type of MCCUP is squamous cell carcinoma (SCC), and it remains difficult to identify the primary site pathologically. Therefore, it seems necessary and urgent to develop novel and effective methods to determine the primary site in MCCUP. In the present study, the RNA sequencing data of four types of SCC and Pan-Cancer from the cancer genome atlas (TCGA) were obtained. And after data pre-processing, their differentially expressed genes (DEGs) were identified, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these significantly changed genes of four types of SCC share lots of similar molecular functions and histological features. Then three machine learning models, [Random Forest (RF), support vector machine (SVM), and neural network (NN)] which consisted of ten genes to distinguish these four types of SCC were developed. Among the three models with prediction tests, the RF model worked best in the external validation set, with an overall predictive accuracy of 88.2%, sensitivity of 88.71%, and specificity of 95.42%. The NN model is the second in efficacy, with an overall accuracy of 82.02%, sensitivity of 81.23%, and specificity of 93.04%. The SVM model is the last, with an overall accuracy of 76.69%, sensitivity of 74.81%, and specificity of 90.84%. The present analysis of similarities and differences among the four types of SCC, and novel models developments for distinguishing four types of SCC with informatics methods shed lights on precision MCCUP diagnosis in the future.

Phytochemical compounds from Jurinea macrocephala subsp.elbursensis and their cytotoxicity evaluation

The aim of the study was to evaluate phytochemicals of Jurinea macrocephala subsp. elbursensis and determine their cytotoxic activity against human metastatic breast carcinoma (MDA-MB231) and human cervical carcinoma (HeLa) cell lines. Normal phase column chromatography on dichloromethane extract of J. macrocephala subsp. elbursensis led to the isolation of three compounds, including two germacranolide-type sesquiterepene lactones, hydroxypectorolide-14-o-acetate (a), 4-hydroxy pectorolide (b), and one furofuran-type lignan, pinoresinol monomethyl ether-β-D-glucoside (PMG) (c). Structures of the isolated compounds were established based on NMR and Mass spectrometry. Full assignments of NMR data of two isolated sesquiterpene lactones were reported for the first time. All the isolated compounds were evaluated for their cytotoxic activities against cancer cells using MTT assay at two exposure times. Among them, only compound (c) exhibited a strong activity with the IC50 value of 3.54 μg/ml against HeLa cells. IC50 values in all experiments were reduced by the increasing exposure time from 24 h to 48 h, and cytotoxicity was dependent on compound concentration. Molecular docking predicted that compound (c) could interact with the p53 site residues of the HPV18 E6 ocoprotein in HeLa cells. Therefore it can be considered as a promising agent for future research of cervical cancer.