Low-grade Serous Ovarian Cancer Research Articles

796P Initial management and long-term outcome of advanced low-grade serous ovarian cancer (LGSOC) exploring role of surgery and maintenance therapy in the French multicentre ESME database

796P Initial management and long-term outcome of advanced low-grade serous ovarian cancer (LGSOC) exploring role of surgery and maintenance therapy in the French multicentre ESME database

Bevacizumab Treatment for Low-Grade Serous Ovarian Cancer: A Systematic Review.

Serous epithelial ovarian cancer, classified as either high-grade (90%) or low-grade (10%), varies in molecular, histological, and clinicopathological presentation. Low-grade serous ovarian cancer (LGSOC) is a rare histologic subtype that lacks disease-specific evidence-based treatment regimens. However, LGSOC is relatively chemo-resistant and has a poor response to traditional treatments. Alternative treatments, including biologic therapies such as bevacizumab, have shown some activity in LGSOC. Thus, the objective of this systematic review is to determine the effect and safety of bevacizumab in the treatment of LGSOC. Following PRISMA guidelines, Medline ALL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase all from the OvidSP platform, ClinicalTrials.gov, International Clinical Trials Registry Platform, International Standard Randomised Controlled Trial Number Registry were searched from inception to February 2022. Articles describing bevacizumab use in patients with LGSOC were included. Article screening, data extraction, and critical appraisal of included studies were completed by two independent reviewers. The effect of bevacizumab on the overall response rate, progression-free survival, overall survival, and adverse effects were summarized. The literature search identified 3064 articles, 6 of which were included in this study. A total of 153 patients were analyzed; the majority had stage IIIC cancer (56.2%). The overall median response rate reported in the studies was 47.5%. Overall, bevacizumab is a promising treatment for LGSOC, with response rates higher than traditional treatment modalities such as conventional chemotherapy, and is often overlooked as a treatment tool. A prospective clinical trial evaluating the use of bevacizumab in LGSOC is necessary to provide greater evidence and support these findings.

Identifying mechanisms of therapeutic resistance in low-grade serous ovarian cancer (2282)

Identifying mechanisms of therapeutic resistance in low-grade serous ovarian cancer (2282)

Stage I low-grade serous ovarian cancer: Is there a benefit to chemotherapy? (2252)

Stage I low-grade serous ovarian cancer: Is there a benefit to chemotherapy? (2252)

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer.

We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59). Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

Impressive clinical response following combined BRAF and MEK inhibition in a low-grade serous ovarian carcinoma patient with a BRAF V600E mutation

Introduction: Low-grade serous ovarian cancer (LGSOC) accounting for less than 10% of all serous ovary cancers. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. 
 Case report: We present a case report of a 58-year-old woman with LGSOC FIGO stage IIIC who presented recurrence of the tumor process after total abdominal hysterectomy and systemic treatment. Thereafter, she underwent molecular profiling, which revealed a BRAF V600E mutation; accordingly, the patient was administered dabrafenib and trametinib combination therapy. The patient noted significant clinical improvement with normalization of CA 125 and radiological partial response. To date, the patient still maintains partial response, with good treatment tolerance and performance status ECOG 0/1 and good quality of life. 
 Conclusions: LGSOC represents the challenge that is managing a rare cancer with scarce therapeutic options. Given the prevalence of BRAF mutations in this type of tumour, it might be relevant to consider genetic testing. It may provide new treatment opportunities for patients with a known chemoresistant tumour, by identifying potential actionable targets and avoid potential toxicities associated with chemotherapy. Here we demonstrate that impressive clinical responses can be achieved in BRAF mutated LGSOC treated with combined BRAF and MEK inhibitor treatment.

The highs and lows of serous ovarian cancer.

