August 22, 2011 — Infertility has been associated with an increased risk for ovarian cancer. A new study now shows that circulating antibodies to mesothelin, a well-characterized ovarian cancer antigen, occur in women with increased epidemiologic risk for ovarian cancer.
These results suggest that it may be possible to identify which women with infertility are at high risk for ovarian cancer. The study is published online in Cancer Epidemiology, Biomarkers & Prevention.
"The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high," said lead author Judith Luborsky, PhD, professor of pharmacology, obstetrics and gynecology, and preventive medicine at Rush University Medical Center, Chicago, Illinois.
As for the immediate clinical significance of this research, Dr. Luborsky told Medscape Medical News that it is related to increased awareness. "It has been known for some time through epidemiology studies that women with infertility, or those so designated because they seek treatment assistance to become pregnant, and women who never had children, are at increased risk for ovarian cancer" she said. "However, we do not know which women among this group are at high risk."
"The significance of our study was to show that we can identify an additional risk factor that would help identify a high risk group for more intense monitoring," she continued. "The actual tests will take a little longer to develop, but meanwhile increased awareness and regular check-ups are warranted, particularly for women with premature ovarian failure and/or signs of prematurely reduced ovarian function."
The authors found that mesothelin antibodies were significantly more frequent in women with prematurely reduced ovarian function, including ovulatory dysfunction (59%), ovarian failure (44%), and unexplained infertility (25%), as compared with a control group. Conversely, women with endometriosis, who also are at high risk for ovarian cancer, did not have mesothelin antibodies.
Chasing Biomarkers for Ovarian Cancer
Ovarian cancer is often detected at an advanced stage, which generally results in a poor prognosis. Current diagnostic tests are ineffective for early detection. Identifying potential biomarkers could help in diagnosing the disease at an earlier stage, as well as provide targets for improved treatment of the disease during all stages.
As previously reported by Medscape Medical News, researchers have identified CA125, HE4, and mesothelin as biomarkers for evidence of ovarian cancer before a clinical diagnosis is made.
That study showed a modest but statistically significant increase in risk associated with CA125, HE4, and mesothelin. This finding was consistent with many of the established epidemiologic risk factors for ovarian cancer.
But for women at average risk, none of the biomarkers — either alone or together — were accurate enough to justify their use, explained lead author Garnet Anderson, PhD, who is with the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington.
"I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted," Dr. Anderson told Medscape Medical News at the time.
Association Between Infertility and Cancer?
Many epidemiologic studies have demonstrated an association between infertility and ovarian cancer, and the relationship is independent of infertility drug treatment. The different categories of infertility have varying risks for ovarian cancer, note the authors, who point out that some patients with unexplained infertility have antiovarian antibodies that indicate an autoimmune disorder targeting the ovary.
In addition, a subgroup of women with all types of infertility have poor ovarian estrogen responses to follicle-stimulating hormone, and this has also been associated with antiovarian antibodies. Patients with ovarian cancer, they also note, have antiovarian antibodies that are similar to those found in women with infertility, indicating that there is a similar autoimmune response.
The concept that autoimmunity is a risk factor for certain cancers is present in the literature, explained Dr. Luborsky. "Thus, the relationship of ovarian cancer to ovarian autoimmune reactions may be more significant than the particular antigen reaction," she said. "Interestingly, the same group of women in which we found antimesothelin antibodies are also the same group we previously described an autoimmune disease of the ovary."
For this latest study, Dr. Luborsky and colleagues collected a total of 329 sera from women with infertility (n = 109), ovarian cancer (n = 28), benign ovarian tumors or cysts (n = 24), and healthy women (n = 152). Infertility categories included those with a risk for ovarian cancer: endometriosis (n = 23), ovulatory dysfunction (n = 17), premature ovarian failure (n = 25), and unexplained infertility (n = 44).
They found that mesothelin antigen levels in serum were significantly higher in women with ovarian cancer (P = .00003), benign conditions (P = .01), or unexplained infertility (P = .01) than in healthy women.
Within the individual categories, mesothelin antigen and antibody were not significantly correlated except in cases of ovarian cancer (correlation coefficient = 0.49; P = .015). However, they note that this association is scattered because some individuals have higher levels of mesothelin, some have mesothelin antibody, and some have both.
Finally, the authors also evaluated sera for circulating mesothelin and found, as they expected, that most patients with ovarian carcinoma had circulating antigen. But with the exception of unexplained infertility, circulating antigen was not significantly higher in the other infertility subsets as compared with normal women.
"We are currently working to identify additional antibody reactions to a panel of proteins that could be used for a screening test and then to identify specific factors within the positive group that would signal the onset of a malignancy for a diagnostic test," Dr. Luborsky said. "Based on the work of many other scientists, it is clear that different women may have different antibody profiles, but the common risk factor is likely to be the presence of specific autoantibodies."
The study was supported by grants from the National Institutes of Health, Rush University Segal award, Cancer SPORE Development Award, and a grant from Fujirebio Diagnostics, Inc. The authors have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. Published online August 16, 2011.
