Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.

BACKGROUND: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). METHODS: Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. RESULTS: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10(-11)). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10(-5) and 10(-29)), and identified breast and pancreatic cell lines with BRCA defects. CONCLUSION: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Cyclin G1 regulates the outcome of taxane-induced mitotic checkpoint arrest.

Anti-mitotic chemotherapeutic agents such as taxanes activate the spindle assembly checkpoint (SAC) to arrest anaphase onset, but taxane-exposed cells eventually undergo slippage to exit mitosis. The therapeutic efficacy of taxanes depends on whether slippage after SAC arrest culminates in continued cell survival, or in death by apoptosis. However, the mechanisms that determine these outcomes remain unclear. Here, we identify a novel role for cyclin G1 (CCNG1), an atypical cyclin. Increased CCNG1 expression accompanies paclitaxel-induced, SAC-mediated mitotic arrest, independent of p53 integrity or signaling through the SAC component, BUBR1. CCNG1 overexpression promotes cell survival after paclitaxel exposure. Conversely, CCNG1 depletion by RNA interference delays slippage and enhances paclitaxel-induced apoptosis. Consistent with these observations, CCNG1 amplification is associated with significantly shorter post-surgical survival in patients with ovarian cancer who have received adjuvant chemotherapy with taxanes and platinum compounds. Collectively, our findings implicate CCNG1 in regulating slippage and the outcome of taxane-induced mitotic arrest, with potential implications for cancer therapy.

Does preoperative positron emission tomography with computed tomography predict nodal status in endometrial cancer? A pilot study.

Fewer than 20% of women with endometrial cancer have positive nodes, and an accurate noninvasive imaging modality to assess lymph node status would be helpful in selecting those who need lymphadenectomy. The objective of this pilot study was to evaluate positron emission tomography with computed tomography (pet-ct) in predicting nodal status before surgery for endometrial cancer. Twelve patients were enrolled at a single tertiary care centre. The sensitivity and specificity of preoperative pet-ct in predicting nodal status were 53.3% and 99.6% respectively. Using pet-ct, all metastatic nodes may not necessarily be detected, especially nodes with microscopic disease. The sensitivity of this imaging modality has to be improved before it can routinely be used in the preoperative evaluation of endometrial cancer.

The prognostic effects of performance status and quality of life scores on progression-free survival and overall survival in advanced ovarian cancer.

OBJECTIVE: Performance status (PS) is an important prognostic factor in advanced ovarian cancer. The purpose of this study was to evaluate the prognostic significance of PS and quality of life (QoL) assessment on progression-free survival (PFS) and overall survival (OS) in patients with advanced ovarian cancer. METHODS: We studied Canadian patients participating in an intergroup study in ovarian cancer (NCIC-OV10), which randomized patients to receive either standard chemotherapy using cisplatin/cyclophosphamide or cisplatin/paclitaxel chemotherapy. QoL was assessed using the EORTC quality of life questionnaire (QLQ-C30+3). The effects of multiple variables including the relevant clinical variables, PS and QoL scores were analyzed by Cox stepwise regression at baseline and again 3 months after completion of chemotherapy. RESULTS: At baseline and at 3 months after chemotherapy, there were 151 and 93 patients respectively who completed the QLQ-C30+3 questionnaires. Baseline PS, global QoL score and treatment were independent predictors for both PFS and OS. Baseline cognitive functioning score was also an additional independent predictor for OS. At 3 months after completion of chemotherapy global QoL score, PS and grade were significant independent predictors of OS; however, only physical functioning score, emotional functioning score and tumor grade predicted for PFS. CONCLUSIONS: Performance status and global quality of life scores at baseline are prognostic factors in advanced ovarian cancer for both PFS and OS. Higher baseline cognitive functioning scores were also associated with improved survival. Global QoL scores at 3 following completion of chemotherapy proved to be of prognostic significance for OS but not PFS.

Is adjuvant therapy necessary for stage IA and IB uterine papillary serous carcinoma and clear cell carcinoma after surgical staging?

Adjuvant therapy of early-stage uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) is controversial. We conducted a prospective cohort study to evaluate outcomes of patients with early-stage UPSC or CCC who were followed without adjuvant therapy after complete surgical staging. From 2000 to 2006, we evaluated all consecutive patients with stage IA/IB UPSC or CCC who had surgical staging by a gynecological oncologist at the London Health Sciences Centre, Canada. Follow-up consisted of history and physical examination every 3 months for 2 years, then every 6 months for the next 3 years. Primary outcome measure was 2-year disease-free survival. There were 22 evaluable patients. Mean patient age was 63.4 years. Median number of pelvic and para-aortic lymph nodes resected was 15 (range 2-39) and 4 (range 0-12), respectively. Thirteen had UPSC, seven had CCC, and two had both UPSC and CCC. Nine had stage IA and 13 had stage IB disease. Median follow-up was 25 months (range 6-72). Only one patient has recurred (stage IB UPSC, isolated vault recurrence 10 months after surgery), but she is well 9 months after receiving pelvic radiotherapy and vault brachytherapy. Two-year disease-free survival was 95%. These results suggest that adjuvant therapy may not be necessary for stage IA and IB UPSC and CCC after surgical staging. Further prospective evaluation of different adjuvant therapy practices is required for early-stage UPSC and CCC, which may be useful in the design of future clinical trials.

