Recognizing patients with (a higher risk of) endometrial cancer; the rol of fat distribution and inflammation in the origin of endometrial cancer, a study that focuses on prevention and prediction

Endometrial cancer is the most common malignancy in women in the higher
developed countries. The incidence of endometrial carcinoma is increasing
because of the influence of increasing life expectancy and increasing obesity.
Of all the malignancies, the endometrial cancer is most positively correlated
to a body mass index (BMI) and with each increase of 5 BMI units, there is 50%
higher risk of developing endometrial cancer. The underlying mechanisms between
obesity and cancer are complex. For endometrial cancer, prolonged estrogen
stimulation plays a role due to, among other things, increased aromatase
activity in peripheral fat. In addition, obesity-related inflammation and
insulin resistance appear to be important. The latter may also explain that not
only the endometrioid (traditionally considered as estrogen sensitive) subtype,
but also the non- endometrioid subtypes of endometrial cancer show an increased
incidence in weight gain. This obesity-related inflammation also plays a role
in the onset of other diseases, such as cardiovascular disease and type 2
diabetes.

Due to increasing obesity worldwide and in the more developed countries in
particular, it is expected that the incidence of endometrial cancer will
continue to increase significantly, also in premenopausal women. Most women
with endometrial cancer have a favorable prognosis because the disease leads to
symptoms of abnormal blood loss at an early stage. However, endometrial cancer,
especially in obese women, can also be seen as an expression of unhealthy
patient environment, and is associated with co-morbidities such as diabetes and
hypertension. This is explained by overlap in underlying mechanisms such as the
above mentioned inflammation. The increase in non- endometrioid endometrial
cancer, which is insufficiently explained by estrogens and characterized by
poorer prognosis, illustrates the knowledge gap on the relationship between
obesity and endometrial cancer.
Obesity is often expressed in BMI (WHO), an easily applicable but coarse
indicator that does not do justice to the complexity of obesity and weight
distribution (apple/pear figure) and the distribution between subcutaneous and
visceral fat. Internationally, the importance of fat distribution within the
origin of endometrial cancer research is more recognized, as is research of
both applicants, in which BMI and fat distribution on CT appear to be
correlated to hormonal levels and tumor inflammation as well as tumor pathway
activation.
However, regardless of the degree of overweight, there is agreement in the
literature regarding the strong, positive relationship between BMI and
endometrial carcinoma incidence.
The adipose tissue is a very complex cereal that produces hormones such as
adiponectin and leptin, as well as steroids that influence the development and
course of endometrial cancer. The visceral fat is metabolic more active, and
therefore possibly a worse prognostic than subcutaneous fat, while the
subcutaneous fat seems more important for estrogen production in women with
normal BMI. However, after menopause, peripheral adipose tissue is the main
producer due to the presence of aromatase, an enzyme that converts androgens
into estrogens. Finally also the uterus itself partly regulates its local
estrogen metabolism (intracrinology), consisting of a complex mechanism of and
interaction between multiple enzymes, which plays an important role in the
endometrial cancer. This expertise is specifically present within the MUMC+ in
clinical and pre-clinical research.

In light of the differences in the type of fat (visceral versus subcutaneous),
the shift towards a relative increase in central adiposity (visceral fat) due
to the menopausal transition seems important.

The primary treatment of the endometrial carcinoma consists of hysterectomy
with removal of the ovaries (bilateral salpingo-oophorectomy, BSO). Removal of
the ovaries has a dual purpose; 1. It is part of the urbanization of the
endometrial carcinoma. It leads to a reduction of the remaining estrogen and
androgen production and thus reduces the risk of recurrence.
However, the impact of BMI and fat distribution (subcutaneous versus visceral)
on hormone levels, metabolism and inflammation at onset and progression of
enometrial carcinoma is not clear, but is directly relevant for better
understanding and treatment of the endometrial carcinoma in obese patients. The
routine surgical treatment of the endometrial carcinoma, in which one has
direct access to both subcutaneous and visceral adipose tissue in addition to
access to the tumor, however, allows to investigate these important
relationships.

We expect the BMI and the type of fat distribution to have a significant
influence on the change in hormone levels, fat metabolism and systemic
inflammation levels after bilateral salpingo-oophorectomy (BSO). In patients
with endometrial cancer, systemic inflammation is expected to be higher
compared to controls, and proportionally more visceral than subcutaneous fat is
present. It is also expected that bso in obese patients only leads to a
relatively small decrease in estrogen levels.

