Dana M. Chase

Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2

OBJECTIVE Genetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel. METHODS Subjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort. RESULTS In this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%). CONCLUSIONS Although further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.

PREDICTIVE AND PROGNOSTIC ANGIOGENIC MARKERS IN A GYNECOLOGIC ONCOLOGY GROUP PHASE II TRIAL OF BEVACIZUMAB IN RECURRENT AND PERSISTENT OVARIAN OR PERITONEAL CANCER

OBJECTIVE Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.

Colposcopy to evaluate abnormal cervical cytology in 2008

The rates of cervical cancer in the United States are low in comparison with developing nations. Whereas the Papanicolaou smear has performed well in terms of detecting both precursors of squamous cell carcinoma and squamous cell carcinoma of the cervix, this test has been less successful at identifying those women with the highest-risk premalignant disease. The use of human papillomavirus testing has also contributed to the improved sensitivity of screening for cervical cancer. In light of this, the colposcopy clinic retains high referral rates yet has poor diagnostic accuracy. Unfortunately, patients are triaged to follow-up for abnormal Papanicolaou smears based on algorithms that rely on the less evidence-based techniques of colposcopy. Therefore, the need to improve the specificity of colposcopic-guided biopsy remains. The colposcopic procedure is highlighted in this review and evaluated in terms of current literature on technique, the colposcopic impression, cervical biopsy, and methods proposed to enhance appreciation of the highest-risk lesions. By outlining certain flaws in technique and discussing the proposal of new tests to supplement the current standard of care, this review aimed to highlight the need for future research to maintain sensitivity but improve the specificity of colposcopy.

A clinical pathway for postoperative management and early patient discharge: does it work in gynecologic oncology?

OBJECTIVE This study evaluates a postoperative clinical pathway among gynecologic oncology patients. STUDY DESIGN 880 surgical admissions were retrospectively reviewed at an institution which used a clinical pathway consisting of early feeding and ambulation as well as prompt discontinuation of intravenous fluids with conversion to oral analgesics. Readmission, mortality, and complication rates were calculated. Patient proportions were compared by using the chi(2), Mann-Whitney, and t tests. RESULTS 40% of the surgeries were radical and/or staging procedures and 100% underwent open laparotomies. The median length of hospital stay was 2 days. Only 5% required readmission. The median time to readmission was 4 days. Those patients with a longer initial length of hospital stay and higher mean blood loss were more likely to be readmitted (P < .01). The most common diagnosis was endometrial carcinoma (n = 188). This subgroup also had a median length of hospital stay of 2 days and the readmission rate was 3.6%. The perioperative mortality rate was low in the group as a whole with only 1 death (0.2%). There were no reoperations for hemoperitoneum or urinary or intestinal fistulas. CONCLUSION This management approach resulted in a length of hospital stay of 2 days without increasing morbidity or mortality after laparotomy for suspected gynecologic malignancy.

Insurance status and racial differences in uterine cancer survival: A study of patients in the National Cancer Database☆

OBJECTIVE To examine the impact of race and insurance on survival among a large cohort of uterine cancer patients from the National Cancer Database (NCDB). METHODS Women diagnosed with stages I-III uterine cancer between 2000 and 2001 were selected from the NCDB. Kaplan-Meier (KM) and multivariate Cox proportional hazards were used to estimate 4 year survival rates and hazard ratios (HR) and 95% confidence intervals (CIs), respectively. RESULTS Among the 39,510 evaluable patients, African Americans had a higher risk of death compared to whites (HR=1.43 95% CI 1.31-1.56) after adjusting for age, clinical and facility factors and zip code level education. After additional adjustment for treatment, the risk death decreased among African Americans (HR=1.33 95%CI 1.21-1.46) and subsequent adjustment for insurance further reduced the hazard of death (HR=1.28 95% CI 1.17-1.40). Patients with insurance other than private had an increased risk of death (uninsured HR=1.44 95% CI 1.20-1.72, Medicaid HR=1.70, 95% CI 1.46-1.99, Medicare among patients aged 18-64 HR=2.49, 95% CI 2.10-2.95, Medicare among patients aged 65-99 HR=1.22, 95% 1.11-1.34). CONCLUSIONS The largest contributors to African American/white survival disparities in this study were clinical factors, including stage at diagnosis, grade and histopathology. Patients without private health insurance had worse uterine cancer survival that may be improved through future health care reform aimed at improving access to preventive services and adequate treatment.

Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.

Recombination of Human Papillomavirus-16 and Host DNA in Exfoliated Cervical Cells: A Pilot Study of L1 Gene Methylation and Chromosomal Integration as Biomarkers of Carcinogenic Progression

