Endometriosis and cancer

By Lone Hummelshoj, Marina Kvaskoff PhD, Andrew Horne MD FRCOG, and Stacey Missmer ScD

Over the last few years there has been increasing concern amongst women with endometriosis about their risk of developing cancer – ovarian cancer in particular – unfortunately aggravated by confusion around the data that support this link.

Whereas numerous studies have been conducted to investigate a link between endometriosis and the subsequent risk of developing cancer, many had:

• a lack of power (not enough women enrolled in the studies),
• recruitment bias (targeting specific demographics while not including others),
• recall bias (women who already have cancer may view and report on their past differently from currently healthy women),
• lack of specifics of the woman’s cancer subtypes,
• lack of details of the woman’s endometriosis characteristics and symptoms, and
• absence of detailed data about women’s demographics, lifestyle, environment, health history, and medical treatments that may be correlated with or influence both endometriosis and cancer risk [1,2].

In other words: the association between endometriosis and cancer is complex and our knowledge is growing and our understanding evolving.

This must be a focus of future research. To achieve this, we must demand funding for rigorously designed studies that will produce robust findings, and we must expect women with endometriosis and those who care for and about them to participate in this discovery.

First, we must do a better job at relaying health and risk information. All women are at risk for developing cancer. One in ten women have endometriosis.

The critical questions are: are women with endometriosis at greater risk for developing cancer compared to women without endometriosis?; if so, which women with endometriosis have greater risk? and what about endometriosis is increasing their risk?

The next step is to use this information to develop tools for early detection, personalised treatment, and even the potential for prevention.

In the meantime, let’s establish what we know today:

Endometriosis and cancer

Endometriosis has a benign nature, but it shares some characteristics with malignant tumours, such as invasion of local and distant organs, abnormal tissue growth, impacting function of target organs, and genetic damage [3].

There is no direct evidence that endometriotic implants turn into cancer. Genetic changes related to cancer risk have been found in some endometriomas (~20%) from women with cancer on the same ovary [4]. However, these “cancer driver mutations” also have been found in ~20% of deep endometriosis lesions where proximal cancer has not been reported [5].

If ovarian cancer develops in women with endometriosis through transformation of endometriomas into malignant tissue, then only women with endometriomas (and likely endometriomas with a specific genetic signature) are at risk for endometriosis-driven ovarian cancer.

However, this does not explain other cancer risk among women with endometriosis. Therefore, we must consider that endometriosis and cancer are “co-morbid” diseases, meaning that women with certain biology or characteristics or lifestyle or environment are more likely to develop endometriosis and are also more likely to develop cancer.

Conceptually this means that endometriosis is a “marker” of sorts for a group of women who have a higher chance of developing cancer compared to women without this “marker.”

Cancers investigated in association with endometriosis include:

Ovarian cancer and endometriosis

Ovarian cancer is the cancer that has most consistently been associated with endometriosis. However, it should be noted that the subtypes of ovarian cancer that are associated with endometriosis (endometrioid and clear cell) are the types that are most frequently detected at an earlier stage and have a better prognosis than other ovarian cancer types.

Ovarian cancer in the general female population has a rate of 1.3% – which means that a little over 1 in 100 women will develop ovarian cancer in their lifetime.

For women with endometriosis, this rate is 1.8% [6] – which means that a little under 2 in 100 women with endometriosis will develop ovarian cancer in their lifetime.

Let us be clear: most women with endometriosis (a little over 98 out of 100) will NOT develop ovarian cancer. The risk is so low that currently routine screening is not recommended [7,8].

The Lancet recently published facts about endometriosis and ovarian cancer and put the risk into perspective [6]:

According to recent estimates, 39% of women who inherit a harmful BRCA1 mutation, and 11-17% who inherit a harmful BRCA2 mutation (the rare genes that predispose to breast cancer) will develop ovarian cancer by age 70 years.

Furthermore, as a female in the general population, your risk of breast (12%), lung (6%), and bowel (4%) cancers are still higher than your risk of developing ovarian cancer.

Breast cancer and endometriosis

Because endometriosis and breast cancer are both prevalent, it may appear incorrectly that they are related. However, they do share a key pathogenic insult: they are both dependent on the hormone oestrogen, which means that they both proliferate in the presence of higher levels of this hormone in the body.

Fourteen studies have reported on endometriosis and breast cancer. While six of them observed a modest higher breast cancer risk in women with endometriosis, four others reported no difference in risk at all, and four observed a lower breast cancer risk among women with endometriosis [3].

A recent study suggested that while there was no association between endometriosis and breast cancer overall, there may be greater risk for specific hormone receptor-specific subtypes of breast cancer [9].

Based on current evidence, this is inconclusive. Further study is critical, including consideration of the impact that hormonal medical treatments may have on breast cancer risk rather than the endometriosis itself.

Whether or not you have endometriosis: check your breasts regularly and seek medical help if you find irregularities. No one can perceive changes in your body as well as you can.

