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Purpose: To perform Preimplantation Genetic Diagnosis (PGD) on a paternal Brca2 unknown mutation carrier with early-onset breast cancer, whose paternal grandmother and mother had breast cancer at 60s., Method: Elucidating the linkage via single sperm haplotyping on patient's carrier brother, and identifying the genomic deletion via BLAST followed by PCR screening. PGD was subsequently conducted., Result: The mutant allele was found by using 4 microsatellite and 2 intragenic SNP markers. Recombination was detected in 8% of sperms. BLAST was utilized to locate putative hairpin structure(s), followed by PCR screening with seven sets of primers. A novel 2,596 bp deletion containing exon 15 ~ 16 was identified. Due to the severity of phenotype and the integrity of exon 11 encoding RAD51 binding domain, and the fact that the patient's mother also had breast cancer at her 60s, we speculate a possible coexistence of maternal breast cancer risk allele(s). Embryo biopsy was performed on day 3. Unaffected morula and blastocyst were replaced on day 5, resulting in a singleton livebirth. A breast lump appeared in the patient after delivery without the presence of malignant cells., Conclusion: Concerning the assisted reproductive option for breast cancer patients, the possibility of coexistence of multiple familial risk alleles and the significance of each mutation to the phenotype should be evaluated. To eliminate misdiagnosis resulting from recombination and/or allelic drop-out, both direct mutation detection and linkage analysis approaches may be necessary. BLAST is a very useful and cost-effective tool for identifying large genomic deletion.

Our study reports on the interval cancers arising in the subsequent 3 years in women screened as part of the Singapore Breast Cancer Screening Programme that commenced in 1994. Women, the majority of Chinese ethnicity, were either invited or not invited by random allocation to be screened. All women, other than those identified with breast cancer at screening, whether invited or not, were followed for 3 years, and information on all breast cancers arising in this period was obtained through the national registry. In particular, the cancers arising from those women who were deemed free of the disease at screening were noted. The mammographs taken at screening of those women who developed such an interval cancer were rereviewed by 3 radiologists. In the 28,099 women who were screened and deemed free of disease, 59 interval cancers were reported with annual rates of 2.1, 10.6 and 10.8 per 10,000 women-years in the succeeding 3-year periods. In 39,425 women who were invited but declined screening, the rates were 17.0, 15.5 and 11.7, while the corresponding rates from 97,294 women not invited were 12.8, 13.3 and 13.0. Whereas the annual incidence at 1 year in women who have been screened is much lower than those in the 2 groups who were not screened, it is of a similar magnitude by 2 years. This suggests that locally an optimal screening interval may be close to 1 year. The rereview of the mammograms of those 59 women with interval cancers suggested that the maximum possible number of these that might have been detected at screening was 10 (17%)., (Copyright 2002 Wiley-Liss, Inc.)

The study aimed to investigate whether self-reported dietary variables were associated with mammographic parenchymal patterns, which have been shown to predict risk of breast cancer. Among the 3,421 women, ages 45-74 years, common to two independent population-based cohorts, mammographic parenchymal patterns and current dietary habits were assessed for 406 randomly chosen participants. Logistic regression methods were used to compare dietary and other lifestyle profiles between subjects classified as displaying high (cases) and low risk (controls) parenchymal patterns. After adjustment for energy intake and other potential confounders, dietary soy protein intake was inversely related to risk of high-risk parenchymal pattern (odds ratio, 0.41; 95% confidence interval, 0.18-0.94, highest versus lowest quartile of intake). Similarly, the highest versus lowest quartile of dietary soy isoflavone intake was significantly related to low-risk parenchymal patterns (odds ratio, 0.44; 95% confidence interval, 0.20-0.98). The association between high soy intake and a reduced risk of mammographic parenchymal patterns that are associated with high breast cancer risk may have important implications in breast cancer prevention.

Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone- and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. In any case, undesired side effects of antiprogestin may create clinical complications. PR-transfected MDA-MB-231 breast cancer cells provide a model for studying the functions of progesterone analogues.

This study investigates seasonality in the diagnosis of 3219 female breast carcinoma cases reported between 1995-8 in Singapore. There is little evidence of marked seasonal variation. Angular regression suggested that observed differences in peak diagnosis with respect to menopausal status, tumour size, ER and PR status may be chance., (Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.)

