LMLarissa Meyer
Papers(12)
Survival Benefit of P…Neoadjuvant Chemother…Dietary Magnesium Rep…Use Patterns of Levon…Real-world use of imm…Endometrial cancer re…Implementation of a s…Body mass index and a…Randomized phase 2 tr…Cost of ovarian cance…Neuroendocrine cervic…Secondary validation …
Collaborators(10)
Sarah HuepenbeckerNicole D. FlemingRoss HarrisonHui ZhaoPamela T. SolimanShannon N. WestinCharlotte C. SunNingping FengPatrick HwuPaul G. Yeh
Institutions(3)
The University Of Tex…Queen Mary University…School of Public Heal…

Papers

Survival Benefit of Palliative Oophorectomy for Patients With Ovarian Metastasis From Baseline Metastatic Gastric Adenocarcinoma

PURPOSE To compare overall survival (OS) in patients with baseline metastatic gastric adenocarcinoma (GA) with and without ovarian metastasis (OM). Furthermore, within the group that had ovarian metastases, we aimed to assess whether there was a survival benefit (SB) with palliative oophorectomy (PO). PATIENTS AND METHODS This is a single-institution retrospective analysis of the clinicopathological features of women diagnosed with metastatic GA with a comparison of outcomes based on PO status. We identified 240 women with baseline metastatic GAs who were treated at MD Anderson Cancer Center between February 2003 and September 2022. Among these women, we categorized a subgroup of 102 women who had OM from their primary GA. Patients were analyzed whether they underwent PO. RESULTS Patients who developed OM were most often non-Caucasian, had peritoneal involvement, and had tumors that were both human epidermal growth factor receptor 2–negative and PD-L1–negative, with signet ring cell features and diffuse histological type. Among patients with ovarian metastases, those who had PO had an Eastern Cooperative Oncology Group = 0, more comprehensive molecular and immunohistochemical profiling, lower percentage of family history of gastroesophageal malignancies, and lower interval between diagnosis of the GA primary and the OM. PO was associated with significantly improved OS in this subgroup (hazard ratio, 0.5 [95% CI, 0.31 to 0.81]; P = .005). CONCLUSION To our knowledge, this is the largest multiethnic population study assessing SB of PO in patients with GA with OM. Additionally, it is the largest study analyzing survival in this population according to the patient's multiethnic characteristics and metastasis timing and growth patterns. PO presents as a therapeutic option for women with GAs with OM if the patient is clinically suitable for surgical resection.

Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: ASCO Guideline Update

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more . PURPOSE To provide updated guidance regarding neoadjuvant chemotherapy (NACT) and primary cytoreductive surgery (PCS) among patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (epithelial ovarian cancer [EOC]). METHODS A multidisciplinary Expert Panel convened and updated the systematic review. RESULTS Sixty-one studies form the evidence base. RECOMMENDATIONS Patients with suspected stage III-IV EOC should be evaluated by a gynecologic oncologist, with cancer antigen 125, computed tomography of the abdomen and pelvis, and chest imaging included. All patients with EOC should be offered germline genetic and somatic testing at diagnosis. For patients with newly diagnosed advanced EOC who are fit for surgery and have a high likelihood of achieving complete cytoreduction, PCS is recommended. For patients fit for PCS but deemed unlikely to have complete cytoreduction, NACT is recommended. Patients with newly diagnosed advanced EOC and a high perioperative risk profile should receive NACT. Before NACT, patients should have histologic confirmation of invasive ovarian cancer. For NACT, a platinum-taxane doublet is recommended. Interval cytoreductive surgery (ICS) should be performed after ≤four cycles of NACT for patients with a response to chemotherapy or stable disease. For patients with stage III disease, good performance status, and adequate renal function treated with NACT, hyperthermic intraperitoneal chemotherapy may be offered during ICS. After ICS, chemotherapy should continue to complete a six-cycle treatment plan with the optional addition of bevacizumab. Patients with EOC should be offered US Food and Drug Administration–approved maintenance treatments. Patients with progressive disease on NACT should have diagnosis reconfirmed via tissue biopsy. Patients without previous comprehensive genetic or molecular profiling should be offered testing. Treatment options include alternative chemotherapy regimens, clinical trials, and/or initiation of end-of-life care. Additional information is available at www.asco.org/gynecologic-cancer-guidelines . This guideline has been endorsed by the Society of Gynecologic Oncology.

