br Discussion br Although patients diagnosed
Although patients diagnosed with low grade and early stage EC have a favorable prognosis, in some of these patients the disease recur and prognosis is then poor. In this study we used a large prospectively col-lected cohort to select patients who, although their prognosis was favor-able at the time of primary cancer diagnosis, died of their disease within a short period, and matched these women with patients with similar characteristics, but long survival. We aimed at identifying differences between these two patient groups in blood (circulating) steroid profile, tumor gene Ruxolitinib and local steroid metabolism. A cluster analysis revealed that patients with long survival generally had higher steroid levels in plasma compared to patients with short survival, and for DHEA, DHEAS, progesterone (P4), 21OH-P4 and estrone-sulphate
(E1S) the difference was statistically significant. Both endometrioid and non-endometrioid ECs were included in this analysis and although endometrioid EC is considered more closely linked to hormonal stimu-lation than non-endometrioid, our data suggests that non-endometrioid EC is not completely hormone independent, as the increased steroid levels in relation with survival was independent of histologic subtype. This is in line with the contention that different histological subtypes may to a certain extent have similar pathogenesis [27,28]. Some differ-ences between histologic subtypes were observed, and although the sample size is small we observed that also within the non-endometrioid EC an increased level of several steroids was associated with long survival.
Obesity is a risk factor for developing several cancer types, includ-ing EC and the specific fat distribution pattern has also been found to be associated with cancer development. Individuals with a high per-centage of visceral fat have increased risk of developing breast-, colorectal- and esophageal cancer compared with individuals with less visceral fat . We have previously found that a high percent-age of visceral fat is an independent predictor of reduced disease specific survival in patients with EC . After menopause, circulat-ing estrogens are primarily produced in the adipose tissue , and it has been shown that an increased BMI is associated with increased circulating E2 concentration in healthy postmenopausal women . The relation between fat distribution and E2 levels is however less studied. In a study by Mongraw-Chaffin et al. a significant posi-tive association between visceral fat and E2 levels and between E2 levels and amount of subcutaneous fat was observed in postmeno-pausal women . In this study we explored a potential correlation between fat distribution pattern and E2 levels in postmenopausal EC patients. Patients with a high VAV% had significantly increased plasma E2 levels compared to patients with a low VAV%. This could indicate that in postmenopausal women with EC the visceral fat is a larger contributor to E2 production compared to the subcutaneous fat.
Clinical-pathological characteristics for included patients with long and short survival.
Variable Long n (%)
Lymph node status
a Chi-square test.
c Only FIGO-stage I and II included. r> In line with the known protective and anti-estrogenic effect of P4 in EC, this hormone was among the compounds with increased levels in the long survival group. P4 is known to have a tumor-suppressor effect
Median steroid level (25th percentile and 75 percentile) for endometrial cancer patients with long (n = 19) and short (n = 19) survival.
Metabolite Long survival group Short survival group p-Value
Mann-Whitney U test.
Correlations (Spearman rho) between BMI, CT-assessed obesity variables and plasma E2 values.
Spearman P-value Spearman P-value
VAV: Visceral abdominal fat volume, SAV: Subcutaneous abdominal fat volume, TAV: Total
abdominal fat volume, VAV%: Visceral fat percentage.
in EC through inhibition of proliferation and induction of differentiation, and progesterone therapy is also used in treatment of patients with EC [1,33]. Other compounds with increased circulating levels in patients with favorable prognosis included precursors or intermediates in the steroid biosynthetic pathway. Together with the observation that most enzymes involved in the local steroid metabolism are expressed in EC (especially the HSD17Bs, ACR1Cs and SRD5As), this suggests that these compounds are further metabolized locally to produce various an-drogenic and estrogenic compounds with various activities. Since this local metabolism of steroids affects the tissue steroid levels without af-fecting the blood concentration, it is not surprising that the circulating levels of active estrogens and androgens did not differ between groups. Previous studies showed that unbalanced intracrine metabolism and enzyme levels are associated with EC [18,34–37].