Gynecologic Cancers

Clinical Implication of the Acquisition of BRCA1/2 Function in BRCA1/2-deficient Ovarian Cancer

Elizabeth M Swisher, MD

Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal, we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA1/2-deficient hereditary and sporadic ovarian carcinomas.

First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcome of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in the acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in the presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression.

With these studies, we will assess the clinical significance of restoration of BRCA1/2 function in the treatment of BRCA1/2-deficient ovarian carcinoma.

Funding Source: Fred Hutchinson Cancer Research Center (FHCRC)
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 6/30/2014

OCRF Symptom Study

Barbara A Goff, MD

Recent studies have shown that symptoms may be predictive of ovarian cancer. In April 2008 we began an NIH-funded (R21) pilot study to examine prospective screening of average-risk women for ovarian cancer in a primary care clinic setting using a symptom index followed by diagnostic testing using the CA125 blood test and transvaginal sonography (TVS) in index positive women. The goal of this pilot is to determine the feasibility of this multi-modal screening process and its acceptability to patients and clinic staff. We anticipate screening 3,000 women during this pilot effort.

The proposed GCF/OCRF project would allow us to expand our pilot project, enrolling additional women and adding an additional clinical site, allowing us to screen a total of 13,000–15,000 women. the specifi c aims of this expanded pilot study would include determination of the percentage of women referred for further evaluation using the diagnostic tests because of a positive symptom index when the symptom index is used prospectively in a primary care clinic population over the age of 50; and estimatiion of the specifi city of diagnostic testing using CA125 and TVS when used in a population of index positive women with symptoms potentially indicative of ovarian cancer.

We anticipate identification of 500–600 women with a positive index score and 6–7 ovarian cancers, giving the expanded study the power to determine the rate of index positivity among average risk women over tp to within 1–2 percentage points, and to estimate the specifi city of the multi-modal screening process as a whole.

Funding Source: Gynecologic Cancer Foundation
Contact: Barbara A Goff, MD, (206) 543-3669
Ends 12/31/2010

A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly PROTEIN Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Relapsed, Platinum-Resistant Epithelial Ovarian Cancer

Ron E Swensen, MD

Abraxis Bioscienc is providing Abraxane™ for use in the clinical trial titled "A Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) with Weekly Protein Bound Paclitaxel (Abraxane™) as Chemoimmunotherapy for Relapsed, Platinum-Resistant Epithelial Ovarian Cancer."

The Clinical trial is sponsored by Berlex under a separate contract. The study drug will be provided free of charge to the University of Washington by Abraxis Bioscience for the purpose of this trial.

Funding Source: Berlex
Contact: Ron E Swensen, MD, (206) 543-3669
Ends 12/31/08

Defining a Premalignant Phenotype in Fallopian Tube Epithelium (R01)

Elizabeth M Swisher, MD

The lack of an identifiable precursor lesion for ovarian carcinoma hinders attempts to design rational surveillance and chemoprevention for this deadly disease. Indeed, it is uncertain which are the specifi c cells in the female genital tract that transform into ovarian and primary peritoneal malignancies. A better understanding of the early steps in ovarian tumorigenesis would facilitate the development of new screening and prevention strategies. Women with a high risk of ovarian carcinoma may have early neoplasms identifi ed at the time of preventive surgery, providing a rare glimpse of the earliest detectable disease. Inherited mutations in BRCA1 result in an ~40% lifetime risk of ovarian, tubal or peritoneal carcinoma. Current clinical recommendations for women with BRCA1 mutations include risk-reducing salpingo-oophorectomy (RRSO) by age 40 after completion of childbearing.

Our group and others have identified a high rate of high-grade serous neoplasia in the Fallopian tubes of BRCA1 mutation carriers undergoing RRSO. The frequency of occult tubal neoplasia exceeds that of ovarian neoplasia when using a detailed surgical and pathological protocol. We hypothesize that most ovarian and peritoneal carcinomas arising in BRCA1 mutation carriers are seeded from neoplastic cells arising in the Fallopian tubes. This phenomenon could have important implications for the development of sporadic as well as hereditary ovarian carcinoma. The overall goal of the current proposal is to defi ne a premalignant ovarian or tubal phenotype in women with inherited BRCA1 mutations.