Mammography detected 34 (25%) cases of ductal carcinoma in situ (DCIS) of the breast out of a total of 135 cancers diagnosed in 28, 231 participating women during the Singapore breast screening project. Radiologic findings in these 34 women with DCIS were calcifications only in 25 (74%); mass only in 2 (6%); and mass with calcifications in the remaining 7 (20%) cases. Calcifications were classified mammographically as powderish in 2 (6%), crushed stone-like in 16 (50%) and casting in 14 (44%) cases. Pathologic assessment revealed 11 (32%) cases with pure comedo, 16 (47%) mixed, 3 (9%) cribriform, 2 (6%) papillary, 1 (3%) micropapillary and 1 (3%) solid patterns. Histologic nuclear grade was low in 6 (18%), intermediate in 9 (26%) and high in 19 (56%). Necrosis was observed in 26 (77%) cases and absent in the rest. Pathologic-radiologic correlations yielded a significant association between the mammographic and pathologic lesional size, with the degree of agreement improved when there was histologic necrosis. A trend for radiologic crushed stone-like and casting-type calcifications to be associated with DCIS with necrosis and of higher nuclear grade was noted. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 231-236 (2000)., (Copyright 2000 Wiley-Liss, Inc.)

Background: In recent years, although BRCA1 has been extensively investigated, the contribution of inherited BRCA1 mutations to breast carcinoma in Asian populations is largely unknown. The authors undertook this study to determine the prevalence and spectrum of germline BRCA1 mutations among women in Singapore with early onset breast carcinoma., Methods: Forty-three of 72 eligible patients whose breast carcinoma was diagnosed before the age of 36 years were studied, independent of family history. DNA samples from 50 unrelated individuals randomly selected from the National Thalassemia Registry served as controls. Mutational screening was performed by single-strand conformation polymorphism analysis and protein truncation test, and alterations were confirmed by sequencing. First-degree relatives of patients with definite BRCA1 mutations were offered screening., Results: A total of 6 novel alterations in BRCA1 were identified, including 2 frameshift mutations in exon 11 (2846insA and 2885delA), 3 rare sequence variants, and 1 polymorphism. Three women (7%) carried deleterious mutations, and the mutation was present in at least 1 unaffected first-degree relative of the proband. The same mutation (2846insA) was identified in 2 of the 7 unrelated subjects of Malay ethnicity. One mutation and three rare variants were identified in four women with no family history of breast or ovarian carcinoma whereas all women with affected first-degree relatives did not harbor BRCA1 mutations. No mutation was identified in the controls., Conclusions: The spectrum of germline BRCA1 mutations among the patients in this study was distinct from that in Caucasian populations although a similar prevalence was observed. Larger studies are necessary to clarify the significance of the mutation 2846insA in the Malay community and the penetrance of specific mutations in the Singapore population., (Copyright 2000 American Cancer Society.)

Introduction: The ability to categorise mammographic features according to their likelihood of malignancy would be valuable in the management of women with abnormal mammograms. The aim of our study was to correlate abnormal mammographic features in a screened population with their histology to identify those features which are predictive of malignancy. The study also examined the spectrum of mammographic features in an Asian population., Materials and Method: This prospective study involved 28,231 women who were randomly selected from a population registry and underwent two-view screening mammography without physical examination. Women with suspicious lesions were recalled for further mammographic views or to a joint assessment clinic prior to biopsy. Mammographic abnormalities and their corresponding histology were assessed., Results: The spectrum of mammographic abnormalities was similar to that in Caucasian populations. The positive predictive value for malignancy was 44.1% of all biopsied cases. Mammographic features could be broadly classified into low-, moderate- and high-risk categories for malignancy. Those features which correspond to high malignancy rates (9.8% to 16.0%) include multiple abnormalities or parenchymal lesions with microcalcifications. The presence of microcalcifications was a good predictor of ductal carcinoma-in-situ (DCIS): 46% of lesions in which the microcalcifications were the sole abnormality were DCIS only. Further, 71% of cancers with any microcalcification on the mammogram had a focus of DCIS on histology., Conclusion: Mammographic abnormalities can be segregated into three risk groups for malignancy, and this in turn can improve the selection criteria for breast biopsy, hence reducing unnecessary intervention. Furthermore, the presence of microcalcifications denotes the presence of DCIS, and would be an important determinant of the extent of surgical excision.

