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Examination of the effect of nongenetic risk factors on the familial risk of breast cancer among relatives of postmenopausal breast cancer patients.

Relatives of postmenopausal breast cancer patients have a greater risk of breast cancer than do women with no family history of the disease. However, no study has previously examined the contribution of other breast cancer risk factors to risk in these relatives, thus precluding the ability to discern between shared environment or genes as the cause of familial aggregation. We conducted a nested case-control study of 251 index case families and 234 index control families. Incident breast cancer cases occurring in 1988-1989 and cancer-free controls were selected from a prospective cohort study. A pedigree development form was mailed to identify female relatives, who were then mailed a health history questionnaire. Index cases were significantly more likely than index controls to have at least one first-degree female relative with breast cancer [odds ratio = 1.62; 95% confidence interval = 1.03-2.54] after controlling for the total number of first-degree female relatives. After excluding the index cases and controls, logistic regression models were used to predict the odds of breast cancer in sisters (n = 72 cases). Sisters of index cases had slightly, although not statistically significant, elevated risk of both early-onset (age < 50 years; odds ratio = 1.34; 95% confidence interval = 0.54-3.30) and late-onset (age > or = 50 years; odds ratio = 1.56; 95% confidence interval = 0.87-2.79) breast cancer. Adjustment for nongenetic risk factors increased the odds ratio to 1.41 and 1.81, respectively. These data suggest that risk to sisters of postmenopausal breast cancer cases may be increased for both early- and late-onset breast cancer and this risk is apparently independent of measured risk factors.

Aged↗

Psychological and psychosocial aspects of breast cancer and breast cancer treatment. A literature review.

The aim of the investigation was to study psychological and psychosocial aspects of breast cancer. A literature search was done covering the period 1989-1992. The following research areas were studied: the relationship between psychological characteristics and breast cancer, and between psychosocial interventions and breast cancer; quality of life after breast cancer surgery and treatment; and the relationship between social support and breast cancer. The results showed that the medical community is divided into "believers" and "nonbelievers" with respect to whether or not psychosocial factors influence breast cancer outcomes. One of the best predictors of a women's postcancer adjustment is her psychological state before the breast cancer. The results also showed that the difference in psychological outcome between mastectomy and breast-conserving surgery was small and nonsignificant. Another finding was that the social context and social support from partner, family, friends, relatives and medical professions are important for survival. In conclusion, methodological problems were common in studying psychological and psychosocial aspects of breast cancer.

Breast Neoplasms↗

[Analysis of the results of 137 subclinical breast lesions excisions. Value of ultrasonography in the early diagnosis of breast cancer].

OBJECTIVE: Ultrasonography is invaluable for evaluation of palpable masses and masses detected by mammography. Ultrasound has no proved role in breast screening. Between 1991 and 1994, we included ultrasonography routinely in our screening mammography prescription, not only for evaluation of mass detected by mammography but also in radiographically dense, non-radiolucent breast. One hundred and thirty-seven suspicious but non palpable breast lesions were detected. We analyzed the results of the surgical excision biopsies of these lesions and evaluated the contribution of ultrasonography combined with mammography to detect occult breast cancers. MATERIAL AND METHODS: From 1991 to 1994, our institution performed 8,489 individual screening mammographies. All women underwent physical examination before mammography. Women with abnormal clinical breast examination are not included in the study. Ultrasonography was routinely performed for characterization of a mass detected by mammography and also in normal breast with dense, non-radiolucent tissue. One hundred and thirty-seven suspected breast lesions were removed after immediate preoperative stereotaxic or US-guided needle localization. Screened women were aged 29-72 years (mean 51 years). 48% of all screened women were aged 50 years and older. RESULTS: The histopathologic findings were as follow: invasive ductal carcinoma (IDC) 40 cases (59%), invasive lobular carcinoma (ILC) 7 cases (10%), ductal carcinoma in situ 21 cases (31%). Infracllnic cancer was identified by mammography alone in 45% of cases, by mammography and sonography in 43.2% of cases, by sonography alone in 11.8% of cases. About 31% of infraclinic cancer occur prior to the age of 50 (age range: 29-72, mean: 54). Cancer less than 10 mm in diameter were found in 57.5% of lesions. Axillary dissection was performed in 46 cases of invasive cancer, with a incidence of axillary node metastases of 15%. CONCLUSION: The combination of mammography and ultrasonography is effective to detect a greater number of occult breast cancers and we recommend ultrasonography not only for evaluation of a mass detected by mammography but also in radiographically dense non-radiolucent breast lesions.