The specific aims of this proposal are:

  1. To characterize tubal epithelium in unaffected women with BRCA1 mutations and in women with BRCA1-associated or sporadic ovarian and peritoneal carcinomas
  2. To identify priority genes that drive premalignant or early neoplastic alterations in pathologically normal tubal epithelium from women with BRCA1 mutations
  3. To evaluate priority genes from Specific Aim 2 in inherited and sporadic ovarian and peritoneal carcinomas


Funding Source: National Institutes of Health (NIH)
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 2/28/2014

Falloposcopy: A Novel Approach to Ovarian Cancer Detection and Prevention

Elizabeth M Swisher, MD

Recent data suggest that many presumed ovarian or peritoneal carcinomas may actually arise in the Fallopian tubes. If true, then early detection of ovarian carcinoma should focus on viewing and sampling the Fallopian tube. Minimally invasive optical surveillance in the Fallopian tube is unavailable due to the lack of ultrathin and fl exible endoscopic tools that provide high-quality imaging.

The current technology which forms the basis for all flexible endoscopes has a severe trade-off of image quality with reduction of endoscope diameter when reaching the size of a single strand of spaghetti. A new technology has been developed at the University of Washington, providing high resolution (HDTV), small size and the flexibility needed to enter and transverse the Fallopian tube. Since the imaging uses low power laser light (essentially 3 laser pointers of red, green and blue), new spectroscopic capabilities for delineating between diseased, distressed and healthy tissue are now possible with or without fluorescence biomarkers. In future projects, a cell sampling tool will be used to remove cells from tissues of the Fallopian tube that appear suspicious for cancer or precancer (neoplasia). The ability to sample cells under direct visualization at high optical resolution in the Fallopian tube could revolutionize early detection of ovarian cancer.

This study will provide the pilot data from 8 women to demonstrate that Fallopian tube imaging in women at high risk for ovarian cancer is safe and effective and could be performed in an outpatient clinical setting. With our combined expertise in the molecular profi ling of Fallopian tube in high-risk women and in the development of novel technologies for ultrathin endoscopy, our team is uniquely positioned to develop an entirely new approach for screening to prevent or treat early pelvic serous carcinoma.

Funding Source: Marsha Rivkin Center for Ovarian Cancer Research
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 4/30/2010

The Fanconi Anemia-BRCA Pathway and Chemosensitivity of Human Cancer

Elizabeth M Swisher, MD

One of the most difficult problems in the treatment of cancer is acquired resistance to chemotherapy. Defects in DNA repair are likely to play a critical role in the sensitivity of cancer cells to chemotherapeutic drugs, many of which are DNA-damaging agents.

Fanconi Anemia (FA) is a genetic disorder characterized by cancer susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin and melphalan. FA proteins and breast/ovarian cancer susceptibility gene products (BRCA1 and BRCA2) cooperate in a common DNA damage-activated signalling pathway (the FA-BRCA pathway), which controls DNA repair. We hypothesize that interity of the FA-BRCA pathway is a critical determinant of resistance of tumor cells to chemotherapy with DNA crosslinking agents.

The goals of our proposed research are 1) to elucidate the role of the FA-BRCA pathway in cisplatin sensitivity/resistance of cancer cells, 2) to determine if the sensitivity of tumor cells to DNA crosslinking agenst can be increased by modulating the FA-BRCA pathway using small molecule inhibitors of the pathway, and 3) to further elucidate the mechanism of regulation of the FA-BRCA pathway. We plan to determine the role of one of the FA genes, BRCA2/FANCD1, in acquired resistance to cisplatin using two BRCA2-deficient cell lines we recently identified.

Funding Source: Fred Hutchinson Cancer Research Center (FHCRC)
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 6/30/12

Identification of an Immunologic Signature of Ovarian Cancer for Use as an Early Cancer Screen

Heidi J Gray, MD

The goal of this proposal is to develop a serum-based assay that evaluates the use of antibody immunity as a diagnostic tool for early detection of ovarian cancer. There is ample evidence in the literature demonstrating the immunogenicity of ovarian cancer. Previous work has described several tumor-associated antigens and has shown patients have an ability to mount a T cell response to these antigens. It is well documented that evidence of exposure to tumor antigens exists by assaying for antibodies to tumor -associated antigens (TAAs). Evidence of this antibody response has been shown to occur early in tumorigenesis and therefore has potential for use as an early detection screen.

The work proposed here will identify the immunologic signature of ovarian cancer composed of a panel of serum antibodies. The study will be done using serum samples from ovarian cancer patients and age-matched volunteer donors. The samples will be analyzed using a high-throughput technique that combines the use of a phage display library and protein array. This technique makes it possible to evaluate hundreds of phage-expressed proteins simultaneously to identify those that define the immunologic signature associated with ovarian cancer.

