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Ovarian cancer research takes center stage

Pronounced expression (red) of one or more survival-associated genes (such as the microfibrilassociated glycoprotein 2, or MAGP2) may dramatically enhance the aggressiveness of serous ovarian cancer, indicate poor prognosis, and suggest a different therapeutic strategy.

Most women with ovarian cancer are diagnosed in their 60s and 70s with advanced stage disease that has spread throughout the abdomen. Although the cancer usually responds to chemotherapy, it frequently recurs and the patient dies from resistant disease.

To tackle these vexing clinical features, investigators in the DF/HCC Gynecologic Cancer Program are making fundamental and potentially transformative observations in screening, disease biology, and molecular tools for targeted prevention, treatment, and prognosis.

“We’re learning a lot,” says program leader Michael Birrer, MD, PhD (MGH). “I believe the landscape will change radically in the next five years. This is encouraging for women with ovarian cancer.”

In the DF/HCC program, current ovarian cancer research spans an individualized screening algorithm in a definitive clinical trial to identify cancer at an earlier stage, a rethinking of the biological beginnings, and an evolving story in personalized medicine. Taken together, the varied approaches are revealing “clever new twists in old stories and the power of careful science,” Birrer said.

Testing a new screening algorithm for an early molecular marker

One reason the mortality rate for ovarian cancer has improved only slightly over the last three decades could be the lack of an adequate early detection assay. Find and treat the cancer earlier, according to this hypothesis, and fewer women may die from the disease.

Biostatistician Steven Skates, PhD (MGH), has developed a new algorithm for an old biomarker (CA125) and is part of a team testing it in a large randomized controlled U.K. study of 200,000 women, which is slated to end in 2015. The same personalized algorithm approach may also apply to other ovarian cancer biomarkers being sought by Skates and colleagues.

Oncologists know CA125 as a good indicator of a tumor's response to treatment after surgery or during chemotherapy. Developed by Dana-Farber researchers in the 1980s, the simple blood test can give warning of a recurrence with rising protein levels. But as a screening tool to find early stage disease in healthy postmenopausal women, studies showed a standardized cutoff for CA125 levels was a notoriously unspecific and insensitive marker.

Skates took a fresh look at the data from a Stockholm screening study conducted in the late 1980s. By plotting individual trajectories over time, Skates found that each woman had her own normal levels of CA125. From this personal baseline, a statistically significant rise above a woman’s normal levels was far more accurate than a standard cut-off to indicate the presence of a fast-growing tumor.

Skates developed the risk of ovarian cancer algorithm (ROCA) and validated it with a retrospective analysis of another large screening trial performed in London. A follow-up pilot prospective study of nearly 14,000 women, half screened and half not, produced sufficiently compelling data to launch the more definitive U.K. Collaborative Trial of Ovarian Cancer Screening, a randomized trial now underway.

In the first published report of the screening arm of the pilot study, 16 women ultimately underwent surgery, which revealed three cases of primary invasive epithelial ovarian cancer in the early stage, one ovarian recurrence of breast cancer, and one borderline pathology.

In the larger ongoing U.K. study, the women are randomized into three groups—one using ROCA as a first-line screen, another using transvaginal ultrasound as the first line, and lastly a control group. Anecdotally, an increased CA125 level below the old standardized CA125 threshold has triggered a high-risk score on the ROC algorithm, leading to follow-up ultrasound and, ultimately, surgery with ovarian cancer found in early stage.

 “The idea would be that postmenopausal women would have an annual test in the same blood draw as a cholesterol test,” Skates says. “But until we get definitive results in 2015, we cannot advocate this screening for ovarian cancer in the general postmenopausal population.”

The ROC algorithm also appears promising in a smaller study of 2,500 pre- and postmenopausal high-risk women conducted by the U.S. Cancer Genetics Network and other collaborative groups where women are at high risk of ovarian cancer because of multiple blood relatives with ovarian or breast cancer.