Since the effects of progesterone are mediated mainly via estrogen-dependent progesterone receptor (PR), the expression of the effects of progesterone may be masked or overridden by the influence of estrogen under conditions in which priming with estrogens is required. We have established a PR-positive but estrogen receptor-alpha (ER-alpha) negative breast cancer cell model by transfecting PR cDNA into ER-alpha- and PR-negative MDA-MB-231 cells in order that the functions of progesterone can be studied independently of estrogens. We have demonstrated using this model that progesterone markedly inhibited cell growth. We have also discovered that progesterone induced remarkable changes in cell morphology and specific adhesion structures. Progesterone-treated cells became considerably more flattened and well spread than vehicle-treated control cells. This was associated with a striking increase of stress fibers, both in number and diameter, and increased focal contacts as shown by the staining of focal adhesion proteins paxillin and talin. There were also distinct increases in tyrosine phosphorylation of focal adhesion protein paxillin and focal adhesion kinase in association with increased focal adhesion. The staining of tyrosine-phosphorylated proteins was concentrated at focal adhesions in progesterone-treated cells. More interestingly, monoclonal antibody (Ab) to beta1 integrin was able to inhibit progesterone-induced cell spreading and formation of actin cytoskeleton. To our knowledge, this is the first report describing a direct effect of progesterone in inducing spreading and adhesion of breast cancer cells, and beta1-integrin appeared to play an essential role in the effect. It is known that the initial step of tumor metastasis is the breakaway of tumor cells from primary tumor mass when they lose the ability to attach. Hence, progesterone-induced cell spreading and adhesion may have significant implications in tumor metastasis.

Background: The objective of this study was to assess the effect of mammographic parenchymal patterns on risk of breast cancer detected at first screen or in the period following a negative screen., Methods: The study utilizes a nested case-control design with 132 breast cancer patients detected at first screen (from a total of 29 193 screened) and 42 breast cancer patients detected in the period following the first screen. These patients were matched to 348 screened-negative controls. The mammograms were classified according to Tabar's classification for parenchymal pattern and statistical analysis was done by conditional logistic regression., Results: The risk of breast cancer for women with Tabar pattern IV was significantly high when compared to the remaining patterns (odds ratio 2.59). Risk factors for Tabar pattern IV coincided largely with established risk factors for breast cancer., Conclusion: The study confirms the increased risk of breast cancer associated with Tabar pattern IV (approximately Wolfe pattern P2), in an Asian population. This pattern is associated with nulliparity and high educational status and is strongly associated with grade 3 cancers.

Objective: Recent studies have demonstrated the presence of the IGF-binding proteins (IGFBPs) and prostate specific antigen (PSA), an IGFBP protease. in human breast tissue. We sought to investigate the differences in serum IGFs, IGFBP-1, -3 and -6, and PSA between patients with surgically proven breast cancer and patients with benign breast disease., Design and Methods: Concentrations of IGFs, IGFBP-1, -3 and -6, and PSA were determined in the sera from 57 patients with breast cancer (CA), and 46 women with benign breast disease (BBD) using immunoassays for IGFs and IGFBPs and an ultrasensitive ELISA for PSA., Results: The mean (+/- S.E.M.) serum IGFBP-6 level in the CA group, 127 (16) ng/ml, was statistically significantly lower than in the BBD group, 157 (10) ng/ml (P = 0.016). Patients with CA had an elevated geometric mean serum PSA level of 0.018 (range: 0.0015-0.107) ng/ml, compared with 0.007 (range: 0.0015-0.019) ng/ml in women with BBD (P = 0.025). Mean serum IGFBP-1 concentrations were significantly lower in the CA group, 16 (2) ng/ml, versus 37 (4) ng/ml in the BBD group (P = 0.001). Mean serum IGFBP-3 concentrations were also lower in the CA group versus the BBD group, at 1981 (65) ng/ml, versus 2603 (140) ng/ml (P = 0.002) respectively. In the CA group, statistically significant correlations between PSA and IGFBP-6 (r = 0.413; P = 0.001), and between PSA and IGFBP-1 (r = -0.329; P = 0.021) were seen. Differences in IGF-I and -II between the two groups were not statistically significant., Conclusion: Lower serum concentrations of IGFBP-6, -3 and -1, but higher PSA concentrations were seen in the breast cancer group, and collectively these would suggest that there is an increase in bioavailable IGF-I in breast cancer.

