Sarah E. Ferguson

Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas

Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2‐targeted treatment in a small series of women with recurrent HER2‐amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non‐amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2‐overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2‐targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

Prognostic features of surgical stage I uterine carcinosarcoma.

Uterine carcinosarcomas (CSs) are aggressive neoplasms, with 5-year overall survival (OS) rates of less than 35%. They are customarily separated into types harboring either heterologous or homologous mesenchymal elements, but the prognostic significance of this finding is controversial. Our goal was to study clinicopathologic features of possible prognostic relevance in surgical stage I uterine CS. A retrospective clinical and histopathologic review was performed for all women diagnosed with surgical stage I uterine CS. These tumors were compared with stage I high-grade endometrial (HGEm) carcinomas for clinical outcomes. There were 42 cases of surgical stage I uterine CS identified between January 1990 and January 2004. The disease-free survival and OS rates for patients with stage I CS were significantly worse compared with stage I HGEm (P=0.001; P=0.01). The median disease-free survival for patients with heterologous CS was 15 months and had not been reached for women with homologous CS (P=0.001). The 3-year OS rates were 45% versus 93% in women with heterologous compared with homologous stage I CS (P<0.001). The 3-year OS rates for homologous CS and HGEm were both >90%. Homologous stage I CSs have survival outcomes that are similar to HGEm. This further supports the concept that homologous stage I CSs are carcinomas with sarcomatoid features, not sarcomas. More importantly, the presence of heterologous sarcomatous elements is a powerful negative prognostic factor in surgical stage I uterine CS.

Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor found in children. Up to 20% of RMS tumors in children originate in the genital tract making this the second most common site. RMS of gynecologic origin in adults is much less common. The purpose of this study was to describe the clinical and pathologic features of RMS of the adult female genital tract. We reviewed the histologic slides of women 16 years of age and older and included them in our study if they contained the classic histologic features of RMS as described by the 2002 World Health Organization classification of tumors. Rhabdomyoblastic components present in other established malignancies were not studied. We identified 15 patients, with a median age of 48 years (range, 16 to 69). Eleven (73%) of the tumors were of embryonal histology (cervix, 8; uterus, 2; and ovary, 1). Of the remaining 4 tumors, 2 were of alveolar (vulva) and 2 of pleomorphic (uterus, 1; fallopian tube, 1) histologic subtype. The majority (79%) of these patients presented with locoregional disease and had surgery as their primary intervention (73%). The median progression-free survival (PFS) and disease-specific survival was 9 months [95% confidence interval (CI), 1-24] and 21 months (95% CI, 14-28), respectively. The 5-year disease-specific survival was only 29%. There was a significant difference in PFS between cases of embryonal compared to cases with nonembryonal histology (19 vs. 3 mo, respectively) (P=0.04). Adult RMS of gynecologic origin presents with locoregional disease and most are morphologically similar to pediatric RMS; however, adult RMS behaves more aggressively, with worse overall survival. It is unclear whether these divergent outcomes are the result of differences in clinical management or because these tumors are biologically distinct.

A prospective randomized trial comparing patient-controlled epidural analgesia to patient-controlled intravenous analgesia on postoperative pain control and recovery after major open gynecologic cancer surgery

OBJECTIVE To determine the effect of perioperative patient-controlled epidural analgesia (PCEA) compared to postoperative intravenous (IV) patient-controlled analgesia (PCA) on postoperative recovery parameters after major open gynecologic surgery. METHODS A randomized controlled clinical trial included women undergoing laparotomy for a gynecologic disorder. Patients were randomized to postoperative IV morphine PCA (control arm) or to postoperative morphine-bupivacaine PCEA (treatment arm). Postoperative outcomes such as pain, and length of hospital stay were compared with an intention-to-treat analysis. The primary endpoint was postoperative pain at rest and when coughing--assessed by a 10-point visual analog scale (VAS). RESULTS Between 9/04 and 6/07, 153 patients were randomized and 135 were evaluable (PCEA=67; PCA=68). Over 75% of the women in this study had gynecologic cancer. Patients in the PCEA arm had significantly less postoperative pain at rest on Day 1 and during the first 3 postoperative days when coughing compared to the PCA arm (P<0.05). The mean pain score at rest on Day 1 was 3.3 for the PCEA group compared to 4.3 for the PCA group (P=0.01). Overall, postoperative pain at rest and while coughing in the first 6 days was less in women treated with PCEA compared to PCA (P<0.003). CONCLUSIONS PCEA offers superior postoperative pain control after laparotomy for gynecologic surgery compared to traditional IV PCA. Women requiring major open surgery for gynecologic cancer should be offered PCEA for postoperative pain management if there are no contraindications.

The Prevention of Congenital Anomalies with Periconceptional Folic Acid Supplementation

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0.4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologic anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.