Adult↗

[Hormone replacement therapy and cancer of the breast. 1. Does replacement therapy increase the risk of cancer of the breast?].

It has been extensively demonstrated that hormonal replacement therapy (HRT) constitutes an effective treatment of menopausal symptoms. There is also substantial epidemiological evidence suggesting that this treatment protects women against cardiovascular disease and osteoporosis. The possible increase in breast cancer risk appears as its principal disadvantage and is often invoked as the reason why both doctors and patients decline this therapy. In this paper we review the current knowledge on HRT and breast cancer risk. A computerised bibliographical search (MEDLINE) of literature in the English language published in the last 15 years was conducted, followed by a manual search of references. We focused our attention on four main questions: 1) Does HRT increase the risk of breast cancer? 2) Are different doses and drugs associated with different risks? 3) What effect on risk have the association of a progestin does? 4) Does HRT increase the risk of breast cancer in women with major risk factors for the disease? Overall, epidemiological studies suggest that women who have used HRT before have a slightly higher risk of breast cancer than those who have never used it, in most studies not exceeding 10%. The use of HRT for less than 5 years does not seem to be associated with increased risk, while some studies have shown relative risks in the order of 1.20-1.30 with therapies exceeding 10-15 years in duration. Different doses of conjugated equine estrogens do not seem to be associated with different risks of breast cancer. Data on the risk of other estrogen preparations is scarce and far from conclusive, but the majority of studies suggest a similar risk to that of conjugated estrogens. Evidence on opposed HRT is also scarce and contradictory. A substantial body of evidence exists to suggest that HRT in women with benign breast disease does not increase the risk of breast cancer. Data on HRT in women with a family history of breast cancer is inconclusive; some studies have found an increased risk with this therapy, while others have found no difference. It has to be taken into account that current knowledge on this subject is based on observational studies subject to numerous bias, evaluating dissimilar populations and mostly conducted with currently less favoured HRT regimens, such as unopposed conjugated estrogens. Studies on the currently prevailing HRT regimens are urgently needed.

Breast Neoplasms↗

Risk factors for breast cancer in women with a breast cancer family history.

Family history (FH) is an important indicator of a woman's future risk of developing breast cancer. Using data collected in a large population-based case-control study (6705 cases and 9341 controls), we examined the associations of breast cancer with known risk factors in women reporting a first-degree FH (mother or sister), with an emphasis on lifestyle determinants that may be altered to reduce risk. First-degree FH was reported by 18.4% (n = 1234) of cases and 11.3% (n = 1058) of controls; the overall relative risk (RR) for breast cancer associated with a positive history was 1.70 [95% confidence interval (CI), 1.55-1.87] and 2.34 (95% CI, 1.80-3.02) for breast cancer at age 45 years or younger. Among women with a FH, statistically significant inverse associations were observed for increasing parity (RR per birth = 0.90; P < 0.0001), intake of carotene-rich foods (RR for >2000 IU/day = 0.73; P = 0.02), and strenuous activity as a young adult (RR per episode/week = 0.93; P = 0.02). Recent alcohol consumption increased risk (RR per 13 g/week = 1.21; P = 0.02), as did weight gain during adult life in postmenopausal women (RR per 5 kg = 1.08; P = 0.001). Breast-feeding for any duration was associated with a lower RR in parous, premenopausal women (RR = 0.59; P = 0.04). Associations for most risk factors with breast cancer were similar among women with and without a FH of breast cancer; however, a stronger inverse association was observed for parity in women with a positive history (P for interaction = 0.04). Based on these data, women with a FH may reduce their excess risk of breast cancer through adjustments in lifestyle and reproductive choices. The risk associated with FH of breast cancer seems to be largely independent of other known risk factors.

Adolescent↗

mRNA expression of components of the insulin-like growth factor system in breast cancer cell lines, tissues, and metastatic breast cancer cells.