Dietary Magnesium Replacement for Prevention of Hypomagnesemia in Patients With Ovarian Cancer Receiving Carboplatin-Based Chemotherapy

PURPOSE Hypomagnesemia is a common side effect of platinum-based chemotherapy and predicts poor overall survival in some cancers. Standard magnesium replacement strategies are often inadequate for maintaining magnesium levels. We hypothesized that a daily dietary magnesium replacement approach through magnesium-rich foods would help maintain adequate magnesium levels during platinum-based treatment. MATERIALS AND METHODS We conducted a prospective feasibility study of magnesium-rich diets in patients 18 years and older with previously untreated ovarian cancer scheduled to receive carboplatin-containing chemotherapy of at least six consecutive cycles. Education about magnesium-rich diets was provided at enrollment and then weekly during chemotherapy. Feasibility was defined as ≥60% completion of dietary recalls and ≥280 mg average daily dietary magnesium intake across all patients. RESULTS Twenty-one of 26 patients enrolled completed at least five chemotherapy cycles and were included in the analysis. Adherence to the study diet was 76%. Daily dietary magnesium intake was 100.5 mg at baseline and increased throughout each cycle: 6% of patients at baseline, 24% after the first cycle, and 67% after the fifth cycle reached ≥280-mg/day magnesium intake. Seven (33%) of 21 had at least one incident of hypomagnesemia. Patients who were adherent had significantly lower incidence of hypomagnesemia (19% v 80%, P = .03) and less need for intravenous magnesium (6% v 60%, P = .03) than those who were nonadherent. CONCLUSION The study achieved primary feasibility objectives of retention and adherence to the study intervention. Weekly education about magnesium-rich diets was effective in increasing dietary magnesium intake. Adequate dietary magnesium appeared to be protective against hypomagnesemia.

Use Patterns of Levonorgestrel-Releasing Intrauterine System among American Women

Abstract Levonorgestrel-releasing intrauterine system (LNG-IUS) use is approved by the FDA for contraception and heavy menorrhagia. More importantly, it effectively treats endometrial hyperplasia, a precursor to endometrial cancer. Therefore, LNG-IUS use is associated with potential endometrial cancer risk reduction, but current use patterns in the United States are unknown. We analyzed LNG-IUS use prevalence among women ages 18 to 50 years using a weighted statistical analysis of the 2017 to 2019 National Survey of Family Growth. Summary statistics were stratified by race and ethnic group and known endometrial cancer sociodemographic and health risk factors and assessed statistically with bivariate Rao–Scott χ2 tests. A multivariable logistic regression model was developed to explore LNG-IUS use predictors. Current LNG-IUS use in the United States was 6.9% [95% confidence interval (CI), 5.9%–8.1%]. LNG-IUS use was lower in Hispanic women compared with White women [adjusted OR (AOR), 0.7; 95% CI, 0.5–1.0]. Compared with women with ≤high school education, LNG-IUS use was higher for women with ≥college degree (AOR, 2.0; 95% CI, 1.3–3.1). Parous (AOR, 2.6; 95% CI, 1.7–3.9) and insured (AOR, 1.7; 95% CI, 1.0–3.1) women had higher odds of LNG-IUS use, whereas women with diabetes (AOR, 0.3; 95% CI, 0.1–0.7) had lower odds of LNG-IUS use. No differences in LNG-IUS use were observed by endometrial cancer risk factors of women’s body mass index, age of menarche, hypertension, and personal history of cancer. More research is needed to establish the potential benefits of LNG-IUS use on endometrial cancer, which will further highlight potential opportunities for population-level primary prevention to address the growing incidence of endometrial cancer. Prevention Relevance: This study describes the characteristics of American women using the LNG-IUS. Reproductive-age women (especially Hispanic, with lower education, nulliparous, uninsured, and with diabetes) have lower LNG-IUS use odds. These groups may benefit from LNG-IUS use for endometrial cancer primary prevention, conditioned that LNG-IUS use is proven effective in reducing endometrial cancer incidence.

