Clare L. Scott

HCMV as an Oncomodulatory Virus in Ovarian Cancer: Implications of Viral Strain Heterogeneity, Immunomodulation, and Inflammation on the Tumour Microenvironment and Ovarian Cancer Progression

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies.

Poor Concordance Between Cancer Antigen-125 and RECIST Assessment for Progression in Patients With Platinum-Sensitive Relapsed Ovarian Cancer on Maintenance Therapy With a Poly(ADP-ribose) Polymerase Inhibitor

PURPOSE Cancer antigen-125 (CA-125) is recommended by treatment guidelines and widely used to diagnose ovarian cancer recurrence. The value of CA-125 as a surrogate for disease progression (PD) and its concordance with radiologic progression are unclear, particularly for women with platinum-sensitive relapsed ovarian cancer (PSROC) who have responded to chemotherapy and treated with maintenance poly(ADP-ribose) polymerase inhibitor (PARPi). METHODS In this pooled analysis of four randomized trials of maintenance PARPi or placebo (Study 19, SOLO2, ARIEL3, and NOVA), we extracted data on CA-125 PD as defined by Gynecologic Cancer InterGroup criteria and RECIST v1.1. We evaluated the concordance between CA-125 and RECIST PD and reported on the negative predictive value (NPV) and positive predictive value (PPV). RESULTS Of 1,262 participants (n = 818 PARPi, n = 444 placebo), 403 (32%) had CA-125 PD, and of these, 366 had concordant RECIST PD (PPV, 91% [95% CI, 88 to 93]). However, of 859 (68%) without CA-125 PD, 382 also did not have RECIST PD (NPV, 44% [95% CI, 41 to 48]). Within the treatment arms, PPV remained high (PARPi, 91% [95% CI, 86 to 94]; placebo, 91% [95% CI, 86 to 95]) but NPV was lower on placebo (PARPi, 53% [95% CI, 49 to 57]; placebo, 25% [95% CI, 20 to 31]). Of 477 with RECIST-only PD, most (95%) had a normal CA-125 at the start of maintenance therapy and the majority (n = 304, 64%) had CA-125 that remained within normal range. Solid organ recurrence without peritoneal disease was more common in those with RECIST-only PD than in those with CA-125 and RECIST PD (36% v 24%; P < .001). CONCLUSION In patients with PSROC treated with maintenance PARPi, almost half with RECIST PD did not have CA-125 PD, challenging current guidelines. Periodic computed tomography imaging should be considered as part of surveillance, particularly in those with a normal CA-125 at the start of maintenance therapy and on treatment.

Impact of chemotherapy on patients with mismatch repair deficient advanced endometrial carcinomas—a meta-analysis

Abstract Background Chemo-immunotherapy is standard of care for women with recurrent or advanced mismatch repair deficient endometrial carcinoma. However, it is uncertain whether patients with mismatch repair deficient advanced or recurrent endometrial carcinoma derive less benefit from chemotherapy than those with mismatch repair proficient endometrial carcinoma. Methods We performed a meta-analysis of randomized controlled trials (RCTs) in advanced or recurrent endometrial carcinoma to determine the difference in the benefit of chemotherapy in mismatch repair deficient vs mismatch repair proficient endometrial carcinoma. Data on chemotherapy outcomes including objective response rate, progression-free survival (PFS), and overall survival were retrieved. We pooled these data using the inverse variance method and examined subgroup difference by mismatch repair status. We also compared differences in PFS and overall survival outcomes by creating individual patient data from the Kaplan–Meier curves of trial publications for sensitivity analyses. Results A total of 5 RCTs with 1137 participants (mismatch repair deficient, 26%; mismatch repair proficient, 74%) were included. All participants were treated with carboplatin-based chemotherapy. There was no difference between the mismatch repair deficient and mismatch repair proficient subgroups for objective response rate (66.5% vs 64.0%; P = .20 for subgroup difference), PFS (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.77 to 1.12; P = .44; median PFS = 7.6 vs 9.5 months) or overall survival (HR = 1.03, 95% CI = 0.73 to 1.44; P = .88; median overall survival = not reached vs 28.6 months). Conclusions Objective response rate, PFS, and overall survival were similar among those with mismatch repair deficient vs mismatch repair proficient endometrial cancer treated with front-line, platinum-doublet chemotherapy in RCTs. These findings reinforce the importance of combining chemotherapy together with immune checkpoint inhibitors until the results of trials comparing immune checkpoint therapy alone with combination therapy are available.

Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer

Lay Summary Endometrial cancer is common, and a subset recurs and requires additional treatment. Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). However, this clinical trial highlights which cases are more likely to respond well: those containing mutations in genes known as Lynch genes and also some with mutations in POLE/POLD1 (“ultra‐hypermutation” genes). In contrast, the majority of dMMR endometrial cancers have silencing or DNA methylation of one of these genes, MLH1, and do not seem to be as responsive to single‐agent immune therapy. The availability of combination therapies may be important to consider for these women.