Stratification of Intermediate-Risk Endometrial Cancer Patients into Groups at High Risk or Low Risk for Recurrence Based on Tumor Gene Expression Profiles

Purpose: Endometrial cancers classified as “intermediate risk” based on clinical and/or pathologic features are associated with a 15% to 20% risk of recurrence. Here, we test whether global gene expression profiling can distinguish intermediate-risk tumors into high-risk and low-risk subgroups. Experimental Design: Tumor specimens were obtained from 75 intermediate-risk endometrial cancer patients, 13 who had recurred and 62 who had not recurred with a median follow-up of 24 months. Gene expression profiles were obtained using the Affymetrix U133A GeneChip oligonucleotide microarray. The genes most associated with risk of recurrence were used to create a risk score using a leave-one-out cross-validation method and the univariate Cox proportional hazards regression model. Time to recurrence curves for the high-risk and low-risk subgroups were estimated using the Kaplan-Meier method, and the difference in time to recurrence between these two subgroups was tested using the log-rank test. Results: There was a significant difference in time to recurrence between high-risk and low-risk patients using risk scores as defined above (P = 0.04). The estimated hazard ratio (95% confidence interval) was 3.07 (1.00-9.43). Conclusions: Patients with intermediate-risk endometrial cancers identified as high-risk for recurrence according to a gene expression–based risk score have a significantly increased risk for recurrence compared with those classified as low risk. These findings suggest that gene expression profiling can potentially contribute to the clinical classification and management of intermediate-risk endometrial cancers.

Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behavior of high risk endometrial cancers

OBJECTIVES The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure. METHODS This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected. RESULTS 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001). CONCLUSION This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers.

Progesterone receptor expression is associated with longer overall survival within high-grade histotypes of endometrial carcinoma: A Canadian high risk endometrial cancer consortium (CHREC) study

OBJECTIVE To assess the association of hormone receptor expression with outcome in high-grade endometrial carcinomas. METHODS This study included three sites participating in the Canadian High Risk Endometrial Cancer (CHREC) consortium. Sections from tissue microarrays containing cases with a diagnosis of endometrioid grade 3 (EC3) and endometrial serous carcinoma (ESC) were assessed for estrogen (ER) and progesterone receptor (PR) expression by immunohistochemistry. Expression was considered present if >1% of tumor cell nuclei were labeled. Associations with overall survival were assessed. RESULTS ER expression was present in 168/216 (78%) of EC3 and 124/192 (65%) of ESC. PR expression was present in 148/212 (70%) of EC3 and 83/196 (42%) of ESC. PR expression was significantly associated with favorable overall survival in EC3 and ESC (log rank, p=0.018 and p=0.0024) but ER expression was not. PR expression was significantly associated with favorable overall survival in EC3 independent of age, stage, center and lymph-vascular invasion (hazard ratio=0.457, 95% CI 0.257-0.811, p=0.0075) as well as in stage I and II ESC (hazard ratio=0.266, 95% CI 0.094-0.750, p=0.0123). CONCLUSION Our data provide support for the assessment of the PR expression status in EC3 and ESC. Future work will be required to determine how PR expression may be incorporated into management of patients with EC3 and ESC.

The sooner the better: Genetic testing following ovarian cancer diagnosis

OBJECTIVE As treatment based genetic testing becomes a reality, it is important to assess the attitudes and preferences of women newly diagnosed with ovarian cancer regarding genetic testing. The objective of this study was to determine when women with a diagnosis of high grade serous ovarian cancer would prefer to undergo genetic testing and factors that influence this preference. METHODS Women over 18years of age with a known diagnosis of high grade serous ovarian cancer diagnosed between October 2010-2013 were identified via the Princess Margaret Cancer Center Registry. Participants completed a questionnaire, which obtained preferences and attitudes towards genetic testing, cancer history, and demographic information. RESULTS 120 of the 355 women identified (33.8%) completed the questionnaires. The median age at time of ovarian cancer diagnosis was 57years (range 35-84). The majority of participants in this study were offered (94.6%) and pursued (84.8%) genetic testing. In this cohort, testing was most frequently offered at diagnosis (41.8%) or during treatment (19.1%). In this study, women with high grade serous ovarian cancer felt that genetic testing should be offered before or at the time of diagnosis (67.8%). Having a family history of breast or ovarian cancer was significantly (p=0.012) associated with preferring genetic testing at an earlier time point in the disease course. CONCLUSIONS Our results demonstrate that women with high grade serous ovarian cancer acknowledge the personal and clinical utility of genetic testing and support test implementation at the time of cancer diagnosis.

The optimal time for surgery in women with serous ovarian cancer.

BACKGROUND Advanced high-grade serous ovarian carcinoma (HGSC) is commonly treated with surgery and chemotherapy. We investigated the survival of patients treated with primary or interval surgery at different times following neoadjuvant chemotherapy. Their survival was compared with that of patients treated with primary cytoreductive surgery and adjuvant chemotherapy. METHODS Patients with stage III or IV HGSC were included in this retrospective cohort study. Clinical data were obtained from patient records. Patients were divided into 2 groups based on treatment with neoadjuvant chemotherapy and interval cytoreductive surgery (NAC) or with primary cytoreductive surgery and adjuvant chemotherapy (PCS). Study groups were stratified by several clinical variables. RESULTS We included 334 patients in our study: 156 in the NAC and 178 in the PCS groups. Survival of patients in the NAC group was independent of when they underwent interval cytoreductive surgery following initiation of neoadjuvant chemotherapy (p < 0.001). Optimal surgical cytoreduction had no impact on overall survival in the NAC group (p < 0.001). Optimal cytoreduction (p < 0.001) and platinum sensitivity (p < 0.001) were independent predictors of improved survival in the PCS but not in the NAC group. Patients in the NAC group had significantly worse overall survival than those in the PCS group (31.6 v. 61.3 mo, p < 0.001). CONCLUSION Women with advanced HGSC who underwent PCS had better survival than those who underwent interval NAC, regardless of the number of cycles of neoadjuvant therapy. Optimal cytoreduction did not provide a survival advantage in the NAC group.