“There is good reason to pursue this approach with other biomarkers,” says Skates. He and his colleagues are looking for other biomarkers that indicate early stage disease, including for the 20 percent of ovarian cancers that do not secrete CA125.

Scouting a new pathway for prevention

In another fresh look at existing evidence, pathologist Christopher Crum, MD (BWH), and his colleagues have observed that a significant proportion of ovarian cancer may not originate in the ovary.

Crum and his colleagues have characterized precancerous lesions in the ruffled tips of the distal fallopian tube. These small changes may be the first of multiple genetic changes that gradually accumulate to cause cancer that in more advanced stages may spill over to the ovary. The model adds a third potential etiologic pathway, each with its own genetic events, to cancers arising either from surface of the ovary or from the dings and divots that amass in the ovary over time.

“Understanding where tumors start doesn’t solve the problem, but it may give us a window into other possibilities for prevention, diagnosis, and treatment,” Crum says.

As analogy, Crum cites the major accomplishments in cervical cancer prevention. First, regular PAP smears monitored the precancerous lesions of the cervix, which can remain non-invasive for as long as 20 years. More recently, vaccines now may prevent the precancerous lesions caused by exposure to the human papilloma virus. (Crum participated in pivotal studies linking the virus to the precancerous lesions.)

In 2005, Crum began following up on surprising observations of early cancers found in women who, at high risk of malignancy because of BRCA mutations, had their ovaries removed. Of the 5-10 percent of women with early cancers, 80 percent have been discovered in the distal tube, not the ovary.

Crum developed a protocol for analyzing surgical specimens, called Sectioning and Extensively Examining the Fimbriated end (SEE-FIM). Designed to increase detection of early tubal cancer, the technique exposes about 60 percent more surface area of the fimbria.

Upon closer investigation, Crum found small islands of 25-100 secretory cells in the fimbria of women with and without the BRCA mutations. In healthy fallopian tubes, individual secretory cells are normally interspersed among the ciliated cells that move eggs down to the uterus. Scientists think secretory cells normally mature into cilia, Crum says, rather than grow in long stretches.

The aberrant clonal cell expansions stain strongly for activity of the mutated oncogene P53. In related cell culture studies, Ronny Drapkin, MD, PhD (DFCI), found the cells were vulnerable to genetic damage. Based on small pathology studies, Crum speculates the precancerous lesions may exist in nearly half of all women and set the stage for other mutations that eventually turn cells into serous cancers. Similar islands may be caused by other founding mutations, which are under study. As a group, Crum calls them “generic” secretory cell outgrowths, or SCOUTs. Those with p53 mutations are termed “p53 signatures.”

Crum invites pathologists and gynecologists to participate in The Pelvic-Ovarian Cancer Interception (POINT) Project (http://www.pointproject.org). The multi-investigator collaborative study is designed to identify and accrue early stage pelvic-ovarian cancers in women, specifically early malignancies in the distal fallopian tube, or tubal intraepithelial carcinomas (TIC). Crum and his colleagues hope to track the transitions from precursor to cancer and publish results in collaboration with the participants.

The findings may have major implications for early detection and prevention or treatment strategies. For example, detecting the limited number of cells for early intervention poses big challenges for biomarker detection. And there seems to be a wide gulf between the molecular events associated with advanced ovarian cancer and the early stages of serous carcinogenesis, Crum says.

Current ovarian cancer detection and prevention strategies—and funding priorities in the field—have only recently begun to account for the possibility that many ovarian cancers may arise in the feathery fimbria, says Crum. He is conducting small-scale collaborations with colleagues, such as Judy Garber, MD (DFCI). Plans to conduct more detailed fallopian tube pathology on 2,000 specimens from a Gynecologic Oncology Group (GOG) sponsored by the National Cancer Institute and on a smaller in-house cohort of 300 cases at BWH and MGH have been tabled until funding becomes available.

