Distribution of prostate specific membrane antigen (PSMA) on PET-MRI in patients with and without ovarian cancer.

OBJECTIVES: Ovarian cancer is the most lethal cancer and future research needs to focus on the early detection and exploration of new therapeutic agents. The objectives of this proof-of-concept study are to assess the feasibility of PSMA 18F-DCFPyl PET/MR imaging for detecting ovarian cancer and to evaluate the PSMA distribution in patients with and without ovarian cancer. METHODS: This prospective pilot proof-of-concept study in patients with and without ovarian cancers occurred between October 2017 and January 2020. Patients were recruited from gynecologic oncology or hereditary ovarian cancer clinics, and underwent surgical removal of the uterus and ovaries for gynecologic indications. PSMA 18F-DCFPyl PET/MRI was obtained prior to standard of care surgery. RESULTS: Fourteen patients were scanned: four patients with normal ovaries, six patients with benign ovarian lesions, and four patients with malignant ovarian lesions. Tracer uptake in normal ovaries (SUVmax = 2.8 ± 0.4) was greater than blood pool (SUVmax = 1.8 ± 0.5, p < 0.0001). Tracer uptake in benign ovarian lesions (2.2 ± 1.0) did not differ significantly from blood pool (p = 0.331). Tracer uptake in ovarian cancer (SUVmax = 7.8 ± 3.8) was greater than blood pool (p < 0.0001), normal ovaries (p = 0.0014), and benign ovarian lesions (p = 0.005). CONCLUSION: PET/MR imaging detected PSMA uptake in ovarian cancer, with little to no uptake in benign ovarian findings. These results are encouraging and further studies in a larger patient cohort would be useful to help determine the extent and heterogeneity of PSMA uptake in ovarian cancer patients.

Adnexal Lesion Imaging: Past, Present, and Future.

Currently, imaging is part of the standard of care for patients with adnexal lesions prior to definitive management. Imaging can identify a physiologic finding or classic benign lesion that can be followed up conservatively. When one of these entities is not present, imaging is used to determine the probability of ovarian cancer prior to surgical consultation. Since the inclusion of imaging in the evaluation of adnexal lesions in the 1970s, the rate of surgery for benign lesions has decreased. More recently, data-driven Ovarian-Adnexal Reporting and Data System (O-RADS) scoring systems for US and MRI with standardized lexicons have been developed to allow for assignment of a cancer risk score, with the goal of further decreasing unnecessary interventions while expediting the care of patients with ovarian cancer. US is used as the initial modality for the assessment of adnexal lesions, while MRI is used when there is a clinical need for increased specificity and positive predictive value for the diagnosis of cancer. This article will review how the treatment of adnexal lesions has changed due to imaging over the decades; the current data supporting the use of US, CT, and MRI to determine the likelihood of cancer; and future directions of adnexal imaging for the early detection of ovarian cancer.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Surgical outcomes of adnexal masses classified by IOTA ultrasound simple rules.

IOTA (International Ovarian Tumor Analysis) Simple Rules classifies adnexal masses as benign, malignant, or indeterminate based on sonographic features. We seek to determine if IOTA inappropriately directed women to surgery, or more aggressive surgery, than their final diagnosis warranted. This is a retrospective study of sonographically detected adnexal masses with known clinical outcomes from two institutions (n = 528). Surgically managed patients (n = 172) were categorized based on pathology and compared using Chi-square and t-test for categorical and continuous variables respectively. A logistic regression was used to predict characteristics that predicted surgery or imaging follow up of indeterminate masses. Of the 528 masses imaged, 29% (n = 155) underwent surgery for benign pathology. Only 1.9% (n = 10) underwent surgery after classification as malignant by IOTA for what was ultimately a benign mass. Surgical complications occurred in 10 cases (5.8%), all benign. Fifteen (3.2%) patients went into surgically induced menopause for benign masses, one of which was inaccurately classified by IOTA as malignant. Of the 41 IOTA indeterminate masses, the presence of soft tissue nodules on ultrasound was the only statistically significant predictor of the patient being triaged directly to surgery (OR 1.79, p = 0.04). Our findings support that the IOTA ultrasound classification system can provide clinical guidance without incurring unnecessary surgeries or surgical complications.