Ovarian cancer

Epithelial ovarian cancer (EOC) describes a group of diseases characterized by differing pathogeneses, molecular profiles, histologies and prognoses. The low incidence of each distinct histological type of EOC poses challenges for obtaining an accurate diagnosis, robust evidence to guide management, and a mechanistic understanding to ensure availability of effective therapies. Most EOCs, including high-grade serous ovarian cancer, predominantly originate from the fimbriated ends of the fallopian tube, whereas low-grade serous, clear cell, endometrioid and mucinous EOCs are thought to originate from other tissues. Despite recognized genetic susceptibilities for the disease, no effective screening is available and late-stage diagnosis remains common. Known genetic susceptibilities are addressed by risk reduction surgery including removal of both fallopian tubes and both ovaries. Management is predominantly based on adequate surgery and chemotherapy with carboplatin and paclitaxel, with the addition of anti-angiogenic therapy as indicated. The incorporation of poly(ADP-ribose) polymerase inhibitors into first-line therapy has considerably altered outcomes in some women with EOC who have defective homologous recombination DNA repair, including in those with BRCA1 and/or BRCA2 mutations. Other molecular characteristics are important in distinct types of EOC, but the use of matched targeted therapies remains under investigation, as does the role of immunotherapy for EOC, for which trial data have been disappointing to date. Translationally enriched clinical trials will be important to further explore and validate accurate biomarkers to better guide clinical care.

Insights into ovarian cancer care: report from the ANZGOG Ovarian Cancer Webinar Series 2020

Epithelial ovarian cancer (EOC) is among the top ten causes of cancer deaths worldwide, and is one of the most lethal gynecological malignancies in high income countries, with incidence and death rates expected to rise particularly in Asian countries where ovarian cancer is among the 5 most common cancers. Despite the plethora of randomised clinical trials investigating various systemic treatment options in EOC over the last few decades, both progression-free and overall survival have remained at approximately 16 and 40 months respectively. To date the greatest impact on treatment has been made by the use of poly (ADP-ribose) polymerase (PARP) inhibitors in women with advanced EOC and a

CHK2 Inhibition Provides a Strategy to Suppress Hematologic Toxicity from PARP Inhibitors

Abstract Patients with cancer treated with PARP inhibitors (PARPi) experience various side effects, with hematologic toxicity being most common. Short-term treatment of mice with olaparib resulted in depletion of reticulocytes, B-cell progenitors, and immature thymocytes, whereas longer treatment induced broader myelosuppression. We performed a CRISPR/Cas9 screen that targeted DNA repair genes in Eμ-Myc pre-B lymphoma cell lines as a way to identify strategies to suppress hematologic toxicity from PARPi. The screen revealed that single-guide RNAs targeting the serine/threonine kinase checkpoint kinase 2 (CHK2) were enriched following olaparib treatment. Genetic or pharmacologic inhibition of CHK2-blunted PARPi response in lymphoid and myeloid cell lines, and in primary murine pre-B/pro-B cells. Using a Cas9 base editor, we found that blocking CHK2-mediated phosphorylation of p53 also impaired olaparib response. Our results identify the p53 pathway as a major determinant of the acute response to PARPi in normal blood cells and demonstrate that targeting CHK2 can short circuit this response. Cotreatment with a CHK2 inhibitor did not antagonize olaparib response in ovarian cancer cell lines. Selective inhibition of CHK2 may spare blood cells from the toxic influence of PARPi and broaden the utility of these drugs. Implications: We reveal that genetic or pharmacologic inhibition of CHK2 may offer a way to alleviate the toxic influence of PARPi in the hematologic system.

Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin

Abstract Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.

Olaparib, durvalumab, and cyclophosphamide, and a prognostic blood signature in platinum-sensitive ovarian cancer: the randomized phase 2 SOLACE2 trial

Abstract SOLACE2 (ACTRN12618000686202) investigates whether 12-weeks of olaparib, or cyclophosphamide-olaparib priming, improves subsequent durvalumab-olaparib progression-free survival (PFS), and is superior to olaparib monotherapy without any priming, in platinum-sensitive recurrent ovarian cancer (n = 114). We also evaluate the utility of CUP-CC assay, an immune signature of C-C chemokine receptor type 4 up-regulation, chemokines, and cytokines. Priming with olaparib, or cyclophosphamide-olaparib, followed by durvalumab-olaparib, are both associated with longer PFS compared to olaparib monotherapy, but do not reach the pre-specified primary endpoint of 36-week trial threshold (PFS36). PFS36 rates are 47.4% (95% CI, 31.0-62.1; olaparib priming then olaparib-durvalumab), 48.7% (32.5-63.2; olaparib-cyclophosphamide then olaparib-durvalumab) and 35.1% (20.4-50.3; olaparib monotherapy). PFS is significantly longer for the homologous recombination deficient (N = 71) as compared to the proficient (HRP) (N = 29) subgroups (Hazard Ratio (HR) 0.55, 0.35-0.87). CUP-CC+ subgroup (N = 58) has a significantly longer PFS (HR 0.31, 0.19-0.49) than CUP-CC- (N = 46). Future studies should investigate whether CUP-CC has the potential to personalize poly (ADP-ribose) polymerase inhibitor therapies for patients who are BRCA wild-type, including HRP patients.