Τετάρτη 23 Μαρτίου 2011

PROPHYLACTIC OOPHORECTOMY FOR BRCA MUTATIONS

Only 5%-10% of epithelial ovarian cancers are currently known to be associated with a defined genetic abnormality within a given family. Yet, BRCA1 and BRCA2 mutations have been shown to underlie the vast majority of such cases.[1] The relevance of this observation is enhanced when it is recognized that there is currently neither a known effective screening strategy for this malignancy, nor a well-characterized symptom complex that might permit detection of early-stage (and highly curable) disease.
Following the landmark recognition that it was possible to identify a rather substantial increased lifetime risk in an individual woman for the development of epithelial ovarian cancer based on the documented presence of a BRCA mutation, it was natural to inquire whether the performance of prophylactic surgery to remove the ovaries in this well-defined population could provide a clinically meaningful reduction in that risk. This question is particularly important with regard to the risk for ovarian cancer because the majority of patients with this malignancy typically present with advanced-stage disease when the 5-year survival rate is less than 30%.[2]
Over the past decade, several reports of relatively large individual institutional or multicenter experiences have confirmed a rather striking reduction in the subsequent incidence of epithelial ovarian cancer in patients with BRCA mutations who undergo bilateral prophylactic oophorectomy.[3-5] Although the total duration of follow-up after such surgery remains relatively limited (< 10 years), existing evidence strongly suggests that there is as much as an 80%-90% reduction in the anticipated development of a peritoneal malignancy over this time period.
These data are clearly both clinically relevant and potentially highly meaningful to all women known to have a family history of ovarian cancer and to possess these genetic abnormalities. However, before an individual woman with a documented BRCA1 or BRCA2 mutation decides to undergo prophylactic surgical intervention, it is critical that a number of issues be fully addressed.

Risk Reduction, Not Risk Elimination

First, it must be acknowledged that removal of the ovaries does not completely eliminate the risk for the development of an "ovarian-like" malignancy. The entire peritoneal lining is composed of cells that are essentially identical to the epithelial cells within the structure of the ovary itself, and these cells are capable of undergoing malignant transformation.[6]
[It is interesting and reasonable to contrast the absolute inability to eliminate all tissue within the peritoneal cavity that may be influenced by the genetic and environmental background leading to cancer vs the far more realistic potential to remove essentially all relevant tissue following prophylactic total mastectomy to prevent the development of breast cancer in women with apparently identical genetic mutations.]
The finding of a primary peritoneal malignancy is well described in women who have undergone successful prophylactic removal of both nonmalignant ovaries.[1-3] The point to be stressed here is that these studies have unequivocally documented the clinical utility of such surgery to substantially reduce the risk for the subsequent development of epithelial ovarian cancer, but surgery cannot completely eliminate that risk.

Short- and Long-Term Effects of Surgical Menopause

Second, the performance of a bilateral oophorectomy in a premenopausal woman, so-called "surgical menopause," can result in very distressing menopausal symptoms, such as hot flashes, depression, sleep disturbances, vaginal dryness, painful intercourse, etc.[7] It is important to acknowledge that these symptoms are often described as being substantially worse than those experienced following natural menopause. The impact of these symptoms on an individual woman's overall quality-of-life should not be underestimated.
Again, the point of noting this concern is not to deny the utility of this surgery in women with a substantial risk of developing ovarian cancer. Rather, it is to be certain that this issue is discussed with the individual woman prior to the performance of the procedure. In this way, she can include this information in her decision-making process.
In addition, there is a legitimate, but currently poorly undefined risk that premature elimination of physiologic ovarian function will negatively impact the future noncancer-related heath of a woman,[7] and may even increase the risk for early noncancer-related death.[8] The particular concern here is for the loss of estrogen activity in normal bone tissue, potentially leading to severe osteoporosis, and possibly on heart and neurological function, potentially leading to dementia.
Unfortunately, the overall effectiveness of strategies to replace the roles of estrogen in normal physiology between the time of surgery up to the point where natural menopause would have occurred remains to be determined.

Optimal Timing for Surgical Intervention

Finally, it is important to consider the optimal timing for performance of prophylactic surgery. It is not possible to know when the malignant process is initiated in any one individual woman and, as previously noted, there are no effective screening tests for ovarian cancer. Therefore, if surgery is to serve as an effective cancer prevention strategy, it is essential that the oophorectomy be completed before invasive cancer can be histologically detected or at least prior to the time the cancer has the biological potential to metastasize.
One rational recommendation is to determine the youngest age that an ovarian malignancy has been documented to have occurred in a particular family, and to prophylactically remove the ovaries of female family members known to be mutation carriers approximately 10 years prior to this date.
While this specific proposal can certainly be defended based on an understanding of the biology of malignant disease, the implications of such a recommendation for an individual woman may be profound. It is one thing to recommend surgical castration in a 45-year-old women who has completed childbearing, and something quite different to make such a pronouncement of a medical opinion suggesting the need for prophylactic removal of the ovaries to a 25-year-old woman with a BRCA1 mutation whose aunt was found to have stage III epithelial ovarian cancer at age 35. In the latter situation, compromise on the age of surgery may be indicated, recognizing that substantial delay (eg, to age 35 or later) may realistically increase the theoretical risk for the development of the malignancy.

The Promise of Future Research

It is reasonable to anticipate that future research will assist individual patients, and their physicians, in the process of deciding whether and when a prophylactic bilateral oophorectomy should be performed. Such investigative efforts will, hopefully, better define the negative impact of surgery on both short-term and long-term health, as well as document the utility of efforts designed to mitigate or eliminate those undesirable effects.

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