Updates in the Use of Targeted Therapies for Gynecologic Cancers.

Targeted therapies have changed the treatment landscape in gynecologic cancer. Studies released over the past year have led to the incorporation of immunotherapy (IO) into the treatment for all patients with endometrial and cervical cancers at some point during their disease course. Poly(ADP-ribose) polymerase (PARP) inhibitors continue to play a role in women with ovarian carcinoma, particularly in homologous repair deficient tumors. Furthermore, the benefit of PARP inhibitors in challenging subgroups continues to be elucidated. Biomarker identification has led to the approval or compendium listing of several antibody-drug conjugates (ADCs). This review will update on IO, ADCs, and PARP inhibition for the treatment of gynecologic cancers.

Immuno-Molecular Targeted Therapy Use and Survival Benefit in Patients with Stage IVB Cervical Carcinoma in Commission on Cancer®-Accredited Facilities in the United States.

PURPOSE: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. METHODS: Patients diagnosed with stage IVB cervical cancer during 2013-2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. RESULTS: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64-0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. CONCLUSIONS: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer.

TP53 mutation and abnormal p53 expression in endometrial cancer: Associations with race and outcomes.

OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.

Advances in antibody-drug conjugates for gynecologic malignancies.

PURPOSE OF REVIEW: Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule delivering the potent cytotoxic payload directly to tumor cells. This review summarizes the current literature demonstrating their use in the treatment of gynecologic malignancies. RECENT FINDINGS: Tisotumab vedotin is the first U.S. Food and Drug Administration (FDA) approved ADC for the treatment of gynecologic cancers. While in the phase 3 randomized controlled trial in platinum resistant ovarian cancer patients, FORWARD 1, mirvetuximab did not meet its primary endpoint of progression-free survival. But we await more recent data from the two ongoing phase 3 trials of mirvetuximab in recurrent ovarian cancer patients. HER2/neu, Napi2b, mesothelin, and human trophoblast cell-surface marker (Trop-2) overexpression have also been exploited as excellent targets by novel ADCs in multiple tumors including ovarian, endometrial, and cervical cancers. SUMMARY: Current evidence strongly supports the use of ADCs and ongoing clinical trials will provide further information into the potential of making these drugs part of current standard practice allowing patients to be treated with a higher level of personalized cancer care.

Cervical cancer geographical burden analyzer: An interactive, open-access tool for understanding geographical disease burden in patients with recurrent or metastatic cervical cancer.

OBJECTIVE: Cervical cancer (CC) disproportionately affects women based on socioeconomic status and racial/ethnic background. There is limited research in quantifying and visualizing whether substantial geographical disparities in the US exist with respect to CC burden, and especially with respect to recurrent or metastatic CC (r/mCC) disease burden. Identifying regions with higher r/mCC burden may help inform effective healthcare resource allocation and navigating patients to appropriate care. METHODS: We conducted a retrospective analysis of the 2015-2020 MarketScan® Commercial and Supplemental Medicare claims data; r/mCC burden was estimated as the number of patients initiating r/mCC systemic therapy over CC-diagnosed patients for each of the 410 metropolitan statistical areas (MSAs) considered. We developed a public, web-based tool, the Cervical Cancer Geographical Disease Burden Analyzer (Cervical Cancer Geo-Analyzer, http://www.geo-analyzer.org), that allows users to visualize r/mCC burden across MSAs over multiple years. RESULTS: There was considerable variation in r/mCC burden across MSAs, with a range of 0-83.3%. Burden increased in Boston-Cambridge-Newton, MA (r/mCC to CC ratio: 41% in 2018 to 50% in 2020), and Sacramento-Roseville-Arden-Arcade, CA (33% in 2018 to 50% in 2020). On the other hand, while r/mCC burden remained high, it decreased in Grand Rapids, MI (55% in 2018 to 31% in 2020) and San Francisco-Oakland-Hayward, CA (40% in 2018 to 26% in 2020). There were regions with sparse or no data, suggesting a need for more representative data capture. CONCLUSION: The Cervical Geo-Analyzer is a tool to visualize areas with high need for CC interventions. It also builds the foundation for further work to understand local risk factors of disease burden, identify populations of interest, characterize health disparities of CC or r/mCC and inform targeted interventions.