Patterns of practice and outcomes in intermediate- and high-risk stage I and II endometrial cancer: a population-based study.

To evaluate patterns of practice and outcomes in intermediate- and high-risk stage I and II endometrial cancer in the province of Ontario, Canada. This was a retrospective population-based study of women diagnosed with stage I and II endometrial cancer in Ontario from 1996 to 2000. After excluding low-risk (stages IA and IB, grades 1 and 2) and nonendometrioid histologies, the population was stratified into two risk groups: intermediate risk (stages IA and IB, grade 3; stages IC and IIA, grades 1 and 2; stage IIA, grade 3 if <50% myometrial invasion) and high risk (stage IC, grade 3; stage IIA, grade 3 if >50% myometrial invasion, and all stage IIB). Patterns of practice were assessed in each risk group, including use of surgical staging and adjuvant pelvic radiotherapy (APRT). Cox proportional hazards models determined effects of prognostic factors on 5-year overall survival (OS), including age, income, comorbidities, lymphvascular space invasion (LVSI), surgical staging, and APRT. There were 995 women in this study: 748 intermediate risk (75.2%) and 247 high risk (24.8%). Only 69 (9.2%) and 40 (16.2%) women underwent surgical staging in the intermediate- and high-risk groups, respectively. Surgical staging did not reduce rates of APRT. Determinants of survival included age >60 and comorbidities in the intermediate-risk group, and age >60, income, and LVSI in the high-risk group. In this population-based study, there were variable patterns of practice for intermediate- and high-risk stage I and II endometrial cancer. Surgical staging and APRT did not affect OS.

Surgery as sole treatment for serous borderline tumors of the ovary with noninvasive implants.

OBJECTIVES: The objectives were to describe the clinical characteristics and prognosis of surgically treated patients with stage II and III serous borderline tumors of the ovary with noninvasive implants. MATERIALS AND METHODS: From 1990 to 2000, 16 patients with stage II and III ovarian serous borderline tumors and noninvasive implants were diagnosed and prospectively followed at our center. All patients underwent surgical treatment including staging and their pathology was reviewed. Fifteen patients had thorough surgical staging by laparotomy, while one patient was staged laparoscopically. No patient was treated with adjuvant therapy (radiation or chemotherapy) after surgical treatment and none were lost to follow-up. RESULTS: The mean age at diagnosis was 42 years (range 26-59). Fourteen patients were treated by abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and multiple peritoneal biopsies, while 2 patients were treated conservatively for fertility preservation. Two patients underwent pelvic and para-aortic lymph node dissection. Fifteen of 16 patients had ovarian surface involvement with tumor. All patients but 2 had clinical evidence of extraovarian disease at the time of surgery. The mean duration of follow-up was 60.7 months (range 2-134 months). Thirteen patients (81%) are alive without evidence of disease. Four patients (25%) required subsequent surgery for recurrent disease and all are still alive. Two patients have been treated with chemotherapy (paclitaxel/carboplatin) for progressive borderline disease, while an additional patient was treated after first relapse with chemotherapy for an invasive recurrence. CONCLUSIONS: Carefully staged patients with advanced serous borderline tumors of the ovary and noninvasive implants have a good prognosis without adjuvant therapy.

Progress of clinical oncology guidelines development using the Practice Guidelines Development Cycle: the role of practitioner feedback.

