Involvement of Endogenous Digitalis-like Compounds in Breast Cancer
Involvement of Endogenous Digitalis-like Compounds in Breast Cancer
The endogenous digitalis-like compounds (DLC)are steroid hormones synthesized and released
 from the adrenal gland.They are integrated in the feed-back system of the
 Hypothalami-Pituitary-Adrenal gland axis.One of their remarkable function is to induce
 apoptosis in malignant cells. Recently, accumulating data point to the possibility of using
 synthetic DLC as new anti-cancer drugs. Less is known about the endogenous metabolism of
 these compounds in cancer patients.

 Proceeding from preliminary clinical data which demonstrated significantly reduced DLC plasma
 levels in breast cancer patients and from in vitro data which showed an impaired release of
 DLC towards stress stimuli in athymic nude mice,we put up the hypothesis that a latent
 adrenal insufficiency with low DLC levels facilitates the induction and progression of tumor
 diseases.
To pursue this question about endogenous DLC metabolism in cancer patients we intend to start
 with the measurement of DLC plasma levels in breast cancer patients at the time of first
 diagnosis and compare them to women with benign breast disease as well as healthy women.

 Aim of the Study

 -  To evaluate the basal DLC plasma concentrations in cancer patients at the time of first
 diagnosis and the function of the HPA axis, with focussing on breast cancer patients.

 -  To analyze a potential change of HPA function and, in parallel, DLC plasma
 concentrations in the course of therapy, with special respect to treatment failure.

 -  To establish a potential correlation between DLC plasma concentrations and risk factors
 in BC.

 Patients and Methods

 Patients:

 I. 50 - (100) patients with breast cancer at the time of first diagnosis

 II. 50 - (100) patients with a benign disease of the breast

 III. 50 - (100) women undergoing plastic surgery of the breast

 IV. 50 - (100) women who need no further exploration after visit in ambulance (=normal
 population)

 V. additionally a group of 25 - 50 students (age 20-40) will be analyzed in a pilot study

 Methods:

 Time-schedule for Group I (Group II. - IV. alike, according to disease and/or situation)

 -  Day of first presentation of the woman at the clinic

 -  Day of first diagnosis, i.e. biopsy/FNA

 -  Day of start of treatment: operation, chemo-/radiotherapy (tst = 0)

 -  Day + 30, + 60, + 90

 -  6 month and 1 year after start of treatment

 The Group V. (students) will be analyzed in a special schedule, preceding the study 1-2
 months:

 -  4 weeks before an important exam

 -  a day before the exam (-3 days)

 -  a day after the exam (+ 3 days)

 -  2 weeks after the exam

 -  6 weeks after the exam

 Parameters

 Biochemistry (Group I. - V.)

 -  Basal DLC plasma concentration

 -  Basal serum Cortisol concentration

 -  Basal plasma ATCH concentration

 -  Basal Aldosterone/Renin concentration

 -  Electrolytes (potassium, sodium, calcium, chloride)

 Pathology/Immunohistochemistry (Group I. + II., when benign, including last 4 points)

 -  Tumor size

 -  lymph node status

 -  E/P receptors

 -  Grade

 -  HER2/neu

 -  Bcl-2

 -  Ki67

 -  p53

 Radiology (Group I.)

 If abdominal CT available measurement of size of the adrenal glands

 Endocrinologic tests (Group I. - IV.)

 -  Dexamethasone-test (low dose):

 -  2 mg Dexamethasone p.o. at 24:00

 -  measurement of Cortisol and DLC at 8:00 the next morning

 -  ACTH-test:

 -  basal plasma concentrations of Cortisol, DLC and ACTH

 -  administration of 250 µg ACTH (Synachten®) i.v.

 -  measurement of Cortisol and DLC after 30 min. and 60 min.

 -  Facultative: Metapyrone test

 at following time intervals:

 1. Dexamethasone-test

 -  around the time of first presentation (± 5 days)

 -  around the time of start of treatment (± 5 days); corresponding times for Group
 II.- IV.

 -  Day + 30, +60, +90

 -  6 month and a year after start of treatment

 2. ACTH-test

 -  On the day of first presentation

 -  On the day of start of treatment; corresponding times for Group II.- IV.

 -  Day + 30, +60, +90

 -  6 months and one year after start of treatment

 Psychometric test for Stress Evaluation (Group I. - V.)

 -  at the day of first presentation (Students: in between the last 2 weeks before an exam)

 -  at the end of the study
Inclusion Criteria:

 -  first visit to a Breast Disease Ambulance for consultation

 -  no pregnancy

 Exclusion Criteria:

 -  no severe heart disease (EF > 40%)

 -  no therapy with digitalis

 -  no acute/chronic inflammatory disease (e.g. RA, M. Crohn)

 -  no dysfunction of the Hypothalamo-Pituitary-Adrenal system

 -  no severe mental disorder