Real-world use of immune checkpoint inhibitors in advanced or recurrent endometrial cancer

The aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer. Adult women with advanced or recurrent endometrial cancer who received at least one line of systemic treatment between January 1, 2014 and November 1, 2020, then followed to May 31, 2021 in a nationwide electronic health record-derived de-identified database. Chi-Squared test or Welch's 2-sample t-tests were used to compare patient and clinical factors associated with immune checkpoint inhibitor treatment. Time to next treatment analyses were performed based on the treatment line of the immune checkpoint inhibitor. Sankey plots depicted patient-level temporal systemic treatment. During our study period, 326 women received their first immune checkpoint inhibitor treatment, increasing from 12 patients in 2016 to 148 in 2020. Factors associated with ever receiving immune checkpoint inhibitors included disease stage (p=0.002), mismatch repair (MMR)/microsatellite instability (MSI) status (p<0.001), performance status (p=0.001), and prior radiation receipt (p<0.001) and modality (p=0.003). The most common immune checkpoint inhibitor regimen was pembrolizumab (47.9%) followed by pembrolizumab and lenvatinib (34.7%). Immune checkpoint inhibitors were given as first, second, and third or greater lines of therapy in 24.5%, 41.7%, and 46.1% of evaluable patients. The median time to next treatment was significantly longer if given as an earlier line of treatment (p=0.008). There were significant differences in treatment line of immune checkpoint inhibitor by region (p=0.004), stage (p<0.001), and prior radiation receipt (p=0.014) and modality (p=0.009). Among 326 patients who received immune checkpoint inhibitors, 114 (34.9%) received subsequent treatment including chemotherapy (43.9%), additional immune checkpoint inhibitors (29.8%), and other (26.3%) with no differences in demographic or clinical characteristics based on the type of post-immune checkpoint inhibitor treatment. In an observational retrospective real-world database study, immune checkpoint inhibitors were used in 14.7% of patients with advanced or recurrent endometrial cancer across multiple lines of treatment, including after initial immune checkpoint inhibitor treatment.

Implementation of a sentinel lymph node mapping algorithm for endometrial cancer: surgical outcomes and hospital charges

The purpose of this study was to compare operative times, surgical outcomes, resource utilization, and hospital charges before and after the implementation of a sentinel lymph node (SLN) mapping algorithm in endometrial cancer. All patients with clinical stage I endometrial cancer were identified pre- (2012) and post- (2017) implementation of the SLN algorithm. Clinical data were summarized and compared between groups. Total hospital charges incurred on the day of surgery were extracted from the hospital financial system for each patient and all charges were adjusted to 2017 US dollars. A total of 203 patients were included: 71 patients in 2012 and 130 patients in 2017. There was no difference in median age, body mass index, or stage. In 2012, 35/71 patients (49.3%) underwent a lymphadenectomy. In 2017, SLN mapping was attempted in 120/130 patients (92.3%) and at least one SLN was identified in 110/120 (91.7%). Median estimated blood loss was similar between groups (100 mL vs 75 mL, p=0.081). There was a significant decrease in both median operative time (210 vs 171 min, p=0.007) and utilization of intraoperative frozen section (63.4% vs 14.6%, p<0.0001). No significant differences were noted in intraoperative (p=1.00) or 30 day postoperative complication rates (p=0.30). The median total hospital charges decreased by 2.73% in 2017 as compared with 2012 (p=0.96). Implementation of an SLN mapping algorithm for high- and low-risk endometrial cancer resulted in a decrease in both operative time and intraoperative frozen section utilization with no change in surgical morbidity. While hospital charges did not significantly change, further studies are warranted to assess the true cost of SLN mapping.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum‐resistant ovarian cancer

AbstractBackgroundSingle‐agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%–40% of patients achieve stable disease. The primary objective was to estimate progression‐free survival (PFS) after sequential versus combination cytotoxic T‐lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum‐resistant high‐grade serous ovarian cancer (HGSOC).MethodsPatients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune‐related PFS (irPFS).ResultsSixty‐one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77–2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77–2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient‐reported outcomes were similar in both arms.ConclusionsThere was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum‐resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

