Monica Prasad-Hayes

Role of FDG PET/CT in Staging of Recurrent Ovarian Cancer

Ovarian cancer is the fifth leading cause of cancer death among women in the United States and has a high likelihood of recurrence despite aggressive treatment strategies. Detection and exact localization of recurrent lesions are critical for guiding management and determining the proper therapeutic approach, which may prolong survival. Because of its high sensitivity and specificity compared with those of conventional techniques such as computed tomography (CT) and magnetic resonance (MR) imaging, fluorine 18 fluorodeoxyglucose positron emission tomography (PET) combined with CT is useful for detection of recurrent or residual ovarian cancer and for monitoring response to therapy. However, PET/CT may yield false-negative results in patients with small, necrotic, mucinous, cystic, or low-grade tumors. In addition, in the posttherapy setting, inflammatory and infectious processes may lead to false-positive PET/CT results. Despite these drawbacks, PET/CT is superior to CT and MR imaging for depiction of recurrent disease.

Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers

Background High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools. Methods and Findings Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival. Conclusions Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection point in precision medicine. This study suggests that the use of personalized ctDNA biomarkers in gynecologic cancers can identify the presence of residual tumor while also more dynamically predicting response to treatment relative to currently used serum and imaging studies. Of particular interest, ctDNA was an independent predictor of survival in patients with ovarian and endometrial cancers. Earlier recognition of disease persistence and/or recurrence and the ability to stratify into better and worse outcome groups through ctDNA surveillance may open the window for improved survival and quality and life in these cancers.

Ovarian Cancer Treatment and Survival Trends Among Women Older Than 65 Years of Age in the United States, 1995-2008.

OBJECTIVE: To evaluate whether overall survival is improving among women in the United States with advanced ovarian cancer. METHODS: This retrospective cohort study evaluated trends in treatment and overall survival for women older than 65 years diagnosed with stage III and IV epithelial ovarian cancer between 1995 and 2008 using Surveillance, Epidemiology, and End Results–Medicare data. Parametric and semiparametric multivariate survival analyses were used to assess comparative treatment survival rates and factors affecting survival and recurrence. RESULTS: Of 7,938 women who met study criteria, 2.9% received no treatment, 15.4% underwent surgery only, 24.8% received chemotherapy only, 41.8% underwent primary debulking surgery and chemotherapy in an optimal timeframe, and 15.1% had primary debulking surgery and chemotherapy, but the timing was not optimal or patients did not complete all six cycles of chemotherapy. Those who underwent surgery only had similar survival as those who received no treatment (2.2 compared with 1.7 months), whereas those who received chemotherapy only had a better overall survival (14.4 months). Optimal treatment was associated with the longest survival time (P<.001, median overall survival 39.0 months). Additionally, survival time associated with optimal treatment increased over the past decade. However, the proportion of women who received optimal treatment has decreased over the past decade. CONCLUSION: Elderly women with advanced ovarian cancer have the best survival with optimal therapy. When this is not offered or possible, chemotherapy alone offers better survival than surgery alone.

Interferon regulatory factor 1 is an independent predictor of platinum resistance and survival in high-grade serous ovarian carcinoma

OBJECTIVE High-grade serous ovarian cancer (HGSOC) that is resistant to platinum-based chemotherapy has a particularly poor prognosis. Response to platinum has both prognostic survival value and dictates secondary treatment strategies. Using transcriptome analysis, we sought to identify differentially expressed genes/pathways based on a tumors platinum response for discovering novel predictive biomarkers. METHODS Seven primary HGSOC tumor samples, representing two extremes of platinum sensitivity/timing of disease recurrence, were analyzed by RNA-Seq, Ingenuity Pathways Analysis (IPA) and Upstream Regulator Analysis (URA), and used to explore differentially expressed genes and prevalent molecular and cellular processes. Progression-free and overall survival (PFS, OS) was estimated using the Kaplan-Meier method in two different sample sets including GEO and TCGA data sets. RESULTS IPA and URA highlighted an IRF1-driven transcriptional program (P=0.0017; z-score of 3.091) in the platinum sensitive improved PFS group. QRT-PCR analysis of 31 HGSOC samples demonstrated a significant difference in PFS between low and high IRF1 expression groups (P=0.048) and between groups that were platinum sensitive versus not (P=0.016). In a larger validation data set, increased levels of IRF1 were associated with both increased PFS (P=0.043) and OS (P=0.019) and the effect on OS was independent of debulking status (optimal debulking, P=0.025; suboptimal, P=0.041). CONCLUSION Transcriptome analysis identifies IRF1, a transcription factor that functions both in immune regulation and as a tumor suppressor, as being associated with platinum sensitivity and an independent predictor of both PFS and OS in HGSOC.