Background: Chest wall resection and reconstruction has been proven to be a safe surgical procedure. This is particularly useful for breast cancer patients with chest wall recurrences or for those who first present with locally advanced cancer in the chest wall where there is both a large soft tissue and bony defect that need repair. In addition, many of these patients have had irradiation or chemotherapy, which can significantly impair wound healing., Methods: Thirty-four patients underwent chest wall resection and primary reconstruction over an 8-year period., Results: Twenty-three patients had breast carcinomas and six had breast and chest wall sarcomas. Of the breast carcinoma patients, 12 had local recurrences and 11 presented with locally advanced primary disease. Bony resection of the chest wall was required in 16 (47%) cases. Thirty myocutaneous flaps (18 rectus abdominis, four pectoralis major, eight latissimus dorsi) and three omental flaps were used for reconstruction. One required a deltovertebral skin flap. Skeletal reconstruction was necessary in four cases. All except one (97%) achieved primary wound healing. There was one mortality (3%) and three patients required further surgery for complications that were related to the reconstruction. Post-resection metastases occurred in 13 (42%) patients and only 2 (6%) had local recurrences. The 2-year survival rate was 78% with a mean survival time of 25.5 months., Conclusions: Primary reconstruction for curative or palliative purposes is a useful and safe surgical procedure for patients with recurrent or locally advanced chest malignancies after extensive chest wall resection. Pedicled myocutaneous flap is the preferred option for skeletal and soft-tissue coverage.

Background: Recent data suggest that tamoxifen may act by altering serum levels of insulin-like growth factors (IGFs) and their binding proteins (BPs). This prospective paired cohort study evaluated the influence of tamoxifen on serum levels of IGFs and BPs in postmenopausal patients with breast cancer., Methods: Blood was collected from 32 postmenopausal patients with breast cancer before and during tamoxifen therapy for at least 6 months. All patients had undergone primary surgery. Serum concentrations of IGF-I, IGF-II, BP-1, and BP-3 were determined by immunoradiometric assays, and Western ligand blots provided a semiquantitative measurement of BP-2, BP-3, and BP-4. Statistical analysis was performed by paired Student's t-test., Results: Mean serum IGF-1 level was significantly lower after tamoxifen treatment (pretreatment: 116.2 ng/mL+/-13.6 [SEM] vs. posttreatment: 77.5 ng/mL+/-7.8; P=.003). In contrast, mean IGF-II levels increased from 651.5+/-62.2 ng/mL to 812.5+/-35.1 ng/mL during treatment (P=.006). Posttreatment levels of BP-1 (92.9 ng/mL+/-7.5) were significantly higher compared to the pretreatment values (28.1 ng/mL+/-4.7; P <.001). Serum concentration of BP-3 also was elevated (pretreatment: 2228.1 ng/mL+/-145.2 vs. posttreatment: 3539.1 ng/mL+/-172.3; P <.001). Densitometric measurements showed a similar significant increase in BP-3 (P <.001) as well as BP-4 (P=.017) after hormonal therapy. Levels of BP-2 were not influenced by tamoxifen treatment., Conclusions: These significant alterations in serum concentrations of IGFs and BPs with tamoxifen therapy suggest that the IGF system is a potential mechanism by which tamoxifen exerts its growth inhibitory effect on breast carcinomas.

