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Purpose: To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects., Methods: Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS) with lower limits of quantification (LLOQ) of 5 pmol/L. QoL was measured at baseline and at 12 months with the EORTC QLQ-C30 and QLQ-BR23 and the Women's Health questionnaires, and menopause-related symptoms with the modified Kupperman Index., Results: Of 100 screened patients 90 completed the trial. Baseline mean LC-MS/MS E2 and E1 were 12 pmol/L (range < 5-57) and 66 pmol/L (< 5-226), respectively. E2 levels measured by immunoassay and LC-MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months). Pain, side effects of systemic therapy, vasomotor symptoms, joint and muscle aches, and vaginal dryness increased during letrozole treatment. A high baseline E2 was significantly associated with increased aching joints and muscles, but not with the other side effects., Conclusions: Letrozole supresses E2 and E1 completely below the LLOQ of the LC-MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity., (© 2023. The Author(s).)

Purpose: To analyze whether monitoring serum estradiol (E2) levels using a highly sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method may identify patients with AI failure with E2 levels below the lower limit of quantification (LLOQ) after schwitching from tamoxifen to letrozole., Methods: In a prospective study of breast cancer patients switching to letrozole treatment after previous tamoxifen, plasma estrogen levels were measured at baseline and after 3- and 12-months using LC-MS/MS., Results: Forty-six patients were classified postmenopausal and entered into the final analysis. Thirty-nine (85%) patients had three- and 12-month E2 concentrations below the LLOQ (5 pmol/L). In the seven patients classified as AI-failures during letrozole treatment, serum E2-MS level rose above 5 pmol/L at 3 months with a mean E2-MS 77.5 pmol/L or 12 months with a mean E2-MS 21 pmol/L. None of the baseline variables i.e., age at diagnosis, age at study entry, age at menarche, BMI, endometrial thickness, total ovarian volume, baseline FSH, E2-IA, or E2-MS were significantly associated with the risk of AI failure in logistic regression. E2 levels at baseline measured by E2-IA did not significantly correlate to the levels measured by E2-MS., Conclusions: There is a relatively high risk of inadequate estrogen suppression in patients who switch from tamoxifen treatment to AIs. The use of sensitive and specific assays, such as LC-MS/MS methods, to monitor estrogen levels during AI treatment is essential to minimize the risk of a proceeding inefficient endocrine therapy.

Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E 1 ) was the predominant estrogen in premenopausal breast adipose tissue, and E 1 and mRNA expression of CYP19A1 in adipose tissue correlated positively with BMI. Adipose tissue estradiol (E 2 ) concentrations fluctuated during the menstrual cycle, similarly to the serum concentrations. In women with breast cancer median adipose tissue E 1 (1519 vs. 3244, p < .05) and E 2 (404 vs. 889 pmol/kg, p < .05) levels were lower in the follicular than in the luteal phase whereas in control women no significant differences were observed. In the follicular phase, mRNA expressions of HSD17B1 (median 0.06; interquartile range 0.05-0.07 vs. 0.17; 0.03-0.2, p = .010) and CYP19A1 (0.08; 0.07-0.14 vs. 0.22; 0.09-0.54, p = .025) were lower in women with breast cancer than in controls. In conclusion, the changes in adipose tissue E 1 and E 2 concentrations and the estrogen-regulating CYP19A1 and HSD17B1 during the menstrual cycle may be related to dysfunctional local estrogen metabolism in women with breast cancer.

Context: It has been shown that breast tumor actively produces and metabolizes steroid hormones. However, little is known about the possible mechanisms through which the nonmalignant adipose tissue contributes to steroid hormone metabolism., Objective: We compared the metabolic pathways producing active estradiol in breast sc adipose tissue of postmenopausal women with or without breast cancer., Design and Setting: Serum and adipose tissue samples were obtained during elective surgery., Patients: We studied postmenopausal women undergoing mastectomy due to an estrogen receptor-positive breast tumor (n = 14) and women undergoing breast reduction mammoplasty (n = 14)., Interventions: Estrone, estradiol, and estradiol fatty acyl ester concentrations were determined by liquid chromatography-tandem mass spectrometry. mRNA expression levels of estrogen-converting enzymes were analyzed by quantitative RT-PCR., Results: Estradiol concentration in breast sc adipose tissue was lower in women with cancer than in controls (median 33 vs 62 pmol/kg; P = .002), whereas the serum concentrations did not differ. Also, the mRNA expression for 17β-hydroxysteroid dehydrogenase type 12 was lower in the adipose tissue of women with cancer compared with controls (0.19 ± 0.10 vs 0.37 ± 0.21, P = .018)., Conclusions: Estrogen metabolism is differentially regulated in the adipose tissue of women with or without cancer. In the sc adipose tissue proximal to breast tumor 17β-hydroxysteroid dehydrogenase type 12 expression is lower than in controls, which could indicate that the conversion of estrone to estradiol is decreased. Further studies are needed to establish the clinical significance of our findings in the development and growth of breast cancer in postmenopausal women.

