Christina A. Bandera

BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: Relationship to family history and implications for genetic testing

OBJECTIVE Our purpose was to determine the prevalence of BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in a large, unselected population of ovarian cancer patients and to evaluate the relationship between mutation status and a routinely obtained family history of cancer. STUDY DESIGN One hundred sixteen consecutive ovarian cancer patients seen for routine clinical care were examined for BRCA1, BRCA2, hMSH2, and hMLH1 gene mutations with use of the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct gene sequencing. Fishers exact test was used to evaluate possible associations between BRCA1 and BRCA2 mutation status and specific familial characteristics. RESULTS Among 116 unselected ovarian cancer patients we identified a total of 13 germline mutations in 12 patients: 10 in BRCA1, one each in hMSH2 and hMLH1, and a single BRCA2 mutation, which occurred in a patient also carrying a BRCA1 mutation. More than half the patients with BRCA1 mutations had family histories that would generally be considered unremarkable. Of 22 family history variables analyzed, only two (maternal family history of breast or ovarian cancer, p=0.037, and maternal family history of any cancer, p=0.020) conferred a significantly increased risk of carrying a BRCA1 mutation compared with ovarian cancer patients without such a history. However, the majority of ovarian cancer patients with these family histories and other suggestive histories tested negative for mutations. CONCLUSIONS Approximately 10% of ovarian cancers occur in association with genetic mutations known to predispose to the disease. A routinely obtained family history is an unreliable way to identify patients who might harbor mutations. The majority of ovarian cancer patients with suggestive family histories test negative for known gene mutations, perhaps suggesting the existence of additional undiscovered genes predisposing to ovarian cancer.

BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum

Objective To compare BRCA1 mutations in papillary serous carcinoma of the peritoneum and papillary serous ovarian carcinoma. Methods Germline DNA from 17 consecutive patients with peritoneal carcinoma was screened for mutations in the BRCA1 gene using single-strand conformation polymorphism analysis. Shifted DNA bands were sequenced. Patients with germline BRCA1 mutations were screened for allelic loss in tumor DNA at the BRCA1 locus. Results Two of the 17 patients (11%, 95% confidence interval 0.07, 0.37) exhibited the 185 delAG germline BRCA1 mutation described in the Ashkenazi Jewish population. The family history of one patient was notable for a mother and five aunts with breast or ovarian cancer. The other patient had a personal history of breast cancer. Both patients exhibited allelic loss of the normal BRCA1 allele in their tumor. A third patient was found to have a previously undescribed exon 11 single base pair substitution at nucleotide 1239 (CAG to CAC) resulting in a missense mutation (Gln to His). The patient had no family or personal history of breast or ovarian cancer, and her tumor did not exhibit loss of heterozygosity. Conclusion Germline BRCA1 mutations occur in papillary serous carcinoma of the peritoneum with a frequency comparable to the BRCA1 mutation rate in ovarian cancer. Although the penetrance is unknown, peritoneal carcinoma should be considered a malignancy expressed in the familial breast ovarian cancer syndrome.

Selenium binding protein 1 in ovarian cancer

Selenium binding protein 1 (SELENBP1) was identified to be the most significantly down‐regulated protein in ovarian cancer cells by a membrane proteome profiling analysis. SELENBP1 expression levels in 4 normal ovaries, 8 benign ovarian tumors, 12 borderline ovarian tumors and 141 invasive ovarian cancers were analyzed with immunohistochemical assay. SELENBP1 expression was reduced in 87% cases of invasive ovarian cancer (122/141) and was significantly reduced in borderline tumors and invasive cancers (p < 0.001). Cox multivariate analysis within the 141 invasive cancer tissues showed that SELENBP1 expression score was a potential prognostic indicator for unfavorable prognosis of ovarian cancer (hazard ratio [HR], 2.18; 95% CI = 1.22–3.90; p = 0.009). Selenium can disrupt the androgen pathway, which has been implicated in modulating SELENBP1 expression. We investigated the effects of selenium and androgen on normal human ovarian surface epithelial (HOSE) cells and cancer cells. Interestingly, SELENBP1 mRNA and protein levels were reduced by androgen and elevated by selenium treatment in the normal HOSE cells, whereas reversed responses were observed in the ovarian cancer cell lines. These results suggest that changes of SELENBP1 expression in malignant ovarian cancer are an indicator of aberration of selenium/androgen pathways and may reveal prognostic information of ovarian cancer.

