Tissue inhibitor of metalloproteinases-1 (TIMP-1) is shown to be a potential marker for poor prognosis in breast cancer, but the biology of TIMP-1 is only partially understood. In this study, TIMP-1 production was studied in a co-culture model of hormone-independent breast cancer cell lines and mesenchymal stem cells mimicking the stromal components of the tumor. In addition, the prognostic value of TIMP-1 was histologically evaluated in a clinical material of 168 patients with hormone-independent breast tumors. The hormone-independent breast cancer (BC) cell lines MDA-MB-231, M4A4 and NM2C5 did not produce TIMP-1 protein in measureable quantities. Six tested primary mesenchymal stem cell lines all produced TIMP-1. Co-culturing of mesenchymal stem cells and breast cancer cells resulted in positive immunocytochemical diffuse staining for TIMP-1 for both cell types. Culturing breast cancer cells with MSC-conditioned media resulted in a positive cytoplasmic immunoreactivity for TIMP-1, and TIMP-1 protein concentration in cell lysates increased 2.7-fold (range 1.1-4.7). The TIMP-1 mRNA levels remained unaffected in BC cells. This might suggest that breast cancer cells can take up TIMP-1 produced by stromal cells and are thus displaying cellular immunoreactivity. In addition, TIMP-1 was shown to improve stratification of prognosis in clinical material.

Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.

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.

OBJECTIVE: The authors review their recent experience with resected pancreatic ductal adenocarcinoma. SUMMARY BACKGROUND DATA: Ductal adenocarcinoma of the pancreas has traditionally had a 5-year survival rate less than 10% after curative resection. Recently, several groups have reported markedly improved 5-year survival rates (approaching 25%) for patients undergoing curative resection. METHODS: Institutional experience with 186 consecutive patients (1981-1991) with pathologic diagnoses of ductal adenocarcinoma undergoing pancreatic resection was reviewed. Histologic specimens of all 3-year survivors (n = 31) were re-reviewed by two pathologists, one internal and one external; nonductal pancreatic cancers then were excluded. RESULTS: After histologic re-review, 12 patients did not have ductal adenocarcinoma, leaving a total of 174 patients for analysis (102 men, 72 women; mean age 63 years, range 34-82 years). Mean follow-up was 22 months (range 4-109). Classical pancreaticoduodenectomy was performed in 71%, pylorus-preserving resection in 9%, and total pancreatectomy in 20%. Hospital mortality was 3%. Twenty-eight patients (16%) had macroscopically incomplete resections; 98 (56%) had lymph node metastases within the resected specimens, and 21 patients (12%) had extensive perineural invasion. Overall actuarial 5-year survival was 6.8%. Five-year survival was greater for node-negative versus node-positive patients (14% vs. 1%, p < 0.001), and for smaller (< 2 cm) versus larger tumors (20% vs. 1%, p < 0.001). The 5-year survival for the subset of patients with negative nodes and no perineural or duodenal invasion (69 patients) was 23%(p < 0.001). Mean survival of the 12 excluded patients was 53 +/- 7 months compared with 17.5 +/- 1 months in the 174 patients with ductal pancreatic cancer. CONCLUSIONS: Five-year survival for patients undergoing pancreatic resection for lesions deemed to be clinically "curable" intraoperatively and histologically reviewed/confirmed to be ductal adenocarcinoma of the pancreas is approximately 7%. Survival is greater (23%) in the subset of patients with negative nodes and no duodenal or perineural invasions. Pathologic review of all patients with pancreatic ductal cancer adenocarcinoma is mandatory if survival data are to be meaningful.

