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Purpose: This paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer. Methods: This was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel. Results: A total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91‐2.3] p =.935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43–1.14] p =.064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response. Conclusion: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity. Randomized study of cediranib compared with olaparib and the combination for advanced or recurrent endometrial cancer demonstrated progression‐free survival of 3.8, 2.0, and 5.5 months respectively. The treatment toxicities were manageable but the study did not meet its primary end point. [ABSTRACT FROM AUTHOR]

In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in the United States, yet significant portions of the US population remain under screened or unscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high‐quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research is needed to produce improvements in cervical cancer survival within the United States. Mortality from cervical cancer is a direct reflection of resource distribution. Future research to decrease mortality must account for systemic failures to eradicate inequities in addition to the development of novel agents against this disease. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. Methods: Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3–6 and as maintenance monotherapy in cycles 7–34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. Results: An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. Conclusions: The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: As a class, PARPis work by disrupting DNA repair; however, they are metabolized by different pathways. Niraparib is metabolized by carboxylesterase-catalyzed amide hydrolysis, whereas olaparib and rucaparib are metabolized by the cytochrome P450 (CYP) system. Drugdrug interactions (DDIs) with other medications may change PARPi efficacy or safety in patients with aOC. Objective: This US-based, real-world study aimed to quantify and characterize patients with aOC who received CYP-inhibiting/inducing (CYP-i/i) medications when they initiated treatment or were eligible to receive PARPi first-line maintenance therapy (1LMT), to better understand the potential for DDIs with PARPis and other CYP-metabolized medications. Methods: This retrospective cohort study used data from Optum's de-identified Market Clarity Data with Optum® Enriched Oncology, which deterministically links medical and pharmacy claims with electronic health record data from providers across the continuum of care. Eligible patients were diagnosed with aOC between January 1, 2015, and March 31, 2021; were aged ≥18 years at end of first-line platinum-based chemotherapy (index date); had confirmed CYP-i/i medication use (≥1 claim between 90 days before to 120 days after index date); and had received or were eligible to receive PARPi 1LMT. Strong/moderate CYP-i/i medications were defined based on estimates of how much they increased/decreased drug exposure over time (area under the plasma concentration--time curve ratio). Patients in the PARPi-treated group received PARPi monotherapy for 1LMT (olaparib/rucaparib/niraparib). Patients in the PARPi-eligible group did not receive 1LMT within 120 days or start second-line treatment within 60 days of the index date. Descriptive statistics were used for patient characteristics. Results: The analysis included 1411 patients (PARPi treated, n=158; PARPi eligible, n=1253). Median age was 63 years for PARPi-treated patients and 64 years for PARPi-eligible patients. Among PARPi-treated patients, 46% (n=73) used niraparib, and 54% (n=85) used other PARPis metabolized by the CYP system (olaparib, 49% [n=77]; rucaparib, 5% [n=8]). The percentage of patients taking a strong/ moderate CYP-i/i medication was 38% (n=60) for the overall PARPi-treated group, 42% (n=36) for PARPi-treated patients who received olaparib or rucaparib, and 33% (n=414) for the PARPi-eligible group. For each group, the most common strong/moderate CYP-i/i medications were antiemetics and fluoroquinolone antibiotics (overall PARPi treated, 48% [n=29] and 28% [n=17], respectively; PARPi-treated olaparib/rucaparib, 50% [n=18] and 25% [n=9], respectively; and PARPi eligible, 41% [n=169] and 37% [n=154], respectively). Other common strong/moderate CYP-i/i medications were imidazole-related antifungals, calcium channel--blocking blood pressure medications, and topical antifungals. Conclusions: Patients with aOC may be treated with PARPi 1LMT to delay or prevent recurrence. Multiple PARPi options exist, including niraparib, which is metabolized by carboxylesterase-catalyzed amide hydrolysis, and olaparib and rucaparib, which are metabolized by the CYP system. In this analysis, 38% of PARPi-treated and 33% of PARPi-eligible patients with aOC also received medications that were strong/moderate CYP-i/i. Cotreatment with CYP-metabolized PARPis and CYP-i/i medications could potentially lead to DDIs that could alter the efficacy and tolerability of the PARPis. Additional studies are needed to understand this important issue. Funding: Funding for this study was provided by GSK. [ABSTRACT FROM AUTHOR]

Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results. [ABSTRACT FROM AUTHOR]

BRCA1 or 2 mutations result in higher cancer risk for breast cancer (BC) and epithelial ovarian cancer (EOC) for carriers than exists in the general population. Optimal breast imaging surveillance in these patients has not been well defined. An Institutional Review Board-approved, multi-institutional retrospective chart review was performed. Patients diagnosed with BRCA-associated EOC between 1990-2015 were identified; demographic and clinical data were collected and analyzed. 192 BRCA mutation-positive patients with EOC were identified. 16/192 (8.3%) women were diagnosed with BC following EOC, at a median of 50 (range 5-327) months following EOC diagnosis and median age 59.5 (45-84) years. Breast cancer was most commonly detected on mammogram 7/16 (44%) or clinical exam 7/16 (44%). 2/16 (12.5%) had occult BC found during risk-reducing mastectomy. 14 (88%) had early-stage (0-2) disease. At mean follow-up of 8.1 years, 6 (37.5%) patients with BC following EOC had died due to EOC. The risk of BC diagnosis following EOC in BRCA mutation carriers is low; most of these BCs are early stage and diagnosed with mammography or physical exam. Overall, survival in BRCA mutation carriers is dominated by EOC-related mortality. Breast cancer surveillance in BRCA mutation carriers following EOC should prioritize nonsurgical strategies. [ABSTRACT FROM AUTHOR]

