Danielle Vicus

Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube

OBJECTIVES The purpose of this study is to determine the prevalence of BRCA1 and BRCA2 mutations among a large series of women with carcinoma of the fallopian tube. METHODS Two series of women diagnosed with carcinoma of the fallopian tube were studied. Women identified from the Ontario Cancer Registry who were diagnosed with fallopian tube cancer between 1990 and 1998 and between 2002 and 2004. A second, hospital-based series was identified at Cedars Sinai Medical Centre, Los Angeles, California. These women were diagnosed between 1991 and 2007. Each subject was approached to provide her family history and ethnic background and to provide a blood sample for genetic testing for mutations in the BRCA1 and BRCA2 genes. RESULTS In total, 108 patients with fallopian tube cancer were recruited (70 from Ontario and 38 from Los Angeles). Thirty-three patients (30.6%) were found to have a deleterious mutation; 23 in BRCA1 (21.3%) and 10 in BRCA2 (9.3%). The prevalence of mutations was 55.6% in Jewish women and was 26.4% in non-Jewish women. A family history of ovarian or breast cancer was positive for 24 women (23.3%); of these, 14 had a mutation (58.3%). Fourteen (14.4%) of the patients had a previous history of breast cancer; of these, 10 (71.4%) had a mutation. 40.3% of the women who were diagnosed with fallopian tube cancer before age 60 had a mutation, compared with 17.4% of the women diagnosed at age 60 and above. CONCLUSIONS Approximately 30% of women with fallopian tube cancer have a mutation in BRCA1 or BRCA2. The highest frequencies of BRCA mutations were seen in women with fallopian tube cancer diagnosed under age 60, in Jewish women, in women with a family history of breast or ovarian cancer, and in women with a personal history of breast cancer. All patients diagnosed with invasive fallopian tube cancer should be considered candidates for genetic testing.

Pure dysgerminoma of the ovary 35 years on: A single institutional experience

OBJECTIVE The aim of this study was to evaluate clinicopathologic characteristics, long-term outcome and reproductive function in women diagnosed with pure dysgerminoma of the ovary. METHODS Sixty-five women with stage IA to IIIC pure ovarian dysgerminoma were identified and included in this retrospective study. Patients were treated at one institution between 1970 and 2005. RESULTS Median age at diagnosis was 22.2 years (range 8.2-64.1 years). 72.3% of patients presented with stage I, 4.6% stage II and 21.5% stage III disease (1.5% stage unknown). Initial management was surgical for all patients: unilateral oophorectomy in 47 patients (72.2%), bilateral oophorectomy +/- hysterectomy in 14 (21.5%) and cystectomy alone in 3 (4.6%). Seventeen patients received chemotherapy (15 adjuvant, 2 for residual disease), 20 received adjuvant radiotherapy and one patient received both. Recurrence occurred in 6 (9.2%) patients (5 stage IA, 1 stage IIA). All recurrences occurred within 19 months of primary diagnosis. All patients were successfully salvaged with radiotherapy (2 patients), chemotherapy (1 patient) or a combination of surgery and chemotherapy (3 patients). Overall, median follow up from time of recurrence was 22.5 years (range 9.3-31.4 years). Median follow-up of all patients was 10.5 years (range 1.1-31.9 years). Fifteen patients reported an attempt to conceive posttreatment resulting in 12 pregnancies and 12 live births in 8 women. CONCLUSION The long-term outcome of patients with pure ovarian dysgerminoma is excellent. Recurrences occur within 2 years of diagnosis and are treatable. Patients can be treated with fertility-sparing surgery and can expect good reproductive outcomes.

Is venous thromboprophylaxis necessary in patients undergoing minimally invasive surgery for a gynecologic malignancy

OBJECTIVES Current recommendations for the use of venous thromboprophylaxis in patients undergoing minimally invasive surgery (MIS) for a gynecologic malignancy are derived from patients undergoing open surgery. Our objective was to determine the 30-day prevalence of symptomatic venous thromboembolism (VTE) after laparoscopic gynecologic oncology procedures in patients who received no thromboprophylaxis. METHODS Between January 2006 and September 2013, women who underwent MIS for endometrial, cervical or ovarian cancer at a single institution were included. Data on patient demographics, diagnosis, comorbidities, perioperative characteristics, use of thromboprophylaxis, and diagnosis of VTE were collected retrospectively. RESULTS Of the 419 patients who underwent MIS for a gynecologic cancer, 352 (84%) received no VTE prophylaxis. At least a total laparoscopic hysterectomy (simple or radical) or pelvic lymph node dissection was performed in 95% of these patients. The median length of surgery was 137 min and 95% of patients were discharged home within 1 day of surgery. The rate of VTE in the 352 untreated patients was 0.57% (1 pulmonary embolism and 1 deep vein thrombosis). There were no VTE diagnosed within 30 days of surgery in the 67 patients who received anticoagulant thromboprophylaxis. CONCLUSION The rate of VTE is low in patients undergoing minimally invasive surgery for a gynecologic malignancy despite no VTE prophylaxis. The benefits of routine use of VTE prophylaxis in this population are questionable.

