Breaking Out of the Silence

Ovarian cancer has long been known as a silent killer; for the most common form of the disease, symptoms and diagnosis usually occur only at an advanced stage when treatment is rarely curative. It is equally quiet on another front—historically, there have been few headlines extolling breakthroughs in the treatment of this most lethal of gynecological cancers.

But today, the physicians and researchers who treat and study ovarian cancer are anything but silent. They see a revolution taking place in the understanding of ovarian cancer.

Scientists are learning that ovarian cancers differ widely from each other—some even look like kidney or colon cancer—and that many may not have even originated in the ovary, which now gives them new leads on how ovarian cancer may develop. New methods to screen for the cancer are being tested, as are methods to classify individual tumors, and targeted therapies are now being examined in ovarian cancer patients, with encouraging results.

Combine these advances with continuing improvement in management of the disease, “and this is a very, very exciting time in the field of ovarian cancer,” says Beth Karlan, MD, director of gynecologic oncology at the Women’s Cancer Research Institute at Cedars-Sinai Medical Center in Los Angeles. “It is a changing landscape—one that offers a lot of promise.”

To understand the changing landscape ovarian cancer represents to Karlan and her colleagues, you only need to talk to Annette Leal Mattern.

She is atypical in many ways for an ovarian cancer patient—she has a rare subtype of ovarian cancer (granulosa cell) and has been living with the disease for 24 years, which is much longer than most. But she also represents the classic ovarian cancer patient: “Lots of recurrences, lots of surgery, ugly chemo, just about everything medicine has come up with to keep my disease at bay,” she says.

Mattern was 37 when she experienced pain so intense she could not walk. She soon learned she had an ovarian tumor the size of a grapefruit that had ruptured and bled internally for a number of days, blanketing her abdomen with cancer cells. She had three surgeries to remove the tumor “and everything the doctors thought I could live without.”

Twelve years later, the cancer recurred in her pancreas, and it wasn’t clear it was operable. “That was my first life-and-death decision,” she says. “I could do high-risk surgery and possibly live longer, or go home and be with my family.”

She decided to have a Whipple procedure, which removes parts of the pancreas and bile duct, the gallbladder and the duodenum. She followed the surgery with the standard chemotherapy protocol of bleomycin, etoposide and cisplatin, and lost 60 pounds in short order. Years later, the cancer popped up in her liver and peritoneal cavity.

Mattern then had eight surgeries that did not affect the course of her cancer but “just cut out tumors after the fact.”

Her experience mirrors that of many ovarian cancer patients because there is only so much that standard treatment can do, oncologists say. Around 70 percent of patients have a recurrence, which indicates the tumors are not responding in a meaningful way to repeated bouts of chemotherapy and surgery.

Still, survival has increased over the past several decades. “When I was in training about 20 years ago, it was not unusual for median survival for ovarian cancer being 18 months to two years,” Karlan says. Now, about 46 percent of patients celebrate a five-year survival benchmark.

The difference, according to oncologists, has been more aggressive surgery, better chemotherapy, radiation therapy and surveillance for recurrences.

Yet these approaches ultimately fail many women. Although ovarian cancer is relatively rare (a woman’s risk of developing it is 1 in 72, compared with 1 in 8 for breast cancer), it is often resistant to treatment. In 2010, more than 21,000 women received an ovarian cancer diagnosis, and about 13,000 died of the disease. Ovarian cancer is the fifth leading cause of cancer death among women in the U.S.

The coming revolution in ovarian cancer care—the rapid movement away from a cookie-cutter approach and toward individualized treatment—is based on a new understanding of the “heterogeneity” of ovarian cancer, says Robert Coleman, MD, vice chair of clinical research and a professor in the department of gynecologic oncology at M.D. Anderson Cancer Center in Houston.

Given advances in molecular analyses, oncologists now know that, like breast cancer, ovarian cancer comes in many subtypes—even subtypes within subtypes, Coleman says. There are more than 30 different subtypes, with epithelial, germ cell and stromal being the most common.

Epithelial ovarian cancers make up about 85 to 90 percent of cases and include many different classes. Within the most common class, serous, there are low- and high-grade tumors that have distinct biological profiles. Low-grade cancers are chemo resistant but don’t grow fast, and high-grade tumors respond to chemotherapy but are more likely to recur, Coleman says. Most are found at later stages because they don’t bulk up and cause symptoms until they are advanced—but by then most have spread and are difficult to treat.