Factors associated with receipt of second-line recurrent or metastatic cervical cancer treatment in the United States: A retrospective administrative claims analysis.

Purpose: Contemporary, real-world data on eligible patients receiving treatment following progression on first-line (1L) recurrent or metastatic cervical cancer (r/mCC) therapy are needed to inform treatment algorithms and identify potential gaps in the r/mCC care continuum. Methods: This study estimated the prevalence and predictors of second-line (2L) r/mCC therapy among 1L-treated patients using the 2015-2020 IBM MarketScan® commercial claims database. Women ≥ 18 years diagnosed with cervical cancer and treated with first-line systemic therapies were identified and followed for 12 months from their 1L therapy end date. Women with claims for a new therapy after 60 days but no later than 365 days from the end of 1L treatment were identified as those who progressed and received 2L therapy for r/mCC. Descriptive statistics examined baseline cohort characteristics and multivariable logistic regression model examined the factors associated with receiving 2L treatment. Results: We identified 384 1L-treated patients with r/mCC with ≥ 12 months of follow-up post-1L treatment. During follow-up, over half (51.0 %) of the 1L-treated r/mCC patients received 2L treatment. Patients from the South and Midwest had a lower likelihood of receiving 2L treatment compared with those living in the Northeast (adjusted odds ratio [aOR] = 0.43; 0.23-0.84) and (aOR = 0.52; 0.28-0.95, respectively). Patients not treated with bevacizumab in 1L were also less likely to receive 2L therapy (aOR = 0.65; 0.43-0.99). Conclusion: Additional research and targeted outreach efforts are needed to understand geography-, population-, or practice-specific barriers impacting access to 2L therapy among patients with r/mCC.

Resistance to Poly (ADP-Ribose) Polymerase Inhibitors (PARPi): Mechanisms and Potential to Reverse.

PURPOSE OF REVIEW: This review will focus on the most common mechanisms for poly (ADP-ribose) polymerase inhibitors' (PARPi) resistance and the main strategies for overcoming acquired or de novo PARPi resistance. RECENT FINDINGS: Initial approvals for PARPi as part of treatment for advanced epithelial ovarian cancer (EOC) started in 2014 with patient with recurrent cancer characterized by BRCA mutations in the 3rd and 4th line and now have approvals for front-line maintenance in both the BRCA mutated and BRCAwt populations. As with all therapies, patients will eventually develop resistance to treatment. The most common mechanisms for PARPi resistance include reversion mutations, methylation events, and restoration of homologous recombination deficiency (HRD) through combinations and targeting replication stress. As more and more patients receive initial treatment (and potential retreatment with PARPi), we need to better understand the mechanisms in which tumors acquire PARPi resistance.

Factors associated with receipt of second-line recurrent or metastatic cervical cancer treatment in the United States: A retrospective administrative claims analysis.

Purpose: Contemporary, real-world data on eligible patients receiving treatment following progression on first-line (1L) recurrent or metastatic cervical cancer (r/mCC) therapy are needed to inform treatment algorithms and identify potential gaps in the r/mCC care continuum. Methods: This study estimated the prevalence and predictors of second-line (2L) r/mCC therapy among 1L-treated patients using the 2015-2020 IBM MarketScan® commercial claims database. Women ≥ 18 years diagnosed with cervical cancer and treated with first-line systemic therapies were identified and followed for 12 months from their 1L therapy end date. Women with claims for a new therapy after 60 days but no later than 365 days from the end of 1L treatment were identified as those who progressed and received 2L therapy for r/mCC. Descriptive statistics examined baseline cohort characteristics and multivariable logistic regression model examined the factors associated with receiving 2L treatment. Results: We identified 384 1L-treated patients with r/mCC with ≥ 12 months of follow-up post-1L treatment. During follow-up, over half (51.0 %) of the 1L-treated r/mCC patients received 2L treatment. Patients from the South and Midwest had a lower likelihood of receiving 2L treatment compared with those living in the Northeast (adjusted odds ratio [aOR] = 0.43; 0.23-0.84) and (aOR = 0.52; 0.28-0.95, respectively). Patients not treated with bevacizumab in 1L were also less likely to receive 2L therapy (aOR = 0.65; 0.43-0.99). Conclusion: Additional research and targeted outreach efforts are needed to understand geography-, population-, or practice-specific barriers impacting access to 2L therapy among patients with r/mCC.