Robotic surgery in gynecologic oncology

Purpose of review Robotic surgery is rapidly taking the place of laparoscopy in many gynecologic oncology practices. Numerous practitioners have published their experience with this new technology. A review of their findings is timely and relevant. Recent findings The majority of case series of robotic surgery for hysterectomy and lymphadenectomy show that the procedure is feasible and at least comparable to laparoscopic surgery. Similarly, case series of robotic radical hysterectomy for cervical cancer also compare favorably to laparoscopic surgery. Less common procedures such as robotic trachelectomy, parametrectomy, and retroperitoneal lymphadenectomy have also been described. Numerous patient and practitioner advantages are discussed in this review. Summary Robotic surgery is a minimally invasive alternative to laparoscopy for the surgical treatment of endometrial cancer and cervical cancer. Its role in ovarian cancer is just starting to be explored.

Use of a Combination of Approaches to Identify and Validate Relevant Tumor-Associated Antigens and Their Corresponding Autoantibodies in Ovarian Cancer Patients

Purpose: Novel biomarkers are urgently needed to increase the sensitivity of CA125 for the early detection of ovarian cancer. Indeed, it has been shown that as much as 20% of early-stage patients do not express significant levels of this biomarker. Therefore, the possibility of using autoantibodies directed against tumor-associated antigens as putative cancer markers is being more examined. Indeed, many autoantibodies have recently been shown to correlate with cancer patient prognosis or to be suitable for detection of the disease. Experimental Design: In this study, we have used a new approach involving the use of proteomics, immunology, and ELISA methods to identify relevant autoantibodies in the plasma of ovarian cancer patients. To do so, we developed an innovative technique called two-dimensional differential gel electrophoresis analysis of immunoprecipitated tumor antigens. Results: This strategy allowed us to successfully identify novel circulating autoantibodies directed against the S100A7 protein in the plasma of ovarian cancer patients. Further real-time reverse transcription-PCR and immunohistochemical studies confirmed that the S100A7 mRNA and protein were highly expressed in ovarian tumors but absent in normal and benign tissues. Moreover, a preliminary study involving 138 patients confirmed that the plasma levels of anti-S100A7 antibodies are significantly elevated in early- and late-stage ovarian cancer patients compared with healthy controls and with patients with benign gynecologic diseases. Conclusions: This shows that our approach is a valuable tool to successfully identify autoantibodies and tumor-associated antigens in cancer patients and that future research assessing their putative clinical usefulness would be worthwhile.

Vaginal cuff recurrence of endometrial cancer treated by laparoscopic-assisted vaginal hysterectomy.

BACKGROUND Laparoscopic-assisted vaginal hysterectomy (LAVH) has been suggested as an alternative to total abdominal hysterectomy (TAH) for the treatment of early endometrial cancer. Although studies have reported good results with equivalent rates of recurrence and survival, the need for use of intrauterine manipulators during the LAVH raises the concern for operative dissemination of tumor cells. CASES We report three patients with stage I, noninvasive or superficially invasive endometrial cancer with vaginal cuff recurrence within 9 months of treatment by LAVH. CONCLUSION While LAVH may be a technically acceptable alternative to TAH for the management of early-stage endometrial cancer, its routine use should be undertaken with caution, as the long-term risks for recurrence and survival have yet to be defined in a randomized, controlled fashion.

New technologies for the identification of markers for early detection of ovarian cancer.

Purpose of review The ovarian cancer screening regimens in current use fail to identify disease at an early curable stage. Recent findings New technologies are emerging that facilitate the identification of diagnostic tumor markers. In particular, high throughput techniques using microarray technology and proteomic screening have enriched the study of protein expression by ovarian cancer cells. Summary Further evaluation of serum proteins associated with ovarian cancer holds promise for the development of a tumor marker panel that could aid in the early diagnosis of ovarian cancer, and save lives.

