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Ovarian Cancer –  A Force to be Reckoned With

Conquest - Spring 2007

By Eileen A. Ellig

Mary Glenn Rice, Kim Podraza, Judith Buelow.

Three women, one diagnosis – ovarian cancer.

Although (from left) Mary Glenn Rice, Kim Podraza and Judith Buelow, don’t know each other, they share two things in common — a diagnosis of ovarian cancer and a mission to help others overcome the disease.

“I was shocked. A cancer diagnosis was the furthest thing from my mind,” says Rice, who learned she had stage IIIc ovarian cancer.

Ditto for Podraza, who was diagnosed with a stage III mixed germ cell tumor, a rare form of the disease accounting for only 3% to 5% of all ovarian cancers.

For Buelow, she couldn’t believe the grapefruit-sized tumor in her belly was real. “I kept thinking I’m going to wake up and realize this all has been a big nightmare.”

But it wasn’t. Buelow, too, had advanced ovarian cancer.

She thought, “Well, this may be it.”

A force to be reckoned with

“Unrelenting” best describes ovarian cancer’s hold on the more than 22,000 women who are diagnosed with the disease every year.

Although the rate of ovarian cancer has decreased slightly, the ratio of deaths to new cases has remained virtually unchanged for decades, with three-fourths of women ultimately succumbing to the disease.

Rice, Podraza and Buelow are the exceptions. Each now has been cancer free for six, 23 and 18 years, respectively.

The reason why a significant shift in survival has yet to occur is because ovarian tumors escape early detection and evade the killing effects of anti-cancer agents.

Aside from the fact that there is not any reliable way to mass screen women for the disease, ovarian tumors get a little help from Mother Nature. The very positioning of the ovaries makes it difficult to detect developing ovarian tumors early.

About the size and shape of an almond, the ovaries flank each side of the uterus and are embedded deep in the lower abdomen. As a result, ovarian cancer typically is not detected until its late stages because, when early symptoms appear, they often mimic other more common ailments, according to David Gershenson, M.D., chair of the Department of Gynecologic Oncology. This is the case for nearly 75% of all women who are diagnosed with the disease.

“At the time, I had a lot of symptoms that most women with the disease have but tend to overlook until they get to be too much,” says Podraza, who thought a simple prescription from her doctor could cure all her ills — bloating, indigestion and intermittent bouts of constipation and diarrhea. Least of all did she suspect she would need emergency surgery, which revealed two large tumors, one on each ovary.

Although the majority of women respond to postoperative chemotherapy, most relapse within a year because their tumors progress or recur, Gershenson notes. Initially taken down by the onslaught of chemotherapy, ovarian tumors often become resistant to therapy by turning on specific growth factors, or proteins, which promote survival.

Clever as they may be, ovarian tumors are now coming up against a force that looks toward their elimination. Nearly 50 members strong, the Blanton-Davis Ovarian Cancer Research Program team is deep into the search for answers to ovarian cancer.

Turning discoveries into solutions

Ovarian cancer is a complex disease, characterized by many genetic and molecular abnormalities — some of which are known, others that are yet to be uncovered.

Although the majority of ovarian cancers are considered sporadic, occurring  because of a chance combination of many different factors, 5% to 10% of cases are associated with an alteration in one of two genes — BRCA1 or BRCA2 — that are passed down from generation to generation.

David Gershenson, M.D., and his team are deep into the search for answers to ovarian cancer, a disease that affects more than 22,000 women every year.

With increasing knowledge of these and other genes responsible for tumor growth and progression, investigators are testing to see whether any of these abnormalities are good targets for therapy or viable markers for screening and prevention.

While targeting specific genes in tumors is an ongoing approach, investigators also are looking to the tumor microenvironment for answers.

“By nature, ovarian tumors are genetically unstable and can evolve and become resistant to therapy,” says Anil Sood, M.D., professor in the Department of Gynecologic Oncology. “The cells surrounding them, however, tend to be more stable and potentially better targets.”

Specifically, investigators are focusing on the vascular endothelial growth factor (VEGF), which instructs cells to grow and multiply and helps recruit new blood vessels to the tumor. They are testing several approaches that target various components of the tumor blood supply, namely one that deploys a decoy receptor capable of attracting and binding to all of the VEGF signaling molecules in the area and preventing new blood vessel growth.

Moving beyond the microenvironment are research strategies that attempt to silence cancer-promoting genes and proteins deep inside the tumor rather than only on the cell surface. Investigators are pioneering siRNA technology, which uses short fragments of RNA to block gene activation. These fragments are wrapped in a liposome, or lipid particle, and delivered directly into the tumor.

In preclinical studies, “we found that we could turn off proteins critical to tumor growth and decrease new blood vessel development,” Sood says. “The best effect was seen when combined with chemotherapy. We hope to see equally positive results in the clinic.”