Endometrial and cervical cancer with endometriosis

Studies into endometrial and cervical cancers are based on very low numbers of women. However, they all report either no association, or, for cervical cancer – a lower risk in women with endometriosis [3].

It is possible that this is due the demonstrated access to care that women with endometriosis have to have received a diagnosis and also their vigilance about keeping up with regular smears and examinations. Cervical cancer is preventable if changes in the cervix are caught early and treated before they become cancer.

Keep those smears up!

Melanoma skin cancer and endometriosis

Among non-gynaecological cancers, melanoma skin cancer has been the most studied in relation to a history of endometriosis.

Out of the 12 studies that explored this potential connection, seven suggested a positive association, while five studies reported no clear relation between endometriosis and melanoma risk [3].

So, the evidence is not yet conclusive – but don’t forget to cover up and have routine skin checks at your annual physical!

Non-Hodgkins lymphoma and endometriosis

Humoral immunity abnormalities have been documented in women with endometriosis, and there may be a link between B-cell activation in endometriosis and the development of B-cell lymphoma [10].

The largest population-based studies have documented an association with non-Hodgkin’s lymphoma and endometriosis – but not consistently and based on very small numbers so far [10].

Other cancers and endometriosis

Investigations of associations with other cancers have been sparse. Consequently, no firm conclusions can be drawn with regards to subsequent risk of other malignancies in women with endometriosis [3].

Conclusion about endometriosis and cancer

Before endometriosis can be linked with evidence to any type of cancer, more methodologically-robust research will need to be undertaken. This research must be large enough, and detailed enough, with advanced methods applied to account for the inter-relationships among these detailed data, to tease apart whether or not cancers can be attributed to:

1. the physiological changes induced by endometriosis (chronic pain, infertility, chronic inflammation, aberrant hormonal and immunologic responses);
2. treatments for endometriosis-associated symptoms including lifestyle changes that women take on, medications prescribed to treat chronic pelvic pain or painful intercourse or irritable bowel, medications prescribed to achieve pregnancy in those who also experience infertility;
3. common aetiological factors yet to be identified, such as genes, methylation patterns, protein expression, and micro-RNAs to name just a few of the emerging areas for disease-causing discovery [10].

It is important to note here too that, just as there are important subtypes identified for all cancers (for example the ovarian cancer[1] and breast cancer types mentioned above),

we must discover the different types of endometriosis and what defines them. This is critical to determine for those cancers that are found to be associated with endometriosis, which type is the root of that association.

Knowing that will help us to determine an individual woman’s risk more accurately and to develop targeted screening and intervention. This will also further our understanding of the physiology underlying this relationship with cancer that is crucial to discover ways of prevention.

This, however, requires financial investment in and participant commitment to research!

WERF EPHect is a global collaboration of research institutions utilising standardised data collection tools

Consistent, prospective, data collection is what WERF EPHect is all about.

Through the commitment of women, clinicians, and scientists across the globe, theses collaborators’ collection of large and comparable data sets may collectively ensure that we will know a lot more about endometriosis in the next few years – including the truth about endometriosis and cancer risk.

What can I do to lower my cancer risk?

Half of cancers are preventable, with several key actions that you can take to lower your risk.

In general, to improve health and lower risk of any cancers, try to have a balanced diet with a low intake of alcohol, exercise regularly, maintain a healthy weight, and do not smoke [6].

More detailed information on cancer risk and prevention can be calculated for you individually at:
→ Your disease risk: the source on prevention.

At all times: if you are detecting changes in your body or symptoms that worry you, then do seek medical help.

References

1. Thomsen LH, et al. Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review. Acta Obstet Gynecol Scand 2017;96(6):761-778.
2. Guo S-W, et al. Endometriosis and ovarian cancer. Lancet Oncol 2012;13(5):e189-90.
3. Kvaskoff M, et al. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update 2015;21(4):500-516.
4. Anglesio MS, et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J Pathol 2015;236:201-209.
5. Anglesio MS, et al. Cancer associated mutations in endometriosis without cancer. N Engl J Med 2017;376(19):1835-1848.
6. Kvaskoff M, et al. Informing women with endometriosis about ovarian cancer risk. Lancet 2017;390:2433-34.
7. Johnson NP, et al. Consensus on current management of endometriosis. Hum Reprod 2013;28(6):1552-68.
8. Dunselman GA, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29(3):400-12.
9. Farland LV, et al. Laparoscopically Confirmed Endometriosis and Breast Cancer in the Nurses’ Health Study II. Obstet Gynecol 2016;128(5):1025-1031.
10. Vigano P, et al, 2012 (in: Giudice, Evers, and Healy, Endometriosis: Science and Practice)

See also

• Endometriosis and comorbidities
• Endometriosis and ovarian cancer
• The Endometriosis Phenome and Biobanking Harmonisation Project (WERF EPHect)