IGF-1 and 2 are thought to be important growth factors for breast cancer. However, gene expression of IGFs or IGF receptors in breast cancer tissues, and especially in metastatic breast cancer cells, is not well known. Expression of mRNA encoding for IGF-1, IGF-2, IGF-receptor 1 and 2, IGF binding proteins- 1 to -6, insulin receptor and insulin was determined in the NIH MCF-7 breast cancer cell line, in specimens from breast cancer tissues, and in 6 primary breast cancer cell cultures obtained from metastatic breast cancer, using rT-PCR technique. Specific mRNA sequences encoding for IGF-receptor 1 and 2, IGFBP-2, -4 and insulin receptor were identified in all cell cultures and most of the tissue specimens. Though in most of the tissues additional expression of IGF-1 and IGF-2 was detected, there was no mRNA encoding for these proteins in MCF-7 cell cultures as well as in the primary cell cultures of metastatic breast cancers. In none of our specimens mRNA encoding for IGFBP-1, -3, -5, -6 and insulin was detectable. IGF-receptor expression in cancer tissues and metastatic breast cancer cells supports the hypothesis that IGFs increase tumor cell proliferation in vivo. Expression of IGF-1 and IGF-2 in tumor tissues but not in cancer cell cultures indicates an IGF expression located predominantly in stromal parts of cancer tissues.

Breast Neoplasms↗

Analysis of telomerase activity levels in breast cancer: positive detection at the in situ breast carcinoma stage.

Telomerase activity has been implicated to be associated with most human malignant tumors, including breast cancer. To evaluate possible associations with well-known prognostic factors in breast cancer, we performed a semi-quantitative analysis of telomerase activity levels using the very sensitive PCR-mediated telomeric repeat amplification protocol. Telomerase activity was detected in 99 of 104 breast cancer samples analyzed (95.2%), whereas no activity was detected in 10 of 10 adjacent nonmalignant breast tissues. Analysis of five breast fibroadenoma samples revealed telomerase activity in one (20%). In contrast to previous observations, we observed that 100% of stage I breast tumors were positive for telomerase activity. More interestingly, we detected telomerase activity in six of six ductal carcinoma in situ samples (i.e., stage 0). In our semiquantitative analysis of levels of enzymatic activity, we found no statistically significant correlation at the P < h 0.05 level between telomerase levels and lymph node metastasis status, estrogen and progesterone receptor status, tumor size, S-phase fraction, and ploidy. The only statistically significant correlation was found with patient age (rho = -0.3; P = 0.03). We observed no statistically significant difference in the telomerase activity levels of early tumors (stages 0 and 1) versus more advanced lesions (stages II to IV). Nevertheless, stage IV tumors displayed a tendency for higher telomerase activity levels. In summary, no clear association was observed between telomerase levels and known breast cancer prognostic indicators. However, telomerase detection by the telomeric repeat amplification protocol method, due to its high sensitivity, may be of value in early breast cancer diagnosis and detection, because our data indicate that telomerase reactivation appears to constitute a relatively early event in breast carcinogenesis.

Biomarkers, Tumor↗

The etiology and prediction of breast cancer. Fourier transform-infrared spectroscopy reveals progressive alterations in breast DNA leading to a cancer-like phenotype in a high proportion of normal women.

BACKGROUND: The authors previously have shown by gas chromatography-mass spectrometry that the hydroxyl radical (.OH) induces alterations in the DNA base structure of the female breast, which are premalignant markers of breast cancer. Fourier transform-infrared (FT-IR)-spectroscopy also has a high potential for revealing a broad array of structural changes in DNA that may provide important new insight into breast cancer etiology and prediction. METHODS: DNA from normal reduction mammoplasty tissue, invasive ductal carcinoma, and nearby microscopically normal tissue was analyzed by FT-IR spectroscopy. Statistical models based on DNA spectral properties were developed and compared with a statistical model previously used with base modifications. RESULTS: Substantial differences were found in the spectral properties of DNA from women with normal and cancerous breast tissue, indicating an ability to discriminate cancerous tissue from noncancerous tissue with a sensitivity and specificity of 83%. Most importantly, the normal population was divided into subgroups in which a nonrandom progression was identified and a cancer-like DNA phenotype that was highly correlated (r > or = 0.90) with that of the patients with cancer was exhibited in 59% of the women. The spectral data, which also were highly correlated with the base-model data, were used to establish a model for predicting the probability of breast cancer. Consistent with the high cancer reoccurrence rate in the ipsilateral breast, 8 of 10 of the microscopically normal tissue specimens remaining after tumor excision were classified as cancerous using this model. CONCLUSIONS: Progressive structural changes in the DNA of the normal female breast, leading to a premalignant cancer-like phenotype in a high proportion of women, are the basis for a new paradigm for understanding the etiology of breast cancer and predicting its occurrence at early stages of oncogenesis. The results also suggest therapeutic strategies for potentially reversing the extent of DNA damage, which may be useful in disease prevention and treatment.

