Why is ovarian cancer a disease of the elderly at a time when the ovaries are inactive already for a long time?

Posted in ovarian cancer, demographics, diagnosis; Comments 2 ; Posted 12 years ago

While young women in their teens and twenties can also be diagnosed with ovarian cancer, the majority of women diagnosed with ovarian cancer are aged 60 years or older. The higher the age, the higher the ovarian cancer risks. Statistically, the highest incidence rate is in females aged 85 years and older.

We asked four of the brainiest ovarian cancer experts from Australia, the US and Europe: How come that in females whose ovaries are asleep and inactive for many, many years, the ovarian cancer risk is higher than in young females with lots of activity in the ovaries?

I would like to thank the authors to tackle a tricky question for which we all know, no definitive answer exists. By speculating wildly, the authors offer different ways of approaching the subject, which makes the text an interesting read. Its just amazing how much we don’t know …

Ovarian cancer still remains a mystery and the diagnosis and treatment we have available at present are simply not good enough. Please consider supporting the Battle Against Ovarian Cancer on the 3 FEB 2013 in any way possible.

David Bowtell is a molecular researcher at the MacCallum Cancer Institute in Melbourne and a Principal Investigators of the Australian Ovarian Cancer Study, a nationwide study that produced enormous insight into molecular ovarian cancer development.

Recently, David published a ground breaking paper suggesting that more than 10% of ovarian cancers are caused by mutations in the BRCA1/2 gene and in fact inherited. He also reported that family history is very unreliable in pointing to the possibility of a BRCA1/2 mutation.

There are a couple of potential answers, but we can only speculate:

1. Cancer risks generally rise exponentially past the age of 50 year, and in this context ovarian cancer is no different to other solid cancers such as breast or colorectal cancer. There are several potential reasons:
   1. Longer exposure to carcinogens that can damage DNA;
   2. The immune function that provides a degree of protection against cancers as they are forming wanes with age;
   3. Processes that transform a normal cell to a cancer may take time.  Estimates for the length of time for transformation vary but figures of 20-30 years have been suggested for many human cancers. So one explanation is that it takes time and in most young women, not enough time has elapsed.
2. We now know that ovarian cancer is not one disease but many. Not only we don’t know what the precursor of ovarian cancer is – we don’t even know for sure if "ovarian" cancer cells come from the ovary, actually.  We are currently collecting evidence that a number of "ovarian" cancers arise from the fallopian tubes and they may arise from other tissues as well. It could well be that what is happening in the ovary (active or inactive) doesn't make a lot of difference.  However, we do know that ovulation is a risk factor for the development of ovarian cancer.  Is it possible that ovulation creates an ideal site for early cancer cells, originating from non-ovarian sites, to lodge and develop?  Cells deposited during a time when the ovary is active are seeded, beginning their sequential process to become a full-blown cancer. This might seem a bit far-fetched but we do know that cancers of the stomach and breast can definitely seed to the ovary, even though they are anatomically distant, suggesting that there is something special about the ovary as a site for cancer cells to grow.

Penny Webb is a senior epidemiologist at the Queensland Institute of Medical Research and also a principal investigator of the OPAL Study, an Australia-wide ovarian cancer study running in all states at present. OPAL examines what lifestyle factors (diet, aspirin, exercise, etc.) contribute to improved survival after ovarian cancer treatment.

Penny is also the driver of the Australian Ovarian cancer Study (AOCS), which is to date the biggest epidemiological study on ovarian cancer world-wide, funded by the US Department of Defence. This study collected information from more than 1000 ovarian cancer patients Australia-wide.

Cancer develops when cells in the body grow out of control. This can happen when the DNA in our cells gets damaged – for example by smoking (lung cancer) or sunlight (skin cancer) – but we know that it can take many years before these early changes turn into cancer.

