Stener Kvinnsland

Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis

PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.

Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III).

Women with both a history of high grade cervical intraepithelial neoplasia (CIN III) and breast carcinoma as second primary cancer were selected for studying the presence of HPV in breast carcinomas. Paraffin embedded material from 38 patients with 41 breast carcinoma cases after CIN III were examined by polymerase chain reaction (PCR) and in situ hybridization. By PCR we detected HPV 16 DNA in 19 out of 41 cases (46%) of the breast carcinomas. One case proved to be HPV 16 positive also by in situ hybridization. HPV 16 was also detected in 32 out of the 38 patients with CIN III (84%). All HPV 16 positive breast carcinomas were HPV 16 positive in their corresponding CIN III lesions. Eight patients with diagnosed breast cancer before the CIN III lesions were used as controls. None of these had HPV positive breast carcinomas. No cases were positive for HPV 11, 18, or 33. HPV 16 was detected in the primary tumours, in local metastases from HPV 16 positive tumours, in a distant HPV 16 positive breast carcinoma metastasis to the colon, and in other primary cancers in patients with HPV 16 positive breast carcinomas and HPV 16 positive CIN III. Estrogen and progesterone receptors were quantified in the HPV positive and HPV negative breast carcinomas, and there was no significant difference in the fraction positive in the two groups. Oncogenic HPV DNA might be transported from an original site of infection to other organs by blood or lymph, and possibly be a factor in the development of cancer in different organs.

Prospective Study of Height, Body Mass Index and Risk of Breast Cancer

The associations of breast cancer risk with height and body mass index have been examined in 291 cases of breast cancer that occurred among 25,967 Norwegian women during a mean follow-up of approximately 14 years (range 12-16 years). There was an overall increased risk of breast cancer with increasing body height, and the relative risk of women in the fourth quartile of height (mean = 170 cm) was 1.43 (95% confidence limits, 1.18-1.73) compared to women in the lowest quartile (mean = 155 cm), after adjusting for age, parity, age at first birth, and county of residence. Simultaneously, there was an overall inverse relation between body mass index (BMI) and breast cancer risk, which, however, was confined to women 50 years or younger. After adjustment for age, parity, age at first birth, and county of residence, the relative risk of women (less than or equal to 50 years) in the highest quartile of BMI (mean Quetelet = 30) was 0.63 (95% confidence limits, 0.48-0.82), compared to women in the lowest (mean Quetelet = 21). We propose that the lower breast cancer risk in shorter women may reflect caloric restriction during the pre- and peripubertal period, which may affect hyperplastic growth, and lead to a reduced number of breast tissue cells. The negative association with BMI may be related to a lower rate of cell division of breast tissue among obese premenopausal women.

Body height and risk of breast cancer. A prospective study of 23,831 Norwegian women.

The association between body height and the incidence rate of breast cancer has been examined in 236 cases of breast cancer that occurred among 23,831 Norwegian women during 11-14 years of follow-up. At the time of height measurement they were 35-51 years of age. The age-adjusted incidence rate ratio (IRR) of breast cancer was 2.03 (95% of confidence limits 1.36 and 3.01) for women taller than or equal to 167 cm (mean = 170 cm) compared to women who were less than 159 cm (mean = 155 cm). The positive association with height was stronger among women who were diagnosed before the age of 51 (IRR = 2.63; 95% confidence limits 1.48 and 4.68), than among women diagnosed after this age. Moreover, the association appeared to be confined to women who had lived through their peripubertal growth during a period (1940-45) of nationally increased nutritional variability with reduction in dietary fat and restricted caloric intake. Among women born between 1929 and 1936, the relation with height displayed a strong positive linear trend (chi 2 trend = 13.4, P less than 0.001), which was not present among women born between 1925 and 1928 (chi 2 trend = 0.7, P = 0.40), nor among women born in 1937 or later (chi 2 trend = 1.5, P = 0.20). We hypothesise that a time-dependent diversity in nourishment, which may be of particular importance for women in their peri-menarcheal development, may explain the different association between body height and breast cancer risk that was observed for women in different birth cohorts.

CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING OF THE BREAST

Contrast-enhanced magnetic resonance imaging (MRI) of 28 patients with known breast tumors was compared with clinical findings and histopathology, and for 12 of the patients also with mammography. The dynamic measurements performed in 18 patients showed that signal intensity in gradient echo (FFE) images increased rapidly in malignant tumors after contrast injection and reached a plateau level at 1-3 min postcontrast. Fibroadenomas showed slower contrast enhancement continuing throughout the whole examination period of 10 min. The most enhancing parts of the tumors were selected for intensity measurements. The differentiation between malignant and benign tumors in dynamic contrast-enhanced MRI was in accordance with the histopathological findings in all cases. The tumor diameter as measured by MRI showed very good agreement with the size of the tumor specimens. Comparison of tumor size measurements in mammography and MRI showed that MRI had the most accurate correlation to the measured size of the tumor specimens.

Overall survival of breast cancer patients in relation to preclinically determined total serum cholesterol, body mass index, height and cigarette smoking: a population-based study.