Cost of ovarian cancer by the phase of care in the United States

Ovarian cancer is associated with delayed diagnosis and poor survival; thus, interest is high in identifying predictive and prognostic biomarkers and novel therapeutic agents. Although the costs of ovarian cancer care are likely to increase as newer, more effective, but more expensive treatment regimens become available, information on the current costs of care for ovarian cancer-across the care continuum from diagnosis to the end of life-are lacking. This study aimed to estimate real-world mean and median costs of ovarian cancer care within the first 5 years after diagnosis by patients' phase of care, age, race/ethnicity, and geographic region. We performed a retrospective cohort study of ovarian cancer patients diagnosed between January 1, 2015 and December 31, 2020. We used claims data from Optum's deidentified Clinformatics Data Mart database, which includes inpatient, outpatient, and prescription claims for commercial insurance and Medicare beneficiaries nationwide. Cost of ovarian cancer care were calculated for the start of care (ie, the first 6 months), continuing care (ie, period between the initial and end-of-life care), and end-of-life care (ie, the last 6 months) phases and reported in 2021 U.S. dollar amounts. Ovarian cancer care costs were stratified by age, race/ethnicity, and geographic region. Due to the skewed nature of cost data, the mean cost data were log-transformed for modeling. Ordinary least-squares regression was conducted on the log costs, adjusting for patient categorical age, race/ethnicity, and geographic region. A total of 7913 patients were included in the analysis. The mean cost per year for ovarian cancer care was >$200,000 during the start of care, between $26,000 and $88,000 during the continuing care phase, and >$129,000 during the end-of-life care phase. There were statistically significant associations between age and costs during each phase of care. Compared to younger patients, older patients incurred higher costs during the continuing care phase and lower costs during the end-of-life care phase. Geographic differences in the costs of ovarian cancer care were also noted regardless of the phase of care. There were no associations between cost and race/ethnicity in our cohort. Ovarian cancer care costs are substantial and vary by the phase of care, age category, and geographic region. As more effective but expensive treatment options for ovarian cancer become available with potential survival benefit, sustainable interventions to reduce the cost of care for ovarian cancer will be needed throughout the cancer care continuum.

Neuroendocrine cervical carcinomas: genomic insights, controversies in treatment strategies, and future directions: a NeCTuR study

Neuroendocrine cervical carcinomas are rare, aggressive tumors with a high risk of early metastasis and poor survival outcomes. Despite existing therapies, over half of patients experience recurrence or progression after primary treatment, and survival after recurrence remains limited. Survival rates have not significantly improved over the past several decades, underscoring an urgent need for better therapeutic options. The rarity of neuroendocrine cervical carcinoma has precluded randomized trials, leaving treatment strategies to be guided by small retrospective studies or adapted from protocols for small cell lung cancer. However, as we gain a deeper understanding of its unique origin, genomic landscape, and biological characteristics, it has become clear that neuroendocrine cervical carcinoma requires distinct management strategies. Key questions in managing neuroendocrine cervical carcinoma remain unanswered: does adjuvant radiation therapy improve outcomes for early-stage disease? Should neoadjuvant chemotherapy be considered for patients with bulky, localized tumors? Can immunotherapy improve outcomes when added to chemoradiation in locally advanced cases? Should immunotherapy be a standard option for recurrent disease? Addressing these questions requires a thorough understanding of the unique molecular and biological characteristics of neuroendocrine cervical carcinoma and its clinical behavior. This review aims to provide an updated summary of the molecular landscape of neuroendocrine cervical carcinoma, highlighting features that distinguish it from small cell lung cancer and align with other types of cervical cancer. We discuss current treatment approaches, identify gaps in knowledge, and examine paradigm-shifting clinical trials that have significantly impacted survival outcomes in cervical cancer and small cell lung cancer, translating these insights into potential strategies for neuroendocrine cervical carcinoma. By focusing on the unique aspects of neuroendocrine cervical carcinoma, this review emphasizes the need for specialized treatment strategies for this challenging disease.

Secondary validation of an ovarian cancer-specific comorbidity index in a US population

The Ovarian Cancer Comorbidity Index (OCCI) is an age-specific index developed and previously found to be more predictive of overall and cancer-specific survival than the Charlson Comorbidity Index (CCI). The objective was to perform secondary validation of the OCCI in a US population. A cohort of ovarian cancer patients undergoing primary or interval cytoreductive surgery from January 2005 to January 2012 was identified in SEER-Medicare. OCCI scores were calculated with the regression coefficients determined from the original developmental cohort for five comorbidities. Cox regression analyses were used to calculate associations between the OCCI risk groups and 5-year overall survival and 5-year cancer-specific survival in comparison to the CCI. A total of 5052 patients were included. Median age was 74 (range 66-82) years. 47% (n=2375) had stage III and 24% (n=1197) had stage IV disease at diagnosis. 67% had a serous histology subtype (n=3403). All patients were categorized as moderate (48.4%) or high risk (51.6%). The prevalence of the five predictive comorbidities were: coronary artery disease 3.7%, hypertension 67.5%, chronic obstructive pulmonary disease 16.7%, diabetes 21.8%, and dementia 1.2%. Controlling for histology, grade, and age-stratification, worse overall survival was associated with both a higher OCCI (hazard ratio (HR) 1.57; 95% confidence interval (CI) 1.46 to 1.69) and CCI (HR 1.96; 95% CI 1.66 to 2.32). Cancer-specific survival was associated with the OCCI (HR 1.33; 95% CI 1.22 to 1.44) but was not associated with the CCI (HR 1.15; 95% CI 0.93 to 1.43). This internationally developed comorbidity score for ovarian cancer patients is predictive for both overall and cancer-specific survival in a US population. CCI was not predictive for cancer-specific survival. This score may have research applications when utilizing large administrative datasets.