Risk factors for carcinoma of the fallopian tube in women with and without a germline BRCA mutation

OBJECTIVE The purpose of this study was to identify risk factors for fallopian tube cancer in women with and without a BRCA mutation. METHODS Subjects with fallopian tube cancer were identified from two sources: 1) a large international registry of women who carry a BRCA1 or BRCA2 mutation (n=56), and; 2) a population-based study of ovarian and fallopian tube cancer conducted in Ontario, Canada (n=66). BRCA mutation status was established for all subjects. Each subject was matched to one or more unaffected controls, for date of birth (within four years), for BRCA mutation status (negative, BRCA1, and BRCA2), for country of residence and for past history of breast cancer (yes/no). All subjects completed a questionnaire about medical history and lifestyle factors. Odds ratios and 95% confidence intervals were calculated for parity, oral contraceptive use, tubal ligation, hormone replacement therapy and body mass index, using conditional logistic regression. RESULTS We studied 103 women with fallopian tube cancer (48 with a BRCA1 mutation, 12 with a BRCA2 mutation and 43 with no identified BRCA mutation) and 980 matched controls. Increasing parity was associated with a decreased risk of fallopian tube cancer in non-carriers (trend per birth odds ratio 0.71 (95% CI 0.52-0.97), p=0.03), in BRCA1 carriers (OR=0.79 (0.62-1.02) p=0.07) and in BRCA2 carriers (OR=0.62 (0.34-1.15), p=0.13), but was statistically significant only for non-carriers. Oral contraceptive use was associated with a reduced risk in BRCA1 carriers (trend per year of use odds ratio=0.91 (0.83-0.99), p=0.03) but not for non-carriers (OR=0.97 (0.87-1.09), p=0.64) or for BRCA2 carriers (OR=0.94 (0.80-1.11), p=0.47). Hormone replacement therapy was associated with an increased risk for fallopian tube cancer in all subjects (OR=1.07 (1.01-1.13), p=0.03), and in the subgroups stratified by mutation, however the association was not significant in the subgroups. Tubal ligation was associated with a decreased risk of fallopian tube cancer for all subjects (OR=0.64 (0.31-1.28), p=0.21), however the reduction was not significant. CONCLUSIONS Parity and oral contraceptive use are associated with reduced risks of fallopian tube cancer. In contrast, hormone replacement therapy may be associated with an increase in the risk of fallopian tube cancer.

Ovarian immature teratoma: Treatment and outcome in a single institutional cohort

OBJECTIVE The aim of this study was to evaluate clinicopathologic characteristics, treatment outcome and reproductive function in women diagnosed with ovarian immature teratoma. METHODS Thirty-four women with ovarian immature teratoma stages IA to IIIA were identified and included in this study. Patients were treated at one institution; Princess Margaret Hospital, Toronto, Canada between 1970 and 2005. RESULTS The median age at diagnosis was 25.0 years (range: 9.8-60.2 years). Twenty seven (79%) presented with stage IA disease, 5 (15%) with stage IC, 1 (3%) with stage 2B, and 1 (3%) with stage IIIA disease. Thirteen (38%) of the tumors were found to be grade 1, 12 (35%) grade 2, and 9 (27%) grade 3. Initial management was surgical for all patients: 22 (65%) unilateral oophorectomy, 7 (20%) cystectomy only, and 5 (15%) bilateral oophorectomy (4 with hysterectomy). Fourteen (41.8%) patients received adjuvant therapy. The median follow up was 4.8 years (range 0.2-24.3 years). Four patients recurred (histological grade 2 or 3) within 22 months (87.1% 2-year progression free survival). Only one clinical stage I patient who received adjuvant chemotherapy developed a recurrence. Three of the patients who recurred died from their disease. Eleven patients reported an attempt to conceive resulting in 11 pregnancies in 6 women (3 post chemotherapy). CONCLUSION The majority of patients diagnosed with an immature teratoma are cured of their disease. However, grade 2 or 3 tumors are associated with a greater chance of recurrence that can be fatal, predominantly within 2 years of diagnosis.

Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers.

OBJECTIVE BRCA1 mutation carriers have a high rate of both breast and ovarian cancer. Tamoxifen is a selective estrogen receptor modulator (SERM), which is used for the treatment of primary breast cancer and for the prevention of contralateral breast cancer. Our objective is to assess if tamoxifen treatment is associated with an increase in the subsequent risk of ovarian cancer among women with a BRCA1 mutation. METHODS A matched case-control study was performed. Cases were 154 women with ovarian cancer and a previous history of breast cancer. Controls were 560 women with no ovarian cancer and a history of breast cancer. All cases and controls carry a deleterious BRCA1 mutation. Cases and controls were matched for year of birth, age at diagnosis of breast cancer and country of residence. The effect of tamoxifen treatment on the risk of subsequent ovarian cancer was estimated using conditional logistic regression. RESULTS The unadjusted odds ratio for ovarian cancer, given previous tamoxifen treatment was 0.89 (95% CI 0.54-1.49, p=0.66). After adjusting for other treatments, the odds ratio was 0.78 (95% CI 0.46-1.33, p=0.36). CONCLUSION Tamoxifen treatment for breast cancer does not appear to increase the risk of ovarian cancer in BRCA1 mutation carriers.

