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Usefully requesting and applying serum tumour markers in diagnosis and treatment can be difficult. It should be noted that tumour markers are used for varying purposes: screening, diagnosis, staging and prognostic evaluation, detection of recurrence and treatment monitoring. Due to the poor sensitivity and specificity of current tumour markers, most are not suitable for screening an asymptomatic population. Further, the benefits of an improved prognosis by early detection should be weighed against a poorer quality of life and the cost of substantial over-diagnosis and over-treatment. Serum tumour markers are particularly applicable in treatment monitoring and detection of recurrence. Sometimes they can be used to support the diagnostic process and give useful prognostic information.

Insulin-like growth factor I (IGF-I) is a potent mitogen for human breast-cancer cells in vitro. In circulation, most of IGF-I is bound to IGF-binding protein 3 (IGFBP-3). This high-affinity binding is thought to have an important limiting effect on the availability of IGF-I for biological activity. To assess the availability of IGF-I for receptor binding, we determined serum levels of IGF-I and IGFBP-3 and IGF-I/IGFBP-3 ratios. In a case-control study, 150 women aged 38 to 75 years presenting with stage-I or -II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population-based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF-I serum concentrations, decreased IGFBP-3 levels and increased IGF-I/IGFBP-3 ratios. The IGF-I/IGFBP-3 ratio was a significant breast-cancer risk factor, also after adjustment for age, family history, height, body-mass index, body-fat distribution, and serum levels of C-peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF-I/IGFBP-3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF-I in the circulation of pre-menopausal women may contribute to the development of breast cancer.

Life-style has a major influence on the incidence of breast cancer. To evaluate the effects of life-style related metabolic-endocrine factors on breast cancer risk we conducted a case-control study comparing 223 women aged 38 to 75 years presenting with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer, who participated in a population-based breast cancer screening program. Women reporting diabetes mellitus were excluded. Sera from 110 women of the same age group presenting with early stage melanoma, lymphoma or cervical cancer were used as a second 'other-cancer control group'. Serum levels of C-peptide were significantly higher in early breast cancer cases compared to controls. The same was found for the ratios C-peptide to glucose or C-peptide to fructosamine, indicating insulin resistance. Sex hormone binding globulin was inversely, triglycerides and available estradiol were positively related to C-peptide. Serum C-peptide levels were related to body mass index (BMI), and to waist/hip ratio (WHR), in particular in controls. However, the relative increase of C-peptide, C-peptide to glucose or C-peptide to fructosamine in cases was independent of BMI or WHR. The log relative risk was linearly related to the log C-peptide levels. Relative risk according to quintiles, and adjusted for age, family history, BMI and WHR, for women at the 80% level was 2.9 as compared with those at the 20% level for C-peptide. Elevated C-peptide or C-peptide to fructosamine values were not observed in the sera from women belonging to the 'other-cancer control group'. This study suggests that hyperinsulinemia with insulin resistance is a significant risk factor for breast cancer independent of general adiposity or body fat distribution.

Recent studies on lifestyle-related mechanisms involved in cardiovascular risk offer important clues for a better understanding of breast-cancer epidemiology. Central body-fat distribution promoted by an affluent dietary intake and a sedentary lifestyle over many years is related to elevated serum triglycerides and free fatty acids, with lower levels of sex-hormone-binding globulin (SHBG). The resulting greater availability of estradiol not bound to SHBG could help to explain the high breast-cancer incidence in Western industrialized countries. We conducted a case-control study comparing 225 women aged 38 to 75 years with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer who participated in a population-based breast-cancer screening program. Body fatness, as measured by body mass index (BMI), fat distribution as measured by waist-to-hip girth ratio (WHR), body height, serum lipids, SHBG and the available fraction of estradiol were analyzed in a conditional logistic regression, together with family history for breast cancer, reproductive history and smoking. Post-menopausal cases showed no difference in body fatness (BMI), but a significant preponderance of central adiposity (WHR). In contrast, pre-menopausal cases were significantly leaner, but had a similar body-fat distribution as compared with controls. In all women, WHR, and less strongly BMI, was positively correlated with serum levels of triglycerides and available estradiol fractions. An independent, positive linear correlation between body height and relative risk (RR) was observed. Moreover, a significant correlation between SHBG and menarcheal age was seen in cases, but not in controls. These data support our hypothesis that lifestyle relates to breast-cancer risk by metabolic-endocrine mechanisms which modulate the availability of individual sex-steroid concentrations in plasma. The findings of height as a risk factor and adult SHBG levels being correlated with menarcheal age suggest that lifestyle factors promoting breast-cancer development already act around puberty. The leanness of pre-menopausal cases awaits further explanation.