The results help to better understand the impact of inflammation and obesity on
endometrial cancer. This is a large knowledge gap and, given the huge increase
in obesity, very relevant for the future.
This knowledge can contribute to the decision making regarding the routine
removal of ovaries in obese women with endometrial cancer and gives
opportunities for innovation in the treatment of endometrial cancer.
In addition, these insights can facilitate better risk stratification in obese
women with abnormal vaginal blood loss. For this group, targeted preventive
measures such as weight reduction and promotion of physical activity can be
advised. Especially because there is a large overlay with the underlying
mechanisms of obesity and obesity-related inflammation with cardiovascular
disease and type 2 diabetes, this knowledge can be applied on a broader level.

This is a prospective observational study (pilot)
Inclusion criteria
-CASES (n=80): Subjects with endometrial carncer and atypical endometrial
hyperplasia undergoing hysterectomy including BSO upon inclusion will be
stratified by BMI and menopausal status.
- pre- and perimenopausal BMI >=32 (n=20)
- pre- and perimenopausal BMI 18-25 (n=20)
- postmenopausal BMI >=32 (n=20)
- postmenopausal BMI 18-25(n=20)

CONTROLS (n=80): Subjects undergoing bilateral salpingo-oophorectomy (BSO) for
non-oncological reasons. For this purpose, patients undergoing a trial
laparotomy in which the ovaries are removed and eventually will be diagnosed as
benign, will be approached. Age >40 years due to matchability with cases.
- Pre- and perimenopausal BMI >=32 (n=20)
- pre- and perimenopausal BMI <25 (n=20)
- postmenopausal BMI >=32 (n=20)
- postmenopausal BMI <25(n=20)

Exclusion criteria:
Other malignancy <5 years prior to inclusion, except basal cell carcinoma
Use of hormonal therapy <12 months
Insufficient understanding of the Dutch language
Subjects not allowed to undergo CT-scan

Study activities
Preoperative
-Blood collection for estrogen levels and systemic inflammation markers
-CT for fat segmentation
-Waist / hip circumference and BMI
-Questionnaire on comorbidity, physical activity level, and presence of
menopausal symptoms.
-if still recognizable cycle present: ask cycle day.

Per operative
Collection of adipose tissue subcutaneously, omentum and intestinal epiploica +
tumor

Postoperative (6 weeks)
Collect clinical data on tumor (subtype, stage and treatment)
-Estrogen levels, systemic inflammation markers
-Questionnaire on (changes in) menopausal complaints (hot flashes)
-Follow up for oncological outcome measures for three years

Analyses:
The analyses are aimed at comparing the serum estrogen levels and inflammation
markers before and after removal of the ovaries and comparing the different
groups:
- Pre-/perimenopausal and postmenopausal
- BMI 18-25 and >=32
- Endometrial cancer patients and controls
Characterization of the systemic estrogens (by multiplex system steroid
analysis) and systemic inflammation markers and cytokines (C-reactive protein
(CRP), interleukin 1 beta (IL1β), interleukin 6 (IL6), tumor necrosis factor
alpha (TNFα), insulin-like growth factor 1(IGF1) before and after surgery. In
addition, spijtserum is stored for possible further analyses.
Analyze the fat and fat metabolism that have been shown in the literature to be
important for inflammation and hormone production (macrophages, T cells):
TNF-α, IL-6, and IL-1β, oestron, aromatase, adiponectin, resistin, leptin).
Correlate the results to the different types of fat distribution (visceral and
subcutaneous) as visualized on CT. Hip waist circumference and body image
(apple/pear figure) are also included.

The load and risks for the subjects are minimal.
Extra hospital visit: No.
Extra invasive procedures (including blood draw): Yes, one additional blood
draw at the time of post-OK visit.
Biological material collection:
- Blood: At the same time as routine blood draw and during post-OK visit.
- Tissue: During routine surgery:
- Tumor/metastasis: residual material.
- Subcutaneous fat biopsy: achieved when opening abdomen: biopsy without risk.
- Ometal biopsy: Routine in aggressive subtypes; non-aggressive subtypes:
decrease biopsy. risk: small: minimal blood loss.
- The intestinal fat biopsies: no routine action at the endometrium carcinoma:
emphatically no biopsy of the intestine itself.
Risks:1. small: blood loss; 2. minimal/negligible: intestinal damage (nb If
there is no fat rich spot, no biopsy is taken).