The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes.

OBJECTIVE: Low-grade serous carcinoma (LGSOC) is a rare epithelial ovarian/peritoneal cancer characterized by younger age at diagnosis, relative chemoresistance, prolonged overall survival (OS), and mutations in the mitogen activated protein kinase (MAPK) pathway compared to high-grade serous carcinoma. We describe the genomic profile of LGSOC by next generation sequencing (NGS) and evaluated its potential relationship to clinical outcomes. METHODS: The study included 215 women with LGSOC with: 1) pathologically confirmed LGSOC, 2) availability of NGS data, and 3) adequate clinical data. Clinical subgroups were compared for progression-free survival (PFS) and OS. Multivariable Cox regression analysis was performed. RESULTS: Median age at diagnosis was 46.6 years. The majority had a stage III ovarian primary. One or more mutations were identified in 140 (65.1%) cases; 75 (34.9%) had none. The most common mutations were KRAS (n = 71; 33.0%), NRAS (n = 24; 11.2%), and BRAF (n = 18; 8.4%). Patients with MAPK-mutated tumors (n = 113) (52.6%) had a significantly longer OS compared to those with tumors lacking MAPK pathway mutations (n = 102) (47.4%) [median OS, 147.8 months (95% CI,119.0-176.6) versus 89.5 months (95% CI, 61.4-117.7) (p = 0.01)], respectively. Median OS for patients with MAPK-mutated tumors was also significantly better than for patients whose tumors had no mutations (n = 75) [median OS, 147.8 months (95% CI, 119.0-176.6) versus 78.0 months (95% CI, 57.6-98.3)], respectively (p = 0.001). Median OS for patients with non-MAPK-mutated tumors (n = 27) was 125.1 months (95% CI, 83.9-166.3). In multivariable analysis, having a MAPK mutation was associated with improved OS. CONCLUSIONS: Patients with MAPK-mutated tumors have a significantly improved OS compared to those without MAPK-mutated tumors.

The role of neoadjuvant chemotherapy in the management of low-grade serous carcinoma of the ovary and peritoneum: Further evidence of relative chemoresistance.

OBJECTIVE: Low-grade serous carcinoma of the ovary/peritoneum (LGSC) is relatively chemoresistant in the adjuvant, neoadjuvant, and recurrent settings. We sought to expand our prior work and evaluate response rates of women with LGSC to neoadjuvant chemotherapy (NACT) compared to women with high-grade serous carcinoma of the ovary/peritoneum (HGSC). METHODS: Thirty-six patients with LGSC who received NACT were matched to patients with HGSC. A single radiologist re-reviewed pre- and post-NACT imaging for response using RECIST 1.1. Pre- and post-NACT CA-125 values were compared using paired t-tests. Kaplan-Meier estimates of progression free survival (PFS) and overall survival (OS) were performed. RESULTS: All patients received neoadjuvant platinum-based regimens. LGSC patients received a median of 5 cycles (range 3-9), HGSC patients received a median of 4 cycles (range 3-9). Interval cytoreductive surgery was performed in 29/36 (81%) of LGSC and 32/36 (89%) HGSC patients. Complete cytoreduction was reported and achieved in 11/29 (38%) of LGSC patients and 24/32 (75%) of HGSC patients (p = 0.002). Median pre- and post-treatment CA-125 levels for LGSC patients were 295.5 U/mL and 144 U/mL (52% decrease) (p < 0.001). The median pre- and post-treatment CA-125 levels for HGSC patients were 767.5 and 35.6 (96% decrease) (p < 0.001). For LGSC patients, 4/36 (11%) had partial response (PR), 30/36 (83%) had stable disease (SD), and 2/36 (6%) had progressive disease (PD). In HGSC patients, 27/36 (75%) had PR, and 9/36 (25%) SD. Median PFS for LGSC patients was 18.5 months and median OS was 47.4 months. CONCLUSIONS: This study provides further evidence of relative chemoresistance of LGSC in patients treated with NACT.

Low-grade serous ovarian cancer: State of the science.