Targeted molecular treatment in the pipeline

Ovarian cancer usually initially responds to surgery and platinum-based chemotherapy, the standard of care, but the cancer typically recurs and eventually becomes resistant to standard chemotherapy treatments.

“We know our treatments are not good enough,” says medical oncologist Joyce Liu, MD, MPH (DFCI), who spends part of her time in the clinic managing the care of women with ovarian cancer. Liu also works in the DFCI lab of David Livingston, MD, where she and her colleagues have just identified a new potential molecular target to shut down a subset of ovarian cancers.

In some ovarian cancer cells, abnormal activation of a protein called ErbB3 sustains cell proliferation, Liu’s team reported in the March 16 issue of the journal Cancer Cell. Blocking the protein significantly reduced ovarian tumor growth in a mouse model.

ErbB3 belongs to a family of tyrosine kinase signaling molecules whose overexpression or abnormal activation can sustain certain subsets of cancers. The study of such “addictive oncogenes” has led to a new generation of targeted cancer therapies, such as imatinib for chronic myelogenous leukemia or gastrointestinal stromal tumors; erlotinib for certain non-small cell lung cancers; and trastuzumab for HER2+ breast cancers. So far, a similar targeted molecular therapy has not been identified in ovarian cancer.

“If we can identify and then interfere with one of these cancer-driving molecules, we can study the effects on cancer cells,” says Liu, who used that premise as a starting point to eventually identify ovarian cells dependent upon ErbB3.

In a new twist, she found that only cells with an activated form of the protein (sometimes driven by NRG1) suffered when ErbB3 was blocked. In those vulnerable cells, blocking the activator also stopped cells from proliferating or killed the cells. In a mouse model, removing the protein from the cancer cells halted the growth of some tumors, caused some tumors to shrink, and led to longer lives for the mice.

The pathway has potential to be a therapeutic target in women. In collaboration with co-author Ronny Drapkin, Liu’s team has also found the same activation of ErbB3 in about one-third of human primary ovarian cancer cells isolated directly from abdominal fluid donated by women with chemotherapy-resistant disease through an ongoing DFCI protocol.

In their studies, Liu’s team used RNA interference to block ErbB3 and NRG1, a technology which cannot yet be used in people. They also used a monoclonal antibody, one of two such ErbB3 inhibitors in phase I clinical trials for solid malignancies. Liu is working toward developing clinical trials of antibodies and other agents against ErbB3 and NRG1 in ovarian cancer patients. “Our work really suggests that this may be a type of therapy we should be directly exploring in ovarian cancer,” Liu said.

Liu and her colleagues do not yet know how effective agents targeting the ErbB3 pathway will be in patients with ovarian cancers expressing this molecular activation. “We won’t know until we ask those questions in the setting of well-designed clinical trials, but our experience in the laboratory suggests that drugs targeting this pathway may be a new way to attack certain ovarian cancers,” she said.

Changing views in cancer

Birrer and his colleagues are employing genomic technologies to parse out genetic differences between tumors with different clinical behaviors. The effort is designed to identify biomarkers to stratify patients for therapy and clinical management and to discover new therapeutic targets of disease.

In a recent paper in Cancer Cell, for example, Birrer’s team identified a prognostic gene signature correlating with poor prognosis in ovarian cancer. In the signature, they found an independently associated pro-angiogenic factor (microfibril-associated glycoprotein2, or MAGP2). Expressed in 10 to 15 percent of patients, gene activity may signal a more aggressive tumor, explaining their poorer survival and suggesting a different therapeutic regime better tailored to the biology, such as the EGFR inhibitors first developed for lung cancer.

As in other cancers formerly defined by the tissue of origin, Birrer says, genomic descriptions are redefining ovarian cancers by their genomic makeup, which is opening up new avenues of treatment and potential opportunities to detect deadly cancer at earlier stages for better outcomes.

— Carol Cruzan Morton