C. Bethan Powell

Risk-Reducing Salpingo-Oophorectomy in BRCA Mutation Carriers: Role of Serial Sectioning in the Detection of Occult Malignancy

PURPOSE Women who carry deleterious mutations of BRCA1 or BRCA2 genes have up to a 54% lifetime risk of developing ovarian cancer. After childbearing, women at high risk increasingly choose bilateral risk-reducing salpingo-oophorectomy (RRSO). Two recent studies of BRCA mutation carriers reported occult malignancy in 2.5% of women undergoing RRSO. This study aimed to increase this detection rate using a protocol. METHODS In 1996, the University of California San Francisco Gynecologic Oncology Program instituted a surgical-pathologic RRSO protocol that was composed of complete removal and serial sectioning of both ovaries and fallopian tubes, peritoneal and omental biopsies, and collection of peritoneal washings for cytology. We report the pathologic findings in 67 BRCA mutation carriers according to the degree of adherence to this protocol. RESULTS Of the 67 procedures, the protocol was followed completely or partially in 41 (61%). Seven occult malignancies were discovered, four in the fallopian tube and three in the ovaries. Six of these were microscopic, and all seven (17%) were found in specimens from complete or partial protocol procedures as opposed to standard procedures (P = .026). Other variables such as age, parity, BRCA1 or BRCA2 mutation, or type of surgery did not alter the strong effect of protocol procedure on the cancer detection rate. CONCLUSION A rigorous operative and pathologic protocol for RRSO increases the detection rate of occult ovarian malignancy in BRCA mutation carriers nearly seven-fold. If confirmed, this finding will alter postoperative management because additional staging, chemotherapy, and follow-up may be necessary in affected women.

Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer

Mortality from ovarian cancer may be dramatically reduced with the implementation of attainable prevention strategies. The new understanding of the cells of origin and the molecular etiology of ovarian cancer warrants a strong recommendation to the public and health care providers. This document discusses potential prevention strategies, which include 1) oral contraceptive use, 2) tubal sterilization, 3) risk‐reducing salpingo‐oophorectomy in women at high hereditary risk of breast and ovarian cancer, 4) genetic counseling and testing for women with ovarian cancer and other high‐risk families, and 5) salpingectomy after childbearing is complete (at the time of elective pelvic surgeries, at the time of hysterectomy, and as an alternative to tubal ligation). The Society of Gynecologic Oncology has determined that recent scientific breakthroughs warrant a new summary of the progress toward the prevention of ovarian cancer. This review is intended to emphasize the importance of the fallopian tubes as a potential source of high‐grade serous cancer in women with and without known genetic mutations in addition to the use of oral contraceptive pills to reduce the risk of ovarian cancer. Cancer 2015;121:2108–2120.

Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast & Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk of ovarian, tubal, and peritoneal cancers. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancers as well as a 9-12% lifetime risk of ovarian cancer. Mutations in other genes including TP53, PTEN, and STK11 are responsible for hereditary syndromes associated with gynecologic, breast, and other cancers. Evaluation of the likelihood of a patient having one of these gynecologic cancer predisposition syndromes enables physicians to provide individualized assessments of cancer risk, as well as the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Evaluation for the presence of a hereditary cancer syndrome is a process that includes assessment of clinical and tumor characteristics, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from assessment for the presence of a hereditary breast and/or gynecologic cancer syndrome.