Histopathologic, Genetic and Molecular Characterization of Endometrial Cancer Racial Disparity.

In contrast to the decline in incidence and mortality of most other cancers, these rates are rising for endometrial cancer. Black women with endometrial cancer have earlier diagnosis, more aggressive histology, advanced stage and worse outcomes compared with their White counterparts. Socioeconomic status, a higher incidence of aggressive histology, and comorbid conditions are known factors leading to racial disparity in patients with endometrial cancer; nevertheless, they do not account for the entire racial disparity; which emphasizes the roles of molecular, histopathological and genetic factors. We performed a comprehensive review of all published scientific literature up to January 2021 reporting histopathologic, genetic and molecular factors associated with racial disparities in patients with endometrial cancer. The interactions and pathways of molecules reported to have significant differential expression in endometrial cancers from Black and White patients were identified with Ingenuity Pathway Analysis. The majority of studies compared Black and White patients; however, limited data are available for other racial and ethnic groups. Reported differences that could account for the worse survival of Black endometrial cancer patients include more aggressive histopathologies and molecular alterations, including upregulation of molecules driving cell cycle progression, and p53 and HER2/NEU signaling. Several of these molecules are targeted by existing pharmaceuticals. These findings encourage further study and the development of race-specific treatment strategies.

PARP inhibitors in the treatment of ovarian cancer: a review.

PURPOSE OF REVIEW: This article will review recent changes in the standard of care for olaparib, niraparib, and rucaparib, as well as ongoing trials evaluating this class of drugs in combination with antiangiogenic agents and PD-1/PD-L1 inhibitors. RECENT FINDINGS: Niraparib received FDA approval for use in patients with complete response or partial response to first-line platinum-based chemotherapy regardless of BRCAm or HRD status that was received in April 2020. FDA approval was received for olaparib in combination with bevacizamab for epithelial ovarian cancer patients with complete response/partial response to first-line chemotherapy and bevacizumab and g/sBRCA and/or genomic instability by Myriad myChoice CDx in May 2020. SUMMARY: In the last year, treatment with PARPi has extended to not only include BRCAm and HRD-deficient patients but also have shown improvement in outcomes in HRD-proficient patients. With these advancements, more patients can access these agents and receive benefit. In the upcoming years, it will be exciting to see the potential benefit when PARPs are added to other angiogenic antagonists and immunotherapy agents.

Using a Collaborative, Virtual Discussion Platform to Mobilize Oncologic Expertise for the COVID-19 Pandemic.

PURPOSE: COVID-19 is a rapidly emerging worldwide pandemic that has drastically changed health care across the United States. Oncology patients are especially vulnerable. Novel point-of-care resources may be useful to rapidly disseminate peer-reviewed information from oncology experts nationwide. We describe our initial experience with distributing this information through a private, curated, virtual collaboration question-and-answer (Q&A) platform for oncologists. METHODS: The Q&A database was queried for a 2-month period from March 12 to May 12, 2020. We collected the total number of views and unique viewers for the questions. We classified the questions according to their emphasis (practice management, clinical management, both) and disease type across radiation oncology, medical oncology, gynecologic oncology, and pediatric oncology. RESULTS: Seventy-nine questions were approved, 67 of which were answered and generated 49,494 views with 5,148 unique viewers. Most discussions covered clinical management, with breast cancer being the most active disease site. Ten questions covered pediatric oncology and gynecologic oncology. Forty-seven percent of the 11,010 users of the platform visited the website during the 2-month period. CONCLUSION: Discussions on the Q&A platform reached a substantial number of oncologists throughout the nation and may help oncologists to modify their treatment in real time with the rapidly evolving COVID-19 pandemic.