Adjuvant radiation therapy is associated with improved overall survival in high-intermediate risk stage I endometrial cancer: A national cancer data base analysis

PURPOSE Adjuvant radiation therapy (RT) was shown to improve local control in patients with high-intermediate risk (HIR) stage I endometrial cancer (EC) in randomized trials. Overall survival (OS) was not significantly different with adjuvant RT in these trials or subsequent meta-analyses; however, they were underpowered to assess OS. We used the National Cancer Data Base (NCDB) to examine the impact of adjuvant RT on OS in HIR EC patients. METHODS The NCDB was queried for patients diagnosed with FIGO (2009) Stage I endometrioid adenocarcinoma from 1998 to 2012 who underwent surgery±adjuvant RT. Per ASTRO guidelines, HIR risk was defined as stage IB and/or grade 3. Patients were excluded if: non-surgical primary therapy, RT>180days after surgery, unknown stage/grade/RT status, or RT to targets outside pelvis/vagina. Kaplan-Meier plots and Cox proportional hazards regression were used. RESULTS 33,600 patients met criteria. 18,070 patients (53.8%) received surgery alone, 15,530 patients (46.2%) received surgery+adjuvant RT. Of patients who received adjuvant RT, 42.2% received external beam RT, 44.7% brachytherapy, and 13.1% received both. 5-year OS was 79.2% for the surgery alone group and 83.3% for the surgery+adjuvant RT (p<0.0001). On multivariate analysis, adjuvant RT was independently associated with improved OS vs. surgery alone (HR 0.7; 95% CI 0.8-0.9, p<0.0001). CONCLUSIONS Our results show that surgery+adjuvant RT was associated with a statistically significant 4.1% improvement in 5-year OS vs. surgery alone in stage I HIR EC. This data along suggests that the improvement in local control with adjuvant RT leads to improved OS.

Secondary Surgery Versus Chemotherapy for Recurrent Ovarian Cancer.

Objective: The best course of treatment for recurrent ovarian cancer is uncertain. We sought to determine whether secondary cytoreductive surgery for first recurrence of ovarian cancer improves overall survival compared with other treatments. Materials and Methods: We assessed survival using Surveillance, Epidemiology and End Results-Medicare data for advanced stage ovarian cancer cases diagnosed from January 1, 1997 to December 31, 2007 with survival data through 2010 using multinomial propensity weighted finite mixture survival regression models to distinguish true from misclassified recurrences. Of 35,995 women ages 66 years and older with ovarian cancer, 3439 underwent optimal primary debulking surgery with 6 cycles of chemotherapy; 2038 experienced a remission. Results: One thousand six hundred thirty-five of 2038 (80%) women received treatment for recurrence of whom 72% were treated with chemotherapy only, 16% with surgery and chemotherapy and 12% received hospice care. Median survival of women treated with chemotherapy alone, surgery and chemotherapy, or hospice care was 4.1, 5.4, and 2.2 years, respectively (P<0.001). Of those receiving no secondary treatments, 75% were likely true nonrecurrences with median survival of 15.9 years and 25% misclassified with 2.4 years survival. Survival among women with recurrence was greater for those treated with surgery and chemotherapy compared with chemotherapy alone (hazard ratio=1.67; 95% confidence interval, 1.13-2.47). Women who were older with more comorbidities and high-grade cancer had worse survival. Conclusions: Secondary surgery with chemotherapy to treat recurrent ovarian cancer increases survival by 1.3 years compared with chemotherapy alone and pending ongoing randomized trial results, may be considered a standard of care.

A Validation Study of Administrative Claims Data to Measure Ovarian Cancer Recurrence and Secondary Debulking Surgery

Objective: Administrative claims data offer an alternative to chart abstraction to assess ovarian cancer recurrence, treatment and outcomes. Such analyses have been hindered by lack of valid recurrence and treatment algorithms. In this study, we sought to develop claims-based algorithms to identify ovarian cancer recurrence and secondary debulking surgery, and to validate them against the gold-standard of chart abstraction. Methods: We conducted chart validation studies; 2 recurrence algorithms and 1 secondary surgery among 94 ovarian cancer patients treated at one hospital between 2003–2009. A new recurrence algorithm was based on treatment timing (≥6 months after primary treatment) and a previously validated algorithm was based on secondary malignancy codes. A secondary debulking surgery algorithm was based on surgical billing codes. Results: The new recurrence algorithm had: sensitivity=100% (95% confidence interval [CI]=87%-=100%), specificity=89% (95%CI=78%–95%), kappa=84% (SE=10%) while the secondary-malignancy-=code recurrence algorithm had: sensitivity=84% (95%CI=66%–94%), specificity=44% (95%CI=31%-=57%), kappa=23% (SE=8%). The secondary surgery algorithm had: sensitivity=77% (95%CI=50%–92%), = specificity= 92% (95%CI=83%–97%), kappa=66% (SE=10%).= Conclusions: A recurrence algorithm based on treatment timing accurately identified ovarian cancer =recurrence. If validated in other populations, such an algorithm can provide a tool to compare effectiveness of recurrent ovarian cancer treatments.