Mean overall 5-year survival related to preclinically determined total serum cholesterol, body mass index (BMI), height and cigarette smoking has been analysed among 242 incident cases of breast cancer aged 36-63 years that developed in a population of 24,329 Norwegian women during a mean follow-up of 12 years (range 11-14). The study factors were ascertained at least 1 year prior to diagnosis (mean = 8 years), and the cases have been followed up with respect to death for a mean time of approximately 5 years after diagnosis. Patients whose preclinical total serum cholesterol values were within the highest quartile (greater than or equal to 7.52 mmol/l, mean = 8.58 mmol/l) of the underlying population had a hazard ratio of dying of 2.0 (95% confidence limits, 1.1 and 3.7) compared to cases with cholesterol values in the lowest quartile (mean = 5.28 mmol/l), after adjustment for age at diagnosis, clinical stage, and body mass index. In relation to BMI (Quetelets index: weight/height2) patients who were obese prior to diagnosis were at higher risk of dying than those who were lean. Compared to patients in the lowest quartile of BMI (mean Quetelet = 21), the hazard ratio was 2.1 (95% confidence limits, 1.2 and 3.8) for patients in the highest quartile (mean Quetelet = 30), after adjustment for age at diagnosis, clinical stage, and total serum cholesterol. For height and for cigarette smoking, no relation with survival was observed. A potential problem of this study might be insufficient information about other well known prognostic factors, but the results suggest that preclinical total serum cholesterol and BMI are positively associated with the risk of dying among women who develop breast cancer.

Does early physical maturity influence breast cancer risk

Earlier onset of menarche and tallness in adult women are mainly confirmed as risk markers for breast cancer. Recent disparate case-control studies have reported abdominal-type obesity and higher circulating levels of insulin, testosterone and insulin-like growth factor 1, to be further risk markers for breast cancer. There is evidence that abdominal-type obesity is recognisable in girls even before puberty, and disparate studies have shown it to be correlated with earlier onset of menarche, insulin resistance leading to hyperinsulinaemia, and an abnormal sex steroid profile. The implications are that earlier onset of puberty in a subset of girls can lead to more prolonged exposure of developing breast tissue to an abnormal sex steroid profile and also to a higher circulating level of insulin. It is postulated that these metabolic/endocrine concomitants of abdominal-type obesity could play a role in promoting mammary carcinogenesis at a young age, particularly if genetic predisposition is present.

Plasma changes in breast cancer patients during endocrine therapy — lipid measurements and nuclear magnetic resonance (NMR) spectroscopy

SummarySide-effects following long-term endocrine therapy might have clinical implications. The aim of this study was to study potential methods to detect effects on plasma induced by hormonal therapies. The composite methylene (chemical shift between 1.2-1.4 ppm) and methyl (0.8-0.9 ppm) aliphatic peaks of the1H magnetic resonance spectrum (500 MHz) were analyzed in consecutive plasma samples of 23 cancer patients drawn before and during treatment with hormonally acting drugs. The aliphatic peaks were analyzed for line width at half-height and then averaged. In addition,13C magnetic resonance spectroscopy (125 MHz) analyses were done in selected patients. The blood samples were analyzed for triglyceride, cholesterol, apolipoprotein A1 (apo A1), and apolipoprotein B (apo B) levels.The methylene line width increased significantly after 9 weeks of tamoxifen (41.4 vs. 37.6 Hz). A trend of differences was observed in the saturated part of the13C magnetic resonance spectrum. A significant decrease in total cholesterol (mean decrease, 13%), increases in apo A1 (9%) and in the ratio of apo A1 to apo B (28%), but unchanged total triglycerides were found, indicating a decrease in LDL and increase in HDL lipoproteins in these patients following tamoxifen therapy. During dose escalation with the aromatase inhibitor exemestane, the methylene line width seemed to decrease (31.9 vs. 38.8 Hz, at 12 weeks and baseline, respectively). Significant decreases in total (13%) and HDL (32%) cholesterol, apo A1 (25%), and total triglyceride (16%) levels were found during the same interval. The apo A1/apo B ratio decreased by 25%. For patients on dexamethasone, the proton aliphatic line widths increased one day after the initiation of therapy. The changes in line shape observed during dexamethasone therapy indicated lower levels of triglyceride-rich relative to triglyceride-poor lipoproteins, consistent with results from the lipid analyses.In conclusion, nuclear magnetic resonance spectroscopy might have potential to detect effects on plasma induced by endocrine therapy. The lipid analyses in these patients were in support of the changes in lipid profile as evaluated by nuclear magnetic resonance spectroscopy.

Cigarette smoking and risk of breast cancer: a prospective study of 24 329 Norwegian women

Abstract The association between cigarette smoking and incidence of breast cancer has been analyzed in 242 cases of breast cancer that developed among 24 329 Norwegian women over 11–14 years of follow-up. At baseline they were aged 35–51. There was no overall association between cigarette smoking and the risk of breast cancer. The age-adjusted incidence rate ratio (IRR) was unity (IRR=1.04, 95% CI 0.76–1.42) for regular smokers (10 or more cigarettes daily) compared with non-smoking women. In women who reported smoking between 1 and 9 cigarettes per day there was an age-adjusted IRR of 1.28 (95% CI 0.95–1.73). The lack of association with cigarette smoking was replicated in subgroup analyses of women diagnosed before age 51 (“premenopausal”) and among women diagnosed after this age (“postmenopausal”). However, there was a significant interaction between cigarette smoking, body mass index and age at diagnosis ( P = 0.01), which might indicate that an interaction between cigarette smoking and body mass exerts differential effects on breast cancer risk in premenopausal and postmenopausal women.

Droloxifene--a new anti-estrogen. A phase II study in advanced breast cancer.

Twenty-six patients with advanced breast cancer were treated with a new anti-estrogen, Droloxifene (3-hydroxy-tamoxifen). They had all used tamoxifen either in the adjuvant or the advanced situation. The dose schedule was 100 mg orally daily. Partial remissions were observed in 4 (15%) of the patients, and in another 5 patients stable disease (greater than 24 weeks of duration) was observed. Three of the responders were resistant to tamoxifen. Fourteen of the 26 patients had no side-effect. In 2 patients therapy had to be stopped due to fatigue. Droloxifene seems to be an interesting new anti-estrogen which should be further exploited.