Correlation of surgeon radiology assessment with laparoscopic disease site scoring in patients with advanced ovarian cancer

Radiographic triage measures in patients with new advanced ovarian cancer have yielded inconsistent results. To determine the correlation between surgeon radiology assessment and laparoscopic scoring by disease sites in patients with newly diagnosed advanced stage ovarian cancer. Fourteen gynecologic oncology surgeons from a single institution performed a blinded review of pre-operative contrast-enhanced CT imaging from patients with advanced stage ovarian cancer. Each of the patients had also undergone laparoscopic scoring assessment, between April 2013 and December 2017, to determine primary resectability using the validated Fagotti scoring method, and assigned a predictive index value score. Surgeons were asked to provide expected predictive index value scores based on their blinded review of the antecedent CT imaging. Linear mixed models were conducted to calculate the correlation between radiologic and laparoscopic score for surgeons individually, and as a group. Once the model was fit, the inter-class correlation and 95% CI were calculated. Radiology review was performed on 20 patients with advanced stage ovarian cancer who underwent laparoscopic scoring assessment. Surgeon faculty rank included assistant professor (n=5), associate professor (p=4), and professor (n=5). The kappa inter-rater agreement was -0.017 (95% CI -0.023 to -0.005), indicating low inter-rater agreement between radiology review and actual laparoscopic score. The inter-class correlation in this model was 0.06 (0.02-0.21), indicating that surgeons do not score the same across all the images. When using a clinical cut-off point for the predictive index value of 8, the probability of agreement between radiology and actual laparoscopic score was 0.56 (95% CI 0.49 to 0.73). Examination of disease site sub-scales showed that the probability of agreement was as follows: peritoneum 0.57 (95% CI 0.51 to 0.62), diaphragm 0.54 (95% CI 0.48 to 0.60), mesentery 0.51 (95% CI 0.45 to 0.57), omentum 0.61 (95% CI 0.55 to 0.67), bowel 0.54 (95% CI 0.44 to 0.64), stomach 0.71 (95% CI 0.65 to 0.76), and liver 0.36 (95% CI 0.31 to 0.42). The number of laparoscopic scoring cases, tumor reductive surgery cases, or faculty rank was not significantly associated with overall or sub-scale agreement. Surgeon radiology review did not correlate highly with actual laparoscopic scoring assessment findings in patients with advanced stage ovarian cancer. Our study highlights the limited accuracy of surgeon radiographic assessment to determine resectability.

Enhanced recovery for obese patients undergoing gynecologic cancer surgery

To compare post-operative length of stay and complication rates of matched obese and non-obese patients in an enhanced recovery (ERAS) program after open gynecologic cancer surgery. We performed an observational cohort study of patients (n=1225) undergoing open surgery from November 2014 to November 2018 at a tertiary cancer center. Patients undergoing multidisciplinary procedures, non-oncologic surgery, or procedures in addition to abdominal surgery were excluded (n=190). Obese and non-obese patients were matched by date, age, disease status, and surgical complexity. The primary outcome was post-operative length of stay. Secondary outcomes included 30-day peri-operative complications, re-operation, re-admission, opioid use, and program compliance. After matching, 696 patients (348 obese, 348 non-obese) with median age of 57 years (IQR 48-66) were analyzed. Obese patients had a longer median procedure time (218 min vs 192.5 min, p<0.001) and greater median estimated blood loss (300 mL vs 200 mL, p<0.001). Median (IQR) post-operative length of stay was the same for obese and non-obese patients: 3 days (IQR 2-4). Obese and non-obese patients had similar rates of grade III-IV complications (10.9% and 6.6%, respectively, p=0.06), re-operation (2.3% and 1.4%, respectively, p=0.58), and re-admission (11.8% and 8.0%, respectively, p=0.13). Grade I-II complications were more common among obese patients (62.4% vs 48.3%, p<0.001) because they had more wound complications (17.8% vs 4.9%, p<0.001). Obese patients received more opioids both during surgery (morphine equivalent dose 57.25 mg (IQR 35-72.5) vs 50 mg (IQR 25-622.5), p=0.003) and after surgery (morphine equivalent daily dose 45 mg/day (IQR 10-96.2) vs 29.37 mg/day (IQR 7.5-70), p=0.01). Obese and non-obese patients had similar ERAS program compliance (70.1% and 69.8%, respectively, p=0.32). Neither post-operative length of stay nor the rate of serious complications differed significantly despite longer surgeries, greater blood loss, and more opioid use among obese patients. An ERAS program was safe, effective, and feasible for obese patients with suspected gynecologic cancer.