Molecular classification in endometrial cancer: Opportunities for precision oncology in a changing landscape.

Endometrial carcinoma (EC) classification and risk stratification have undergone a global transformation in the last decade, shifting from a reliance on poorly reproducible histomorphological parameters such as grade and histotype, toward a molecular classification that is consistent and biologically informative. Molecular classification enables reliable categorization of ECs, provides prognostic information, and is now beginning to drive clinical management, including surgery and adjuvant therapy. Within this framework, we now have the ability to further refine both the prognostic and predictive value of molecular classification. As we move toward the routine implementation of this classification system as a stratification tool for research, clinical trials, and patient care, it is imperative that access to these tests be equitable. Furthermore, continued education will be critical for patients and providers to understand the value that this molecular information provides.

Atovaquone: An Inhibitor of Oxidative Phosphorylation as Studied in Gynecologic Cancers.

Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone's potential as a gynecologic cancer therapeutic.

A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782).

BACKGROUND: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel. METHODS: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m2  days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy. RESULTS: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance. CONCLUSION: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer. METHODS: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m2) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m2) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis. INTERPRETATION: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting. FUNDING: US National Cancer Institute.

Using simple radiologic measurements to anticipate surgical challenge in endometrial cancer: a prospective study.

OBJECTIVES: To determine if linear measurements of adiposity from pre-operative imaging can improve anticipation of surgical difficulty among endometrial cancer patients. METHODS: Eighty patients with newly diagnosed endometrial cancer were enrolled. Routine pre-operative imaging (MRI or CT) was performed. Radiologic linear measurements of the following were obtained: anterior-to-posterior skin distance; anterior skin to anterior edge of L5 distance (total anterior); anterior peritoneum to anterior edge of L5 distance (visceral obesity); and posterior edge of L5 to posterior skin distance (total posterior). Surgeons completed questionnaires quantifying preoperative anticipated operative difficulty and postoperative reported operative difficulty. The primary objective was to assess for a correlation between linear measurements of visceral fat and reported operative difficulty. RESULTS: Seventy-nine patients had questionnaires completed, preoperative imaging obtained, and surgery performed. Univariate analysis showed all four linear measurements, body mass index, weight, and anticipated operative difficulty were associated with increased reported operative difficulty (P< 0.05). Multivariate analysis demonstrated that body mass index and linear measurements visceral obesity and total posterior were independently associated with increased reported operative difficulty (P< 0.05). Compared with body mass index, the visceral obesity measurement was more sensitive and specific for predicting increased reported operative difficulty (visceral obesity; sensitivity 54%, specificity 91 %; body mass index; sensitivity 38%, specificity 89%). A difficulty risk model combining body mass index, visceral obesity, and total posterior demonstrated better predictive performance than any individual preoperative variable. CONCLUSIONS: Simple linear measurements of visceral fat obtained from preoperative imaging are more predictive than body mass index alone in anticipating surgeon-reported operative difficulty. These easily obtained measurements may assist in preoperative decision making in this challenging patient population.

Peri-operative allogeneic blood transfusion is associated with poor overall survival in advanced epithelial ovarian Cancer; potential impact of patient blood management on Cancer outcomes.