Low-grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next-generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen-activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo-resistant form of ovarian cancer, recent studies have worked to harness the unique features of low-grade serous ovarian cancer to provide individualized treatment options for patients with this disease.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

ImportanceRandomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.ObjectiveTo investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.Design, Setting, and ParticipantsA retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy.ExposuresExposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group).Main Outcomes and MeasuresTemporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score.ResultsA total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score–weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype–specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas.Conclusions and RelevanceDespite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States

ObjectiveTo describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery. MethodsWe identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004–December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control. ResultsWe observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6–8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07–1.24), and stage IV disease (RR 2.66; 95% CI 2.31–3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65–0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08–1.42). ConclusionNACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.

Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC).

5515 Background: LGSOC is a RAS/MAPK pathway driven cancer that constitutes ≤10% of ovarian cancer. There are no FDA approved treatments specifically for LGSOC. Avutometinib is a novel small molecule RAF/MEK clamp. Focal adhesion kinase (FAK) activation is a resistance mechanism to RAF/MEK inhibition, and defactinib, a small molecule inhibitor of FAK, has shown synergistic antitumor activity with avutometinib in preclinical models. The combination of avutometinib and defactinib has demonstrated a high rate of confirmed and durable responses (overall response rate [ORR] = 46%) in recurrent LGSOC (Banerjee S, ESMO 2021). Methods: A registration-directed phase 2, adaptive, multicenter, randomized study was initiated to evaluate avutometinib ± defactinib in patients with KRAS mutant (mt) and KRAS wild-type (wt) recurrent LGSOC to identify the optimal regimen based on confirmed ORR by blinded independent central review (Part A) and determine the efficacy of the optimal regimen (Part B) (NCT04625270). Pts were randomized to avutometinib 4 mg orally (PO), twice weekly, 3 weeks on, 1 week off (mono) or avutometinib 3.2 mg PO twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off (combo). Key inclusion criteria include histologically confirmed recurrent LGSOC, known KRAS status and prior systemic therapy with platinum chemotherapy. Unlimited additional prior lines, including prior MEK inhibitor, were permitted. Here we present efficacy results from Part A (evaluable patients, N=59) and safety data from all pts enrolled (N=121). Results: In Part A, the median number of prior systemic regimens was 3 for mono, and 4 for combo. In evaluable patients, a confirmed ORR of 7% (2/30) was observed for mono (13% KRAS mt, 0% KRAS wt), and an ORR of 28% (8/29) was observed for combo (27% KRAS mt, 29% KRAS wt). Two of 4 patients previously treated with a MEK inhibitor showed a confirmed partial response (PR) on the combination arm. A high disease control rate (PR or SD ≥ 8 weeks) was observed for both mono (90%) and combo (93%). The majority of treatment related adverse events (AEs, any grade) for combo (N=57) were mild to moderate. The most common Grade ≥3 AEs for combo were blood CPK increase (15.8%), fatigue (5.3%), diarrhea (3.5%), dermatitis acneiform (1.8%), and rash (1.8%). A similar AE profile was observed for mono (N=64). Most AEs were manageable/reversible. On the combo arm, 90.6% (±20%) of planned doses were given and 9% (n=5) of pts discontinued due to AEs [asymptomatic elevated blood CPK (n=3) and fatigue (n=2)]. Conclusions: The interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed, and most AEs were mild to moderate. Enrollment continues in Part B for the combination of avutometinib and defactinib. Clinical trial information: NCT04625270 .

Prognostic risk stratification of low-grade serous ovarian cancer: Model development and validation based on machine learning algorithm.

e17569 Background: Low-grade serous ovarian cancer (LGSOC) is a rare ovarian tumor that lacks a prognostic prediction model. We attempted to construct a clinical nomogram to predict the recurrence and survival of patients with LGSOC. Methods: A multicenter clinical cohort of 199 patients with pathologically confirmed LGSOC was constructed. The predictive model factors were recurrence and survival related clinical factors, which were determined by univariate and multivariate COX regression analysis. The area under receiver operating characteristic curve (AUC), and calibration curve were used to assess the accuracy and discrimination of the nomogram. The concordance index(C-index), net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to evaluate the efficacy of nomogram and FIGO staging in predicting recurrence and survival. Results: A total of 155 patients were included, and four independent prognostic factors were identified to construct the prediction model. The AUC ( > 0.8) showed satisfactory discriminative ability of the nomogram, and the calibration curve showed good agreement between the predicted outcome and the actual outcome. The C-index (PFS: 0.791 vs 0.693; OS: 0.808 vs 0.674), NRI values (0.181 for 3-year and 0.278 for 5-year OS prediction) and IDI values(0.141 for 3-year and 0.147 for 5-year OS prediction, 0.089 for 3-year and 0.079 for 5-year PFS prediction) results showed that nomogram performed better than FIGO staging in predicting prognosis(p < 0.01). Conclusions: We constructed and validated clinical nomogram to individually predict recurrence and survival outcomes in patients with LGSOC, which can help evaluate the prognosis of patients.

Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.

5581 Background: Following the publication of randomized trials demonstrating its noninferiority, the use of neoadjuvant chemotherapy (NACT) for the treatment of advanced stage epithelial ovarian cancer has increased substantially in the United States. However, low-grade serous ovarian cancers (LGSOC) respond poorly to chemotherapy compared with high-grade serous carcinoma. For LGSOC, clinical guidelines favor surgical resection prior to adjuvant therapy. This study seeks to describe patterns and temporal trends in the use of NACT for LGSOC. Methods: This cohort study identified women treated for stage III or IV LGSOC in a Commission on Cancer accredited cancer program between January 1, 2004, to December 31, 2020. We fit Poisson regression models to evaluate temporal trends in the use of NACT and cytoreductive outcomes, and to identify factors associated with receipt of NACT. We considered age, race/ethnicity, Charlson Comorbidity Index, year of diagnosis, insurance status, income, facility type, census region, and stage as potentially associated with NACT. Due to the high rate of missingness in data describing cytoreductive outcomes after surgery, we undertook both multiply imputed and complete case analyses. Results: A total of 3,343 patients received treatment for LGSOC during the study period. The mean age at diagnosis was 54.8 year (SD 15.5) and most patients (82%) were white. The most commonly observed upfront treatment strategies were cytoreductive surgery followed by adjuvant chemotherapy (63.7%) and surgery without chemotherapy (19.2%). Treatment with NACT followed by interval cytoreductive surgery (13.0%) or chemotherapy alone (4.1%) were less common. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to a statistically significant annual percent change (APC) of 7.2% (95% CI 5.6-8.9). Increasing decade of age (risk ratio [RR] 1.15; 95% CI 1.09-1.23), increasing calendar year of diagnosis (RR 1.07; 95% CI 1.05-1.08) and stage IV disease (RR 2.66; 95% CI 2.3-3.07) were associated with a higher probability of receiving NACT. Other variables were not associated with receipt of NACT. Among patients who underwent cytoreductive surgery, the proportion who achieved no gross residual disease remained stable over the course of the study period in both complete case (APC 0.5%; 95% CI -1.8 to 0.9) and multiply imputed (APC -0.1%; 95% CI -1.6 to 1.3) analyses. Conclusions: The use of NACT for patients with LGSOC increased substantially from 2004 to 2020. Despite increased utilization of NACT, the rate of complete cytoreduction has not improved over the study period, possibly calling into question the effectiveness of NACT in reducing tumor burden in this setting.

Diagnostic model of low-grade serous ovarian cancer and borderline serous ovarian tumor: Model development and validation based on radiomics.

e17534 Background: Evidence to date indicates that there is a close relationship between low-grade serous ovarian cancer (LGSOC) and serous borderline ovarian tumor, but there is a significant difference in prognosis. Preoperative imaging and clinical information to assess the nature of lesions as accurately as possible is beneficial to the surgical management of patients. Methods: A total of 104 patients who underwent CT examination and surgical treatment for pelvic masses in Qilu Hospital of Shandong University from 2013 to 2021 were included in the study, including 25 patients with low-grade serous ovarian cancer, 34 patients with serous borderline ovarian tumor, and 45 patients with serous cystadenoma. Quantitative image features were extracted from CT and combined with clinical information to construct a diagnostic model. The diagnostic performance was evaluated by ROC and AUC. Results: The diagnostic model was constructed by RFECV (recursive feature elimination and cross validation) together with SVM (support vector machine), random forest and XGBoost (eXtreme Gradient Boosting) algorithms, among which the RFECV combined random forest algorithm model showed the optimal accuracy (0.78) and AUC (0.92). Combined with clinical features, a new diagnostic model was constructed again by RFECV and random forest, and the accuracy (0.91) and AUC (0.96) were further improved. Conclusions: Through the combination of CT image-based radiomics and clinical features, the clinical diagnosis model was successfully constructed, which can accurately evaluate and predict the pathological types of patients, and is expected to be used in clinical practice and guide surgical decision-making.