OBJECTIVE: The authors reviewed the clinicopathologic characteristics of patients who underwent resection with curative intent for ductal adenocarcinoma of the pancreas between 1983 and 1989. SUMMARY BACKGROUND DATA: Recent studies have demonstrated a reduction in the morbidity and mortality of pancreatic resection and improvement in the actuarial 5-year survival for patients with resected ductal adenocarcinoma. METHODS: Resection with curative intent was performed on 118 of 684 patients (17%) with pancreatic cancer admitted to the authors' institution. Clinical, demographic, treatment, and pathologic variables were analyzed. The original material for all cases was reviewed; nonductal cancers were excluded. RESULTS: The head of the gland was the predominant tumor site (n = 102), followed by the body (n = 9), and tail (n = 7). Seventy-two percent of the patients underwent pancreaticoduodenectomies, 15% underwent total pancreatectomies, 10% underwent distal pancreatectomies, and 3% underwent distal subtotal pancreatectomies. Operative mortality was 3.4%. Median survival was 14.3 months after resection compared with 4.9 months if patients did not undergo resection (p < 0.0001). Twelve patients survived 5 years after surgery (10.2% overall actual 5-year survival rate). Three of the tumors were well differentiated, five were moderately differentiated, and four were poorly differentiated. Extrapancreatic invasion occurred in nine cases (75%), and perineural invasion was present in ten cases (83%). Five tumors exhibited invasion of duodenum, ampulla of Vater, and/or common bile duct, and an additional tumor invaded the portal vein. Lymph node involvement by carcinoma was noted in five cases (42%). Six patients remain alive without evidence of disease at a median follow-up of 101 months (range, 82-133 months). Five patients died of recurrent or metastatic pancreatic cancer at 60, 61, 62, 64, and 64 months, respectively. One patient died at 84 months of metastatic lung cancer without evidence of recurrent pancreatic disease. CONCLUSIONS: This paper emphasizes the grim prognosis of pancreatic ductal adenocarcinoma. Five-year survival cannot be equated to cure. Although pancreatectomy offers the only chance for long-term survival, it should be considered as the best palliative procedure currently available for the majority of patients. This emphasizes the need for the development of novel and effective adjuvant therapies for this disease.

BACKGROUND: This study was designed to ascertain whether immunohistochemical methods could improve the detection of metastases in primary breast-cancer patients whose axillary lymph nodes were classified, by conventional methods, as disease free. METHODS: Ipsilateral lymph nodes (negative for metastases by routine histology) from 736 patients (participants in Trial V of the International [Ludwig] Breast Cancer Study) were examined by serial sectioning and staining with haematoxylin and eosin (two sections from each of six levels) and by immunohistochemistry of a single section (with two anticytokeratins AE-1 and CAM 5.2). After median follow-up of 12 years, disease-free and overall survival were estimated by Kaplan-Meier methods. FINDINGS: Occult nodal metastases were detected by serial sectioning and haematoxylin and eosin in 52 (7%) of 736 patients and by immunohistochemistry in 148 (20%). Only two (3%) of 64 invasive lobular or mixed invasive lobular and ductal cancers had node micrometastases, detected by haematoxylin and eosin, compared with 25 (39%) by immunohistochemistry. Occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Immunohistochemically detected occult lymph-node metastases remained an independent and highly significant predictor of recurrence even after control for tumour grade, tumour size, oestrogen-receptor status, vascular invasion, and treatment assignment (hazard ratio 1.79 [95% CI 1.17-2.74], p=0.007). INTERPRETATION: The immunohistochemical examination of ipsilateral axillary lymph nodes is a reliable, prognostically valuable, and simple method for the detection of occult nodal metastases. Immunohistochemistry is recommended as a standard method of node examination in postmenopausal patients.

BACKGROUND There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process. METHODS The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point. RESULTS There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years. CONCLUSIONS DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy.

BACKGROUND Axillary dissection has been a routine part of breast cancer treatment for more than 100 years. Axillary node involvement is the single most important prognostic variable in patients with breast cancer. Recently, routine node dissection has been eliminated for intraductal carcinoma because so few patients had positive nodes. With the availability of numerous histologic prognosticators and the development of new immunochemical prognostic indicators, it is time to consider eliminating routine node dissection for lesions more advanced than duct carcinoma in situ (DCIS) but with extremely low likelihood of axillary involvement. METHODS Axillary node positivity, disease-free survival, and breast cancer-specific survival were determined for six breast cancer subgroups by T category: Tis (DCIS), T1a, T1b, T1c, T2, and T3. RESULTS Nodal positivity for DCIS was 0%; for T1a lesions, 3%. A large increase in nodal positivity was seen in lesions larger than 5 mm.(T1b, 17%; T1c, 32%; T2, 44%; T3, 60%). The rate of nodal positivity was statistically different as each T category was compared with the next more advanced T category. The disease-free survival and breast cancer-specific survival decreased with every increment in T value. CONCLUSIONS Axillary node positivity increases as the size of the invasive component increases and is an excellent predictor of DSF and breast cancer-specific survival. Consideration should be given to eliminating axillary node dissection for T1a lesions because of the low yield of positive nodes. Axillary node dissection should be performed routinely for T1b lesions and larger.