The results of this study will provide data on the feasibility of multi-parametric immune-based assays in discriminating patients with cancer from non-tumor bearing individuals and provide the basis for a definitive application validating the approach.

Funding Source: Ovarian Cancer Research Fund (OCRF)
Contact: Heidi J Gray, MD, (206) 685-2463
Ends 12/31/10

Premalignant Genetic and Epigenetic Alterations in Tubal Epithelium from Women with BRCA1 Mutations

Elizabeth M Swisher, MD

The overall goal of the current proposal is to identify genetic and epigenetic alterations in tubal epithelium from women with BRCA1 mutations that precede development of overt carcinoma. Approximately 10–15% of ovarian carcinomas occur secondary to inherited mutations in BRCA1 and BRCA2 which confer a 20–50% lifetime risk of ovarian carcinoma. This high risk, combined with the ineffectiveness of current screening methods, has led to the recommendation that women with mutations in BRCA1 and BRCA2 undergo risk-reducing salpingo-oophorectonmy (RRSO) by age 40 after completion of childbearing. A major obstacle in developing improved screening and prevention strategies is the lack of an identifi able premalignant neoplastic lesion that would facilitate study of the early events in malignant transformation.

Our group and others have identified a high rate of high grade serous neoplasia in the Fallopian tubes of BRCA1 mutation carriers undergoing RRSO. We hypothesize that many or most ovarian and peritoneal carcinomas arising in BRCA1 mutation carriers are seeded from neoplastic cells arising in the Fallopian tubes. This phenomenon could have important implications for the screening and prevention of hereditary ovarian carcinoma. BRCA1 is recognized to be important in chromatin remodeling. We have preliminary data that demonstrates our expertise at obtaining tubal or malignant epithelium by laser capture microdissection with RNA adequate for microarray expression analysis and DNA adequate for chromatin precipitation. We will combine analyses of epigenetic alternations with RNA expression studies to find molecular alterations in tubal epithelium in BRCA1 mutation carriers that are most likely to be functionally signifi cant. Identification of precursor alterations and proof of their contribution to malignant progression would facilitate chemoprevention trials in high-risk women and provide new targets for early detection.

Funding Source: US Department of Defense (DOD)
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 10/14/2010

Clinical Implication of the Acquisition of BRCA1/2 Function in BRCA1/2-Deficient Ovarian Carcinoma

Elizabeth M Swisher, MD

Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA1/2-deficient cells are hypersensitive to platinum compounds. Recently we found that platinum resistance of BRCA1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA1/2-deficient hereditary and sporadic ovarian carcinomas.

First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcome of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in the acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in ther presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression. With these studies we will assess the clinical significance of restoration of BRCA1/2 function in the treatment of BRCA1/2-deficient ovarian carcinoma.

Funding Source: Fred Hutchinson Cancer Research Center (FHCRC)/NIH Flow Through
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 6/30/2014

BRCA1/2 Restoration as a Predictor of Response in a GOG Clinical Trial for Recurrent Ovarian Carcinoma

Elizabeth M Swisher, MD

Most women with ovarian cancer have a good response to chemotherapy initially, but if the cancer comes back later, it is likely to become less responsive to chemotherapy. The resistant cancer grows unchecked and eventually kills the patient. We do not understand what makes many ovarian cancers resistant to chemotherapy. About 15% of ovarian cancers are caused by a familial risk, and we call these hereditary ovarian cancers. These cancers are usually caused by inherited mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2.

Hereditary ovarian cancers are sensitive to chemotherapy because they lack functional BRCA1 or BRCA2.We discovered that hereditary ovarian cancers become resistant to chemotherapy by restoring BRCA1 and BRCA2, which allows the cancer cell to repair DNA damaged by chemotherapy. Many non-hereditary or sporadic ovarian cancers also start out deficient in BRCA1 and BRCA2. We think that restoration of BRCA1 and BRCA2 may be an important mediator of resistance to chemotherapy in both hereditary and sporadic ovarian cancers.

We will test this idea by studying cancer tissues from women who are participating in a national clinical trial for the treatment of recurrent ovarian carcinoma. By using tissues and information from this clinical trial, we may develop a better predictor for whether a cancer will respond to a particular chemotherapy. By understanding what makes ovarian cancers resistant to chemotherapy, we may be able in the future to design better therapies for ovarian cancer and identify drugs that will make the cancer more sensitive to chemotherapy.

Funding Source: Mary Kay Ash Charitable Foundation
Contact: Elizabeth M Swisher, MD, (206) 685-2463
Ends 6/30/2012