BACKGROUND: Transfusion related immune modulation associated with red blood cell (RBC) transfusion is thought to result in decreased cancer survival. Results in epithelial ovarian cancer (EOC) have been mixed however most suggest worse oncologic outcomes in patients who were transfused at the time of debulking surgery. The impact of restrictive transfusion strategies on this patient population is currently not known. METHODS: We conducted a retrospective study of women with EOC. The study population was divided into two groups based on whether they were transfused RBCs during the peri-operative period or not. Clinical characteristics and prognosticators were compared between groups. Overall survival was compared between groups based on transfusion status and other known prognostic factors. Cox proportional hazard modeling was used to examine the association between the prognostic factors and the study endpoint. RESULTS: Sixty-six percent of women were transfused. Transfusion was associated with CA125, the use of neoadjuvant chemotherapy (NACT), surgical blood loss, and anemia. The mean pre-transfusion Hgb was 7.8 + 0.6 g/dL and 94% had a hemoglobin level greater than the transfusion threshold of 7 g/dL. RBC transfusion, suboptimal debulking, anemia, and NACT were associated with decreased survival. Only RBC transfusion and suboptimal debulking status remained significant in a multivariate model. CONCLUSIONS: Peri-operative RBC transfusion compromises survival in ovarian cancer supporting the need to minimize the use of transfusion at the time of debulking surgery. Adherence to evidence-based transfusion guidelines offers an opportunity to reduce transfusion rates in this population with a resulting positive influence on survival.

The role of radiation therapy in the treatment of Stage II endometrial cancer: A large database study.

PURPOSE: The optimum adjuvant treatment for Stage II endometrial cancer patients is unknown. External beam radiation therapy (EBRT) is often considered the standard of care; however, retrospective series suggest that brachytherapy (BT) alone may be sufficient for selected patients. As randomized data are lacking, we used a large database to explore this question. METHODS AND MATERIALS: The National Cancer Data Base was queried for patients with pathologic International Federation of Gynecology and Obstetrics Stage II disease. Demographic, clinic-pathologic, and treatment details were compared between patients. Multivariable analysis was used to determine factors associated with receiving radiation therapy (RT). To account for imbalances between groups, a matched-pair analysis was completed. RESULTS: Eight thousand one hundred forty patients were included. RT was associated with overall survival (OS), with EBRT (hazard ratio [HR] 0.64), BT (HR 0.47), and combination (HR 0.54) showing increased OS on univariate analysis. Facility, urban location, diagnosis year, hysterectomy type, and chemotherapy did not reach significance. On multivariate analysis, RT was associated with OS, with EBRT (HR 0.69), BT (HR 0.60), and combination (HR 0.54) showing benefit. Using propensity-score matching, RT continued to show improved OS regardless of type: BT (82% vs. 73% 5-year OS) and EBRT (77% vs. 71%). BT as compared to EBRT had equivalent survival (81% vs. 79%, not statistically significant). CONCLUSION: This study of over 8,000 patients demonstrates that adjuvant RT confers a survival benefit in Stage II endometrial cancer and supports the continued use of RT in these patients. BT alone may be reasonable in carefully selected patients.

Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center.

OBJECTIVE: To review and update the subsequent reproductive outcomes in patients with complete, partial, and recurrent hydatidiform moles, as well as gestational trophoblastic neoplasia (GTN) at the New England Trophoblastic Disease Center. STUDY DESIGN: Patients with complete and partial hydatidiform mole, recurrent hydatidiform mole, and GTN were identified from the Donald P. Goldstein, M.D., Trophoblastic Tumor Registry. Questionnaires regarding subsequent pregnancies were mailed to patients with current mailing addresses available. Additional patient data was obtained from electronic medical records. RESULTS: A total of 2,432 subsequent pregnancies have been reported since 1965. Of those, 1,388 pregnancies were after complete mole, 357 after partial mole, and 667 after GTN. The subsequent reproductive outcomes in patients with complete and partial molar pregnancies and persistent GTN remain similar to those in the general population. However, approximately 1.7% of patients with a prior molar pregnancy had a molar pregnancy in a later gestation. Furthermore, after successful chemotherapy for GTN the incidence of stillbirth was slightly increased to 1.3% in later pregnancies. CONCLUSION: Patients with molar pregnancies and GTN should expect similar reproductive outcomes as compared to the general population. However, patients receiving chemotherapy for GTN have a slightly increased risk stillbirth in subsequent pregnancies.

