Survivorship Care For Women Living With Ovarian Cancer: Protocol For a Randomized Controlled Trial

BACKGROUND: Ovarian cancer ranks 12th in cancer incidence among women in the United States and 5th among causes of cancer-related death. The typical treatment of ovarian cancer focuses on disease management, with little attention given to the survivorship needs of the patient. Qualitative work alludes to a gap in survivorship care; yet, evidence is lacking to support the delivery of survivorship care for individuals living with ovarian cancer. We developed the POSTCare survivorship platform with input from survivors of ovarian cancer and care partners as a means of delivering patient-centered survivorship care. This process is framed by the chronic care model and relevant behavioral theory. OBJECTIVE: The overall goal of this study is to test processes of care that support quality of life (QOL) in survivorship. The specific aims are threefold: first, to test the efficacy of the POSTCare platform in supporting QOL, reducing depressive symptom burden, and reducing recurrence worry. In our second aim, we will examine factors that mediate the effect of the intervention. Our final aim focuses on understanding aspects of care platform design and delivery that may affect the potential for dissemination. METHODS: We will enroll 120 survivors of ovarian cancer in a randomized controlled trial and collect data at 12 and 24 weeks. Each participant will be randomized to either the POSTCare platform or the standard of care process for survivorship. Our population will be derived from 3 clinics in Texas; each participant will have received some combination of treatment modalities; continued maintenance therapy is not exclusionary. RESULTS: We will examine the impact of the POSTCare-O platform on QOL at 12 weeks after intervention as the primary end point. We will look at secondary outcomes, including depressive symptom burden, recurrence anxiety, and physical symptom burden. We will identify mediators important to the impact of the intervention to inform revisions of the intervention for subsequent studies. Data collection was initiated in November 2023 and will continue for approximately 2 years. We expect results from this study to be published in early 2026. CONCLUSIONS: This study will contribute to the body of survivorship science by testing a flexible platform for survivorship care delivery adapted for the specific survivorship needs of patients with ovarian cancer. The completion of this project will contribute to the growing body of science to guide survivorship care for persons living with cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT05752448; https://clinicaltrials.gov/study/NCT05752448. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/48069

A Multi-Institutional Analysis of Adjuvant Chemotherapy and Radiation Sequence in Women With Stage IIIC Endometrial Cancer

PURPOSE: Our purpose was to evaluate the effect of sequence and type of adjuvant therapy for patients with stage IIIC endometrial carcinoma (EC) on outcomes. METHODS AND MATERIALS: In a multi-institutional retrospective cohort study, patients with stage IIIC EC who had surgical staging and received both adjuvant chemotherapy and radiation therapy (RT) were included. Adjuvant treatment regimens were classified as adjuvant chemotherapy followed by sequential RT (upfront chemo), which was predominant sequence; RT with concurrent chemotherapy followed by chemotherapy (concurrent); systemic chemotherapy before and after RT (sandwich); adjuvant RT followed by chemotherapy (upfront RT); or chemotherapy concurrent with vaginal cuff brachytherapy alone (chemo-brachy). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. RESULTS: A total of 686 eligible patients were included with a median follow-up of 45.3 months. The estimated 5-year OS and RFS rates were 74% and 66%, respectively. The sequence and type of adjuvant therapy were not correlated with OS or RFS (adjusted P = .68 and .84, respectively). On multivariate analysis, black race, nonendometrioid histology, grade 3 tumor, stage IIIC2, and presence of adnexal and cervical involvement were associated with worse OS and RFS (all P \u3c .05). Regardless of the sequence of treatment, the most common site of first recurrence was distant metastasis (20.1%). Vaginal only, pelvic only, and paraortic lymph node (PALN) recurrences occurred in 11 (1.6%),15 (2.2 %), and 43 (6.3 %) patients, respectively. Brachytherapy alone was associated with a higher rate of PALN recurrence (15%) compared with external beam radiation therapy (5%) P \u3c .0001. CONCLUSIONS: The sequence and type of combined adjuvant therapy did not affect OS or RFS rates. Brachytherapy alone was associated with a higher rate of PALN recurrence, emphasizing the role of nodal radiation for stage IIIC EC. The vast proportion of recurrences were distant despite systemic chemotherapy, highlighting the need for novel regimens

LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment

Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities

24 Correlation of clinical outcomes and poly ADP ribose polymerase activity in high grade serous ovarian cancer

Objectives: PARP proteins are regulators of DNA damage repair in the cell. PARP inhibitors (PARPi) are a class of drugs used to treat ovarian cancer especially in patients with BRCA 1/2 gene mutations and homologous recombination deficiencies. These have previously been used as biomarkers to predict response to PARPi. Preclinical studies suggest that the levels of PARP-1, DDX21, and poly ADP ribosylation (PAR) are indicators of PARP activity. ADP ribosylation (PAR/ MAR) have been suggested as biomarkers to predict PARPi sensitivity. We sought to evaluate the correlation between PARP-1, DDX21, and mono-ADP ribosylation (MAR) expression with response to treatment with PARPi and survival outcomes. Methods: Tissue samples were collected from primary or metastatic sites of 49 patients with high grade serous ovarian cancer who had been prescribed a PARPi. A tumor microarray was made and immunohistochemistry (IHC) for MAR, PARP-1, and DDX21 was performed. IHC staining was graded on a 3-point scale. Clinical data collected included demographics, stage, presence of BRCA mutation, cytore-ductive status, time on PARPi, other adjuvant and salvage treatments, and survival outcomes. Kaplan-Meier analysis and Cox regression analysis were used to determine the effect of the biomarkers on survival outcomes and time on PARPi. Results: We found longer treatment with PARPi was associated with improved overall survival (p<0.01). PARP-1 expression directly correlated with DDX21 expression but it did not reach statistical significance (p=0.062). On Cox regression analysis cytoplasmic MAR approached significance (p=0.055) in predicting progression free survival (PFS) after frontline treatment. Conclusions: In our patient cohort, we saw a direct correlation between PARP-1 and DDX21 and an inverse correlation between MAR and PARP-1. Mono ADP ribosylation may predict PFS after frontline treatment. Pre-treatment biopsies and poly ADP ribosylation should be studied to further explore these biomarkers in predicting PARPi response

45 Lenvatinib for endometrial cancer: reducing healthcare disparities and emphasizing equitable medication access through quality improvement

Objectives: Combination pembrolizumab with lenvatinib (len/pem) has revolutionized second-line treatment and survival outcomes for patients with mismatch repair-proficient (MMRp) recurrent endometrial cancer (EC). We sought to define existing barriers to medication access and, through quality improvement (QI) techniques, improve access and decrease healthcare disparities in a high risk, medically underserved population. Methods: Following IRB approval, we identified all patients with MMRp EC dispositioned to receive len/pem in our institution. Clinico-demographic data were abstracted from medical records. Lag time was defined as time from decision to treat until specialty medication received or initiation of len/pem. QI interventions included internal process mapping, multidisciplinary roundtable collaboration, and engagement of pharmaceutical access resources. The effect of the interventions on lag time were then assessed after a 10-month follow-up period. Comparative statistics were performed for pre/post-intervention metrics using Chi square, Fisher's exact, and t-tests. Results: From Oct 2019 to Mar 2023, 41 patients were identified and included in analysis. 32 and 9 patients received len/pem in thepre- and post-intervention groups, respectively. Average age was 60 years old, 55% were Hispanic, 29% were non-Hispanic black patients, and 80% had either Medicaid or county/charity healthcare coverage. After interventions, average lag time significantly decreased from 32.5 days (range 10–74) to 15.7 days (range 7–31, p=.005). Utilization of patient access resources (PAP) increased from 40 to 78%. Barriers to medication access were identified to be internal communication breakdowns, uncertainty regarding PAP usage, patient distrust of unverified outside calling numbers, and external specialty pharmacy communication breakdowns. Conclusions: Medication access disparities can be significantly reduced among vulnerable patients with MMRp EC through QI interventions

Biophysicochemical motifs in T cell receptor sequences as a potential biomarker for high-grade serous ovarian carcinoma.

We previously showed, in a pilot study with publicly available data, that T cell receptor (TCR) repertoires from tumor infiltrating lymphocytes (TILs) could be distinguished from adjacent healthy tissue repertoires by the presence of TCRs bearing specific, biophysicochemical motifs in their antigen binding regions. We hypothesized that such motifs might allow development of a novel approach to cancer detection. The motifs were cancer specific and achieved high classification accuracy: we found distinct motifs for breast versus colorectal cancer-associated repertoires, and the colorectal cancer motif achieved 93% accuracy, while the breast cancer motif achieved 94% accuracy. In the current study, we sought to determine whether such motifs exist for ovarian cancer, a cancer type for which detection methods are urgently needed. We made two significant advances over the prior work. First, the prior study used patient-matched TILs and healthy repertoires, collecting healthy tissue adjacent to the tumors. The current study collected TILs from patients with high-grade serous ovarian carcinoma (HGSOC) and healthy ovary repertoires from cancer-free women undergoing hysterectomy/salpingo-oophorectomy for benign disease. Thus, the classification task is distinguishing women with cancer from women without cancer. Second, in the prior study, classification accuracy was measured by patient-hold-out cross-validation on the training data. In the current study, classification accuracy was additionally assessed on an independent cohort not used during model development to establish the generalizability of the motif to unseen data. Classification accuracy was 95% by patient-hold-out cross-validation on the training set and 80% when the model was applied to the blinded test set. The results on the blinded test set demonstrate a biophysicochemical TCR motif found overwhelmingly in women with HGSOC but rarely in women with healthy ovaries, strengthening the proposal that cancer detection approaches might benefit from incorporation of TCR motif-based biomarkers. Furthermore, these results call for studies on large cohorts to establish higher classification accuracies, as well as for studies in other cancer types