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Gynecologic malignancies continue to be a major cause of morbidity and mortality in the United States despite recent advances in oncologic therapies. To realize the promise of immunotherapy and biomarker-driven approaches to improve clinical outcomes for patients, better communication among stakeholders in the drug development and approval pathways is needed. To this end, the FDA-AACR-SGO Drug Development in Gynecologic Malignancies Workshop brought together clinicians, patient advocates, researchers, industry representatives, and regulators in June 2018, to review the state of the science in gynecologic cancers and explore how scientific advances impact approval processes. Topics of discussion and key takeaways are summarized in this Perspectives in Regulatory Science and Policy article. Single-agent immunotherapies have demonstrated variable and often modest response rates among gynecologic cancers. Combination therapies and other novel approaches, such as cell-based therapies, may show improved efficacy compared with single-agent immunotherapies; however, utilizing innovative clinical trial designs will be necessary to progress further. Companion and complementary diagnostics inform physicians of potential benefits of specific therapeutics for patients; however, they serve different functions that have important regulatory implications, thus trialists should understand the distinctions between diagnostic types. PARP inhibitors hold great promise for treating ovarian cancers, both as monotherapies and in combination with chemotherapeutics, other targeted agents, and immunotherapies. Rare gynecologic cancers often exhibit unique molecular characteristics that can serve as effective targets to which novel therapeutics can be developed. This workshop highlighted the importance of future open discussions on scientific and regulatory challenges in drug development for gynecologic malignancies., (©2019 American Association for Cancer Research.)

We previously mapped a nonrandom frequent loss of heterozygosity (LOH) region in cervical cancers to 1 Mb of 6p23. Here, we describe the identification of a novel cervical cancer susceptibility gene, CD83. The gene was identified by several complementary approaches, including a family-based association study, comparison of transcript expression in normal and cancerous tissue, and genomic sequencing of candidate. CD83 encodes an inducible glycoprotein in the immunoglobulin superfamily and is a marker for mature dendritic cells. The association study that includes 377 family trios showed that five single nucleotide polymorphisms (SNP) within 8 kb of its 3'-end showed significant allelic association that was strengthened in a subgroup of women with invasive cancers infected by high-risk human papillomavirus type 16 and 18 (rs9296925, P = 0.0193; rs853360, P = 0.0035; rs9230, P = 0.0011; rs9370729, P = 0.0012; rs750749, P = 0.0133). Investigation of CD83 uncovered three alternative transcripts in cervical tissue and cell lines, with variant 3 (lacking exons 3 and 4) being more frequent in cervical cancer than in normal cervical epithelium (P = 0.0181). Genomic sequencing on 36 paired normal and cervical tumors revealed several somatic mutations and novel SNPs in the promoter, exons, and introns of CD83. LOH was confirmed in >90% of cervical cancer specimens. Immunofluorescence colocalized CD83 protein to the Golgi apparatus and cell membrane of cervical cancer cell lines. None of seven nearby genes was differentially expressed in cervical cancer. The importance of CD83 in epithelial versus dendritic cells needs to be determined, as does its role in promoting cervical cancer.

Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment.

Purpose: The aim of this study was to evaluate number and types of synchronous and metachronous malignancies in patients with endometrial carcinoma with and without microsatellite instability (MSI)., Experimental Design: From a series of 413 endometrial cancer patients, we identified 94 patients with MSI-positive (MSI+) cancers and grouped them by tumor MLH1 promoter methylation status. These 94 patients were matched by year of surgery to 94 patients with MSI-negative (MSI-) endometrial cancers from the same series. Medical records were reviewed for clinicopathologic information including rates and types of synchronous and metachronous malignancies. Hereditary nonpolyposis colorectal cancer (HNPCC)-associated second and third cancers were analyzed for MSI and MSH2, MSH6, and MLH1 expression for comparison with the corresponding endometrial cancers., Results: The MSI+ and MSI- cohorts were similar with regard to age, race, grade, and histology. Twenty-eight MSI+ endometrial cancers (29.8%) were MLH1 unmethylated. Rates of synchronous and metachronous cancers were also similar in the MSI+ and MSI- groups at 20 and 23%, respectively. However, patients with MSI+ MLH1 unmethylated endometrial cancers had an excess of HNPCC-associated second and third cancers compared with those with MSI+ MLH1 methylated and MSI- endometrial cancers (18% versus 4.5%, P = 0.034, and 2.1%, P = 0.002). Six of seven second tumors from 5 patients with MSI+ MLH1 unmethylated endometrial cancers showed concordant MSI and mismatch repair protein expression status., Conclusions: Our observation that patients with MSI-positive MLH1 unmethylated endometrial carcinoma are at increased risk for HNPCC-associated synchronous and metachronous malignancies suggests inherited cancer susceptibility. These patients and their families may warrant more intense cancer surveillance.

Purpose: This study was designed to determine whether there is a methylator phenotype in stage I and II endometrioid endometrial adenocarcinoma, and if so, whether methylation correlates with recurrence., Experimental Design: Bisulfite-converted DNAs from 24 stage I and II primary cancers (12 recurrent and 12 nonrecurrent), and 5 endometrial cancer cell lines were analyzed for methylation in the promoter regions of seven genes. A methylation index (MeI) was calculated for each tumor. Frequent HOXA11 and THBS2 methylation prompted analysis of case-matched bloods and 25 additional nonrecurrent primary cancers. Statistical analysis included Fisher's exact and Student t tests., Results: Rates of methylation in the initial tumor series were as follows: HOXA11, 70.8%; THBS2, 62.5%; MLH1, 33.3%; CTNNB1, 16.7%; VDR, 4.2%; CDKN2A, 4.2%; and THBS1, 0%. There was no difference in the MeI of recurrent and nonrecurrent cases. However, cell lines had higher mean MeI. High rates of HOXA11 and THBS2 methylation were confirmed in the additional nonrecurrent tumors. None of the 24 case-matched bloods had HOXA11 methylation, whereas three blood DNAs showed THBS2 methylation. There was a statistically significant difference in the rate of HOXA11 methylation in recurrent and nonrecurrent tumors (P = 0.0167)., Conclusions: Endometrial adenocarcinomas have a methylator phenotype. No correlation between MeI and clinicopathologic variables in early stage tumors was observed. High rates of methylation were found in the HOXA11 and THBS2 promoter regions. HOXA11 promoter methylation was significantly more frequent in recurrent than nonrecurrent cases. HOXA11 methylation in early stage endometrial cancer is associated with poor outcome.

Thirty-seven endometrial cancers were subjected to an allelotype analysis in an attempt to identify chromosomal regions that are lost in a significant portion of tumors and to identify tumors characterized by replication errors. Thirty-nine highly polymorphic microsatellite markers representing all chromosomal arms, excluding the X and the short arms of the acrocentrics, were examined. An average of 20 informative cases were evaluated for each marker. Genetic alterations were detected in 30 of the 37 tumors. Replication errors were identified in 8 tumor specimens. Loss of heterozygosity was observed for loci on all chromosomes examined with the exception of chromosomes 4 and 20. The two most frequent sites of loss were at the marker loci examined on 10q (40%) and 17p (29%). Six additional simple sequence repeat markers from 10q were genotyped in an effort to refine the region of 10q loss. The chromosome 10 markers used in these studies were physically mapped with the use of a panel of somatic hybrids that retain defined portions of chromosome 10. The observed patterns of loss of sequences on 10q suggest a role for a tumor suppressor gene in the 10q23-26 region in the development or progression of endometrial cancers.