Gene expression in histologically normal epithelium from breast cancer patients and from cancer-free prophylactic mastectomy patients shares a similar profile.

INTRODUCTION: We hypothesised that gene expression in histologically normal (HN) epithelium (NlEpi) would differ between breast cancer patients and usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomy (PM) samples from high-risk women would resemble HN gene expression. METHODS: We analysed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 samples, we used microarrays to compare gene expression between 18 RM patients and 18 age-matched HN (9 oestrogen receptor (ER)+, 9 ER-) and 6 PM patients. Data were analysed using a Bayesian approach (BADGE), and validated with quantitative real-time PCR (qPCR) in 31 independent NlEpi samples from 8 RM, 17 HN, and 6 PM patients. RESULTS: A total of 98 probe sets (86 genes) were differentially expressed between RM and HN samples. Performing hierarchical analysis with these 98 probe sets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM compared with HN patients, and lower (58%), but more heterogeneous, in RM compared with PM patients. The 86 genes were implicated in many processes including transcription and the MAPK pathway. CONCLUSION: Gene expression differs between the NlEpi of breast cancer cases and controls. The profile of cancer cases can be discerned in high-risk NlEpi from cancer-free breasts. This suggests that the profile is not an effect of the tumour, but may mark increased risk and reveal the earliest genomic changes of breast cancer.

Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators.

BACKGROUND: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen-progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD. METHODS: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided. RESULTS: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk. CONCLUSION: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects.

Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial.

BACKGROUND: We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS. METHODS: 1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57-93). We compared annual event rates and cumulative probability of invasive or non-invasive ipsilateral and contralateral tumours over 5 years. FINDINGS: Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 vs 13.4%, p=0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis. INTERPRETATION: The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35-4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease.

Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17.

PURPOSE: In 1993, findings from a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate the worth of radiation therapy after lumpectomy concluded that the combination was more beneficial than lumpectomy alone for localized intraductal carcinoma-in-situ (DCIS). This report extends those findings. PATIENTS AND METHODS: Women (N = 818) with localized DCIS were randomly assigned to lumpectomy or lumpectomy plus radiation (50 Gy). Tissue was removed so that resected specimen margins were histologically tumor-free. Mean follow-up time was 90 months (range, 67 to 130). Size and method of tumor detection were determined by central clinical, mammographic, and pathologic assessment. Life-table estimates of event-free survival and survival, average annual rates of occurrence for specific events, relative risks for event-specific end points, and cumulative probability of specific events comprising event-free survival are presented. RESULTS: The benefit of lumpectomy plus radiation was virtually unchanged between 5 and 8 years of follow-up and was due to a reduction in invasive and noninvasive ipsilateral breast tumors (IBTs). Incidence of locoregional and distant events remained similar in both treatment groups; deaths were only infrequently related to breast cancer. Incidence of noninvasive IBT was reduced from 13.4% to 8.2% (P = .007), and of invasive IBT, from 13.4% to 3.9% (P < .0001). All cohorts benefited from radiation regardless of clinical or mammographic tumor characteristics. CONCLUSION: Through 8 years of follow-up, our findings continue to indicate that lumpectomy plus radiation is more beneficial than lumpectomy alone for women with localized, mammographically detected DCIS. When evaluated according to the mammographic characteristics of their DCIS, all groups benefited from radiation.

Primary leiomyosarcoma of the abdominal aorta.

Primary malignancies of the aorta are extremely rare. A review of the literature indicates that 35 documented cases of primary tumors of the aorta have been reported over the past 120 years. The histologic and morphologic characteristics of these lesions may be variable. In this case, progressive claudication of the left leg and buttocks with absent femoral pulses in a middle-aged woman was found to be a primary leiomyosarcoma of the abdominal aorta. A magnetic resonance imaging study defined a retroperitoneal space-occupying mass on the left side of the aorta at the level of the fourth lumbar vertebrae. A magnetic resonance angiographic scan of the abdominal aorta and an aortogram revealed total occlusion of the distal abdominal aorta with reconstitution at the level of the common femoral arteries bilaterally, with normal vessels more distal to that region. The patient underwent surgical exploration and resection of the retroperitoneal, infrarenal, occluding aortic mass. The mass was found to be a high-grade sarcoma displaying smooth muscle cell differentiation. The resection of this lesion, perioperative management, and pathologic characteristics of a rare primary neoplasm of the aorta are discussed in this review.