Objectives: Endometrial cancer due to loss of mismatch repair proteins may be caused by epigenetic or genetic factors. Complete profiling is not routinely performed in clinical practice. We sought to explore outcomes of women with mismatch repair deficiency (MMRd) due to epigenetic MLH-1 promoter hypermethylation (MMRd-MLH). We hypothesize that MMRd-MLH correlates with worse clinical outcomes in endometrial cancer. Methods: Under an IRB protocol, we retrospectively identified patients with endometrioid endometrial adenocarcinoma undergoing hysterectomy at our institution from 2016-2020. These patients underwent routine immunohistochemical testing for MMRd, with subsequent genetic testing or methylation studies for loss of MMR proteins. We examined patient data in three cohorts: MMR proficient (MMRp), MMRd-MLH, and MMRd deficiency due to germline mutation (MMRd-G). We excluded patients who did not undergo MMR testing and those who were MMR deficient due to other causes. We examined clinical data via univariate and multivariate tests and Kaplan-Meier survival analyses. Results: We identified 327 patients who met the criteria for review. The majority (243, 74%) were MMRp, 74 (23%) were MMRd-MLH, and ten (3%) were MMRd-G. On univariate analysis, we observed no differences in the history of post-menopausal hormone replacement therapy, family history of cancer, personal history of hypertension or diabetes mellitus, or body mass index. We found that when compared to the other two groups, MMRd-MLH patients were more like to have grade 2-3 tumors (p < 0.01) and LVSI (p < 0.001). We identified statistically significant associations between age at surgery (60, 67, and 60 years, respectively) and depth of invasion (0.41cm, 0.67cm, and 0.18cm). We did not observe significant differences in the stage. We identified that MMRd-MLH was associated with pathologic high-intermediate risk factors leading to increased adjuvant therapy in stage I disease (p=0.04). We observed a 4.1% recurrence rate in MMRp compared to 8.1% in the MMRd-MLH group compared to no recurrences in MMRd-G (p = NS). When comparing MMRp and MMRd-MLH in Kaplan-Meier analyses, we observed a statistical difference in disease-free survival favoring those who were MMRp (p = 0.02). Median survival was not reached. There were no significant differences in overall survival between MMRp and MMRd-MLH. We did not identify independent prognostic factors for recurrence when controlling for age, stage, grade, or MMR status. [Display omitted] Conclusions: MMRd-MLH is associated with LVSI, higher grade, deeper tumor invasion, and a significantly higher rate of adjuvant therapy. We observed patients with MMRd-MLH were more likely to recur despite adjuvant therapy. MMRd-MLH may represent a poor prognostic factor and a target for further adjuvant therapy. [ABSTRACT FROM AUTHOR]

Objectives: Surveillance follow-up for women with vaginal and vulvar cancer, extrapolated by National Comprehensive Cancer Network (NCCN), includes a physical exam every 3-6 months during the first two years, followed by every 6-12 months for three to five years after treatment. For VAIN, general recommendations for follow-up suggest a physical exam every six months for the first two years and yearly after. For VIN, physical exams every six months for the first five years are recommended. Little is known regarding rates of retention for follow-up in these rare cancers and dysplasia. We sought to explore post-treatment retention for patients with vaginal and vulvar cancer and dysplasia at our institution. Methods: After IRB approval, we retrospectively identified patients treated for vaginal and/or vulvar intraepithelial neoplasia or carcinoma between 2011-2016. Baseline demographic, pathologic, treatment, surveillance, and recurrence data were collected. We examined the continuous and total retention of post-treatment surveillance visits for patients diagnosed with cancer VIN, VAIN, or concomitant VIN and VAIN. Continuous retention was defined as sequential visits no longer than one year apart. Descriptive statistics were used to analyze the data. Results: We identified 40 patients who met the criteria for review. The median age of treatment was 60 years old. Most patients were White (75%), followed by Asian (10%), Black (5%), other (8%), and American Indian (3%). The most common diagnoses were VIN III (25%), VAIN III (22%), and squamous cell carcinoma (22%). Most were treated with wide local excision (42.5%), followed by radical surgery (30%), and laser surgery (15%). The median times for total and continuous post-treatment retention were 27.5 and 21 months, respectively. The median number of visits and pap smears in the first post-treatment year were 2 and 1, respectively. The median number of visits and pap smears in the second post-treatment year were 1 and 1, respectively. Only 29% of patients continued with surveillance in the third post-treatment year. Recurrence was noted in ten patients (25%) with a median time of recurrence of 29 months with a range of 1-69 months. The most common primary diagnoses associated with recurrence were VIN III (40%), VAIN III (20%), VIN II (20%), and squamous cell carcinoma (20%). Conclusions: This is the first baseline assessment of post-treatment surveillance retention for VAIN, VIN, or vulvovaginal carcinoma. We observed that our population generally adheres to NCCN surveillance guidelines during the first year; however, the adherence drops in the following years with a median continuous retention rate of less than two years. Further work is needed to enhance post-treatment surveillance and identify barriers to follow-up for patients. [ABSTRACT FROM AUTHOR]