Knowledge of endometrial cancer risk factors in a general gynecologic population.

OBJECTIVES: To determine knowledge regarding endometrial cancer (EC) risk factors in a general gynecologic patient population. STUDY DESIGN: A questionnaire survey regarding health behaviors and knowledge of risk factors of EC was administered to patients presenting for routine gynecologic care at two general gynecologic practices affiliated with a tertiary-care center between August and October 2014. Patient demographics, lifestyle information, and knowledge regarding EC risk factors were assessed. Data were analyzed using univariable and bivariable analyses, Χ2 tests, Fischer's exact tests, and t-tests. RESULTS: 231 women responded. Median age was 56 years old (IQR 25-64), and 87% were Caucasian. Median BMI was 24.9 (IQR 22.3-29.2). 24.7% were overweight and 24.3% obese. The majority (69.4%) of patients received a college or graduate degree. Over half of the women (52.1%) did not know that obesity was associated with increased risk of EC. When dichotomized based on obese vs non obese, there was no difference in patients' knowledge of the association between obesity and EC (47% vs 48%, respectively, p = .93). 91% of all respondents reported that their gynecologist or primary care physician had never discussed the risks of EC with them. CONCLUSIONS: Regardless of education level, age or obesity status, the majority of women did not know the common risks of EC. Increased efforts towards educating women regarding obesity and other risk factors of EC are necessary in order to reduce the rising incidence of EC, a predominantly obesity-driven disease. Interventions must include general obstetrician-gynecologists and primary care providers.

Olaparib in the treatment of ovarian cancer.

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

Update in the use and evaluation of poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer: current and pending clinical research.

PURPOSE OF REVIEW: This review will provide an update of recently presented clinical data as well as discuss ongoing trials focused on the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into the treatment paradigm for ovarian cancer. RECENT FINDINGS: As of this publication, PARPi have indications in many parts of the globe as maintenance therapy following response to platinum-based chemotherapy in the setting of platinum-sensitive recurrence. In addition, in the United States, two PARPi have indications as monotherapy treatment for recurrent ovarian cancer in patients with a BRCA mutation and at least two prior lines of therapy. Exciting data was published in October 2018, demonstrating an unprecedented benefit to utilization of olaparib following response to front-line platinum-based chemotherapy among patients with a BRCA mutation and this data is expected to expand the indication for olaparib globally. SUMMARY: Ongoing studies will seek to expand the benefit of PARPi beyond the BRCA population in front-line therapy as well as to overcome inherent and acquired resistance to PARPi with studies of novel combinations with antiangiogenesis agents, immune-oncology agents and chemotherapy. These efforts may identify more settings and populations in which PARPi provide clinical benefit.

Dimercapto-1-propanesulfonic acid (DMPS) induces metaphase II mouse oocyte deterioration.

In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2-0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasing concentrations of DMPS alter oocyte quality as judged by changes in microtubule morphology (MT) and chromosomal alignment (CH) of metaphase II mice oocyte. The oocytes were directly exposed to increasing concentration of DMPS (10, 25, 50, 100 and 300µM) for four hours (time of peak plasma concentration after administration) and reactive oxygen species (mainly hydroxyl radical and superoxide) and zinc content were measured. This data showed DMPS plays an important role in deterioration of oocyte quality through a mechanism involving zinc deficiency and enhancement of reactive oxygen species a major contributor to oocyte damage. Our current work, for the first time, demonstrates the possibility of DMPS to negatively impact fertility. This finding can not only help in counseling reproductive age patients undergoing such treatment but also in the development of potential therapies to alleviate oxidative damage and preserve fertility in people receiving heavy metal chelators.