Addressing clinical trials: Can the Multidisciplinary Tumor Board improve participation? A study from an academic women's cancer program☆

OBJECTIVE The Tumor Board (TB) allows for an interdisciplinary approach to cancer treatment designed to encourage evidence-based treatment. However, its role in facilitating clinical trial participation has not been reported. We aimed to determine whether a prospective TB is an effective strategy for trial recruitment and to identify steps within the TB process that facilitate discussion of trial eligibility and optimize accrual. METHODS We conducted a retrospective cross-sectional analysis of women presented to Gynecologic Oncology TB between March and December 2008. Patient demographics, TB recommendations, and post-TB patient discussions were abstracted. These were compared to data derived from the Department of Oncology Research to determine research team awareness of eligible patients and confirm trial enrollment(s). Data analysis was completed with Chi-square test; risk ratios and confidence intervals were calculated as summary measures. RESULTS We reviewed 1213 case presentations involving 916 women. Overall, 358 TB recommendations (30%) identified eligible patients, of which enrollment consisted of 87 (24%) trials (6% therapeutic trials and 18% non-therapeutic trials). Compared to other types of TB recommendations, those involving trials were discussed less frequently at post-TB patient visits (79% vs. 44%). Documentation of trial discussion at the post-TB visit was more likely to result in trial participation, versus solely relying on the research staff to communicate enrollment eligibility with the treating team (RR 2.5, p=0.006). CONCLUSIONS Patients identified by the TB were 2.5-times as likely to enroll in a clinical trial, but trials were mentioned only 44% of the time. Interventions that facilitate trial discussions during post-TB meetings are needed to improve trial participation.

Cyclin E Amplification and Overexpression in Clear Cell Adenocarcinoma of the Ovary

Objective: The purpose of this study is to compare DNA, mRNA and protein levels of the cyclin E between clear cell (CC) and serous (SC) ovarian carcinomas, and evaluate the relationship between cyclin E and p53 status. Method: We examined the DNA, mRNA and protein levels of cyclin E and the protein level of p53 in 44 CCs and 39 SCs using microdissected tissues. Results: Relative cyclin E mRNA expression was significantly higher in CC (3.62, 95% CI, 2.24–4.99) than in SC (1.75, 95% CI, 1.05–2.45; p = 0.0098). The percentage of positive nuclear staining of cyclin E was significantly higher in CC (48.3, 95% CI, 40.4–56.1) than SC (25.3, 95% CI, 17.4–33.3; p = 0.0001). The mRNA and protein expression of cyclin E was significantly correlated (r = 0.66, p < 0.0001). However, the correlation between relative DNA copy number and relative mRNA expression was not significant (r = –0.063; p = 0.66). Percentage of positive nuclear staining of cyclin E was significantly higher in p53 positive cases (51.8, 95% CI, 40.0–63.5) than p53 negative cases (36.2, 95% CI, 28.2–44.2; p = 0.028). Conclusions: Cyclin E expression is significantly higher in CC than in SC. Cyclin E expression is significantly related with p53 positivity.

Genetic imbalance on chromosome 17 in papillary serous carcinoma of the peritoneum

We extend the evaluation of allelic loss patterns on chromosome 17 to papillary serous carcinoma of the peritoneum (PSCP) which is histologically identical to papillary serous ovarian carcinoma (PSOC). DNA was obtained from 11 archival cases of PSCP, with 1–11 tumor sites per case. Using ten loci spanning chromosome 17, loss of heterozygosity (LOH) was identified in all 11 cases (100%). Furthermore, 75–100% of informative cases exhibited LOH at the loci p53, D17S1322 (intragenic to the tumor suppressor gene BRCA1), D17S1327 and MPO. PSCP cases exhibit a higher rate of LOH at most loci when compared with PSOC. Alternating allelic loss at different tumor sites was identified in three cases supporting a multifocal origin of PSCP. Microsatellite instability (MI) is an uncommon event which was identified in four cases. These data implicate chromosome 17 as a potential location of genetic events important in the pathogenesis of PSCP as well as ovarian cancer.