These results suggest that it may be possible to identify which women with infertility are at high risk for ovarian cancer. The study is published online in Cancer Epidemiology, Biomarkers & Prevention.
"The finding is extremely important because at present medical tests are unable to detect ovarian cancer in its early stages, which is why death rates from this disease are so high," said lead author Judith Luborsky, PhD, professor of pharmacology, obstetrics and gynecology, and preventive medicine at Rush University Medical Center, Chicago, Illinois.
As for the immediate clinical significance of this research, Dr. Luborsky told Medscape Medical News that it is related to increased awareness. "It has been known for some time through epidemiology studies that women with infertility, or those so designated because they seek treatment assistance to become pregnant, and women who never had children, are at increased risk for ovarian cancer" she said. "However, we do not know which women among this group are at high risk."
"The significance of our study was to show that we can identify an additional risk factor that would help identify a high risk group for more intense monitoring," she continued. "The actual tests will take a little longer to develop, but meanwhile increased awareness and regular check-ups are warranted, particularly for women with premature ovarian failure and/or signs of prematurely reduced ovarian function."
The authors found that mesothelin antibodies were significantly more frequent in women with prematurely reduced ovarian function, including ovulatory dysfunction (59%), ovarian failure (44%), and unexplained infertility (25%), as compared with a control group. Conversely, women with endometriosis, who also are at high risk for ovarian cancer, did not have mesothelin antibodies.
Chasing Biomarkers for Ovarian Cancer
Ovarian cancer is often detected at an advanced stage, which generally results in a poor prognosis. Current diagnostic tests are ineffective for early detection. Identifying potential biomarkers could help in diagnosing the disease at an earlier stage, as well as provide targets for improved treatment of the disease during all stages.
As previously reported by Medscape Medical News, researchers have identified CA125, HE4, and mesothelin as biomarkers for evidence of ovarian cancer before a clinical diagnosis is made.
That study showed a modest but statistically significant increase in risk associated with CA125, HE4, and mesothelin. This finding was consistent with many of the established epidemiologic risk factors for ovarian cancer.
But for women at average risk, none of the biomarkers — either alone or together — were accurate enough to justify their use, explained lead author Garnet Anderson, PhD, who is with the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center in Seattle, Washington.
"I do not know of any other currently identified biomarkers that hold more promise than these, but there has been a massive effort over the last few years to identify candidates and not all have been thoroughly vetted," Dr. Anderson told Medscape Medical News at the time.
Association Between Infertility and Cancer?
Many epidemiologic studies have demonstrated an association between infertility and ovarian cancer, and the relationship is independent of infertility drug treatment. The different categories of infertility have varying risks for ovarian cancer, note the authors, who point out that some patients with unexplained infertility have antiovarian antibodies that indicate an autoimmune disorder targeting the ovary.
In addition, a subgroup of women with all types of infertility have poor ovarian estrogen responses to follicle-stimulating hormone, and this has also been associated with antiovarian antibodies. Patients with ovarian cancer, they also note, have antiovarian antibodies that are similar to those found in women with infertility, indicating that there is a similar autoimmune response.
The concept that autoimmunity is a risk factor for certain cancers is present in the literature, explained Dr. Luborsky. "Thus, the relationship of ovarian cancer to ovarian autoimmune reactions may be more significant than the particular antigen reaction," she said. "Interestingly, the same group of women in which we found antimesothelin antibodies are also the same group we previously described an autoimmune disease of the ovary."
For this latest study, Dr. Luborsky and colleagues collected a total of 329 sera from women with infertility (n = 109), ovarian cancer (n = 28), benign ovarian tumors or cysts (n = 24), and healthy women (n = 152). Infertility categories included those with a risk for ovarian cancer: endometriosis (n = 23), ovulatory dysfunction (n = 17), premature ovarian failure (n = 25), and unexplained infertility (n = 44).
They found that mesothelin antigen levels in serum were significantly higher in women with ovarian cancer (P = .00003), benign conditions (P = .01), or unexplained infertility (P = .01) than in healthy women.
Within the individual categories, mesothelin antigen and antibody were not significantly correlated except in cases of ovarian cancer (correlation coefficient = 0.49; P = .015). However, they note that this association is scattered because some individuals have higher levels of mesothelin, some have mesothelin antibody, and some have both.
Finally, the authors also evaluated sera for circulating mesothelin and found, as they expected, that most patients with ovarian carcinoma had circulating antigen. But with the exception of unexplained infertility, circulating antigen was not significantly higher in the other infertility subsets as compared with normal women.
"We are currently working to identify additional antibody reactions to a panel of proteins that could be used for a screening test and then to identify specific factors within the positive group that would signal the onset of a malignancy for a diagnostic test," Dr. Luborsky said. "Based on the work of many other scientists, it is clear that different women may have different antibody profiles, but the common risk factor is likely to be the presence of specific autoantibodies."
The study was supported by grants from the National Institutes of Health, Rush University Segal award, Cancer SPORE Development Award, and a grant from Fujirebio Diagnostics, Inc. The authors have disclosed no relevant financial relationships.
Cancer Epidemiol Biomarkers Prev. Published online August 16, 2011.
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