Breast↗

Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinoma.

BACKGROUND: Intensive screening is an alternative to prophylactic mastectomy in women at high risk for developing breast carcinoma. The current article reports preliminary results from a screening protocol using high-quality magnetic resonance imaging (MRI), ductal lavage (DL), clinical breast examination, and mammography to identify early malignancy and high-risk lesions in women at increased genetic risk of breast carcinoma. METHODS: Women with inherited BRCA1 or BRCA2 mutations or women with a >10% risk of developing breast carcinoma at 10 years, as estimated by the Claus model, were eligible. Patients were accrued from September 2001 to May 2003. Enrolled patients underwent biannual clinical breast examinations and annual mammography, breast MRI, and DL. RESULTS: Forty-one women underwent an initial screen. Fifteen of 41 enrolled women (36.6%) either had undergone previous bilateral oophorectomy and/or were on tamoxifen at the time of the initial screen. One patient who was a BRCA1 carrier had high-grade ductal carcinoma in situ (DCIS) that was screen detected by MRI but that was missed on mammography. High-risk lesions that were screen detected by MRI in three women included radial scars and atypical lobular hyperplasia. DL detected seven women with cellular atypia, including one woman who had a normal MRI and mammogram. CONCLUSIONS: Breast MRI identified high-grade DCIS and high-risk lesions that were missed by mammography. DL detected cytologic atypia in a high-risk cohort. A larger screening trial is needed to determine which subgroups of high-risk women will benefit and whether the identification of malignant and high-risk lesions at an early stage will impact breast carcinoma incidence and mortality.

Adult↗

Localization of hyaluronan in normal breast tissue, radial scar, and tubular breast carcinoma.

Hyaluronan (hyaluronic acid [HYA]) is one of the extracellular matrix components involved in normal cell physiology and is localized mainly in bodily fluids and connective tissues. Increased amounts of HYA in serum have been demonstrated in a number of neoplastic and inflammatory conditions, among them breast cancer. Tubular breast carcinoma (TC) and radial scar (RS) are two breast lesions that microscopically display characteristic stromal alterations and possess gross and microscopic similarities. Due to the importance of HYA as a component of the extracellular matrix, we investigated its presence in these lesions and in normal breast tissue. Using a biotinylated HYA-binding region for the in situ detection of HYA, we noted an increased amount of HYA in both TC and RS as compared with that in normal breast tissue specimens. A strong reactivity was observed predominantly around glandular structures and in the interlobular stroma of both TC and RS. Perivascular HYA staining also was distinctly observed in these lesions (TC and RS). Some HYA was observed in the connective tissue of the intralobular regions, around small blood vessels, and in the perivascular connective tissue of the normal breast. The distribution of HYA adjacent to the epithelium in the normal breast suggests a role for HYA in the interaction between epithelium and stroma of the normal breast. Its increase in the connective tissue of both TC and RS reflects the derangement of the stroma commonly observed in these conditions and supports the notion that these lesions may be associated.

Adenocarcinoma↗

Mammographic densities and the prevalence and incidence of histological types of benign breast disease. Reference Pathologists of the Canadian National Breast Screening Study.

There is now a large amount of evidence indicating that women with extensive areas of mammographic densities are 4-6 times more likely to develop breast cancer than those with little or no density in the mammogram. We have examined one potential biological explanation for this association by estimating the incidence of various histological types of benign breast disease in relation to mammographic density. We studied the large cohort of women taking part in the National Breast Screening Study (NBSS), a randomized trial of screening with mammography. Mammograms from subjects with biopsies (n = 423) and from a comparison group of subjects randomly selected from the NBSS (n = 465) were included. Histological slides from biopsied subjects (n = 353) were classified independently by the pathologists of the NBSS and by a review pathologist (H.M.J.). Mammographic density in more than 75% of the breast area was associated with an increased risk of incidence of hyperplasia without atypia, and of atypical hyperplasia and/or carcinoma in situ. The classifications of the review pathologist showed that, compared to women with no density, the relative risk of incident lesions for women with density in more than 75% of breast was 13.85 (95% CI 2.65-72.49) for hyperplasia, and 9.23 (95% CI 1.66-51.48) for atypical hyperplasia and/or carcinoma in situ. These findings suggest that the association between extensive mammographic density and breast cancer risk may, at least in part, be attributable to biological processes in the breast that give rise to these histological features that are known to be related to breast cancer risk.

