Oral Contraceptives and the Risk of Hereditary Ovarian Cancer
October 1, 1998 6 minutes read
Oral Contraceptives and the Risk of Hereditary Ovarian Cancer
ABSTRACT & COMMENTARIES
Synopsis: Oral contraceptive use seems to decrease the risk of ovarian cancer in patients with BRCA gene mutation.
Source: Narod SA, et al. N Engl J Med 1998;339:424-428.
Women with mutations of brca1 or brca2 genes have an increased risk of ovarian cancer. Although the estimate of risk varies among studies, it may be as high as 50% with the BRCA1 mutation. In several studies, the use of oral contraceptives by the general population has been shown to decrease the risk of ovarian cancer development in women who have taken the medication. This decreased risk is greatest in those who have taken OCPs for prolonged periods of time. Narod and associates developed their study to determine whether the subpopulation of women with a BRCA1 gene mutation also had a decreased risk if OCPs were used.
Narod et al identified 207 women with a diagnosis of invasive epithelial ovarian cancer. All living sisters of the patients were identified and asked to be used as controls for this case-control study. Sisters of the cases had to have been born during the same years (1925-1960), not have a diagnosis of ovarian cancer, and be able to complete the study questionnaire. A total of 161 control women were identified. BRCA1 and 2 status was known for all of the cases of ovarian cancer, as well as for 95 of the 161 control women. Many of the control sisters had previously undergone bilateral oophorectomy because of their increased risk of ovarian cancer. Data were collected on various demographic factors, as well as for history of oral contraceptive use.
The case and control groups were similar for age, area of residence, race, and parity. Mean age at first childbirth and last childbirth were identical. Oral contraceptive use significantly differed between the two groups, with only 50% of the cases using oral contraceptives and 70% of the controls. The average duration of use of birth control pills was four years for the cases and six years for the controls. All of the cases had BRCA1 or 2 mutations. Of the 95 controls that were tested, 53 were carriers for one of the two gene mutations.
The risk of ovarian cancer decreased with use of oral contraceptives and decreased with increasing use of the medication. Sixty-three of the cases also had breast cancer and used oral contraceptives for an average of five years. Twenty-nine control women had breast cancer and used oral contraceptives for an average of six years.
Narod et al discuss at some length the strengths and weaknesses of this study. Specifically, they commented on the fact that the large number of control women who had undergone oophorectomy limits the strength of their study.
COMMENT BY KENNETH NOLLER, MD
This was an interesting paper. For those of you who choose to read it, I would suggest you also read the accompanying editorial that further discusses the strengths and weaknesses of this paper.
In all case-control series, it is possible to find fault with the controls. In some papers, this requires considerable deep thought, and in others, the shortcomings are so evident that it becomes immediately clear that the study is seriously limited.
While I was happy to see this publication, the problems with the controls do make the results somewhat tenuous. A large percentage of the controls did not have gene mutations, and many had undergone oophorectomy. In addition, only living cases and siblings were used for this study. Therefore, we know nothing about the occurrence of ovarian cancer among siblings who had previously died. Despite all of these problems, it is quite likely that oral contraceptives do confer some decreased risk for the development of ovarian cancer among women with the BRCA1 and 2 gene mutations.
This is important information because of the very high risk of women with the specified mutations developing cancer. It has been known for a long time that oral contraceptives decrease the risk of ovarian cancer in the general population. Although it has been suspected that oral contraceptives would also decrease the risk among women with hereditary ovarian cancer gene mutations, this is the first article to provide reasonable data to support this hypothesis.
It appears that among women with BRCA1 and 2 mutations (not just women with a family history of ovarian cancer), the use of oral contraceptives until fertility is no longer necessary followed by bilateral oophorectomy might provide a significant degree of protection. However, even among women who have had bilateral oophorectomy, the risk remains approximately 2-3 times that of the general population. Perhaps these women should remain on oral contraceptives even after oophorectomy, rather than conventional HRT. At the present time, that is pure speculation. In addition, one must weigh the possible increased risk of breast cancer in this very high-risk group against the benefits of any hormonal therapy.
COMMENT BY SARAH L. BERGA, MD
A despondent, tearful 24-year-old woman sat in my office. Her mother had died in her early forties when my patient was in her teens. Dad was a very busy and very successful man who had quickly remarried. The stepmom and my patient did not like one another much. My patient got pregnant in her late teens, did not marry, tried to live with the child's father, but the relationship was unstable and stormy. Her dad bought her a house, and she currently lived alone and was trying to attend undergraduate school. At age 20, she tested positive for BRCA1. She had bilateral subcutaneous mastectomies with reconstruction, but she developed bilateral wound infections and both implants had to be removed. Now, she felt alone, disfigured, and ambivalent about the oncologist recommendation that she should have her ovaries removed when she had completed childbearing and certainly no later than age 30. She did not want children now, so she was taking birth control pills. Would they help or hinder her chance of ovarian cancer?
You only have to see one patient like this to want to know the answer. While we have evidence that oral contraceptives protect against ovarian cancer in women at no special risk for this disease, we have no evidence to buttress the reasonable assumption that their use might also protect those at high risk. As the introduction of this article points out, the lifetime risk of ovarian cancer in women with BRCA1 mutations is 45% and 25% in those with BRCA2 mutations. While this study was not specifically designed to address whether oral contraceptive use in women with these mutations will increase their chance of breast cancer, they found no difference in the history of breast cancer in those who had and those who had not used oral contraceptives.
For the patient in my office, this was a relatively moot issue. Her clearest need was to gain some measure of normalcy, so she could focus on her education and the needs of her child. She was in no state to make a major decision regarding oophorectomy. At the time, we decided to continue the oral contraceptive therapy until her mental state improved. In retrospect, it appears we made a good decision based on the limited available information. While the conclusions of the present study cannot be considered as fact, they certainly provide an interim measure of reassurance.
One might wonder why BRCA1 results in such high rates of breast and ovarian cancer. Recent evidence also sheds light on this molecular conundrum (Gowen LC, et al. Science 1998;281:1009-1012). The removal of many types of DNA damage occurs by transcription-coupled repair, a process in which damage is repaired more rapidly in transcriptionally active DNA than in the genome as a whole. The loss of the wild-type BRCA1 allele during neoplastic transcription indicates that BRCA1 functions as a tumor suppressor by acting in concert with another cellular factor, Rad51, to maintain the integrity of the genome during periods of rapid growth. Embryonic stem cells with this mutation were hypersensitive to ionizing radiation and H2O2 but not ultraviolet light. The early embryonic death of BRCA1 homozygote embryos and the importance of this gene in tumorigenesis suggest a role for BRCA1 in the growth and development of normal cells.
We have now entered the era when our understanding of a common clinical situation depends on being able to couple insights obtained via clinical research with those garnered from hard-core molecular physiology. Thankfully, information processing is trophic for neurons.
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