Background: Although increasing rates of breast carcinoma incidence have been observed in Asian countries, appropriate strategies for detecting early stage breast carcinoma in such communities have been difficult to formulate, particularly because no large population screening trial specifically involving Asian women has been reported. The objective of this study was to evaluate the effectiveness and quality of mammography as a screening technique for Singaporean women, who are predominantly Chinese., Methods: In this prospective study, 166,600 women in Singapore ages 50-64 years were randomized to either 2-view mammography without physical examination (67,656) or observation (97,294, controls) over 2 years., Results: Of these women, 28,231 (41.7%) responded and were screened; they were more likely to be married, have more formal education, be working, be Chinese, and be in a higher socioeconomic group (P < 0.001 for all variables). To assess for response bias that could affect outcome, results were also evaluated for nonrespondents (n = 39,425). The incidence rate of cancers among nonrespondents (1 per 1000 woman-years) was less than the 1.3 in women not invited to have screening (P = 0.03, relative risk [RR], 1.3; 95% confidence interval [CI], 1.0-1.7). However, cancers arising from nonrespondents did not differ significantly in stage distribution when compared with cancers within the control group. For every 1000 women screened, 4.8 cancers were detected. The prevalence ratio (the number of cancers detected per 1000 women at first screening divided by the corresponding incidence rate in controls per year) was 3.6 for screened women and 2.4 for women invited to have screening. The majority of cancers detected through screening were early stage, with 64% as either ductal carcinoma in situ (26%) or Stage I disease (38%) and was significantly more than the corresponding 26% in women not invited to have screening (P < 0.001). When only invasive cancers were considered, screened women still had more early cancers, with 65% having no lymph node involvement, compared with 47% in the group not invited to have screening (P = 0.001; RR, 1.4; 95% CI, 1.2-1.7). Women who were screened had half the risk of having Stage II or later cancers (P < 0.0001; RR, 0.5; 95% CI, 0.4-0.7) when compared with women not invited to have screening. This higher detection rate of early cancers through screening was accomplished with acceptable recall rates of 8% for further mammographic films or physical examination and a biopsy rate of 1.0% (10 per 1000 women screened). The interval cancer rate was 2.1 per 10,000 women screened in the first year of follow-up., Conclusions: These positive results of intermediate measures suggest that, in Asian communities, screening mammography could be an important modality for detecting early stage breast carcinoma. However, the low compliance rates suggest that health education efforts must focus on issues related to acceptability if such programs are to succeed.

Metabolism of estradiol occurs via two mutually exclusive hydroxylative pathways, yielding metabolites of divergent biological properties. 2-hydroxyestrone (2OHE1) is anti-estrogenic while 16 alpha-hydroxyestrone (16 alpha OHE1) is a potent estrogen. The ratio of 2OHE1 to 16 alpha OHE1 (2/16 alpha-OHE1 ratio) represents the net in vivo estrogenic activity. In this study, we sought to determine if the urinary 2/16 alpha-OHE1 ratio could be a predictor of breast cancer risk and the factors which influence this ratio. Variables analysed included age at diagnosis, menopausal status, parity, use of oral contraceptives, body mass index, serum levels of insulin-like growth factor-I (IGF-I), IGF binding proteins (BPs) and the presence of breast cancer. Serum and urine were collected from 65 breast cancer patients and 36 controls after an overnight fast. Urinary estrogen metabolites were measured by enzyme immunoassays while serum levels of IGF-I, BP-1 and BP-3 were determined by immunoradiometric assays. 2OHE1 levels and 2/16 alpha-OHE1 ratios were significantly lower (P < 0.05) while 16 alpha OHE1 levels were higher (P < 0.01) in cancer patients. Multiple linear regression analysis showed that levels of urinary metabolites were influenced by parity and breast carcinoma. 2/16 alpha-OHE1 ratio correlated positively with serum BP-3 level (P = 0.03). By multiple logistic regression, 2/16 alpha-OHE1 ratio was the most significant factor predictive of breast cancer. The odds ratio for women with higher 2/16 alpha-OHE1 ratios was 0.10 (0.03-0.38, 95% confidence interval). In conclusion, the profile of urinary estradiol metabolites was distinctly altered in breast cancer patients. In addition, BP-3 may be a potential mechanism by which estradiol metabolites influence breast cancer progression. As 16 alpha OHE1 has been shown to initiate neoplastic transformation of mammary epithelial cells, the 2/16 alpha-OHE1 ratio may serve as a biomarker of increased risk of breast cancer.