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)]. Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Risk management options elected by women after testing positive for a BRCA mutation

OBJECTIVE To assess the uptake of risk-reducing options for the management of ovarian and breast cancer risk in BRCA mutation carriers in a large community based integrated health system in Northern California. METHODS A retrospective cohort of deleterious BRCA mutation carriers (1995-2012) was evaluated for consistency with NCCN guidelines for risk reducing salpingo-oophorectomy (RRSO) by age of 35-40, risk reducing mastectomy (RRM), as well as surveillance practices, including pelvic ultrasound, CA 125, mammogram, and breast MRI. Secondary outcomes included the use of chemoprevention and hormone replacement. RESULTS Of the 305 eligible women, 170 were BRCA1 positive, and 135 were BRCA2 positive. Seventy four percent underwent RRSO with only 17% under age 40, while 44% underwent RRM. The median time from the test to both RRSO and RRM was 6 months. In the first year after BRCA diagnosis, 45% underwent a pelvic ultrasound, dropping to 2.3% by year 5. In year 1, 47% had a CA 125, dropping to 2% by year 5. The number of women undergoing annual MRI and mammogram fell similarly over time. Sixteen percent of BRCA carriers used oral contraceptives (OCPs) and only one patient used tamoxifen for chemoprevention. CONCLUSION Uptake of RRSO in BRCA carriers in a population based health system is high, however the majority of women do not have RRSO by the NCCN recommended age. Compliance with surveillance is low and rapidly declines even 1 year out from testing. Attention needs to be focused on the earlier identification of BRCA mutation carriers with consolidated and standardized care to improve risk reduction.

Pulsed low dose rate brachytherapy for pelvic malignancies

PURPOSE The pulsed low dose rate remote afterloading unit was designed to combine the radiation safety and isodose optimization advantages of high dose rate technology with the radiobiologic advantages of continuous low dose rate brachytherapy. This is the first report of a prospective clinical trial evaluating the relative incidence of acute toxicity and local control in patients with pelvic malignancies who underwent interstitial or intracavitary brachytherapy with the pulsed low dose rate remote afterloader. METHODS AND MATERIALS From 5/11/92-6/21/95, 65 patients underwent 77 brachytherapy procedures as part of their treatment regimen for pelvic malignancies. Using the pulsed low dose rate Selectron, equipped with a single cable-driven 0.3-1.0 Ci Ir192 source, target volume doses of 0.40-0.85 Gy per pulse were prescribed to deliver the clinically determined dose. Forty-five intracavitary and 32 interstitial procedures were performed. Fifty-four patients had primary and 11 recurrent disease. Patients were followed closely to assess incidence of Grade 3-5 acute and delayed toxicity, local control, and survival. RESULTS With a median follow-up of 16.1 months (range 1-29), 33 patients are NED, 10 alive with disease, 13 dead with disease, 4 dead of intercurrent disease, and 5 lost to follow-up. Local control was maintained until last follow-up or death in 48 cases, local failure occurred in 11, unknown in 5. Grade 3-5 acute toxicities (requiring medical or surgical intervention) occurred in 5 out of 77 procedures (6.5%), delayed complications in 10 patients (15% actuarial incidence at 2 years). In the 52 procedures performed for 42 patients with cervix cancer, the acute toxicity incidence was 5.8%, with a 14% 2-year actuarial incidence of delayed complications. Of 32 interstitial templates performed on 30 patients for pelvic malignancies, there were three incidences of acute toxicity and five delayed toxicities. CONCLUSION Using the parameters described for this initial clinical study in patients treated for pelvic malignancies, pulsed low dose rate brachytherapy shows no significant increase in acute toxicity above that seen with the standard continuous low dose rate approach. Using the isodose optimization possible with pulsed brachytherapy, local control is excellent in patients treated at initial presentation, although longer follow-up is required for full assessment of local control and late toxicity. Further trials will need to be carried out to determine if larger doses per pulse and shorter total treatment times have comparable therapeutic ratios.