Fertility-sparing treatment in younger women with adenocarcinoma in situ of the cervix.

OBJECTIVE: For women who have completed childbearing, the treatment of choice for adenocarcinoma in situ (ACIS) of the cervix is hysterectomy. In women who desire future fertility, however, conservative therapy is an acceptable alternative. In this study we compare the outcomes for young women who underwent loop conization or were treated with cold knife conization. METHODS: We performed a retrospective analysis in 112 patients with ACIS, age 30 or younger, treated with cold knife conization or loop conization between 1998 and 2010. Decision to perform office loop conization was based on the size of the cervix and the colposcopic lesion. Main outcomes were negative margins after the procedure and recurrence of ACIS. RESULTS: Fifty-eight patients (52%) were treated with cold knife conization and 54 (48%) underwent loop conization. The odds ratio for cold knife conization to achieve negative cone margins compared with loop conization was 1.4 (95% CI 0.6-3.5). We observed no difference in residual or recurrent ACIS between patients treated with loop conization versus cold knife conization. CONCLUSIONS: In select young patients who desire future fertility, loop conization and cold knife conization have equivalent rates of negative margins and negative follow-up. For optimal results, patients must have a lesion which can be removed in one pass of a loop, confirmed by expert colposcopy. Loop excision should be considered the treatment of choice in this specific group of patients.

Activated networking of platelet activating factor receptor and FAK/STAT1 induces malignant potential in BRCA1-mutant at-risk ovarian epithelium.

OBJECTIVES: It is essential to understand the molecular basis of ovarian cancer etiology and tumor development to provide more effective preventive and therapeutic approaches to reduce mortality. Particularly, the molecular targets and pathways involved in early malignant transformation are still not clear. Pro-inflammatory lipids and pathways have been reported to play significant roles in ovarian cancer progression and metastasis. The major objective of this study was to explore and determine whether platelet activating factor (PAF) and receptor associated networking pathways might significantly induce malignant potential in BRCA1-mutant at-risk epithelial cells. METHODS: BRCA1-mutant ovarian epithelial cell lines including (HOSE-636, HOSE-642), BRCA1-mutant ovarian cancer cell (UWB1.289), wild type normal ovarian epithelial cell (HOSE-E6E7) and cancerous cell line (OVCA429), and the non-malignant BRCA1-mutant distal fallopian tube (fimbria) tissue specimens were used in this study. Mutation analysis, kinase microarray, western blot, immune staining, co-immune precipitation, cell cycle, apoptosis, proliferation and bioinformatic pathway analysis were applied. RESULTS: We found that PAF, as a potent pro-inflammatory mediator, induced significant anti-apoptotic effect in BRCA1-mutant ovarian surface epithelial cells, but not in wild type HOSE cells. With kinase microarray technology and the specific immune approaches, we found that phosphor-STAT1 was activated by 100 nM PAF treatment only in BRCA1-mutant associated at-risk ovarian epithelial cells and ovarian cancer cells, but not in BRCA1-wild type normal (HOSE-E6E7) or malignant (OVCA429) ovarian epithelial cells. Co-immune precipitation revealed that elevated PAFR expression is associated with protein-protein interactions of PAFR-FAK and FAK-STAT1 in BRCA1-mutant ovarian epithelial cells, but not in the wild-type control cells. CONCLUSION: Previous studies showed that potent inflammatory lipid mediators such as PAF and its receptor (PAFR) significantly contribute to cancer progression and metastasis. Our findings suggest that these potent inflammatory lipids and receptor pathways are significantly involved in the early malignant transformation through PAFR-FAK-STAT1 networking and to block apoptosis pathway in BRCA1 dysfunctional at-risk ovarian epithelium.