National trends in bowel and upper abdominal procedures in ovarian cancer surgery

In the United States, trends in the initial treatment approach for ovarian cancer reflect a shift in paradigm toward the increased use of neoadjuvant chemotherapy and interval cytoreductive surgery. The aim of this study was to evaluate the trends in surgical cytoreductive procedures in ovarian cancer patients who underwent either primary or interval cytoreductive surgery. This retrospective, population-based study examined patients with stage III/IV ovarian cancer diagnosed between January 2000 and December 2013 identified using SEER-Medicare. Small or large bowel resection, ostomy creation, and upper abdominal procedures were identified using relevant billing codes and compared over time. A 1:1 primary and interval cytoreductive propensity matched cohort was created using demographic and clinical variables. 30-day complications and the use of acute care services were compared. A total of 5417 women were identified. 34% underwent bowel resections, 16% ostomy creation, and 8% upper abdominal procedures. There was an increase in bowel resections and upper abdominal procedures from 2000 to 2013 in patients who underwent primary cytoreductive surgery. Compared with patients who received primary cytoreduction, patients who underwent interval cytoreductive surgery were less likely to undergo bowel resection (OR=0.50; 95% CI [0.41, 0.61]) or ostomy creation (OR=0.48; 95% CI [0.42, 0.56]). Upper abdominal procedures did not differ between groups. For patients who underwent primary cytoreductive surgery, these procedures were associated with intensive care unit stay (4.6% vs <2%, P<0.01). In both primary and interval cytoreductive surgery patients, the receipt of bowel and upper abdominal procedures was associated with multiple 30-day postoperative complications and higher rates of readmission and emergency room visits. The performance of upper abdominal procedures in ovarian cancer patients increased from 2000 to 2013. Interval cytoreductive surgery was associated with decreased likelihood of bowel surgery. In matched primary and interval cytoreductive surgery cohorts, the receipt of these procedures were associated with the increased likelihood of postoperative complications and use of acute care services.

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer

Abstract Purpose: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. Patients and Methods: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. Results: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. Conclusions: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

Factors impacting the time to ovarian cancer diagnosis based on classic symptom presentation in the United States

BackgroundPatients with ovarian cancer often present with late‐stage disease and nonspecific symptoms, but little is known about factors affecting the time to diagnosis (TTD) in the United States.MethodsA retrospective, population‐based study of the Surveillance, Epidemiology, and End Results–Medicare database was conducted. It included women 66 years old or older with stage II to IV epithelial ovarian cancer with at least 1 code for abdominal/pelvic pain, bloating, difficulty eating, or urinary symptoms within 1 year of the cancer diagnosis. TTD was defined from the first claim with a prespecified symptom to the ovarian cancer diagnosis. Kruskal‐Wallis tests were used to assess for differences in TTD by group medians. Univariate and generalized linear models with a log‐link function evaluated TTD by covariables.ResultsFor the 13,872 women analyzed, the mean and median times to diagnosis were 2.9 and 1.1 months, respectively. The median TTD differed significantly by first symptom (P &lt; .001), number of symptoms (P &lt; .001), and first physician specialty seen (P &lt; .001). In a multivariable analysis, TTD differed significantly according to race/ethnicity (P &lt; .001), geographic region (P = .001), urban‐rural location (P = .031), emergency room presentation (P &lt; .001), and number of specialties seen (P &lt; .001). A shorter TTD was associated with a diagnosis in 2006‐2010 (relative risk [RR], 0.92; 95% confidence interval [CI], 0.87‐0.98) or 2011‐2015 (RR, 0.87; 95% CI, 0.81‐0.93) in comparison with 1992‐1999.ConclusionsThe time from a symptomatic presentation to care to a diagnosis of ovarian cancer is influenced by clinical and demographic variables. This study's findings reinforce the importance of educating all physicians on ovarian cancer symptoms to aid in diagnosis.Lay Summary Ovarian cancer is often diagnosed once disease has spread because the classic symptoms of ovarian cancer—abdominal or pelvic pain, bloating, difficulty eating, and urinary issues—can be mistaken for other problems. This study examined the time between when women with classic ovarian cancer symptoms went to a physician and when they received a cancer diagnosis in a large database population. The authors found that the time to diagnosis differed according to the type and number of symptoms and what type of physician a woman saw as well as factors such as race, geographic location, and year of diagnosis.