Safety and efficacy of PIPAC in patients with ovarian cancer with peritoneal metastases: A first-in-US phase I study.

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .

Extraordinary clinical response to ibrutinib in low-grade ovarian cancer guided by organoid drug testing

Low-grade serous ovarian cancer (LGSOC) typically responds poorly to standard platinum-based chemotherapy and new therapeutic approaches are needed. We describe a remarkable response to targeted therapy in a patient with platinum-resistant, advanced LGSOC who had failed standard-of-care chemotherapy and two surgeries. The patient was in rapid decline and entering hospice care on home intravenous (i.v.) opioid analgesics and a malignant bowel obstruction requiring a G-tube. Genomic analysis of the patient’s tumor did not indicate obvious therapeutic options. In contrast, a CLIA-certified drug sensitivity assay of an organoid culture derived from the patient’s tumor identified several therapeutic choices, including Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as the EGFR inhibitors afatinib and erlotinib. Following off-label administration of daily ibrutinib as monotherapy, the patient had an exceptional clinical turnaround over the following 65 weeks with normalization of CA-125 levels, resolution of the malignant bowel obstruction, halting of pain medications, and improvement of performance status from ECOG 3 to ECOG 1. After 65 weeks of stable disease, the patient’s CA-125 levels began to rise, at which point the patient discontinued ibrutinib and began taking afatinib as monotherapy. The patient’s CA-125 levels remained stable for an additional 38 weeks but due to anemia and rising CA-125 levels, the patient switched to erlotinib and is currently being monitored. This case highlights the clinical utility of ex vivo drug testing of patient-derived tumor organoids as a new functional precision medicine approach to identify effective personalized therapies for patients who have failed standard-of-care treatments.

Genetic associations of leisure sedentary behaviors and the risk of 15 site-specific cancers: A Mendelian randomization study.

Leisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site-specific cancers. The causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results. UVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02-1.64, p = 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02-1.60, p = 0.031])，breast cancer (OR = 1.16, 95% CI = 1.04-1.30, p = 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03-1.33, p = 0.015], and ER- breast cancer [OR = 1.55, 95% CI = 1.26-1.89, p = 2.23 × 10-5 ]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07-2.08, p = 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment. LSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.