Adult↗

Risk of breast cancer in Japanese women with benign breast disease.

To investigate the risk of breast cancer development in women with benign breast disease (BBD), 387 screen-detected BBD women and 1,489 normal women, taken from participants in the breast cancer screening program during 1978-1986, were followed through 1991. While 2,811 person-years in the BBD group and 11,018 person-years in the normal group were accumulated, 5 women in the BBD group and 6 women in the normal group developed breast cancer. Using the Mantel-Haenszel method, relative risks (RR) were estimated for all women with BBD and women in some BBD types. Significantly elevated risk of breast cancer was observed in all women with BBD (RR = 3.26, 95% confidence interval (CI) 1.08-9.83). Women with proliferative BBD were at high risk of breast cancer (RR = 8.48, 95% CI 2.99-24.10), but no increased risk was observed for women with non-proliferative BBD (RR = 0.93, 95% CI 0.11-7.66). These results are consistent with those in high-risk countries for breast cancer. In the management of women with BBD, histopathological diagnosis of the breast lesion is essential and women with proliferative BBD should be followed up carefully.

Adult↗

Expression of platelet-derived growth factor B-chain and the platelet-derived growth factor receptor beta subunit in human breast tissue and breast carcinoma.

Breast carcinomas are known to express platelet-derived growth factor (PDGF), a known connective tissue mitogen. In order to further evaluate the potential role of PDGF in these epithelial tumors, expression of the PDGF B chain (PDGF-B) and the PDGF receptor beta subunit (PDGFR) was analyzed by immunocytochemistry and in situ hybridization in 49 benign and malignant breast tissues. PDGF-B expression was analyzed with respect to the expression of the proliferating cell nuclear antigen, as well as tumor grade, p53 overexpression, estrogen receptor, progesterone receptor, and c-erbB-2 expression. Expression of PDGF-B protein and mRNA was restricted to the breast epithelium and tumor cells except for scattered tissue macrophages. A strong correlation was found between increasing proliferating cell nuclear antigen indices and PDGF-B expression in both nonmalignant (P = 0.01) and malignant (P = 0.02) breast specimens. Decreased PDGF-B expression was found in postmenopausal atrophic breast tissue compared with normal breast tissue (P = 0.04). Within the subgroup of malignant tumors, no correlations were found between PDGF-B expression and tumor grade or p53 overexpression. In 16 of the malignant tumors evaluated for estrogen/progesterone receptor status and c-erbB-2 overexpression, no correlations with PDGF-B expression were found. Membranous PDGFR immunostaining was present within the fibroblastic cell population in all of the tissues examined but not in the nonmalignant breast epithelium. Six malignant specimens had detectable cytoplasmic expression of PDGFR. There was no correlation between this PDGFR expression and proliferating cell nuclear antigen indices, but a correlation was noted between increasing estrogen receptor expression and PDGFR cytoplasmic expression (P = 0.04). The results support a paracrine role for PDGF-B in malignant and benign breast epithelial cell proliferation.

Atrophy↗

Risk factors for breast cancer mortality among the National Breast Screening Study of Canada participants.

We studied the relationship between risk factor information and breast cancer mortality by means of a case control study, nested within the population of the National Breast Screening Study of Canada (NBSS). The characteristics of women aged 40-59 years, identified at the initial screen, who subsequently died of breast cancer up to 7 years from the initial screen, were compared with those of controls drawn from the same population. Among the factors evaluated in this study, number of live births and presence of symptoms in the breast revealed on direct questioning were found to be significantly related to breast cancer mortality. The results suggest a decrease in risk of dying of breast cancer associated with one or more live births (OR: 0.79, 95% CI: 0.68, 0.93), and an increase in risk of dying of breast cancer associated with symptoms in the breast revealed on direct questioning at the initial screen (OR: 2.01, 95% CI: 1.20, 3.37).

Adult↗