Estrogen receptor functional status in human breast cancer.

Estrogen receptors (ER) are detected in 50-85% of all breast tumors, and are clinically important because they tend to identify patients with a higher probability of responding to hormonal or endocrine manipulations. However, approximately 30-40% of all ER+ patients do not respond to hormonal manipulations. The lack of response to hormonal manipulations in ER+ patients could be the result of nonfunctional ER, as determined by its inability to recognize and bind to specific DNA-responsive elements and/or its inability to recruit other transcriptional activation factors. The functional status of ER in 34 human breast tumors was assessed determining the structural integrity of the ER DNA-binding domain using site-directed monoclonal anti-estrogen receptor antibody and sucrose density gradient analysis. Based on the fraction of ER containing an intact DNA-binding domain, the tumors were classified into three groups: group I with > 65% of intact ER, group II with > 30% of intact ER, group III with < 30% of intact ER. Clinical and pathologic data were obtained only for patients who were treated with the anti-estrogen tamoxifen and correlated with ER functional status. In group I, 11 of 13 (84.6%) patients were responsive to hormonal therapy with favorable clinical outcome; two patients had unfavorable clinical outcome. In group II, 13 of 15 patients (86.7%) had favourable clinical outcome, and two patients 13.3% had unfavorable outcome. In group III, three of six patients appeared to be hormone responsive with favorable clinical outcome, and three of the patients in this group had unfavorable response to therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

A complementary role for thallium-201 scintigraphy with mammography in the diagnosis of breast cancer.

Physical examination and mammography are currently the only proven and reliable methods of early detection of breast cancer. Although both procedures are highly sensitive, their limited specificity often requires surgical biopsy in order to differentiate between malignant and benign lesions. The purpose of this prospective study is to investigate the diagnostic specificity of thallium imaging for breast cancer and to determine its efficacy as a complement to mammography. Two groups were studied: Group A: Patients found to have breast abnormalities and scheduled for biopsy or surgery and Group B: Patients who were suspected to have a recurrence of cancer after mastectomies or lumpectomies. In Group A, thallium scans of 32 breasts in 30 patients were performed prior to biopsy or surgery, yielding pathological diagnoses of 31 breasts in 29 patients. Results for Group A included seven true-positive thallium scans, twenty-two true-negative scans, two false-negative scans, and one false-positive scan. In Group B, seven patients were scanned to evaluate subcutaneous nodules for breast cancer following mastectomy or lumpectomy. Results for Group B included five true-positive scans, one true-negative scan, one false-negative scan and no false-positive scans. Thallium breast scanning was shown to have high specificity for cancer (specificity 96% and sensitivity 80%), suggesting that this technique should be evaluated in additional patient studies to determine its role in clinical situations.

New surgical method to prevent pelvic radiation enteropathy.

Pelvic radiation doses exceeding 4,000-4,500 cGy are known to be associated with acute and chronic radiation enteropathy. This same radiation dose is, at the same time, only moderately effective in the elimination of microscopic malignancy, let alone gross clinical disease. Numerous medical and surgical attempts to minimize this complication have been uniformly unsuccessful. With the availability of a new synthetic, absorbable, polyglycolic acid mesh, an intestinal sling surgical procedure has been devised to exclude the small bowel from the pelvis and subsequent radiation fields. Twenty-five patients have been treated by this new technique with only one complication presenting as a fungal infection. Small-bowel barium contrast studies in 16 patients referred for postoperative radiation demonstrated 13 satisfactory exclusions of the small bowel from the translateral pelvic irradiation field. In 16 evaluable patients, three had unsatisfactory exclusion two of which were due to technical error. This has permitted high-dose (5,500-6,500 cGy) radiotherapy to the critical treatment volume without posttreatment complication. Mean follow-up time is 14.8 months. Several patients have been reexplored demonstrating complete absorption of the mesh without fibrinous adhesions or other foreign body reaction. It is concluded that this new technique of small bowel exclusion will permit the routine delivery of much higher doses of radiation in patients requiring improved local-regional control of their pelvic cancers and without morbidity from radiation-associated small bowel injury.

Efficacy of polyglycolic acid mesh sling in keeping the small bowel in the upper abdomen after abdominal surgery: a 12-month study in baboons.