Human papillomavirus‐16 DNA replicates in productive infections in circular form, but is found in most carcinomas integrated into the host cell DNA. Because this transition is essential for carcinogenesis, detailed research is desirable and may help to triage patients with abnormal Pap smears. Previous studies addressed the chromosomal integration of HPV‐16 DNA in biopsies of tumors by an indirect biomarker, methylation of the viral L1 gene and by reverse ligation polymerase chain reaction (rliPCR). The pilot study reported here asked whether these techniques can be targeted successfully at DNA prepared from exfoliated cervical cells. Abnormal Pap smears of 21 patients that were positive for HPV‐16 were analyzed for (i and ii) methylation of the L1 gene after bisulfite modification and PCR amplification by direct sequencing and indirectly in cloned DNA and (iii) recombination with chromosomal DNA by rliPCR. Four of these 21 patients contained highly methylated L1 DNA, which was integrated in three of the samples with sufficient DNA for rliPCR analysis. Seven patients contained sporadically methylated L1 DNA, which was integrated in two and episomal in three samples with sufficient DNA. Ten patients contained only unmethylated DNA, which was episomal in six but possibly integrated in two samples. It is concluded that HPV‐16 is found integrated chromosomally in a fraction of precancerous infections, and with higher frequency in methylated than in low or unmethylated samples. Since L1 gene methylation indicates integration, it has the potential to be used as a clinical marker of cancer progression. J. Med. Virol. 82:311–320, 2010.

The vaginal and gastrointestinal microbiomes in gynecologic cancers: A review of applications in etiology, symptoms and treatment

The human microbiome is the collection of microorganisms in the body that exist in a mutualistic relationship with the host. Recent studies indicate that perturbations in the microbiome may be implicated in a number of diseases, including cancer. More specifically, changes in the gut and vaginal microbiomes may be associated with a variety of gynecologic cancers, including cervical cancer, uterine cancer, and ovarian cancer. Current research and gaps in knowledge regarding the association between the gut and vaginal microbiomes and the development, progression, and treatment of gynecologic cancers are reviewed here. In addition, the potential use of probiotics to manage symptoms of these gynecologic cancers is discussed. A better understanding of how the microbiome composition is altered at these sites and its interaction with the host may aid in prevention, optimization of current therapies, development of new therapeutic agents and/or dosing regimens, and possibly limit the side effects associated with cancer treatment.

Surgical management of recurrent ovarian cancer: The advantage of collaborative surgical management and a multidisciplinary approach☆

OBJECTIVE Primary cytoreductive surgery is well accepted in the initial management of ovarian cancer with a goal of maximal tumor reduction. The role of cytoreductive surgery at disease recurrence is controversial and guidelines are not standardized. We aimed to review cases of women with recurrent ovarian cancer who were collaboratively managed by two teams of oncologic surgeons with different areas of surgical expertise. METHODS A list of 616 patients with recurrent ovarian cancer from 1995 to 2009 was generated at a single institution. 20 cases of recurrent ovarian cancer were identified that were managed collaboratively. Data collected included date of diagnosis, initial treatment, recurrence date, location and number of sites of recurrence, secondary cytoreductive procedure performed, residual disease after surgery, pre-operative status, post-operative course, and pathologic findings. RESULTS Of the 20 cases that fit eligibility criteria, 11 were completely resected, 5 were incompletely resected, and 4 were biopsied only. Median disease-free interval following primary surgery was 18 months (6-147). Median interval from diagnosis to collaborative cytoreduction was 63 months (13-170). Our patients had metastatic disease to the liver (11), lymph nodes (8), the diaphragm (7), other locations including colon, pancreas, lung, adrenal, kidney (9). Two patients had additional miliary disease. All patients underwent joint surgical management by gynecologic and surgical oncologists. There were no deaths in the immediate post-operative period. The 5 year survival rate was 45% following the joint surgical effort, with a median post-collaborative surgery survival duration of 42 months. CONCLUSIONS Previous studies document survival benefit of surgery for women with recurrent ovarian cancer when there has been a long disease-free interval, localized pelvic or intra-abdominal recurrences and an optimal performance status. Most gynecologic oncologists do not perform extensive liver or diaphragm resections or lymph node excision above the renal vessels; thus, collaboration with a surgical oncologist is a viable option. In this small descriptive study, the feasibility of this reasonably well-tolerated approach, with possible survival benefit, is documented.

Factors associated with poor quality of life among cervical cancer survivors: Implications for clinical care and clinical trials

INTRODUCTION The purpose of this study is to identify factors that are associated with poor quality of life (QOL) among cervical cancer survivors. METHODS Patients identified through the California Cancer Registry were recruited to participate in a randomized counseling intervention. Patient-reported outcomes (PROs) were collected at study baseline (9-30 months post-diagnosis) and subsequent to the intervention. Multivariable linear models were used to identify independent factors associated with poor baseline QOL. RESULTS Non-Hispanic (N=121) and Hispanic (N=83) women aged 22-73 completed baseline measures. Approximately 50% of participants received radiation therapy with or without chemotherapy. Compared to the US population, cervical cancer patients reported lower QOL and significantly higher levels of depression and anxiety (26% and 28% >1 SD above the general population means, respectively). Among those in the lowest quartile for QOL, 63% had depression levels >1 SD above the mean. In addition, treatment with radiation±chemotherapy (p=0.014), and self-reported comorbidities predating the cancer diagnosis (p<0.001) were associated with lower QOL. Sociodemographic characteristics explained only a small portion of variance in QOL (r(2)=0.23). Persistent gynecologic problems, low social support, depression, somatization, less adaptive coping, comorbidities, sleep problems and low education were all independently associated with low QOL in multivariate analysis (r(2)=0.74). CONCLUSION We have identified key psychological and physical health factors that contribute significantly to poor quality of life subsequent to definitive cancer treatment. The majority of these factors are amenable to supportive care interventions and should be evaluated at the time of primary treatment.