Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk.

PURPOSE: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations. PATIENTS AND METHODS: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). RESULTS: Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. CONCLUSION: In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

Adherence to practice guidelines is associated with reduced referral times for patients with ovarian cancer.

BACKGROUND: Patients with ovarian cancer tend to receive the highest quality of care at high-volume cancer centers with gynecological oncologists. However, the care that they receive prior to gynecological oncology consult has not been examined. We investigated the quantity and quality of care given to patients with ovarian cancer before being seen by a gynecological oncologist. OBJECTIVE: We evaluated the variability, quantity, and quality of diagnostic testing and physician-referral patterns prior to consultation with a gynecological oncologist, in women with suspicious pelvic masses seen on imaging. STUDY DESIGN: A chart review was performed on patients treated for ovarian cancer at a single institution from 2001 to 2014. We evaluated their workup in 4 categories, drawn from National Comprehensive Care Network guidelines: provider visits, abdominal/pelvic imaging, chest imaging, and tumor markers. Workup was classified as guideline adherent or guideline nonadherent. RESULTS: We identified 335 cases that met our criteria. In the provider visit category, 83.9% of patients received guideline-adherent workup: 77% in the abdominal/pelvic imaging, 98.2% in the chest imaging, and 95.2% in the tumor marker categories. Each patient's workup was assessed as a compilation of the 4 categories, yielding 65.7% patients as having received an adherent workup and 34.3% of workup as nonadherent to guidelines. The timeframe to see a gynecological oncologist for patients with guideline-adherent workup was significantly shorter than for those whose workup was nonadherant (20 vs 86 days, P < .001). A suspicious pelvic mass was identified by obstetrics-gynecology in only 23.9% of patients; 42.7% of patients did not have tumor marker testing before a gynecological oncologist consult. When an obstetrics-gynecology specialist discovered the suspicious pelvic mass, the remaining workup was more likely to be guideline adherent prior to gynecological oncologist referral than when initial imaging was not ordered by an obstetrics-gynecology specialist (P = .18). Survival was not significantly different (P = .103). CONCLUSION: With a guideline-adherent workup, including tumor marker testing, gynecological oncologist referral times can be shortened, minimizing cost inefficiencies and delays that can compromise the effectiveness of downstream care for patients with ovarian cancer. Guidelines should be disseminated beyond the obstetrics-gynecology field.

Impact of Payer Constraints on Access to Genetic Testing.

BACKGROUND: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. METHODS: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. RESULTS: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. CONCLUSION: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

Complementary and Alternative Medicine Use in Individuals Presenting for Care at a Comprehensive Cancer Center.

PURPOSE: To define the use of complementary and alternative medicine (CAM) in individuals presenting for care at a comprehensive cancer center. PATIENTS AND METHODS: A total of 17 639 individuals presenting to an NCI-designated Comprehensive Cancer Center (and consortium sites) completed a questionnaire regarding CAM use. Data were analyzed using the univariate χ2 test to assess CAM use associated with a number of variables, including cancer status, age, gender, marital status, ethnicity, race, employment, and education level. RESULTS: Eighty-seven percent of individuals who completed the CAM survey acknowledged CAM therapy use within the previous 12 months. Of the 5 broad categories of CAM, the most commonly used were biologically based approaches (14 759/17 639 [83.67%]), mind-body interventions (4624/17 485 [26.45%]), manipulative and body-based therapies (3957/17 537 [22.56%]), alternative medical systems (429/15 952 [2.69%]), and energy therapies (270/15 872 [1.7%]). CAM use was more prevalent among women, non-Hispanics, Caucasians, patients 60 to 69 years of age, and those who are married, have a higher level of education, and are employed ( P < .005). CONCLUSIONS: This is the largest report of CAM use in individuals presenting for care at a comprehensive cancer center. Our analysis revealed that a very high percentage of patients utilize CAM. Because many of these CAM interventions are not studied in oncology patients, additional research on safety, efficacy, and mechanisms of action are essential. Furthermore, it is important that oncologists understand CAM modalities and counsel their patients about their use.