The purpose of this study was to determine if a "sling" made of polyglycolic acid (PGA) would be a reliable method of preventing small bowel descent into the pelvis following abdominal surgery. Baboons were used, as they respond to infection and ambulate similarly to humans. Animals had the small bowel mobilized to the upper abdomen and had the PGA "sling" sewn into place. Documentation of small bowel position was evaluated by upper gastrointestinal series over the 12-month study. Small bowel descent into the pelvis was prevented by utilization of the PGA "sling." Animals were sacrificed and autopsied, and sections of small bowel were taken. There was no evidence of mesh, obstruction, sepsis, fistulae, or herniation in animals at autopsy. Small bowel sections were considered normal histologically. Utilization of PGA sling appears to be a safe and reliable method of preventing small bowel descent into the pelvis after abdominal surgery.

New surgical approach to minimize radiation-associated small bowel injury in patients with pelvic malignancies requiring surgery and high-dose irradiation. A preliminary report.

Complications associated with small bowel intolerance to radiation therapy at doses higher than 4500 to 5000 cGy have been the limiting factor in delivering pelvic radiation either as an adjuvant to surgery or alone in the treatment of pelvic malignancies. Despite numerous surgical, medical, and radiation therapy technical measures to minimize small bowel injury, none have been uniformly successful in eliminating this problem. With the availability of a new synthetic absorbable mesh, a pelvic sling can be placed at the time of exploration or definitive surgery aimed at suspending the small bowel out of the pelvis. Preliminary work in animal models has shown the mesh sling to be well-tolerated and successful. Barium-contrast simulation studies of seven patients with pelvic malignancies requiring resectional surgery and postoperative radiation therapy in whom the mesh sling was placed at the time of surgery demonstrate total exclusion of the small bowel from the pelvic radiation treatment field. All patients have been followed for at least 4 months since mesh placement, and to date no complications have occurred. It is possible that this technique of bowel exclusion will permit the delivery of larger doses of radiation therapy in patients with pelvic malignancies aiming at more effective local and regional control of cancer without increased complications from radiation-associated small bowel injury.

Small bowel exclusion from the pelvis by a polyglycolic acid mesh sling.

Radiation enteritis is seen in patients receiving radiation therapy for various pelvic malignancies. Attempts to prevent this have included various surgical as well as nutritional approaches with little success. The use of a polyglycolic acid mesh sling sewn above the pelvic inlet has prevented small bowel descent into the true pelvis in rats and in humans. The technique has been successful in both with no attendant morbidity during an 11-month follow up. Several patients have received additional doses of radiation therapy that would not have been given if the small bowel were not removed from the area to be irradiated.

Transformation antigens on stimulated lymphocytes.

Immunologically mediated regulation of lymphoproliferation requires a self-recognition mechanism. This was sought by measuring the ability of blood lymphocytes to recognize transformed, autologous lymphocytes. Human blood lymphocytes incubated with phytohemagglutinin (PHA) for 72 hr, followed by mitomycin C treatment, induced blast transformation of autologous lymphocytes from all 28 healthy adults tested. Blastogenesis was measured by reactor cell incorporation of 3H-thymidine and was greater at 72 than at 144 hr. The role of PHA itself was assessed in several ways. The supernatant of washed, PHA-transformed lymphocytes did not stimulate normal autologous lymphocytes. Lymphocytes incubated with PHA for 1 hr or 72 hr before mitomycin treatment bound equivalent amounts of 131I-PHA; cells treated for 1 hr did not transform and did not stimulate autologous lymphocytes. By contrast, cells incubated for 72 hr did transform and stimulate autologous lymphocytes. Lytic sonication of PHA-transformed lymphocytes abolished their stimulating capability. An identical result was observed in allogeneic mixed lymphocyte reactions after lytic sonication of the stimulating cells. PHA itself maintained its stimulatory capability after sonication. Although N-acetyl-D-galactosamine (NAGAL) competes with PHA for lymphocyte membrane sites, incubation of reactor lymphocytes with NAGAL did not diminish their response to PHA-transformed autologous lymphocytes. These results strongly suggest the presence of autorecognition determinants on membranes of transformed lymphocytes. The relatively rapid reaction to these determinants is consistent with prior in vivo exposure.