The role of diet in breast cancer (BC) risk is unclear. Fiber could reduce BC risk, through the enterohepatic circulation of estrogens. We examined the relationship between diet and sex hormones in postmenopausal women with or without BC. Thirty-one postmenopausal women (10 omnivores, 11 vegetarians, and 10 BC omnivores) were recruited. Dietary records (5 days) and hormone levels (3 days) were evaluated on 4 occasions over 1 yr. Vegetarians showed a lower fat/fiber ratio, a higher intake of total and cereal fiber (g/d)/body weight (kg), a significantly lower level of plasma estrone-sulfate, estradiol, free-estradiol, free-testosterone, and ring D oxygenated estrogens, and a significantly higher level of sex-hormone-binding-globulin than BC subjects. Fiber was consumed in slightly larger amounts by omnivores than by BC subjects. Omnivores had significantly lower plasma testosterone and estrone-sulfate but higher sex-hormone-binding-globulin than BC subjects. No difference was found for the urinary 16-oxygenated estrogens. However, the 2-MeO-E1/2-OH-E1 ratio was significantly lower in omnivores than in BC group. This ratio is positively associated with the fat/fiber ratio. In conclusion, testosterone may contribute to causing alterations in the levels of catechol estrogens and 16-oxygenated estrogens. The fat/fiber ratio appears to be useful in evaluating dietary effects on estrogen metabolism.

Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors., (© 2010 Wiley-Liss, Inc.)

Aims: The aim of this study was to assess the value of lymphoscintigraphy in general and extra-axillary lymph node biopsy in particular, based on our experience with sentinel biopsy in 128 consecutive woman undergoing surgery for breast cancer., Methods: Sentinel node biopsy was performed with the aid of isotope, hand held gamma probe, blue dye and lymphoscintigraphy in 83 patients. Injection technique was peritumoral or intratumoral. Lymphoscintigraphy was performed 2-4 h following isotope injection., Results: Eighteen lymposcintigraphies were negative (21.7%). The sentinel node was found in 14 of these cases. We were unable to identify the sentinel node(s) in four patients (4/83; 4.8%). All in all 20/25 (80%) extra-axillary nodes were located and taken out. Only two of these (2/20, 10%) were positive for metastatic disease on histological examination. The adjuvant treatment plans for these patients were not altered in response to these findings. No positive extra-axillary node(s) with simultaneous normal axillary sentinel node was found., Conclusions: In this serie, lymphoscintigraphy and biopsy of extra-axillary sentinel nodes added nothing but time, risk and cost to the procedure.

The cytosol values of estrogen-regulated proteins cathepsin D and pS2 were evaluated in 166 patients with breast diseases by a receiver-operating characteristic (ROC) curve analysis. Our aim was to compare their diagnostic accuracy and to define optimal cut-off levels for the cytosol values of these proteins in breast cancer (n = 133). The preoperative mean cytosol cathepsin D values in the breast cancer group were higher than in patients with benign breast disease (p < 0.001). The correlation coefficient (Pearson's r) between Cathepsin D and pS2 measurements was 0.286 (p < 0.001) in breast cancer patients. The ROC analysis indicated that the cathepsin D test was more sensitive than the pS2 test at all specificity levels, and the cathepsin D test reached considerably high sensitivity (86%) at the specificity level of 80%. According to present study, it would seem optimal to use the cut-off level of 33.0 pmol/mg for cathepsin D analysis and the level of 31.0 ng/mg for pS2 in breast cancer. In conclusion, the results of ROC curve analysis suggest that the cathepsin D test has advantage over pS2 because of its higher sensitivity in breast cancer.

The aim of the present study was to assess the clinical value of five serum tumour markers AFP, CA 15-3, CEA, TPS and Neu oncoprotein (p 185) in the diagnosis of breast cancer. The serum values were measured in a prospective series of patients with breast cancer (n = 233), benign breast disease (n = 176) and healthy control subjects (n = 215). The cut-off levels (90% specificity) were determined for each test. Using these cut-off levels the diagnostic sensitivity of the CEA test was 0.23, for the AFP test it was 0.16, for the CA 15-3 test 0.27, for the TPS test 0.18 and for the Neu oncoprotein test 0.19 in detecting breast cancer. Correlation coefficients (Pearson's) were statistically significant between CEA and CA 15-3, and between CA 15-3 and Neu oncoprotein measurements in breast cancer patients. In patients with benign breast disease the serum levels of AFP, CA 15-3, CEA and TPS correlated with age, being somewhat higher in older patients. Similarly, in population controls higher age correlated with higher levels of AFP, CA 15-3, Neu and TPS. In breast cancer patients there was no correlation between the age at diagnosis and any of the measured markers. The only marker statistically significantly associated with the stage of breast cancer was CA 15-3. In conclusion, our results indicate that serum CEA, AFP, CA 15-3, TPS and Neu oncoprotein are only of limited value in the diagnosis of breast cancer.