Background: Insulin-like growth factor 1 (IGF-1) has mitogenic properties for breast cancer cell lines and has been proposed to be an important factor in breast carcinogenesis. We hypothesized that differences in IGF-1 or its binding proteins might increase susceptibility to breast cancer. This case-control study was designed to investigate whether patients with breast cancer have altered levels of either IGF-1 or its intermediary modulatory proteins, the IGF binding proteins (BP)., Methods: Serum was collected from 90 patients (63 with breast cancer and 27 with benign breast disease) after an overnight fast and before surgery. IGF-1, BP1, and BP3 levels were determined by immunoradiometric assays. In a subset of 66 patients, Western ligand blots were also performed for a semiquantitative measurement of functioning BP levels. A forward stepwise logistic regression model to adjust for other confounding variables (age, menopausal status, parity, age at menarche, use of oral contraceptives, history of breast biopsy, family history of breast cancer, hormone replacement therapy, and body-mass index) was used in the multivariate analysis., Results: Serum IGF-1 levels were similar in cases and controls. However, levels of BP3 (p < 0.001), BP4 (p < 0.01), and BP1 (p < 0.05) were significantly associated with risk of breast cancer. The level of BP3 was the most significant factor predictive of breast cancer. The odds ratio for breast cancer in women with BP3 levels >2066 ng/ml was 0.18 (95% CI, 0.05-0.55). Correspondingly, women with BP1 levels higher than 39 ng/ml had an odds ratio of 0.21 (95% CI, 0.07-0.68) for breast cancer. When considering only cancer patients (n = 63), decreasing levels of BP4 (p < 0.01) and increasing levels of BP1 (p < 0.02) were significantly associated with progesterone receptor positivity (PR+) in the tumor. The odds ratio of PR+ in patients with BP1 levels higher than 34 ng/ml was 7.49 (95% CI, 1.5-37.4). Better grade of tumor (well and moderately differentiated) was observed in patients with higher levels of BP3 (p < 0.03)., Conclusions: Distinct differences in BP profiles exist among patients with breast cancer and also among those with high-grade, hormonal receptor-negative tumors. These findings suggest that the bioavailability of IGF-1 as mediated by its binding proteins may participate in both breast carcinogenesis and selection of more aggressive breast carcinomas.

Mammographic screening for breast cancer has been shown to be an effective tool for reducing mortality from the disease in many studies in the West, if high technical quality and acceptance by the target population are achieved. The objective of the Singapore Breast Screening Project was to determine if the same results could be obtained among local women by inviting a random sample of 69,500 women aged 50 to 64 years for a screening mammogram over two years. To date, the compliance rate among the women invited has been 41.7%. The objective of the present substudy was to determine participants' views on the accessibility and acceptability of organised mammographic screening. Of the three hundred women interviewed, 85% were satisfied with the information given prior to the visit, while 67% needed to change the original appointment given. The majority were satisfied with aspects of the visit such as waiting time, privacy and explanation given during the test. However, 35.1% reported at least moderate discomfort during mammography. A substantial proportion (39.7%) of attenders felt that there was very little hope of cure even if cancer was detected early. When asked the most important reason for attending, most indicated they had taken the opportunity for a free check-up to be assured they were well. Almost all (95.7%) reported a willingness to be screened again, but most would not be willing to pay for a mammogram at the current rates.

Background: It has been proposed that clones of tumor cells acquire higher metastatic potential as a result of specific genetic alterations. This study was designed to determine the role of the c-met protooncogene in systemic spread by comparing the loss of the c-met protooncogene between primary and metastatic breast carcinomas., Methods: Only patients who had not received chemotherapy or radiotherapy in the preceding 6 months were included in this study. Histologically proven malignant tissue was obtained from the primary tumor, involved nodes, and distant metastatic and recurrent tumors of patients with breast carcinomas. Allelic loss of the c-met protooncogene in tumor tissue was determined by Southern blotting using a polymerase chain reaction-generated 347-bp human met-H probe. Restriction digestion was performed using Taq I and Msp I, with the patient's lymphocyte DNA as controls., Results: Of 52 patients, lymphocyte DNA from 36 patients was heterozygous for the c-met protooncogene (69% informative). Forty-six tumors from these 36 patients were analyzed. Four of 30 primary tumors (13%) showed allelic loss of c-met. Of the nine nodal metastases examined, three (33%) showed allelic loss of the c-met protooncogene. Of seven distant metastatic breast tumors or recurrent disease, two (29%) showed allelic loss (both in patients with skin metastasis in the chest wall)., Conclusions: Allelic loss of the c-met protooncogene was detected in both primary (13%) and metastatic sites (31%) of breast cancer. Although a higher proportion of allelic loss of c-met was noted in nodal and distant/recurrent disease, the difference when compared with the primary tumor was not statistically significant. These findings indicate a limited role of the c-met protooncogene in breast cancer metastases.