A burgeoning area of research is the growing association of chronic stress and ovarian cancer growth and progression. Studies have shown a connection between feelings of distress and the body’s inability to mount an immune response against cancer, but other biological factors had not been explored until recently.

In a major breakthrough, investigators discovered that elevated levels of stress hormones activated a specific pathway responsible for the acceleration of tumor and new blood vessel growth. This pathway, they showed, could be blocked with a targeted drug and prevent future growth.

“This discovery,” Sood says, “opens the possibility of interceding early in the treatment process with interventions that manage stress in these patients, which may affect the clinical course of the disease and ultimate outcome.”

Out of the lab, into the clinic

While investigators know that a drug, or small molecule, that works well in culture or animal models may not always have the same response in humans, they are optimistic that what they bring forward to the clinic will translate into more effective therapies for women with ovarian cancer.

A number of studies are evaluating agents that target both the tumor vasculature and defective genes and proteins thought to be responsible for the growth, proliferation and spread of ovarian cancer.

Anil Sood, M.D., and his colleagues are evaluating approaches that target various components of the tumor blood supply, namely one that deploys a decoy receptor capable of preventing new blood vessel growth.

The goal is to improve responses to frontline therapy, which initially are quite high, and to extend the amount of time patients have without disease.

“Nearly 75% of women with advanced disease respond to several rounds of chemotherapy after undergoing surgery,” says Robert Coleman, M.D., professor in the Department of Gynecologic Oncology. “Unfortunately, for most of these women their disease comes back, requiring additional therapy that may or may not achieve a second remission because their tumor is no longer sensitive to the effects of chemotherapy.”

Investigators are finding alternative ways to overcome chemo-resistance, which is a key reason why many women with advanced disease don’t survive. Several genes have been identified either as being capable of pumping chemotherapy out of cells quicker or sequestering the drug into compartments within cells to circumvent its effects. Once these mechanisms are fully understood, drugs that selectively target these survival factors can be given to achieve greater success, according to Coleman.

Still, the challenge continues to be how best to treat recurrent disease, or prevent it altogether.

Investigators are mixing things up a bit to see if simply changing the dose and timing of chemotherapy may have an effect, or if adding a biologic or molecular-based agent to standard chemotherapy gives the desired outcome.

“We’re also looking at new ways to deliver chemotherapy,” Coleman says. “Traditionally, it’s been given intravenously, but research now shows that administering chemotherapy directly into the abdomen, or intraperitoneally, extends overall survival and may be most effective for women who have small-volume tumors limited to the abdomen.”

With several novel drugs to choose from, investigators are on the verge of making substantial breakthroughs in the treatment of ovarian cancer and making a lasting difference in the lives of women affected by the disease.

Detecting early disease key to survival

If detected early, ovarian cancer often can be managed and treated successfully.

The survival rate among women diagnosed with early-stage disease, or when it’s still confined to the ovary, is 95%. That percentage dramatically decreases when the disease is found late, with less than 10% of women with stage IV disease surviving five years after diagnosis, according to Karen Lu, M.D., associate professor in the Department of Gynecologic Oncology.

Thus, the development of a definitive screening test is of utmost importance.

Capitalizing on advanced technology and the availability of ovarian tissue and blood samples  stored in M. D. Anderson’s tumor bank, investigators are stepping up their efforts to identify markers that could detect early disease.

Investigators like Karen Lu, M.D., are stepping up their efforts to identify tumor markers believed to be elevated in ovarian tumors, which may signal early disease.

CA125 is one marker under examination. While CA125 has been shown to be a useful marker to monitor women undergoing treatment for ovarian cancer, it can only identify 50% of stage I disease. Robert C. Bast Jr., vice president for translational research and developer of the CA125 blood test, is working with Lu in evaluating whether changes in levels of CA125 over time predict with higher probability the presence of early ovarian tumors when compared to a single value.

Investigators realize that a panel of tumor markers, rather than one alone, may be necessary to accurately screen for the disease. They are actively pursuing many leads and testing the viability of several markers believed to be elevated in ovarian tumors. They hope one day to be able to offer a simple, inexpensive blood test.

In the meantime, they are screening women who are considered to be at high risk either because of a strong family history of both ovarian and/or breast cancer or a known BRCA1 or BRCA2 gene alteration, and who wish to know whether they have a genetic predisposition for developing the disease.

Simply having a family member with ovarian or breast cancer doesn’t mean a woman will get ovarian cancer, but it does place her at a higher risk than the general population, according to Lu.

A woman who has an alteration in either the BRCA1 or BRCA2 gene, however, has up to a 40% lifetime risk of developing the disease. The likelihood of a woman of Ashkenazi Jewish ancestry developing the disease is even greater, as one in 40 of these women carry a BRCA alteration.