Thirty postmenopausal women (11 omnivores, 10 vegetarians and 9 apparently healthy women with surgically removed breast cancer) were investigated with regard to the association of their urinary excretion of estrogens, lignans and isoflavonoids (all diphenols) with plasma sex hormone binding globulin (SHBG). A statistically significant positive correlation between urinary total diphenol excretion and plasma SHBG was found which remained statistically significant after elimination of the confounding effect of body mass determined by body mass index (BMI). Furthermore we found a statistically significant negative correlation between plasma SHBG and urinary excretion of 16 alpha-hydroxyestrone and estriol which also remained significant after eliminating the effect of BMI. Furthermore we observed that enterolactone (Enl) stimulates the synthesis of SHBG by HepG2 liver cancer cells in culture acting synergistically with estradiol and at physiological concentrations. Enl was rapidly conjugated by the liver cells, mainly to its monosulfate. Several lignans and the isoflavonoids daidzein and equol were found to compete with estradiol for binding to the rat uterine type II estrogen binding site (the s.c. bioflavonoid receptor). It is suggested that lignans and isoflavonoids may affect uptake and metabolism of sex hormones by participating in the regulation of plasma SHBG levels and in this way influence their biological activity and that they may inhibit cancer cell growth like some flavonoids by competing with estradiol for the type II estrogen binding sites.

We studied 27 postmenopausal women, 9 vegetarians, 10 omnivores, and 8 apparently healthy women with breast cancer (BC), four times during 1 y. Dietary intakes were recorded and plasma androgens and sex-hormone-binding globulin (SHBG) binding capacity were determined. Androstenedione (A), testosterone (T), free T (FT), and SHBG were higher in omnivores than in vegetarians. In multiple correlation analysis, intakes of protein and fat were positively correlated with A, T, and FT, whereas the intakes of carbohydrate, grain, total fiber, and grain fiber showed the opposite correlations. Protein intake was positively correlated with percentage FT (%FT) and negatively with SHBG. BC patients had a similar pattern to omnivores with even higher levels of A and T (significant compared with vegetarians) and they showed significantly higher FT and lower SHBG than both control groups. We conclude that a Western-type diet in postmenopausal women is associated with high A, T, %FT, FT, and low SHBG and this pattern was apparent in the BC patients.

The urinary estrogen profile was studied in the midfollicular phase twice, and diet four times during 1 yr in 10 premenopausal breast cancer (BC) patients consuming an omnivorous normal Finnish diet and in two control groups, one consuming an omnivorous (n = 12) and the other a lactovegetarian (n = 11) diet. Total fat intake in relation to caloric intake was almost identical in all three groups. Only with regard to grain fiber intake did the BC patients differ significantly from both other groups. No differences were found between the groups with regard to urinary excretion of 13 individual estrogens and total estrogens, with the exception of 4-hydroxyestrone (4-OH-E1), which was significantly lower (P less than 0.05) in the BC group than in the vegetarians. A high carbohydrate to protein ratio in the diet had a negative correlation with the excretion of 2-hydroxyestrogens and 2-hydroxyesterone (2-OH-E1) to 4-OH-E1 ratio. The BC group had significantly higher urinary 2-OH-E1 to E1 ratio (P less than 0.05) compared to the vegetarians. The 2-OH-E1 to 4-OH-E1 ratio was highest in the BC group (= 7.1) and differed significantly from that of the omnivores (= 4.3; P less than 0.02) and vegetarians (= 3.6; P less than 0.005). This ratio showed a negative correlation with intake of carbohydrates, starch, total and grain fiber. Urinary excretion of 4-OH-E1 correlated positively with total and grain fiber intake and plasma SHBG. Protein intake correlated positively with urinary 2-methoxy-E1 excretion, and retinol intake positively with catechol estrogen, E1 and E2 excretion. It is concluded that estrogen production and urinary estrogen profile in premenopausal breast cancer patients is normal with the exception of a low 4-OH-E1 excretion and high urinary 2-OH-E1 to 4-OH-E1 ratio. This ratio, which seems to depend on diet, is the only urinary estrogen parameter separating premenopausal BC patients from the control omnivorous and lactovegetarian women.