Abstract CT033: Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors

Abstract Background: RAF dimer inhibition can suppress RAF-dependent MEK reactivation leading to sustained MAPK pathway inhibition. RAF dimer inhibitor lifirafenib (L) synergized with MEK inhibitor mirdametinib (M) in RAS-mutated cancer models. In this ongoing Phase 1b study of L+M in patients (pts) with advanced/refractory solid tumors harboring MAPK pathway aberrations, we investigate preliminary safety, PK, and efficacy. Methods: Pts were enrolled by a 3+3 design and treated with L (15-20 mg QD) + M (2-4 mg QD or BID) across 9 dose levels (DLs). Primary objectives were to evaluate safety/tolerability, estimate MTD, and identify recommended Phase 2 dose (RP2D). Tumor responses were investigator assessed using RECIST v1.1. AEs were graded per NCI CTCAE v5.0. Results: Table 1 presents demographic, efficacy, and safety results as of 01 Sep 2022. Objective responses (1 CR, 14 PRs) were achieved in 15/54 (27.8%) efficacy-evaluable pts, including 10/17 low-grade serous ovarian cancer (LGSOC) (58.8%; median exposure ~23 mo), 2 NSCLC (1 NRAS Q61K, 1 BRAF-V600E), 2 endometrial cancer (1 BRAF ZC3HAv1 fusion, 1 KRAS G12A), and 1 LG serous adenocarcinoma of Mullerian origin (KRAS G12V). For L and M, plasma maximum drug concentration (Cmax) and exposure (AUC) were comparable to that of each compound at same DL in monotherapy studies, suggesting low likelihood of drug-drug interaction. L+M was generally well tolerated, with limited DLTs and discontinuations. There were 2 deaths due to TEAEs considered unrelated to L+M. The MTD/RP2D were not yet determined. Conclusions: L+M demonstrated a favorable safety profile and showed antitumor activity in pts with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including LGSOC, NSCLC, and endometrial cancer. The combination warrants further clinical investigation. (Acknowledgements: We thank patients/their families, investigators, and site staff for participating in this study, which is sponsored by BeiGene. Support for abstract preparation was funded by BeiGene and provided by Traci Ginnona, inSeption Group, Lansdale, PA, USA) Table 1. Demographics (N=56) Age (y), median (range) 59.5 (29-78) ECOG PS 0/1, n (%) 56 (100.0) Prior lines of therapy, median (range) 1 (1-6) Efficacy Set (N=54), n (%) LGSOC (n=17) Other than LGSOC (n=37) All malignancies (n=54) ORR (CR+PR) 10 (58.8) 5 (13.5) 15 (27.8) CR 1 (5.9) 0 1 (1.9) PR 9 (52.9) 5 (13.5) 14 (25.9) SD 6 (35.3) 18 (48.6) 24 (44.4) DCR (CR+PR+SD) 16 (94.1) 23 (62.2) 39 (72.2) Safety Set (N=56), n (%) TEAEa 55 (98.2) SAE 23 (41.1) Grade 3 TEAE 24 (42.9) TEAE leading to treatment discontinuation 3 (5.4) DLT 6 (10.7) CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; LGSOC, low-grade serous ovarian cancer; ORR, objective response rate; PR, partial response; SAE, serious adverse event; SD, stable disease; TEAE, treatment-emergent adverse event. a Commonly reported (>40%): fatigue (55.4%), dermatitis acneiform (46.4%), and diarrhea (44.6%). Citation Format: Benjamin Solomon, Bo Gao, Vivek Subbiah, Michael Millward, Lee Rosen, Jayesh Desai, Eric I. Sbar, Neal Collins, Thuy Hoang, Xi Song, Wenlin Shao, Jaspreet Jaggi, Badreddin Edris, Paraneedharan Ramachandran, Lusong Luo, Michael Friedlander. Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT033.