Role of sentinel lymph node biopsy in cervical cancer: pro.

Sentinel lymph node biopsy in cervical cancer is used to reduce the morbidity of a full lymph node dissection while improving the pickup rate of metastatic lymph nodes. The higher detection rate achieved can be explained by the following: the identification of the sentinel lymph node in an aberrant location which would not be routinely included in a systematic pelvic lymph node dissection, the sentinel lymph node is completely excised, and the routine use of ultrastaging. The higher detection rate achieved through sentinel lymph node biopsy can identify additional patients who could potentially benefit from adjuvant therapy therefore, in our view the gold standard of lymph node assessment in early stage cervical cancer has shifted and sentinel lymph node biopsy has taken the place of a complete lymphadenectomy.

A comparison of the toxicity and tolerability of two intraperitoneal chemotherapy regimens for advanced-stage epithelial ovarian cancer

OBJECTIVES Randomized controlled trials (RCTs) in optimally cytoreduced epithelial ovarian cancer (EOC) patients have demonstrated an impressive survival benefit of intraperitoneal (IP) platinum over intravenous (IV), but its use has been limited by significant toxicity from cisplatin. The aim of this study was to compare the toxicity and tolerability of IP cisplatin to IP carboplatin in women with optimally cytoreduced EOC. METHODS Retrospective analysis of 141 women with EOC who underwent optimal surgical cytoreduction followed by IV paclitaxel and IP cisplatin or IP carboplatin was performed. Toxicities of the two treatment regimens were compared. As a secondary outcome, overall survival (OS) and progression-free survival (PFS) probabilities were obtained using the Kaplan-Meier estimate; the log-rank test was used to compare survival curves. RESULTS Of the 141 patients, 77 (54.6%) received IP cisplatin and 64 (45.4%) received IP carboplatin. Eighty-six percent received at least 4 cycles of IP chemotherapy. IP cisplatin was associated with significantly more grade 3 nausea and vomiting (10.4% vs. 1.6%, p=0.033), grade 3 neuropathy (7.8% vs. 0%, p=0.013) and grade 2-3 neutropenia (22.1% vs. 9.4%, p=0.042). No difference in PFS (p=0.602) or OS (p=0.107) was found between the groups. CONCLUSION IP chemotherapy had a high completion rate in both groups of patients. IP carboplatin required a less resource intense protocol and was tolerated better than IP cisplatin with less gastrointestinal, neurologic and hematologic toxicities.

The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma

OBJECTIVE To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian clear cell carcinoma (OCCC). METHODS Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto, between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to compare survival curves. RESULTS 163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received adjuvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received adjuvant CT and 36 had no adjuvant treatment. The 10year progression free survival (PFS) was 65% for patients treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) patients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly associated with an increased PFS (0.85 (0.44-1.63) p=0.63) or overall survival (OS) (0.84 (0.39-1.82) p=0.66). In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55-2.54) or O S(HR 1.04 (95% CI: 0.40-2.69)). CONCLUSION Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface involvement and stage II patients.

Uterine Clear Cell Carcinoma: Does Adjuvant Chemotherapy Improve Outcomes?

Objectives Women with uterine clear cell carcinoma (UCCC) are at high risk of relapse. Adjuvant chemotherapy (CT) is often recommended, although its effectiveness remains controversial. Our objective was to evaluate treatment-related outcomes of patients with UCCC, particularly those treated with adjuvant CT. Methods In this retrospective cohort study, patients diagnosed with UCCC at 2 academic cancer centers from 2000 to 2014 were included. Clinical, surgical, and pathological data were collected. Survival estimates were obtained using the Kaplan-Meier method and compared by log rank test. Multivariable analysis was used to determine the effect of CT and radiation therapy (RT) on overall survival (OS) and progression-free survival (PFS). Results We included 146 patients with UCCC, with a median follow-up of 27 months (range, 1–160). Ninety-five (65%) patients presented with stage I to II disease and 51 (35%) with stage III to IV disease. Forty-six percent of patients with clinical stage I were upstaged after surgery: 29% were upstaged to stages III and IV. Thirty-one percent of patients with early-stage disease and 70% with advanced-stage received CT. Among recurrences, the majority had distant relapse in both early-stage (61.5%) and advanced-stage (96.3%) diseases. In both patients with early-stage and advanced-stage diseases, adjuvant CT did not improve OS or PFS. On multivariate analysis, CT was not a significant factor associated with improved PFS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.69–2.71; P = 0.37) or OS (HR, 0.58; 95% CI, 0.24–1.38; P = 0.22), whereas RT was associated with improved PFS (HR, 0.51; 95% CI, 0.29–0.90; P = 0.02) and OS (HR, 0.19; 95% CI, 0.09–0.42; P < 0.001). Conclusions The high rate of upstaging after surgery highlights the importance of lymph node assessment. The high rate of distant recurrence questions the effectiveness of current CT regimens and warrants the development of novel systemic approaches. The role of adjuvant RT deserves further study.