CCE Gynecologic Oncology: Cedars-Sinai Medical Center

Cedars-Sinai Medical Center
Los Angeles, California

Patients referred to the Cedars-Sinai Women’s Cancer Research Institute (WCRI) will find not only compassionate, state-of- the art clinical care, and access to leading-edge research, but clinicians dedicated to translational science aimed at one goal – preventing, detecting, and curing gynecologic cancers.

Under the direction of Beth Y. Karlan, MD, the WCRI has a decade-long dedication to translational research to achieve cures for cervical, uterine, and ovarian cancers.

“My faculty members have a recognized commitment to translational science, coupled with our underlying principle – compassionate, cutting-edge, comprehensive, cancer care – which asks ‘why it (disease outcome) happened this way?’ ”

Patients travel across the globe for ovarian cancer treatment at the WCRI because of its reputation in treating the disease with specialized aggressive surgery and targeted molecular treatments. The WRCI is also internationally recognized for its research on how genetic risk interacts with environmental risk factors, explains Karlan.

“Aggressive surgery is a very important factor in some of our survival statistics, with mean survivals well in excess of 5 years and many patients who are 10- to 20-year survivors of stage IV disease,” says Karlan.

World Renowned Ovarian Cancer Research

Early detection is at the heart of the WCRI  program. A primary research focus is on the discovery of ovarian cancer-specific biomarkers and the study of inherited cancer susceptibility, specifically cancers associated with BRCA mutations. 

“When a patient has multiple sisters and one has breast cancer, one has ovarian cancer, and another has neither, but they all have the same BRCA mutation, I try to look at why this has occurred,” says Karlan.

Previously, patients may have been reluctant to be referred for genetic testing but, with the recent passage of the Genetic Information Non-Discrimination Act (GINA), physicians can reassure patients that there is no risk of losing health insurance.  Patients should be able to take advantage of genetic tests and find out if they are at high risk for developing the disease without risking losing their health insurance, adds Karlan.

The WCRI is involved in a large, international collaborative group of researchers – The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) – which is investigating  genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers.

“We are looking at genetic modifiers that may influence penetrance, says Karlan. “Why do I see a daughter with ovarian cancer at age 40 and a mother sitting with her as a carrier at age 65, who has never had cancer?”

Dr. Karlan explains Cedars-Sinai’s commitment to early ovarian cancer detection helped develop the National Institutes of Health’s (NIH) consensus statement on screening for ovarian cancer. Additionally, Dr. Karlan has testified before Congress for the passage of Johanna’s Law (the Gynecologic Cancer Education and Awareness Act) which increases federal funding for ovarian cancer research.

Research Aimed at Early Detection

Existing diagnostic tools to detect ovarian cancer early are not effective and often miss the disease when in its early stage.

“One of the biomarker molecules that came out of our early studies from 1999, in collaboration with the Fred Hutchinson Cancer Research Center, is human epididymis protein 4 (HE4). We discovered this protein was over-expressed in ovarian tumors and during the subsequent decade HE4 appears to be a very good marker for ovarian cancer,” says Karlan. Based in part on this research, last year the Food and Drug Administration approved an HE4 enzyme immunoassay for monitoring ovarian cancer patients.  The assay was developed for use in conjunction with the existing serum CA 125 biomarker to more accurately distinguish between benign and malignant pelvic masses.

Finding a diagnostic screening test for ovarian cancer  has evolved and been a major focus for WCRI in terms of trying to develop a blood test that would lead to the diagnosis of ovarian cancer in asymptomatic women, says Karlan.

Sandra Orsulic, PhD, Director of Women's Cancer Biology, developed a genetically-defined mouse model of ovarian epithelial cancer that will increase understanding of human ovarian cancer development and progression.

“This model allows us to test different genes and how they effect the growth of ovarian cancer.  Do they cause it? Do they stop it?” says Karlan. “Her work has really been groundbreaking in itself.”

Gilda Radner Hereditary Cancer Detection Program

One of the pillars of the WCRI, is the Gilda Radner Hereditary Cancer Detection Program, which provides woman at high risk for breast and ovarian cancers – those with the BRCA1 or BRCA2 gene mutation – an opportunity to participate in a cancer  screening program that uses state-of-the-art and investigational strategies aimed at early detection. With over 1,600 women participating in the program since its inception in 1991, much biomarker, genetic, and familial data have been gathered to better understand the relationship between genes and ovarian cancer growth. 

Dr. Karlan cites an example of a woman who was told she had stage IV ovarian cancer and there was not much that could be done.

“That was about 13 or 14 years ago,” says Karlan.  “It turned out that we found she was a BRCA carrier, as were her mother and sister.  However, the BRCA gene mutation does not explain all cases. I have similar patients that are approaching 10 years survival who do not have the BRCA mutation.”

“The BRCA-positive patients make up a significant number of ovarian cancer patients we see,” says M. William Audeh, MD, a medical oncologist at Cedars-Sinai.  “In a way it is an unmet need in terms of having what I would call a target therapy for ovarian cancer widely available.”

Currently, patients with BRCA mutations are enrolled in a clinical trial using a poly(ADP-ribose) polymerase (PARP) inhibitor. Researchers have found that inhibition of the PARP pathway can eliminate cells deficient in BRCA function. The investigational agent used in the trial blocks the PARP enzyme, which is a key element in DNA repair. When PARP is inhibited, cells with BRCA mutations are destroyed, but the healthy cells are left undamaged. 

“Going forward I think there will be a genetic target of some kind,” says Audeh. “And it could be present in many different kinds of cancer.” He adds that drugs will be developed that will not only treat the cancer they were developed for, but also the genetics underlying the cancer. “This drug-targeted therapy approach, this is what I think is the future of cancer therapy,” says Dr. Audeh.

The results have been promising with this therapy showing a 59 percent response rate in BRCA mutation patients with recurrent ovarian cancer compared to the average 20 percent response rate associated with other therapies.

Commitment to Translational Research

As part of the WCRI research effort, its research laboratory has two valuable registries to promote gynecologic cancer research.

The foundation of the WCRI’s translational research to advance cancer care and cures is a gynecologic cancer tissue/tumor bank, one of the oldest of its kind, which holds one of the world’s most comprehensive gynecologic inventories of malignant and nonmalignant  tissues. 

With more than 2,800 samples from patients all over the world, the tissue/tumor bank and relational database provides the opportunity for affiliated scientists to study cancer at every stage of its development, as well as to better understand the contributing genetic causes of cancer.  In 2008, about 400 samples from the tumor repository were sent to collaborators. 

We began a tumor biorepository over 20 years ago to determine why some women undergoing surgery for ovarian cancer are cured of the disease while others succumb to the disease,” says Karlan.

The Ovarian Cancer Registry, created a decade ago, allows researchers to monitor the success of various treatments over time by linking research data with clinical information.  To date there are more than 500 patients registered, with data including complete cancer histories, surgical and chemotherapy treatment records, and details of follow-up care. 

Cedars-Sinai’s highly renowned GenRISK program offers patients genetic consultative services for patients that may have a genetic susceptibility to ovarian cancer and provides patients with a personalized prevention plan tailored to their specific genetic susceptibilities.

Through early detection, targeted and molecular treatments, and genetic/environmental interactions, WCRI is taking baby steps forward in finding a cure for ovarian cancer, says Karlan.  “We don’t want to leave any piece of the puzzle out.”