A randomized study of the effectiveness of a brief psychosocial intervention for women attending a gynecologic cancer clinic

OBJECTIVES While there are many psychosocial interventions for cancer patients, few are brief in nature. The aim of this study was to investigate the usefulness of a single-visit psychosocial intervention for gynecologic cancer patients. METHODS One hundred women attending a gynecologic cancer clinic as new patients were randomized to receive no intervention or a one-time meeting with a psychologist who discussed issues and concerns the woman might have about her cancer diagnosis. Thirty-eight of the women had a current or previous cancer. The women were given questionnaires measuring mood and quality of life at baseline, two weeks and three months after the intervention. RESULTS At baseline, 43 of the women in the control group completed questionnaires, as did 45 women randomized to the intervention. 21 of these women received the intervention. Women who received the intervention had greater decreases in anxiety, depression and overall distress over time. The control group also had decreases in anxiety and overall distress over time, but had an increase in depression. The women in the intervention group increased in physical, emotional, functional, and overall well being, while the control group only had a slight increase in overall well being over time. The difference between the groups in emotional well being at Time 2 approached significance (p=.08). The intervention group had increases in positive coping at Time 2, while the control group decreased (ps ranged from .02-.10). Three month follow-up data were available for 23 women in the control group and 15 in the intervention group. At Time 3 functional well being was significantly higher in the intervention group (p=.04). Information seeking and affect regulation remained higher in the intervention than the control group (ps=.002 and .02, respectively). When the women with cancer or previous cancer were examined, significant differences were seen for affect regulation at baseline (p=.0007), and anger two weeks later (p=.04), with the women in the control group being more angry. Utilization of other cancer resources was low with 12% of the women reporting that they used the Cancer Resource Center. CONCLUSIONS The results of this study show that there was a positive effect towards coping and quality of life for a one-time psychosocial intervention after the first visit to a gynecologic oncology practice. Women who were randomized to the intervention but did not go were more distressed at baseline than the women who did go. This suggests that incorporating psychosocial services as an integrated part of the new patient consultation may be very important to address patients distress. Future studies with larger sample sizes may reveal more significant differences. Strategies to overcome the poor utilization of the cancer resource center are also clearly needed to improve awareness of these resources.

Perioperative Outcomes Comparing Patient Controlled Epidural Versus Intravenous Analgesia in Gynecologic Oncology Surgery.

OBJECTIVES Our aim was to compare perioperative patient controlled epidural analgesia (PCEA) versus patient controlled intravenous analgesia (PCA) after gynecologic oncology laparotomy. METHODS This was a prospective cohort study where perioperative pain management was decided through patient-centered discussion by anesthesia and surgical teams. The study was designed to accrue 224 patients, to test for equivalence in pain control on postoperative day 1, defined as less than a 10% difference in the proportion of patients with a visual analog scale pain score of <2 (0-10 scale). RESULTS Two hundred forty patients were enrolled, with 205 patients evaluable for outcomes: 98 received PCA, while 107 received a thoracic level PCEA. Utilization of PCEA was associated with longer anesthesia time pre-op (means: 60 vs. 44 min, p<0.0001), as well as more likely use of pressors during surgery (78% vs. 57%, p=0.002). Pain control was comparable between groups on postoperative day 1 (mean VAS: 2.4 vs. 2.5, p=0.56), but patients with PCEA tended to require more supplemental pain medications. Time to first ambulation was longer in the PCEA patients (means: 49 vs. 36 h post-op, p=0.03), with no difference in time to tolerating regular diet (means: 89 vs. 77 h post-op, 0.17) and no difference in readiness for discharge (means: 144 vs. 145 h post-op, p=0.95). CONCLUSIONS In this nonrandomized prospective study, selection of a PCEA for perioperative pain management did not improve pain management for patients undergoing gynecologic oncology surgery.