For ovarian cancer, it is possible that the first DNA damage does occur when a woman is younger and her ovaries are still active, but that it just takes many years for a cancer to develop. We know that pregnancy and use of the oral contraceptive pill greatly reduce a woman’s risk of getting ovarian cancer – women who have had two or more children or who have used the pill for several years are about half as likely to get ovarian cancer as women who have not had children or used the pill. We also know that the protective effects of pregnancy and pill use last for several decades. It is possible that pregnancy hormones and hormones in the pill help prevent DNA damage when a woman is younger, but that when she reaches menopause this protection is lost, DNA damage can start to occur, and the result may be cancer, sometimes 10-20 years later.

Mike Bookman is a graduate of Harvard Medical School and the Massachusetts Institute of Technology. He is now the Professor of Medicine at The University of Arizona. He is a renowned expert in gynecologic medical oncology with a focus on the development of new treatments for gynecologic cancers.  His interests also include medical information technology and the support of under-resourced countries as part of his role in the International Gynaecological cancer Society (IGCS).

Interestingly, the incidence of ovarian cancer corresponds closely with the onset of menopause in the general population, which is a younger age at onset compared to many other cancers.  While we have considered cyclic ovulation to be a potential risk factor for the development of ovarian cancer, it is not that simple, and even short interruptions in ovulation, such as would occur with just one pregnancy or use of oral contraceptives for only 6 months, can reduce the lifetime risk of ovarian cancer.  In addition, changes that promote ovarian cancer probably occur many years before the cancer develops to the point where it is detected.  Taken together, these observations suggest that the connection between ovarian "activity" and cancer development is more complex. 

In addition, during the transition to menopause, there are wide fluctuations in estrogen, progesterone, and other hormonal signals (LH, FSH), which can result in the transient development of cysts and other changes in the ovary.  While these hormonal events are unlikely to directly cause ovarian cancer, they may result in symptoms or findings that could increase the detection of ovarian cancer and other abnormalities. 

Clearly, the ovary is a complex organ with many different functions (hormone production, including estrogens and androgens, as well as follicle maturation).  Even after menopause, when ovulation stops, these other functions can continue. 

Finally, you raised the question of ovarian cancer in younger women, but many of the tumors that occur in younger women are benign (not cancer), or low-grade (borderline tumors), or cancers that are localized and cured easily with surgery (such as mucinous tumors and some clear cell tumors).  The high-grade serous cancers that develop into advanced-stage ovarian cancer are uncommon in younger women before menopause. 

In conclusion, ovarian "activity" can be measured in different ways, and we have much to learn regarding the relationship of age and activity with the development of high-grade serous ovarian cancer.

Christian Marth is the Head and Professor of the Department of Gynaecology and Obstetrics at the Innsbruck Medical University in Austria. Christian published more than 250 articles in peer-reviewed journals and one of this top interests are immunotherapy in patients with ovarian cancer.

Ovarian cancer is not only one disease. We distinguish different types, which also will be caused by different mechanism. Some of them might derive from the fallopian tube, the endometrium, or the intestinal tract. Ovarian cancer is therefore not directly linked to the activity of the ovary. It is more important that over time changes in the DNA occur (e.g. mutations) which turns a normal cell into a cancer cell. Since these changes accumulate during life the probability to develop ovarian cancer is higher in elder women. However, high activity in the ovary such as frequent ovulation increases the probability of mutations and by the way of ovarian cancer. This fact explains why oral contraceptives or frequent pregnancies result in an inhibition of ovulation and protect against ovarian cancer.

The Battle Against Ovarian Cancer will be fought on 3 February 2013 at Nat Cook's Sandstorm Beach Club in Upper Mount Gravatt in Brisbane. The Queensland Firebirds, Former Origin Greats, the Speaker of the Queensland Parliament, the Minister for Sport, and more VIPs have committed to playing Beach Volleyball to help fund better outcomes for ovarian and gynaecological cancer. I thank you for all your support. www.battleagainstovariancancer.org