Association between time to diagnosis, time to treatment, and ovarian cancer survival in the United States

Evaluate the association between time to diagnosis and treatment of advanced ovarian cancer with overall and ovarian cancer specific mortality using a retrospective cross sectional study of a population based cancer registry database. The Surveillance, Epidemiology, and End Results-Medicare database was searched from 1992 to 2015 for women aged ≥66 years with epithelial ovarian cancer and abdominal/pelvic pain, bloating, difficulty eating, or urinary symptoms within 1 year of cancer diagnosis. Time from presentation to diagnosis and treatment were evaluated as outcomes and covariables. Cox regression models and adjusted Kaplan-Meier curves evaluated 5 year overall and cancer-specific survival. Among 13 872 women, better survival was associated with longer time from presentation to diagnosis (overall survival hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.94 to 0.95; cancer specific survival HR 0.95, 95% CI 0.94 to 0.96) and diagnosis to treatment (overall survival HR 0.94, 95% CI 0.92 to 0.96; cancer specific survival HR 0.93, 95% CI 0.91 to 0.96). There was longer time from presentation to diagnosis in Hispanic women (relative risk (RR) 1.21, 95% CI 1.12 to 1.32) and from diagnosis to treatment in non-Hispanic black women (RR 1.36, 95% CI 1.21 to 1.54), with lower likelihood of survival at 5 years after adjustment for time to diagnosis and treatment among non-Hispanic black women (HR 1.15, 95% CI 1.05 to 1.26) compared with non-Hispanic white women. Gynecologic oncology visit was associated with improved overall (p<0.001) and cancer specific (p<0.001) survival despite a longer time from presentation to treatment (p<0.001). Longer time to diagnosis and treatment were associated with improved survival, suggesting that tumor specific features are more important prognostic factors than the time interval of workup and treatment. Significant sociodemographic disparities indicate social determinants of health influencing workup and care. Gynecologic oncologist visits were associated with improved survival, highlighting the importance of appropriate referral for suspected ovarian cancer.

CRISPR-mediated TGFBR2 knockout renders human ovarian cancer tumor-infiltrating lymphocytes resistant to TGF-β signaling

Background The correlation between elevated T-cell infiltration and improved survival of ovarian cancer (OvCa) patients suggests that endogenous tumor-infiltrating lymphocytes (TIL) possess some degree of antitumor activity that can be harnessed for OvCa immunotherapy. We previously optimized a protocol for ex vivo OvCa TIL expansion for adoptive cell therapy, which is now being tested in a clinical trial at our institution (NCT03610490). Building on this success, we embarked on genetic modification of OvCa TIL to overcome key immunosuppressive factors present in the tumor microenvironment. Here, we present the preclinical optimization of CRISPR/Cas9-mediated knockout of the TGF-β receptor 2 (TGFBR2) in patient-derived OvCa TIL. Methods OvCa TILs were generated from four patients’ tumor samples obtained at surgical resection and subjected to CRISPR/Cas9-mediated knockout of TGFBR2 before undergoing a rapid expansion protocol. TGFBR2-directed gRNAs were comprehensively evaluated for their TGFBR2 knockout efficiency and off-target activity. Furthermore, the impact of TGFBR2 knockout on TIL expansion, function, and downstream signaling was assayed. Results TGFBR2 knockout efficiencies ranging from 59±6% to 100%±0% were achieved using 5 gRNAs tested in four independent OvCa TIL samples. TGFBR2 knockout TIL were resistant to immunosuppressive TGF-β signaling as evidenced by a lack of SMAD phosphorylation, a lack of global transcriptional changes in response to TGF-β stimulation, equally strong secretion of proinflammatory cytokines in the presence and absence of TGF-β, and improved cytotoxicity in the presence of TGF-β. CRISPR-modification itself did not alter the ex vivo expansion efficiency, immunophenotype, nor the TCR clonal diversity of OvCa TIL. Importantly for clinical translation, comprehensive analysis of CRISPR off-target effects revealed no evidence of off-target activity for our top two TGFBR2-targeting gRNAs. Conclusions CRISPR/Cas9-mediated gene knockout is feasible and efficient in patient-derived OvCa TIL using clinically-scalable methods. We achieved efficient and specific TGFBR2 knockout, yielding an expanded OvCa TIL product that was resistant to the immunosuppressive effects of TGF-β. This study lays the groundwork for clinical translation of CRISPR-modified TIL, providing opportunities for engineering more potent TIL therapies not only for OvCa treatment, but for the treatment of other solid cancers as well.