Complementary and Alternative Medicine Use in Women With Gynecologic Malignancy Presenting for Care at a Comprehensive Cancer Center.

OBJECTIVE: We evaluated complementary and alternative medicine (CAM) practices among women presenting to a National Cancer Institute-designated Comprehensive Cancer Center with a gynecologic malignancy. METHODS: Women with a gynecologic malignancy who had consented to enrollment in our institutional prospective clinical registry between January 2003 and January 2014 and who had completed a questionnaire assessing sociodemographic characteristics, medical histories, quality of life, and CAM use were considered for analysis. RESULTS: Among the 2508 women identified, responses to questions on CAM use were provided by 534 (21.3%). The majority of CAM question respondents were white (93.5%) and older than 50 years (76%). Overall, 464 women (87% of CAM question respondents) used at least 1 CAM therapy during the previous 12 months. The most commonly used CAM categories were biologically based approaches (83.5%), mind and body interventions (30.6%), and manipulative and body-based therapies (18.8%). The most commonly used individual CAM therapies were vitamins and minerals (78%), herbal supplements (27.9%), spiritual healing and prayer (15.1%), and deep breathing relaxation exercises (13.1%). Complementary and alternative medicine use was greatest in age groups 20 to 30 years and older than 65 years and was more prevalent among those who were widowed (P < 0.005), retired (P = 0.02), and with a higher level of education (P < 0.01). There was no association with cancer type, race, or ethnicity. CONCLUSIONS: Complementary and alternative medicine use is common among women being treated for gynecologic malignancy. Given the potential interactions of some CAM modalities with conventional treatment and the possible benefits in controlling symptoms and improving quality of life, providers should discuss CAM with their patients.

The Chinese herb polyphyllin D sensitizes ovarian cancer cells to cisplatin-induced growth arrest.

PURPOSE: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity. METHODS: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC50. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC50 were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA. RESULTS: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC50 values ranging from 0.2 to 1.4 µm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC50 (mean IC50 reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 (P = 0.014). CONCLUSION: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents.

Evidence of a chemopreventive effect of progestin unrelated to ovulation on reproductive tract cancers in the egg-laying hen.

Epidemiologic, laboratory, and animal evidence suggests that progestins and vitamin D may be potent ovarian cancer preventives. Our objectives were to evaluate progestins as reproductive tract cancer chemopreventives in the chicken, determine whether restricted ovulation affected the incidence of reproductive tract tumors, and assess whether vitamin D would confer cancer protection either alone or in addition to progestin. A total of 2,400 two-year-old Single Comb White Leghorns were randomized into six groups (400 each) with hormonal and dietary manipulation for 2 years as follows: (i) no intervention, regular feed/caloric intake, (ii) control, (iii) vitamin D, (iv) the progestin levonorgestrel, (v) vitamin D plus levonorgestrel, and (vi) the progestin Provera (medroxyprogesterone acetate). Groups 2 to 6 were caloric restricted to inhibit ovulation. Our results indicated that caloric restriction decreased egg production by more than 60%, and was associated with a greater than 70% decrease in reproductive tract cancers. Ovulatory events did not differ among the caloric-restricted groups (groups 2-6), except for the group receiving levonorgestrel, which had fewer ovulatory events than controls (P = 0.046). After correcting for egg production, birds receiving progestins had significantly fewer reproductive tract cancers [OR, 0.61; confidence interval (CI), 0.39-0.95; P = 0.03], with similar proportionate reductions in tumors arising in either the ovary or oviduct. Vitamin D did not significantly affect cancer incidence overall, or add to the cancer preventive effect of progestins. This study suggests a protective effect of progestins against ovarian and oviductal cancers. These data support the concept that progestins provide a chemopreventive effect unrelated to ovulation.

Characterizing the efficacy of fermented wheat germ extract against ovarian cancer and defining the genomic basis of its activity.