“Identifying these women is critically important,” Lu says, “because a number of effective preventive measures can be taken to reduce their risk.”

An ounce of prevention, a pound of cure

Currently, having a bilateral salpingo-oophorectomy (removal of both ovaries and fallopian tubes) before any disease is detected offers the most dramatic effect, Lu notes. For premenopausal women who carry a BRCA1 or BRCA2 gene alteration, prophylactic surgery can reduce their chance of getting ovarian cancer by greater than 95% and their risk of breast cancer by 50%.

Although this procedure is highly effective in preventing ovarian cancer in high-risk women, it doesn’t offer complete protection because there is still a small chance of developing primary peritoneal cancer. This cancer affects the lining of the abdominal wall and has symptoms similar to ovarian cancer.

Realizing surgery may not be a favored option for many women, especially those of childbearing age, investigators also are looking toward approaches to screening and prevention.

As often as every six months, a woman at high risk is encouraged to undergo a pelvic and rectal exam; CA125 blood test; and a transvaginal ultrasound, a radiologic procedure that gives a picture of the ovaries and may detect cysts and small tumors. While there is no data indicating these tests can always pick up a tumor or reduce a woman’s risk of dying from ovarian cancer, they do offer a conservative way to monitor risk.

Until more sophisticated screening tests come online and are sensitive enough to predict and detect early ovarian cancer in the general population, Lu says “bilateral salpingo-oophorectomy offers women the greatest protection against the disease.”

A Legacy of Two Women

The Blanton-Davis Ovarian Cancer Research Program at M. D. Anderson was created in 1996 to change the future for women with ovarian cancer. It was the nation’s first formal, comprehensive ovarian cancer research effort aimed at translating basic discoveries into improved therapies and management of the disease.

The program is named after Laura Lee Scurlock Blanton and Sandra G. Davis.

Mrs. Blanton lent her talents and support to the Ovarian Cancer Research Program as an advisor. She served as honorary chair for the program’s Sprint for Life 5K Fun Run & Walk and was a lifetime member of M. D. Anderson’s Board of Visitors. Mrs. Blanton led a valiant fight against ovarian cancer. She died in 1999 at the age of 71. Her husband, Jack S. Blanton, serves as an advisor to the Ovarian Cancer Research Program and is a member of M. D. Anderson’s Board of Visitors.

Mrs. Davis battled ovarian cancer for four years. Her sweet nature and focused determination inspired her caregivers to accelerate efforts to improve the prevention, early detection and treatment of ovarian cancer. Mrs. Davis died in 1996 at the age of 49 and left two daughters, Kim and Wendy. Lee Davis, her husband, donated seed money for the creation of the Ovarian Cancer Research Program and serves as an advisor.

Life lessons learned

While a diagnosis of ovarian cancer is hard to swallow and “very frightening,” as Buelow interjects, it has forever changed the way she, Rice and Podraza go about their lives.

For them, it’s all about giving back, helping others and rethinking priorities.

“It’s not stuff that is important,” Buelow says, “it’s people. You quickly learn that each day is a gift and that you don’t get to assume you’re going to have it, so any chance I get I try to be helpful, loving and kind.”

In West Virginia, Rice is the talk of the town. Just one year after her diagnosis in 1998, she founded the National Ovarian Cancer Coalition’s West Virginia division.

Rice says she’s all about educating women about ovarian cancer — arming them with information regarding symptoms and risk factors and, most importantly, encouraging them to listen to their bodies.

“Women as caregivers are always worrying about their families and tend to put off their own health care,” Rice says. “We need to stop and take the time to go to the doctor when we have these subtle symptoms and take care of ourselves.”

Podraza literally laces up her running shoes and takes her message to the streets, volunteering her time to help with M. D. Anderson’s Sprint for Life, an annual 5K fun run and walk. More than 2,000 women, men
and children participate in this fundraising event to help bring more attention to ovarian cancer.

Her outreach efforts extend beyond the run and into the clinic, where she supports others being treated for cancer and learns about “life through the people I meet. They come from all over the world and do all sorts of different things. I’m truly blessed to be part of their lives.”

Three women, one mission — to help save lives. 

Symptoms of Ovarian Cancer

Ovarian cancer typically is not detected until its late stages because, when symptoms appear, they often are vague and mimic other more common ailments.

Some symptoms that may suggest ovarian cancer include:

  • Abdominal swelling and/or pain
  • Abnormal bleeding
  • Bloating and/or a feeling of fullness
  • Frequency and/or urgency of urination
  • Persistent gastrointestinal complaints such as gas, nausea and indigestion that can’t be explained by another cause
  • Change in bowel habits
  • Unusual fatigue, backaches
  • Unexpected weight loss or gain

If any of these symptoms lasts more than two to three weeks, women are advised to consult their physician.

© 2015 The University of Texas MD Anderson Cancer Center