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New Findings on Endometriosis-Associated Ovarian Cancer Subtypes May Lead to Novel Therapies

Eastman, Peggy

doi: 10.1097/01.COT.0000419313.51353.c9

WASHINGTON, DC—The recent results of a pooled analysis of nearly 8,000 invasive ovarian cancers from women who self-reported having endometriosis has led to a new understanding of the subtypes that are specifically associated with endometriosis, according to a speaker here at the Ovarian Cancer National Alliance (OCNA) Annual Conference.

This new understanding could eventually lead to better selection of patients for clinical trials and new targeted therapeutic approaches, said Robert Coleman, MD, Professor and Vice Chair of Clinical Research in the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center. But he cautioned against premature use of the new data for clinical decision making.

“We knew that there was already this connection before,” he said. What the new findings from the Ovarian Cancer Association Consortium—published in Lancet Oncology earlier this year (2012;13:385–394)—do, he explained, is to specify the histological subtypes of ovarian cancer for which endometriosis constitutes an increased risk.

The study, which included 13,266 controls, found a significantly higher risk of clear-cell, low-grade serous, and endometrioid invasive cancers in women with a history of endometriosis. No association was found between endometriosis and the risk of mucinous or high-grade serous invasive ovarian cancer; the latter account for about 75 to 80 percent of all ovarian cancers and 90 percent of deaths.

In terms of clinical cause-and-effect implications, though, Coleman—a member of MD Anderson's Center for RNA Interference and Non-Coding RNA—cautioned against overreacting to the results. “Over-interpretation is a risk. Endometriosis does not cause ovarian cancer.”

He pointed out that endometriosis-associated ovarian cancers account for less than 10 percent of all ovarian cancers. He also noted that the number of women with endometriosis is far larger than the small number of women with endometriosis who develop ovarian cancer—“The percentage of endometriosis that transforms into ovarian cancer is very small.”

Therefore, he said, he would strongly caution against seeing the study results interpreted in a way that increases prophylactic surgery to prevent ovarian cancer in women with endometriosis, for example. In addition, he pointed out that since endometriosis was self-reported retrospectively, there may have been some unintended bias in the pooled results.

“What I'm hoping is that we get rid of the all-comer trials,” Coleman said, and studies such as the pooled analysis could lead to better stratification of ovarian cancer patients on clinical trials.

“Developing therapies is really about dividing patients into different subtypes. Endometriosis is likely related to specific types of ovarian cancer via a common biological process,” he added.

He explained that clear cell ovarian cancer tends to occur in younger women and to present at an early stage; it is chemo-resistant at advanced stages, and the prognosis is poor. The incidence is much higher in Japanese women than in U.S. women, and many of these patients have specific genetic mutations, such as the ARID1A mutation.

Low-grade serous ovarian cancer also tends to occur at younger ages, and these patients—the majority of whom have BRAF or KRAS gene mutations—generally have a lower response to chemotherapy, but they tend to have longer survival.

Since endometriosis is thought to be due to retrograde menstruation, the new data on ovarian cancer subtypes could ultimately lead to trials testing a hormonal therapy to treat endometriosis-associated ovarian cancers, for example, in addition to gene-based therapies. But, noted Coleman, “Right now we're nervous. . . .It's hard to abandon a therapy we're familiar with. I do think we're going to get there, though.”

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Fallopian Tubes

In other news from the conference, speakers said there is increasing support for the hypothesis that many high-grade serous ovarian cancers arise in the fallopian tubes, rather than in the ovary itself.

“It's intriguing now that the focus is on the fallopian tubes,” Coleman said. “The mistake we made in the past was to take the ovaries out and leave the fallopian tubes in” when a woman underwent surgery for ovarian cancer. It used to be thought that the majority of ovarian cancers arose from epithelial cells on the ovary's surface, but new data support the tubal origin theory.

“This is a leading theory,” said Robert Burger, MD, Director of the Women's Cancer Center at Fox Chase Cancer Center and Co-chair of the Gynecologic Oncology Group's Development Therapeutics Committee, of the hypothesis that many high-grade serous ovarian cancers arise in the fallopian tubes.

“It remains to be proved,” he told OT, “but I'm willing to take the risk. I think the field is gradually coming around to this theory.” The theory arose from pathologists' observations of fallopian tube tissue removed with the ovaries during prophylactic surgery in women with BRCA1 and BRCA2 mutations. If true, he noted, the ovary may actually be “an innocent bystander” in the development of ovarian cancer.

Burger said that in women past childbearing age who are undergoing abdominal surgery for a diagnosis unrelated to ovarian cancer, he generally finds it reasonable to recommend removal of the fallopian tubes. “It's similar to having the appendix removed if you're having surgery for another reason,” he explained.

He noted that a Canadian study is offering women past childbearing age who are having abdominal surgery unrelated to ovarian cancer the choice of having their fallopian tubes removed.

Currently, the Department of Defense's Ovarian Cancer Research Program is funding research led by Johns Hopkins University on prevention of high-grade serous carcinoma by studying its early changes. The research will test the hypothesis that a lesion in the fallopian tube (and fibria)—a serous tubal intraepithelial carcinoma (STIC)—is the precursor of many, if not most, ovarian high-grade serous cancers. The DoD-funded research will also investigate the ovarian surface epithelium and ovarian cortical inclusion cysts.

Burger said he agreed with Coleman that patients enrolled in clinical trials for ovarian cancer need to be stratified far more specifically. “We need to do smarter clinical trials and address the molecular heterogeneity of ovarian cancer,” he said. “Basically we're finding more and more subtypes that respond to different kinds of therapies—that's exciting.

“The goal is to identify and study subgroups of women who have a specific mutation in common. That's really the way we're going to make some ground.” He urged ovarian cancer survivors to have their tumor tissue block stored somewhere for future research studies.

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Clinical Trials

Also at the meeting, Society of Gynecologic Oncology President Ronald Alvarez, MD, Professor and Director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham, also agreed on the need to better stratify women for clinical trials.

“What we need is a better way to identify women at intermediate risk who don't harbor BRCA mutations,” he said.

Alvarez, who received the Rosalind Franklin Excellence in Ovarian Cancer Research Award at the OCNA meeting, noted that for ovarian cancer—as indeed for all cancers—the key to effective treatments is tailoring it to the individual patient's subtype, knowledge that can come only from clinical research:

“What we really need to do as a country is to embed clinical trials into clinical practice. We should have 70 to 80 percent of people going on clinical trials at all stages of disease.”

Alvarez told OT that the health care reform act, recently upheld by the U.S. Supreme Court, could help to make that vision a reality by expanding insurance coverage for the patient care costs of participating in clinical trials.

As for effective treatments in the era of molecular heterogeneity, he said, “We're probably going to have to have a number of agents for ovarian cancer until we can identify the molecular drivers in an individual woman's ovarian cancer.”

© 2012 Lippincott Williams & Wilkins, Inc.
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