OBJECTIVE: Most women with advanced-stage epithelial ovarian cancer (OVCA) ultimately develop chemoresistant recurrent disease. Therefore, a great need to develop new, more active, and less toxic agents and/or to optimize the efficacy of existing agents exists. METHODS: In this study, we investigated the activity of Avemar, a natural, nontoxic, fermented wheat germ extract (FWGE), against a range of OVCA cell lines, both alone and in combination with cisplatin chemotherapy and delineated the molecular signaling pathways that underlie FWGE activity at a genome-wide level. RESULTS: We found that FWGE exhibited significant antiproliferative effects against 12 human OVCA cell lines and potentiated cisplatin-induced apoptosis. Pearson correlation of FWGE sensitivity and gene expression data identified 2142 genes (false discovery rate < 0.2) representing 27 biologic pathways (P < 0.05) to be significantly associated with FWGE sensitivity. A parallel analysis of genomic data for 59 human cancer cell lines matched to chemosensitivity data for 2,6-dimethoxy-p-benzoquinone, a proposed active component of FWGE, identified representation of 13 pathways common to both FWGE and 2,6-dimethoxy-p-benzoquinone sensitivity. CONCLUSIONS: Our findings confirm the value of FWGE as a natural product with anticancer properties that may also enhance the activity of existing therapeutic agents. Furthermore, our findings provide substantial insights into the molecular basis of FWGE's effect on human cancer cells.

Genomic-directed targeted therapy increases endometrial cancer cell sensitivity to doxorubicin.

OBJECTIVE: We aimed to utilize genome-wide expression analysis to identify molecular pathways that may contribute to endometrial cancer resistance to doxorubicin (DOX) and that also represent therapeutic targets to increase DOX sensitivity. STUDY DESIGN: Ten endometrial cancer cell lines were subjected to gene expression analysis. Sensitivity of each endometrial cell line to DOX was quantified by dimethylthiazoldiphenyltetrazoliumbromide cell proliferation assay. Pearson's correlation test was used to identify genes associated with response to DOX. Genes associated with DOX responsiveness were analyzed, and identified pathways were subjected to targeted inhibition. RESULTS: Pearson's correlation analysis identified 2871 genes associated with DOX resistance (P < .05), which included members of the Src pathway. Targeted inhibition of the Src pathway increased DOX sensitivity in RL 95-2 (P < .0001), HEC 1B (P < .001), MEF 296 (P < .05), and MEF 280 (P = .14) cell lines. CONCLUSION: Genomic analysis can identify therapeutic targets such as the Src pathway that may influence endometrial cancer DOX sensitivity.

Gedunin, a novel natural substance, inhibits ovarian cancer cell proliferation.

The discovery of more active therapeutic compounds is essential if the outcome for patients with advanced-stage epithelial ovarian cancer is to be improved. Gedunin, an extract of the neem tree, has been used as a natural remedy for centuries in Asia. Recently, gedunin has been shown to have potential in vitro antineoplastic properties; however, its effect on ovarian cancer cells is unknown. We evaluated the in vitro effect of gedunin on SKOV3, OVCAR4, and OVCAR8 ovarian cancer cell lines proliferation, alone and in the presence of cisplatin. Furthermore, we analyzed in vitro gedunin sensitivity data, integrated with genome-wide expression data from 54 cancer cell lines in an effort to identify genes and molecular pathways that underlie the mechanism of gedunin action. In vitro treatment of ovarian cancer cell lines with gedunin alone produced up to an 80% decrease in cell proliferation (P < 0.01) and, combining gedunin with cisplatin, demonstrated up to a 47% (P < 0.01) decrease in cell proliferation compared with cisplatin treatment alone. Bioinformatic analysis of integrated gedunin sensitivity and gene expression data identified 52 genes to be associated with gedunin sensitivity. These genes are involved in molecular functions related to cell cycle control, carcinogenesis, lipid metabolism, and molecular transportation. We conclude that gedunin has in vitro activity against ovarian cancer cells and, further, may enhance the antiproliferative effect of cisplatin. The molecular determinants of in vitro gedunin response are complex and may include modulation of cell survival and apoptosis pathways.