Abstract 4258: Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer

Abstract Objective To characterize the mutational landscape of low grade serous ovarian cancer (LGSOC) with racial/ethnic stratification. Methods The AACR Project GENIE database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org) for low-grade serous ovarian cancer (LGSOC) samples. This is a publicly available, de-identified, multi-institutional database of next-generation sequencing genomic profiling results for tumor samples. Mutation frequencies for 9 homologous recombination deficiency (HRD) genes, 4 MAP-Kinase (MAP-K) pathway genes and 6 mismatch-repair (MMR) deficiency genes were reported and compared between racial/ethnic groups using chi-squared or Fischer’s exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Results Among 317 tumor samples of LGSOC, there were high rates of MAP-K pathway gene mutations but low rates of HRD, MMR and TP53 gene mutations (Table 1). Non-Hispanic Black patients had significantly higher rates of KRAS mutations compared to non-Hispanic White patients (6/7, 86% vs 48/178, 27%, p<0.01). There was no difference in KRAS mutation frequency among Asian (6/17, 35%), Hispanic (7/24, 29%) and Native American (2/2, 100%) patients when compared to non-Hispanic White patients. BRAF mutations were less common compared to KRAS mutations (32/317, 10%), with no racial/ethnic differences in mutation frequency. Conclusion High rates of MAP-K pathway mutations in LGSOC support development and trials of drugs targeting this pathway, such as MEK protein inhibitors. Furthermore, prior literature has demonstrated the prognostic advantage of KRAS and BRAF mutations in LGSOC as well as the association of KRAS mutations with progression of serous borderline tumors to LGSOC. These racial/ethnic differences in frequencies of these mutations are thus hypothesis generating for clinical research to evaluate the impact of race/ethnicity on the development and prognosis of this rare ovarian cancer. Mutation frequencies of HR, MAP-kinase, MMR and TP53 genes in low-grade serous ovarian cancer Gene No. of samples with ≥1 mutation No. of samples profiled for mutation Mutation frequency BRCA1 3 287 1.05 BRCA2 7 287 2.44 BRIP1 5 271 1.85 CHEK2 2 278 0.72 BARD1 2 239 0.84 RAD51B - - - RAD51C - - - RAD51D 2 246 0.81 PALB2 2 279 0.72 KRAS 93 317 29.34 NRAS 29 317 9.15 BRAF 32 317 10.09 EIF1AX 14 144 9.72 MSH2 3 275 1.09 MSH3 1 113 0.88 MSH6 6 286 2.10 MLH1 1 317 0.32 MLH3 3 96 3.13 PMS2 1 270 0.37 TP53 12 317 3.79 Citation Format: Muhammad Danyal Ahsan, Emily M. Webster, Sarah R. Levi, Natalie T. Nguyen, Juan R. Cubillos-Ruiz, Evelyn Cantillo, Eloise Chapman-Davis, Melissa K. Frey, Kevin Holcomb. Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4258.

Abstract 162: Individualizing treatment using patient derived organoids, BH3 profiling and microfluidics: A proof of concept in a patient with low-grade serous ovarian carcinoma

Abstract Background N of 1 treatment paradigms represent the pinnacle of personalized medicine in which a patient’s tumors are profiled to guide treatment. Low-grade serous ovarian cancer (LGSC) is a distinct subtype of ovarian cancer, comprising ~10% of serous carcinomas and typically characterized by a younger age of onset. Molecularly, these tumors are often characterized by alterations within the Ras signaling pathway, including KRAS mutations. Clinically, LGSC is often resistant to standard cytotoxic chemotherapy, but may have sensitivity to hormonal therapy or MEK inhibitors. Here we report on a platform and proof of concept in one LGSC patient to evaluate personalized tumor-directed therapy regimens using patient-derived organoids (PDOs), BH3 profiling and viability evaluation in 3D microfluidic devices. Methods A patient with LGSC presented to the Dana Farber Cancer Institute and was treated with carboplatin and paclitaxel before a total abdominal hysterectomy with a bilateral salpingo-oophorectomy. Tissue was obtained under an IRB approved protocol and PDOs were established. Standard of care and non-standard of care treatments including doxorubicin, abemaciclib, letrozole, alpelisib, tamoxifen, trametinib, venetoclax, and navitoclax were evaluated by two orthogonal assays. First, they were tested for delta priming by BH3 profiling (Bhola et.al., Sci Signal. 2020 ) and second for cell viability using 3D microfluidic devices by TMRM/DRAQ7 dual-color fluorescent staining. Standard of care treatments carboplatin and paclitaxel were evaluated as individual treatments and in combination in 3D microfluidic devices. Results We successfully established a PDO model from the patient’s tumor sample in 14 days. BH3 profiling at 24 hours and viability in 3D microfluidic devices after 6 days in treatment showed that from the eight tested drugs, the model was sensitive to navitoclax and venetoclax. Average percent change in viability was -91.5% and -89.9%, respectively, and the drugs had a dynamic BH3 profiling index of 551.4 AUC (+/- 76.63) and 488.9 AUC (+/- 21.46) with the threshold of response being >175 for BH3 profiling. Trametinib showed a clear response in 3D, with an average percent change of -72.6% compared to the control but no significant response in BH3 profiling. Neither carboplatin and paclitaxel alone, nor in combination, elicited a significant change in viability. This observation was consistent with the patient’s history prior to surgery, where the tumor did not demonstrate significant clinical response to neoadjuvant carboplatin and paclitaxel therapy. Conclusions We describe a proof of concept of a N of 1 response assessment platform for LGSC using PDOs, BH3 profiling and live/dead fluorescent staining in microfluidic devices and demonstrate that BH3 profiling and 3D viability assessment assays show good congruity. Citation Format: Brittany Meisenheimer, Ha V. Vo, Kelley E. McQueeney, Aisha L. Saldanha, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Marisa R. Nucci, Anthony Letai, Cloud P. Paweletz, Joyce F. Liu, Ursula A. Matulonis, Elena Ivanova. Individualizing treatment using patient derived organoids, BH3 profiling and microfluidics: A proof of concept in a patient with low-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 162.