When we understand the molecular drivers of these cancers, we can select targeted therapies aimed at these cancers.

Epithelial ovarian cancers make up about 85 to 90 percent of cases and include many different classes. Within the most common class, serous, there are low- and high-grade tumors that have distinct biological profiles. Low-grade cancers are chemo resistant but don’t grow fast, and high-grade tumors respond to chemotherapy but are more likely to recur, Coleman says. Most are found at later stages because they don’t bulk up and cause symptoms until they are advanced—but by then most have spread and are difficult to treat.

Some epithelial ovarian tumors resemble other cancers, Coleman says. Clear cell ovarian cancer looks like kidney cancer, and mucinous ovarian cancer resembles colon cancer. This suggests these ovarian cancer subtypes might best be treated like the cancers they resemble, he says. Then there are the rarer subtypes, germ cell (analogous to testicular cancer in men) and stromal ovarian tumors, both with multiple classifications.

“When we understand the molecular drivers of these cancers, we can select targeted therapies aimed at these cancers,” Coleman says. At M.D. Anderson, every ovarian cancer patient’s tumor is now classified by histological subtype, and researchers are launching two major studies that seek to treat the cancers by their dominant growth pathways.

Other researchers believe that ovarian cancer, in general, may be driven more by cancer stem cells than most tumors, which, if true, provides yet another potential therapeutic strategy. That hypothesis explains why the same chemotherapy repeatedly used in a patient can shrink tumors a little less each time it is used, until it is no longer effective, says Gil Mor, MD, PhD, a professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine. “Each cycle of chemotherapy kills the dwindling number of vulnerable soldiers, the cancer cells, but increases the number of generals in the tumor, the cancer stem cells,” he says.

“I spent 15 years doing the wrong studies,” Mor says. “Now, once you discover who the real enemy is, you can find ways of attacking it.” Which he is now doing.

Even with multiple cancer recurrences, Mattern was not sure she should enroll in a clinical trial. But she changed her mind when she explored the studies open to her after her cancer spread to her liver.

She settled on a study of a monoclonal antibody called apomab that activates a cell receptor to induce cell death in cancer cells, and after two months of therapy, half of her tumors disappeared and half went back “to sleep,” as she says. For the first time in 20 years, she had evidence that “my flavor of ovarian cancer responded to a drug.” This, she says, seemed like a miracle.

Other women with ovarian cancer may be feeling the same way these days with clinical trials gaining some ground.

There are a number of ongoing clinical trials testing antiangiogenic therapies, primarily Avastin (bevacizumab), some of which were presented at the 2010 meeting of the American Society of Clinical Oncology (ASCO). In particular, one large (1,873 patients) phase 3 study (GOG 218) demonstrated that the combination of Avastin and standard chemotherapy, carboplatin and Taxol (paclitaxel), followed by Avastin maintenance offered previously untreated patients a median 3.8 months more before their ovarian cancer returned (progression-free survival, or PFS), compared to patients treated with the same chemotherapy without Avastin (14.1 months versus 10.3 months). Researchers are awaiting “mature” data on ultimate survival.

A 1,528-patient European clinical trial (ICON 7) that is also studying a combination of Avastin and chemotherapy in previously untreated patients, presented in October at the European Society for Medical Oncology, found that women who received Avastin in addition to carboplatin/Taxol had a median PFS of 19 months, compared to 17.3 months for those treated with chemotherapy alone. Survival data is expected in 2012.

The most recent study to announce results, the OCEANS phase 3 trial, tested Avastin with carboplatin/gemcitabine followed by maintenance Avastin in women who have had a recurrence following chemotherapy, and also showed an improvement in PFS. Specific results of the trial have been submitted for presentation at the 2011 ASCO meeting this summer.

Another targeted therapy of special significance to ovarian cancer patients with BRCA mutations are PARP inhibitors, drugs that interrupt the ability of damaged DNA to repair itself. Ten to 15 percent of patients with ovarian cancer have BRCA mutations, which makes them highly susceptible to breast and ovarian cancers.