Clinical problems arise when histology is unable to differentiate between an ovarian carcinoma infiltrating into the rectosigmoid region and a colonic cancer with ovarian metastases. To evaluate the discriminative value of immunohistochemistry we studied four groups: (A) ovarian carcinoma (n = 21), (B) ovarian carcinoma with sigmoid stenosis (n = 18), (C) colonic carcinoma (n = 20) and (D) a group in which the differential diagnosis was a problem (n = 19). Paraffin sections stained with a panel of monoclonal antibodies revealed specific patterns: in group A and B a negative Parlam-4 and positive OC-125; in group C the opposite; in group D the 'colonic' pattern in 15 cases, and the 'ovarian' pattern in only 2. The clinical diagnosis in group D during follow-up was ovarian carcinoma in 7, colonic carcinoma in 8, double tumour in 1 and still unknown in 3. This was based on high levels of serum tumour markers such as carcinoembryonic antigen (n = 5) and CA-125 (n = 4), laparotomy (n = 4), autopsy (n = 1), barium enema and/or endoscopy (n = 5). The response to chemotherapy in group D was extremely poor.

The supposed mechanism of action of aminoglutethimide (AG), medical adrenalectomy, has been challenged. AG is now considered to act as an inhibitor of the aromatization of mainly adrenal androgens to estrogens in peripheral tissues and/or breast cancer itself. To further establish the AG dose required to sufficiently reduce estrogen levels in plasma and the possible role of hydrocortisone (HC) in combination with AG or by itself, postmenopausal advanced breast cancer patients received AG low (125 mg bid) or medium (250 mg bid) dose alone or combined with HC (20 mg bid) or HC alone (20 mg bid). Preliminary hormonal data show a similar reduction of serum estrone and estrone sulphate by at least some 50% at 8 wk in all treatment groups. At 6 months these effects persist except for patients treated with HC alone. In the latter a normalization of estrone levels is observed with effective suppression of adrenal androgen precursors, suggesting increased aromatase activity with prolonged glucocorticoid treatment.

It has recently been found by various authors that despite a normal serum concentration of oestradiol (E2), the percentage of non-protein-bound or free E2 is abnormally high in breast cancer patients. Since it is the free E2 which is considered to be biologically active, confirmation of this finding would be most relevant to the pathogenesis of breast cancer. Using Hammond's centrifugal ultrafiltration dialysis method we have measured free E2 in heparinized plasma from 68 premenopausal women (a) at high familial risk of breast cancer (n = 18), (b) with benign breast disease (n = 17), (c) cured of T1N0M0 breast cancer at least 6 months previously (n = 17) and (d) normal controls matched for age, parity and Quetelet index (n = 16). Sex hormone binding globulin (SHBG) was measured as [3H]-dihydrotestosterone binding capacity. Free E2 and SHBG were also measured in the serum of (e) postmenopausal patients having breast cancer (n = 38) and (f) matched control cancer patients (n = 67). We confirmed a very good inverse correlation between log free E2 per cent and log SHBG (P less than 0.0001). The regression lines for groups (a)-(d) were not statistically different. The regression lines for groups (e) and (f) were identical and ran nearly parallel to those for groups (a)-(d) though somewhat lower. This small difference may be ascribed to menopausal status. Therefore, we found no difference in free E2 percentage, calculated free E2 concentration or SHBG between premenopausal women at risk, women with benign breast disease, patients cured for early breast cancer or having breast cancer and matched controls. However, postmenopausal breast cancer patients had a significantly higher total serum E2 concentration and, by consequence a higher calculated free E2 concentration compared to the carefully matched control group.

A physiological in vivo increase of plasma free fatty acid concentration after an overnight fast was found to be accompanied by a rise of the non-protein bound estradiol fraction. A similar increase was observed after lipase activation by the i.v. injection of 500 IU heparin in 5 healthy non-fasting subjects. In vitro studies showed a direct relationship between non-protein bound estradiol and the concentration of linoleate, linolenate, and arachidonate both in undiluted serum and in Ringer's solution containing human serum albumin (45 g/liter). Moreover, the estradiol sex hormone binding globulin complex bound to a solid concanavalin A-Sepharose matrix was markedly dissociated by oleate and even more by linoleate, linolenate, or arachidonate. These results suggest that physiological diurnal elevations in plasma free fatty acids which are amplified by high fat consumption, obesity, and stress may imply major proportional increases of available estradiol, exerting a promotional effect on breast and endometrial cancer over the years.