Abstract 3402: In vivo efficacy of RAF/MEK clamp avutometinib (VS-6766) in combination with FAK inhibition in low grade serous ovarian cancer

Abstract Objective: Low grade serous carcinoma (LGSC) of the ovary is characterized by a high recurrence rate, resistance to most chemotherapeutic agents, and limited effective therapeutic options. Recently, LGSC has been found to often contain mutations in KRAS (~30%), NRAS (~10%), and BRAF (~8%). Avutometinib (VS-6766) is a RAF/MEK clamp that induces dominant negative complexes of RAF with MEK, and inhibits proliferation of KRAS, NRAS, BRAF, and CRAF mutant cell lines. VS-4718 is a focal adhesion kinase (FAK) inhibitor that has shown synergistic anti-tumor activity with avutometinib in other cancer models, as it blocks the potential of FAK to function as an adaptive resistance mechanism to RAF/MEK inhibition. This study aimed to determine the efficacy of the RAF/MEK clamp avutometinib with FAK inhibition in vivo in LGSC patient derived tumor xenograft (PDX) models. Methods: Whole-exome sequencing was used to evaluate mutations in two primary ovarian LGSC PDX models (OVA(K)250 and PERIT(M)17). OVA(K)250 and PERIT(M)17 cells were injected into SCID mice and animals were treated with either vehicle control (CTRL), RAF/MEK clamp avutometinib (MEKi), FAK inhibitor VS-4718, or the combination (MEKi/FAKi). Tumor volumes were measured twice per week. Results: Both the OVA(K)250 and PERIT(M)17 PDX models express wildtype KRAS and express RAF1 mutations at position 12641679 A>C, V207G. In PDX OVA(K)250 mice treated with MEKi/FAKi, day 9 tumor volume was significantly lower compared to mice treated with CTRL (p=0.0002). At day 9, tumor volume was also significantly lower in mice treated with MEKi alone compared to CTRL (p=0.0007). Mice treated with FAKi alone had tumor volumes that were significantly smaller than CTRL by day 12 (p=0.009). By day 23, CTRL mice had reached tumor volume characteristics requiring sacrifice. Combination MEKi/FAKi treatment resulted in improved overall survival (OS); median OS for combination or MEKi alone was not reached by 60 days. Treatment with FAKi led to median OS of 35 days; CTRL mice had median OS of 23 days (p=0.001). In vivo experiments with PDX PERIT(M)17 and PDX OVA(K)250 are ongoing. Conclusion: Combination of avutometinib with FAK inhibition showed improved in vivo preclinical anti-tumor efficacy relative to either agent alone in an LGSC PDX model with wildtype KRAS and with a RAF1 mutation. These data support an ongoing registration-directed study with avutometinib ± the FAK inhibitor defactinib for patients with recurrent LGSC (NCT04625270). Citation Format: Blair McNamara, Cem Demirkiran, Stefania Bellone, Levent Mutlu, Margherita Zipponi, Miguel S. Verzosa, Justin Harold, Tobias M. Hartwich, Gary Altwerger, Elena Ratner, Gloria Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. Schwartz, Peter Dottino, Alessandro D. Santin. In vivo efficacy of RAF/MEK clamp avutometinib (VS-6766) in combination with FAK inhibition in low grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3402.