Primary Breast and Colon Cancer: Is Hypertension/Preeclampsia during Pregnancy an Independent Marker for Individual Risk Stratification?

Introduction:
Colon and breast cancer are leading causes of cancer-related death in the
Netherlands (10%, 2007 CBS stat line). Survival is directly related to
detection and the type of cancer involved. However, tumor staging
insufficiently discriminates between cancer patients with poor and better
prognosis. Recently Mesker et al, described an independent parameter for
survival using the stroma-percentage within the primary tumor of colon cancer
patients. Patients with high stroma-percentage had a worse survival independent
for either tumor stage, tumor status and lymph node status compared to patients
with a high carcinoma-percentage. The stroma-percentage is available upon
routine HE histological sections. (1,2) For breast cancer this parameter was
validated on a set of 600 patients confirming the results of the former
performed studies. (de Kruijf et al, submitted to JCO)

Pregnancy is also characterized by tumor invasion: adequate placenta invasion
in the uterus is essential in pregnancy outcome.
In normal pregnancy spiral arteries undergo striking remodeling. They change
from typical muscular arteries to flaccid tubes with no muscularis or elastic
lamina with a diameter at least four times greater than that of non-pregnant
vessels. Shortly after the invasion of trophoblasts into the superficial
endometrium, the maternal erythrocytes can be observed within the precursors of
the placental intervillous space. Abnormal placentation is evident in
preeclampsia. Preeclampsia is a pregnancy specific syndrome that is diagnosed
by the new appearance of increased blood pressure and proteinuria. It is a
leading cause of maternal mortality in developed countries and increases
perinatal mortality up to five-fold. Since its etiology is largely unknown,
panoply of pathophysiological abnormalities is described.
Intrauterine growth restriction results also in abnormal placental growth and
angiogenesis with a prevalence of 5%.

Ten percent of the pregnant women will have problems with hypertension during
pregnanacy, of which 3-7% will develop preeclampsia. Inclusion of women with
intrauterine growth restriction will result in at least 5% of the total
population of pregnant women to be involved with abnormal placental growth /
angiogenesis.
Risk factors for abnormal placental growth / angiogenesis / preeclampsia are
advanced maternal age during pregnancy, null parity, multiple gestation,
diabetes, SLE and chronic hypertension. Smoking is a protective factor for
preeclampsia, not for intrauterine growth restriction.


Hypothesis.
In women with preeclampsia endovascular remodeling and invasion of the spiral
arteries is less prominent which will result in overwhelming placental
oxidative stress and pregnancy failure. Abnormal function of trophoblast and
stroma cells and their interaction play an important role in abnormal
placentation.
We hypothesize that preeclampsia during pregnancy is an independent, early
clinical genetic marker of invasion for abnormal placental growth, pregnancy
outcome including preeclampsia, intruterine growth restriction, abruptio
placentae as well as cancer with high stroma formation (and thus worse
prognosis).
The expected percentage of women in the population to be investigated would be
5% (12 patients with breast cancer and 17 patients with colon cancer) However,
when a genetic predisposition is the cause of abnormal invasion this percentage
is expected to be much higher in the series to be investigated.

Hypothesis.
In women with preeclampsia endovascular remodeling and invasion of the spiral
arteries is less prominent which will result in overwhelming placental
oxidative stress and pregnancy failure. Abnormal function of trophoblast and
stroma cells and their interaction play an important role in abnormal
placentation.
We hypothesize that preeclampsia during pregnancy is an independent, early
clinical genetic marker of invasion for abnormal placental growth, pregnancy
outcome including preeclampsia, intruterine growth restriction, abruptio
placentae as well as cancer with high stroma formation (and thus worse
prognosis).
The expected percentage of women in the population to be investigated would be
5% (12 patients with breast cancer and 17 patients with colon cancer) However,
when a genetic predisposition is the cause of abnormal invasion this percentage
is expected to be much higher in the series to be investigated.

Methods.
For women with colon and breast cancer we will determine the stroma-percentage
and gain insight in their pregnancy outcomes. Variables including tumor stage,
tumor status and smoking will be analyzed in a regression analysis.
Abnormal trophoblast invasion is defined in preeclampsia as well as recurrent
abortion, intra-uterine growth restriction and abrutio placentae.

Invitation participation.
Patients included in the databases for breast and colon cancer will receive an
invitation to participate in this trial. An inquiry form will be sent to each
patient.

- Pssible emotional disturbance of these women
- from other research programms interviewing in depth women who have had severe
preeclampsie, this was not a major problem