In The Clinic

Ovarian Cancer:

A Silent Killer "Speaks" through Proteins

Elisa Kohn, M.D.

Elise Kohn, M.D., is passionate about expanding our knowledge of ovarian cancer through teaching. When she is not mentoring the next generation of scientists and physicians, this 22-year veteran of NCI spends her days moving from bench to bedside—literally—as she leads both the Molecular Signaling Section (“bench”) and the Medical Ovarian Cancer Team (“bedside”) within the Medical Oncology Branch of CCR. And when she is not in the clinic or in the lab, Kohn is on the phone providing consultations for other patients across the country who seek her guidance after learning about her program through the Ovarian Cancer National Alliance, National Ovarian Cancer Coalition, and other ovarian cancer networks. CCR has provided Kohn with unparalleled opportunities to advance her science, which may not have received the same funding and support outside of the intramural program. This has allowed her to break ground in the clinical arena as she and her team find new ways to both diagnose and treat the no longer so-called “silent killer” known as ovarian cancer.

The American Cancer Society estimates that 21,650 women in the United States will be diagnosed with ovarian cancer in 2008; 15,000 will die of their disease. The good news is that women who present with Stage I ovarian cancer have a greater than 90 percent chance of being cured. The bad news is that only 20 percent of patients are diagnosed at this early stage of disease. Less than 35 percent of patients with advanced-stage disease—80 percent of all women diagnosed—will survive beyond five years. This sobering statistic is the reason that ovarian cancer is the leading cause of gynecologic cancer death in the U.S. and why it ties with pancreatic cancer for fourth place in women's overall cancer mortality.

Barriers to Early Detection

Early detection, critical for surviving ovarian cancer, is one of the most imperative issues in ovarian cancer care, but it is most certainly not easy. Due to the elusive nature of the disease, there are a number of reasons why ovarian cancer used to be referred to as the “silent killer.” Ovarian cancer is difficult to detect. The ovaries lie deep within the abdominopelvic cavity, making them difficult to view or feel. It was initially believed that ovarian cancer lacked warning signs, although we now know that there are subtle symptoms that may suggest disease. In 2007, the American Cancer Society, the Gynecologic Cancer Foundation, and the Society of Gynecologic Oncologists released a consensus statement claiming that symptoms often do exist for ovarian cancer, even in the early stages. These symptoms include bloating, feeling full quickly, pelvic or abdominal pain, and frequent or urgent urination.1 The problem with these symptoms is that they are common and occur with a number of ailments. But, if they occur almost daily and last for more than a few weeks, women should see a gynecologist. It remains to be seen whether this symptom checklist will help women detect ovarian cancer sooner rather than later.

Another hurdle to early detection is the lack of validated screening tools to identify disease. The Papanicolaou (“Pap”) test is used to screen for cervical cancer and the mammogram to screen for breast cancer, but there is no validated and robust test that can identify ovarian cancer. The biomarker CA-125, a protein in the blood that is sometimes elevated in women with ovarian cancer, is approved to monitor response to treatment as well as to detect recurrent ovarian cancer, but it is not sensitive and specific enough to identify early disease or to have an impact on survival. This lack of effective molecular diagnostics is why there is a great need to identify alternative biomarkers that can detect cancer at Stage I—when the disease is most amenable to cure.

CCR's Ovarian Cancer Medical Team is running a number of clinical trials to achieve two critical goals: to test the use of combinations of molecularly targeted therapies to treat recurrent and refractory disease; to identify diagnostic biomarkers for early detection and recurrent disease; and as a companion diagnostic with treatment. We work from an understanding of the critical role that protein pathways, or networks, play in cancer. We postulated some time ago that future therapeutics will target entire protein networks, not just one protein. For this reason, we have invested our energies into the application of proteomics (the study of proteins and their networks) in both the laboratory and clinic. Blood and/or tissue samples are obtained from all patients for use in analyzing protein networks with the goal of developing life-saving diagnostic tests. This work has allowed the once-silent killer to be heard.

A Mix of Molecularly Targeted Therapies

Ovarian cancer will return in approximately 90 percent of patients who have advanced stage disease. Because recurrent ovarian cancer cannot be cured, it must be treated as a chronic disease, with the understanding that with chronicity comes a need for optimal benefit and minimal risk. We are running early stage clinical trials (Phase I and II) of targeted therapy combinations for recurrent and refractory tumors. These early trials will help determine how a drug might best be given, how often, at what dose and, most importantly, how safe it is in patients. The studies are also designed to address proof of concept, determining whether the drug (or combination) does what it is supposed to do.

Understanding the protein profile of a patient's tumor may help identify treatments that deliver the best outcome for the individual patient. My colleagues and I coined the concept of “personalized molecular medicine” in 2001.2 If a signaling pathway is overactive in a patient's tumor, targeting that pathway at multiple points simultaneously may more effectively control the activity and at potentially lower doses of both agents.