Background: The incidence of breast carcinoma in Singapore has nearly doubled over the past 25 years. This prospective case-control study involving 1086 women (204 cases and 882 controls) was conducted to determine significant factors associated with the risk of breast carcinoma among Chinese women in Singapore ages 45 to 69 years., Methods: A forward stepwise logistic regression model adjusted for confounding variables of age, age at menarche, menopausal status, parity, age at first and last delivery, use of oral contraceptives, hormone replacement therapy, family history of breast carcinoma, history of benign breast biopsy, smoking history, height, weight, body mass index, and waist to hip ratio was used., Results: Central obesity as indicated by women with a larger waist to hip ratio was associated with highest risk for breast carcinoma (odds ratio [OR]: 9.18; 95% confidence interval [CI],4.8-17.5 comparing last and first quintile; P < 0.0001, chi-square test for trend). Significant trends were also noted for increasing height and breast carcinoma risk (P = 0.003, chi-square test). Women who were taller than 159 cm (OR: 2.3; 95% CI, 1.4-3.9) had approximately twice the risk of women shorter than 150 cm. Body mass index as a measure of generalized obesity did not significantly predict risk for breast carcinoma. Reproductive and menstrual factors significantly related to risk for breast carcinoma were number of deliveries (OR: 0.81; 95% CI, 0.7-0.9; P < 0.001), age at last delivery (P = 0.03), and use of hormone replacement therapy (OR: 0.54; 95% CI, 0.3-0.9; P = 0.01). Previous breast biopsy for benign disease was also associated with a higher risk for breast carcinoma (OR: 3.5; 95% CI, 2.1-5.7; P < 0.001)., Conclusions: The authors conclude that the risk of breast carcinoma is strongly associated with changes in lifestyle related to caloric intake (central obesity and height) and reproductive or menstrual factors (number of deliveries, age at last delivery, age at menopause, and breast feeding). Better and excess nutrition in early and later years of life and fewer births (related to rapid urbanization) may explain in part the increasing incidence of breast carcinoma occurring in Singapore.

Breast cancer is the leading cause of cancer deaths in Malaysian and Singaporean women. A study done to compare the epidemiology of the disease, as well as to compare the rate of conservative surgery between Malaysian and Singaporean women was carried out. The results show that the median age at presentation was the same in both countries, and the incidence was lower among the Malays. However, there was a significant difference in the stage at presentation and the tumour size; Singaporean women presented at earlier stages and with smaller tumours compared to Malaysian women. This led to a lower rate of conservation surgery in Malaysian women.

This prospective study sought to determine the width of tumour to fascial margins attainable after mastectomy in Asian women with breast cancers. The narrowest perpendicular distance from tumour to the deep fascia was measured in the mastectomy specimens of 177 consecutive Singaporean women with primary breast carcinomas. A highly significant linear correlation was present between the tumour size (P < 0.001, Pearson's R = -0.34) and the width of deep margins. Furthermore, T staging (P < 0.01, ANOVA) was inversely correlated with the width of deep margins and significant differences were observed between early (T0 to T2) and late (T3 to T4) lesions. In patients with ductal carcinoma in situ (DCIS) and T1 lesions, deep margins greater than 10 mm were achieved in only 23% and 33% of the women respectively. For patients with DCIS, 33% had either positive margins or margins less than 2 mm. The corresponding figures for women with T1 and T2 lesions were 11% and 26%, respectively. The inability to obtain negative deep margins were considerable with large tumours as 10% of the women with T3 tumours and 33% with T4 tumours had positive margins. Thus the proportion of positive or narrow deep margins following mastectomy is appreciable in Asian women and even in those with early tumours. The implications of these findings on the risk of locoregional recurrence or the need for more radical surgery or adjuvant radiotherapy remain uncertain, and will require further elucidation.