While these and other studies of targeted therapies are encouraging, Robert Coleman, MD, warns “the complexity of the disease demands that we understand the most vulnerable targets in each patient’s tumors.

Other studies presented at the ASCO conference showed that using PARP inhibitors produced a significant response in ovarian cancer patients with a known BRCA mutation. One phase 2 trial of olaparib indicated an overall response rate of 41.2 percent, a median PFS rate of 3.8 months and overall survival of 7.6 months. There were also some responses in serous ovarian cancers not associated with a BRCA mutation.

Some oncologists believe these drugs can also be used in serous tumors that demonstrate “BRCA-ness” because these types of tumors have a deficiency in a DNA repair pathway, which is targeted by PARP inhibitors, even without any detected BRCA mutations. But these are early days in the testing of that concept. There are currently dozens of PARP inhibitor clinical trials for ovarian cancer patients.

While these and other studies of targeted therapies are encouraging, Coleman warns “the complexity of the disease demands that we understand the most vulnerable targets in each patient’s tumors. Not everyone is vulnerable to the same target, and it will be important to be selective as to whom we give these drugs to.”

Researchers are attempting to do just that. Ursula Matulonis, MD, medical director of gynecologic oncology at the Dana-Farber Cancer Institute, has shown that single genetic changes or mutations that drive cancer can be detected in advanced ovarian cancer—a development she presented in November at a European cancer symposium. These changes—“hot spot” mutations in KRAS, BRAF, PIK3CA, CTNNB1—all have specific targeted therapies associated with them to treat other cancers.

Matulonis says individual tumor testing is now being done only as part of a clinical trial. None of these tests are ready for clinical use, but they are expected to provide invaluable information in the future—just as tumor testing has become crucial in the treatment of breast cancer.

“This is the leading edge in a new way of thinking about how to treat ovarian cancer,” she says. “We have a huge pipeline of drugs coming out through academic institutions and pharmaceutical research, and so [we] have a lot of medications to choose from. We need to pick them based upon a patient’s tumor profile.”

Oncologists know that the cure rate of ovarian cancer would top 90 percent if tumors were discovered at stage 1, but for many reasons that has not been possible. Around 80 percent of women with ovarian cancer are diagnosed with advanced disease. This may change.

The CA-125 protein marker is the only ovarian cancer biomarker that has provided any utility in detecting ovarian cancer before overt symptoms appear. It has been used to monitor women with BRCA mutations, and the protein is also now being tested in a number of novel studies aimed at screening the general population for ovarian cancer.

CA-125 has been around a long time, but it is known to be an imperfect monitoring and screening test (see "CA-125: What the Numbers Tell Us"). Now researchers are looking to improve the test or find ways to combine it with other screening methods.

“I’m optimistic we’ll have a screening test in the next five years,” says Cedars-Sinai’s Karlan. “I think CA-125 will definitely be a part of the panel, but a screening test will likely include a panel of tumor markers. CA-125 may be a good marker for serous ovarian cancers, but maybe not for other ovarian cancer subtypes.”

Karlan says she looks forward to fundamental answers as to who will develop the cancer, what that cancer will do and which therapies will prove to be of most benefit.

“I sit up at night because I’ll operate on two patients on the same day who have stage 3C ovarian cancer, be in the operating room for eight hours removing all the tumor visible, and one of them dies in two years and one’s alive at 12 years. And I don’t know what I did differently.

“But there is so much energy in this field right now. We are bringing together scientists and clinicians from every specialty possible,” she says. “At Cedars UCLA, we are doing an ovarian cancer screening study with the UCLA School of Dentistry to look at biomarkers in saliva […] We’re going to engineers, working with folks at Cal-Tech and at the Jet Propulsion Lab. There isn’t anything we are not trying now.”

Mattern isn’t likely to say that these advances will come too late for her. Despite the fact that her cancer has recurred several times since her clinical trial and that she also developed breast cancer several years ago, Mattern remains positive.

As one way to cope and to help others, Mattern penned a book about how families pull together and figure out what to do after a diagnosis of ovarian cancer. She is also president of the board of directors at the Ovarian Cancer National Alliance.

“I keep in mind that every woman is worth life, worth saving and fighting for,” she says. “That is what keeps me going.”