Temporal trends of healthcare system use between symptomatic presentation and ovarian cancer diagnosis in the United States

To describe trends in healthcare system use over time between onset of classic ovarian cancer symptoms and ovarian cancer diagnosis in the United States. A population-based study of the Surveillance, Epidemiology, and End Results-Medicare database was conducted on patients aged ≥66 years with stage II-IV epithelial ovarian cancer between 1992 and 2015 with at least one of the following diagnosis codes: abdominal pain, bloating, difficulty eating, and/or urinary symptoms. The outcomes were frequency of visit type, frequency of diagnostic modality, and Medicare reimbursement between first symptomatic claim and cancer diagnosis. Jonckheere-Terpstra and Cochran-Armitage tests were used to evaluate trends over time. Among 13 872 women, 13 541 (97.6%) had outpatient, 6466 (46.6%) had inpatient, and 4906 (35.4%) had emergency room visits. The frequency of outpatient (p<0.001) and emergency room visits (p<0.001) increased while the frequency of inpatient visits (p<0.001) decreased between 1992 and 2015. The median number of outpatient visits (p<0.001) and physician specialties seen (p<0.001) increased over time. The median hospital length of stay decreased from 10 days in 1992 to 5 days in 2015 (p<0.001). Between 1992 and 2015, the frequency of ultrasound decreased (p<0.001) while the frequency of computed tomography, magnetic resonance imaging, positron emission tomography imaging, and cancer antigen 125 tumor immunoassay increased (p<0.001). Median monthly total (p<0.001), inpatient (p<0.001), and outpatient (p=0.006) reimbursements decreased while emergency room reimbursements increased (p<0.001) over time. Healthcare reimbursement between symptomatic presentation and ovarian cancer diagnosis has decreased over time and may reflect the trends in fewer and shorter hospitalizations and increased use of emergency and outpatient management during the evaluation of symptoms of women with ovarian cancer.

Algorithm to Identify Incident Epithelial Ovarian Cancer Cases Using Claims Data

PURPOSE To create an algorithm to identify incident epithelial ovarian cancer cases in claims-based data sets and evaluate performance of the algorithm using SEER-Medicare claims data. METHODS We created a five-step algorithm on the basis of clinical expertise to identify incident epithelial ovarian cancer cases using claims data for (1) ovarian cancer diagnosis, (2) receipt of platinum-based chemotherapy, (3) no claim for platinum-based chemotherapy but claim for tumor debulking surgery, (4) removed cases with nonplatinum chemotherapy, and (5) removed patients with prior claims with personal history of ovarian cancer code to exclude prevalent cases. We evaluated algorithm performance using SEER-Medicare claims data by creating four cohorts: incident epithelial ovarian cancer, a 5% random sample of cancer-free Medicare beneficiaries, a 5% random sample of incident nonovarian cancer, and prevalent ovarian cancer cases. RESULTS Using SEER tumor registry data as the gold standard, our algorithm correctly classified 89.9% of incident epithelial ovarian cancer cases (cohort n = 572) and almost 100% of cancer-free controls (n = 97,127), nonovarian cancer (n = 714), and prevalent ovarian cancer cases (n = 3,712). The overall algorithm sensitivity was 89.9%, the positive predictive value was 93.8%, and the specificity and negative predictive value were &gt; 99.9%. Patients were more likely to be correctly classified as incident ovarian cancer if they had stage III or IV disease compared with early stage I or II disease (93.5% v 83.7%, P &lt; .01), and grade 1-4 compared with unknown grade tumors (93.8% v 81.4%, P &lt; .01). CONCLUSION Our algorithm correctly identified most incident epithelial ovarian cancer cases, especially those with advanced disease. This algorithm will facilitate research in other claims-based data sets where cancer registry data are unavailable.

176Works
22Papers
62Collaborators
1Trials
Ovarian NeoplasmsEndometrial NeoplasmsNeoplasm StagingGenital Neoplasms, FemaleNeoplasm Recurrence, LocalUterine Cervical NeoplasmsStomach Neoplasms
Links & IDs
0000-0002-2687-7463

Scopus: 24484729800