Comparison of risk management strategies between women testing positive for a BRCA variant of unknown significance and women with known BRCA deleterious mutations

Purpose:The aim of this article is to describe cancer risk–reducing behaviors of women with BRCA variants of unknown significance.Methods:A retrospective chart review from 1995 to 2012 identified women with BRCA mutations in a northern California community system. Exclusion criteria included loss of membership/death within 1 year of testing, prior ovarian cancer, or bilateral salpingo-oophorectomy. Primary outcomes were rate of risk-reducing mastectomy and risk-reducing salpingo-oophorectomy.Results:The mean age of the 69 variant of unknown significance carriers was 50 vs. 47 years for the 305 women with a deleterious mutation. Women with a variant of unknown significance were followed for a median of 69 months. Among women with a variant of unknown significance, 30% underwent risk-reducing salpingo-oophorectomy and 11% underwent risk-reducing mastectomy, as compared with 74 and 44%, respectively, for women with a deleterious mutation. Women with a deleterious mutation were more likely to undergo surveillance in the first year after testing. The odds ratios are as follows: 2.1 for mammogram, 6.0 for magnetic resonance imaging, 7.7 for Ca-125, and 5.0 for transvaginal ultrasound. Fifty-six percent of women with a variant of unknown significance were reclassified after a median of 39 months, longer than the median time to risk-reducing salpingo-oophorectomy (18.6 months) or risk-reducing mastectomy (20.1 months).Conclusion:Uptake of risk-reducing strategies among women with a variant of unknown significance is lower than among women with a deleterious mutation. Given the prognostic uncertainty and high rate of reclassification for women with a variant of unknown significance, individualizing counseling and directing efforts toward surveillance, chemoprevention, or salpingectomy are recommended.Genet Med 16 12, 896–902.

Impact of Chemotherapy Dosing on Ovarian Cancer Survival According to Body Mass Index

IMPORTANCE Optimal chemotherapy dosing in obese patients remains uncertain, with variation in practice. Dose reduction strategies are often used to avoid chemotoxicity, but recent American Society of Clinical Oncology guidelines recommend full dose. OBJECTIVE To evaluate the impact of body mass index (BMI) on chemotherapy dosing and of dose reduction on ovarian cancer survival. DESIGN, SETTING, AND PARTICIPANTS Cohort study in Kaiser Permanente Northern California (KPNC) health care setting of patients with primary invasive epithelial ovarian cancers diagnosed from January 2000 through March 2013. Analyses focused on 806 patients receiving adjuvant first-line therapy of carboplatin and paclitaxel with curative intent. MAIN OUTCOMES AND MEASURES Overall and ovarian cancer-specific mortality. Deaths were identified through the KPNC Mortality Linkage System, with median follow-up of 52.5 months. Hazard ratios (HRs) and 95% CIs were estimated from proportional hazards regression, accounting for prognostic variables including age at diagnosis, race, stage, grade, histologic type, chemotoxic effects, comorbidities, cancer antigen 125 levels, and BMI at diagnosis. RESULTS The strongest predictor of dose reduction was a high BMI. Compared with normal-weight women, obese class III women received 38% and 45% lower doses in milligrams per kilogram of body weight of paclitaxel and carboplatin, respectively (P < .001 for each agent). They also received lower relative dose intensity (RDI) for each agent and the combined regimen, calculated as average RDI (ARDI). Mean ARDI was 73.7% for obese class III women and 88.2% for normal-weight women (P < .001). Lower ARDI (<70%) was associated with worse overall (HR, 1.62 [95% CI, 1.10-2.37]) and ovarian cancer-specific survival (HR, 1.69 [95% CI, 1.12-2.55]). Women who were obese at diagnosis appeared to have better survival. In multivariable-adjusted analyses considering joint effects by BMI and ARDI, compared with women with normal weight and no dose reduction, normal-weight women with dose reduction (ARDI < 85%) experienced worse survival (HR, 1.50 [95% CI, 1.02-2.21]). For each BMI category, those with ARDI less than 85% had worse survival than those without dose reduction. The improved survival among obese women was no longer apparent with dose reduction. CONCLUSIONS AND RELEVANCE Lower RDI was an independent predictor of ovarian cancer mortality. This finding was strongest among normal-weight women but seen at all levels of BMI. Our results suggest that body size should not be a major factor influencing dose reduction decisions in women with ovarian cancer.