PURPOSE: To present an update on the development of oncology practice guidelines (PGs) using the Practice Guidelines Development Cycle (Cycle), and to present the results of surveys of oncologists on the first 10 guidelines from the Cancer Care Ontario Practice Guidelines Initiative. METHODS: Practitioners' opinions about guidelines in development were sought using a mail survey method with systematic follow-up. Practitioners were identified by cancer center representatives. Survey packages included evidence-based recommendations (EBRs) and a one-page, nine-item feedback questionnaire. Data were collected between February 1995 and February 1996. RESULTS: Nine hundred fourteen surveys that pertained to 10 guidelines were mailed to 423 practitioners in Ontario. Practitioners included 112 medical oncologists/hematologists, 34 radiation oncologists, 195 surgeons, and 82 practitioners from other medical specialities. One hundred practitioners were located in cancer centers and 323 had community-based practices. The overall response rate by practitioner was 72% and by survey questionnaire, 70%. For the five questionnaire items that assessed guideline quality, approval ratings ranged from 86% to 92%. For the 10 recommendations, 77% ( 63% to 82%) of respondents agreed that the EBR could be approved as a PG. Response and approval rates were consistent across medical specialities and locations of practice. CONCLUSION: The process of obtaining practitioner feedback in the development of PGs is both feasible and useful. The high response rates to the survey indicate that it is possible to obtain broad participation in evidence-based guidelines development throughout Ontario. The changes made to the EBRs in response to feedback suggest that practitioners' opinions can be valuable in shaping evidence-based guidelines.

Good outcome associated with a standardized treatment protocol using selective postoperative radiation in patients with clinical stage I adenocarcinoma of the endometrium.

In 1982, a treatment protocol was instituted for the management of patients with clinical stage I adenocarcinoma of the endometrium. All pertinent historical, operative, and pathologic findings were reviewed by a multidisciplinary committee and 384 patients were prospectively assigned to either high- or low-risk categories. Patients were excluded from the study if they had clinically apparent extrauterine disease, clear cell or serous histologies, or microscopic ovarian metastasis. Patients were considered high-risk if they had one or more of the following factors: grade 3 tumor differentiation, myometrial invasion > 50% of the total wall thickness, pathologic cervical involvement, or adenosquamous histology. Two-hundred twenty-seven (59%) low-risk patients were followed without further treatment after surgery, while pelvic radiation was recommended for 157 (41%) high-risk patients. The 5-year relapse-free survival rates in the low- and high-risk groups were 95 and 81%, respectively. There were no treatment-related deaths. Severe or life threatening chronic radiotherapy complications occurred in 6 (5%) patients. Multivariate Cox analysis identified the following significant prognostic factors: grade, myometrial invasion, cervix involvement, and age. This treatment protocol represents a safe and effective method of managing patients with carcinoma of the endometrium and spares the need for radiation therapy in the low-risk patient.

Conservative surgery for recurrent or persistent carcinoma of the cervix following irradiation: is exenteration always necessary?

Between 1960 and 1988, 47 patients had conservative surgery for postradiation recurrent or persistent cervical carcinoma. Forty-two patients with nonmetastatic disease and available follow-up information were divided into 3 groups based on the extent of disease and type of surgical procedure. Group 1 contained 13 patients with smaller tumors prior to radiation (FIGO Ib and IIa), and recurrent or persistent disease confined to the cervix and/or vaginal vault. Group 2 consisted of 20 patients presenting with more advanced disease than those in Group 1, at the time of either radiation or surgery. Surgical resection of disease was accomplished in both Groups 1 and 2 by either radical vaginal or abdominal hysterectomy. The 8 patients in Group 3 required extended Wertheim operations to encompass locally advanced disease involving the bladder base and/or parametrium. One patient could not be categorized. The 5-year estimated relapse-free survivals for each group were 84, 49, and 25%, respectively. The relapse-free survival of Group 1 was significantly better (P = 0.003) than that of Group 3. Major complications occurred in 4 patients belonging to Group 1 (31%), 10 in Group 2 (50%), and 6 (including two treatment-related deaths) in Group 3 (75%). The most common complication was fistula formation in 11 patients (26%). Radical hysterectomy can be offered as an alternative to exenteration in carefully selected patients.

Testing the validity of a prognostic classification in patients with surgically optimal ovarian carcinoma: a 15-year review.

A retrospectively designed classification using stage, residuum and a variable which combines prognostic information from both grade and histology (histology-grade variable) has been used at our institution to predict prognosis, and choose therapy in patients with ovarian carcinoma, stages I-III having no or small residuum. In this study, multivariate analysis of prognostic factors were performed over two time periods: Group 1 (1971-1978), contains the patients from which the original classification was derived, and Group 2 (1979-1985), contains a different cohort of patients who are used to test the validity and reproducibility of the original classification. Multivariate analysis showed that the prognostic significance of two variables changed over the two study periods: tumor grade, and residuum. It was found that in the ideal combination of grade and histologic type, when used in conjunction with stage and residuum in a prognostic classification, was unique to each patient cohort. Because of these changes, new and more accurate prognostic classifications were derived for Group 2. However, when all classifications were examined, (including the original), the differences in their ability to stratify patients into risk categories was negligible, and there was no major advantage to using one classification over another for clinical applications. Thus, the retrospectively derived prognostic classification using grade, instead of a combined histology-grade variable, in conjunction with the other significant prognostic factors (stage and residuum), is preferred for prospective application, and for its simplicity.