In January 2019, a group of basic, translational, and clinical investigators and patient advocates assembled in Miami, Florida, to discuss the current state of the science of low-grade serous carcinoma of the ovary or peritoneum-a rare ovarian cancer subtype that may arise de novo or following a diagnosis of serous borderline tumor. The purpose of the conference was to review current knowledge, discuss ongoing research by established researchers, and frame critical questions or issues for future directions. Following presentations and discussions, the primary objective was to initiate future collaborations, uniform database platforms, laboratory studies, and clinical trials to better understand this disease and to advance clinical care outside the boundaries of single academic institutions. This review summarizes the state of the science in five principal categories: epidemiology and patient outcomes, pathology, translational research, patient care and clinical trials, and patients' perspective.

Low-grade serous carcinoma: new concepts and emerging therapies.

For the past several years, all women with epithelial ovarian cancer have been treated identically, whether in a clinical trial or off protocol. Over the past decade, we have come to appreciate the magnitude of the heterogeneity of ovarian cancer. The development of the binary grading system for serous carcinoma was a major advance leading to separate clinical trials for patients with this subtype originating from the Gynecologic Oncology Group's Rare Tumor Committee. The mitogen-activated protein kinase (MAPK) pathway appears to play a prominent role in the pathogenesis of this subtype. Approximately 20-40% of low-grade serous carcinomas have a KRAS mutation, while BRAF mutations are rare - about 5%. Primary treatment of low-grade serous carcinoma includes surgery+platinum-based chemotherapy (either adjuvant or neoadjuvant). Clinical behavior is characterized by young age at diagnosis, relative chemoresistance, and prolonged overall survival. Current options for treatment of relapsed disease include secondary cytoreduction in selected patients, salvage chemotherapy, or hormonal therapy. A recently completed trial of a MEK inhibitor for women with recurrent disease demonstrated promising activity. Future directions will include further investigations of the molecular biology and biomarker-driven clinical trials with targeted agent monotherapy and combinations.

Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth.

PURPOSE: The Aurora kinase family plays pivotal roles in mitotic integrity and cell cycle. We sought to determine the effects of inhibiting Aurora kinase on ovarian cancer growth in an orthotopic mouse model using a small molecule pan-Aurora kinase inhibitor, MK-0457. EXPERIMENTAL DESIGN: We examined cell cycle regulatory effects and ascertained the therapeutic efficacy of Aurora kinase inhibition both alone and combined with docetaxel using both in vitro and in vivo ovarian cancer models. RESULTS: In vitro cytotoxicity assays with HeyA8 and SKOV3ip1 cells revealed >10-fold greater docetaxel cytotoxicity in combination with MK-0457. After in vivo dose kinetics were determined using phospho-histone H3 status, therapy experiments with the chemosensitive HeyA8 and SKOV3ip1 as well as the chemoresistant HeyA8-MDR and A2780-CP20 models showed that Aurora kinase inhibition alone significantly reduced tumor burden compared with controls (P values<0.01). Combination treatment with docetaxel resulted in significantly improved reduction in tumor growth beyond that afforded by docetaxel alone (P

PRKRA/PACT Expression Promotes Chemoresistance of Mucinous Ovarian Cancer.

For mucinous ovarian cancer (MOC), standard platinum-based therapy is largely ineffective. We sought to identify possible mechanisms of oxaliplatin resistance of MOC and develop strategies to overcome this resistance. A kinome-based siRNA library screen was carried out using human MOC cells to identify novel targets to enhance the efficacy of chemotherapy. In vitro and in vivo validations of antitumor effects were performed using mouse MOC models. Specifically, the role of PRKRA/PACT in oxaliplatin resistance was interrogated. We focused on PRKRA, a known activator of PKR kinase, and its encoded protein PACT because it was one of the five most significantly downregulated genes in the siRNA screen. In orthotopic mouse models of MOC, we observed a significant antitumor effect of PRKRA siRNA plus oxaliplatin. In addition, expression of miR-515-3p was regulated by PACT-Dicer interaction, and miR-515-3p increased the sensitivity of MOC to oxaliplatin. Mechanistically, miR-515-3p regulated chemosensitivity, in part, by targeting AXL. The PRKRA/PACT axis represents an important therapeutic target in MOC to enhance sensitivity to oxaliplatin.

A long-term surviving patient with recurrent low-grade serous ovarian carcinoma treated with the MEK1/2 inhibitor, selumetinib.

BACKGROUND: Selumetinib is a potent, selective, orally available, and non-ATP competitive small molecule inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2) that has demonstrated single agent activity in a number of solid tumor including recurrent low-grade serous ovarian carcinoma (LGSOC). However, the long-term prognosis of patients who receive selumetinib, as well as the late toxicity of the agent, have not yet been described. CASE PRESENTATION: In this case report, we present a patient with recurrent LGSOC with KRAS mutation whose tumor has not progressed and who has maintained a good general condition without severe toxicities following treatment with selumetinib for more than 7 years. Next generation sequencing of her tumor revealed a G12V mutation in KRAS. MAPK signaling inhibition plays a role in the biology of LGSOC. CONCLUSIONS: Although biomarkers have yet to definitively define patients with LGSOC who are likely to respond to therapy, exploration of specific alterations should be pursued in an excersie to develop a reliable companion diagnostic test.

Impact of Age and Primary Disease Site on Outcome in Women With Low-Grade Serous Carcinoma of the Ovary or Peritoneum: Results of a Large Single-Institution Registry of a Rare Tumor.

PURPOSE: Low-grade serous carcinoma of the ovary (LGSOC) or peritoneum (LGSPC) is a rare subtype of ovarian or peritoneal cancer characterized by young age at diagnosis and relative resistance to chemotherapy. The purpose of this study is to report our updated experience with women diagnosed with LGSOC or LGSPC to assess the validity of our original observations. PATIENTS AND METHODS: Eligibility criteria for patients from our database were: stage I to IV LGSOC or LGSPC, original diagnosis before January 2012, and adequate clinical information. All patients were included in progression-free survival, overall survival, and multivariable Cox regression analyses. A subset analysis was performed among patients with stage II to IV low-grade serous carcinoma treated with primary surgery followed by platinum-based chemotherapy. RESULTS: We identified 350 eligible patients. Median progression-free survival was 28.1 months; median overall survival was 101.7 months. In the multivariable analysis, compared with women age ≤ 35 years, those diagnosed at age > 35 years had a 43% reduction in likelihood of dying (hazard ratio, 0.53; 95% CI, 0.37 to 0.74; P < .001). Having disease present at completion of primary therapy was associated with a 1.78 increased hazard of dying compared with being clinically disease free (P < .001). Similar trends were noted in the smaller patient cohort. In this cohort, women with LGSPC had a 41% decreased chance of dying (hazard ratio, 0.59; 95% CI, 0.36 to 0.98; P = .04) compared with those with LGSOC. CONCLUSION: Women age < 35 years with low-grade serous carcinoma and those with persistent disease at completion of primary therapy have the worst outcomes. Patients with LGSPC seem to have a better prognosis than those with LGSOC.

Targeting SRC in mucinous ovarian carcinoma.

PURPOSE: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. EXPERIMENTAL DESIGN: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). RESULTS: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. CONCLUSIONS: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease.

Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways.

Hepatoblastoma is the most common malignant tumor of the liver of children worldwide. Histologically, hepatoblastomas show marked variation in the type and proportion of epithelial (fetal, embryonal, or small cell) and mesenchymal components with differing prognosis and response to therapy. The pure fetal-type hepatoblastoma, presenting as stage 1 and resectable, has the best prognosis, whereas the small cell histology has been associated with unfavorable outcome. Using gene expression profiling, we demonstrate that in addition to Wnt pathway deregulation, cell growth and survival pathways are also globally deregulated in hepatoblastomas. Furthermore, the different histologic subtypes are characterized by specific gene expression and pathway signatures that give insight into the degree of molecular heterogeneity that is present among these tumors. Although Wnt signaling pathway upregulation is common to all histologic types of hepatoblastoma, this pathway is even more significantly deregulated in aggressive hepatoblastomas. In addition, deregulation of MAPK signaling pathway and antiapoptotic signaling is preferentially upregulated in aggressive epithelial hepatoblastomas with a small cell component. The gene expression signatures reported here provide possible prognostic and diagnostic markers as well as therapeutic targets for this disease.