BACKGROUND Three clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results. The overall evidence supports a reduction in the risk of breast cancer, but whether this benefit outweighs the risks and side-effects associated with tamoxifen is unclear. METHODS We undertook a double-blind placebo-controlled randomised trial of tamoxifen, 20 mg/day for 5 years, in 7152 women aged 35-70 years, who were at increased risk of breast cancer. The primary outcome measure was the frequency of breast cancer (including ductal carcinoma in situ). Analyses were by intention to treat after exclusion of 13 women found to have breast cancer at baseline mammography. FINDINGS After median follow-up of 50 months (IQR 32-67), 69 breast cancers had been diagnosed in 3578 women in the tamoxifen group and 101 in 3566 in the placebo group (risk reduction 32%[95% CI 8-50]; p=0.013). Age, degree of risk, and use of hormone-replacement therapy did not affect the reduction. Endometrial cancer was non-significantly increased (11 vs 5; p=0.2) and thromboembolic events were significantly increased with tamoxifen (43 vs 17; odds ratio 2.5 [1.5-4.4], p=0.001), particularly after surgery. There was a significant excess of deaths from all causes in the tamoxifen group (25 vs 11, p=0.028). INTERPRETATION Prophylactic tamoxifen reduces the risk of breast cancer by about a third. Temporary cessation of tamoxifen should be considered and the use of appropriate antithrombotic measures is recommended during and after major surgery or periods of immobilisation. Prophylactic use of tamoxifen is contraindicated in women at high risk of thromboembolic disease. The combined evidence indicates that mortality from non-breast-cancer causes is not increased by tamoxifen. The overall risk to benefit ratio for the use of tamoxifen in prevention is still unclear, and continued follow-up of the current trials is essential.

PURPOSE: To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. PATIENTS AND METHODS: An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8). RESULTS: The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or =.15). CONCLUSION: The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.

BACKGROUND. The relationships among the involvement of tumor at the final margins of resection, the presence of an extensive intraductal component (EIC), and the risk of local recurrence are important considerations in patients treated with conservative surgery and radiation therapy for early stage breast cancer but have not been defined adequately. METHODS. Between 1982 and 1985, 885 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 181 patients with an infiltrating ductal carcinoma who received a radiation dose to the surgical site of 60 Gy or greater, whose final microscopic margins of resection were evaluable, and who had at least 5 years of follow-up. A positive margin was defined as tumor present at the inked margin of resection, a close margin as tumor within 1 mm of the inked margin, and a negative margin as no tumor within 1 mm of the inked margin. A focally positive margin was defined as tumor at the margin in three or fewer low-power fields. In 157 patients (87%), the tumor was evaluable for the presence or absence of an EIC. The median follow-up was 86 months. RESULTS. In 12 of 181 patients (7%), a recurrence developed at or near the primary site (true recurrence/marginal miss [TR/MM]) within 5 years. The 5-year rate of TR/MM (with 95% confidence intervals) among patients with negative, close, focally positive, and more than focally positive margins was 0%(0-4%), 4%(0-20%), 6%(1-17%) and 21%(10-37%), respectively. Patients with positive margins also were more likely to have a distant failure within 5 years (14%, 8%, 25%, and 32% in the four groups, respectively). However, patients with positive margins more often had positive axillary lymph nodes than patients with negative or close margins (59% vs. 38%, P < 0.02). The 5-year rate of TR/MM was 20% for patients with an EIC-positive tumor and 7% for patients with an EIC-negative tumor. However, among the 127 patients with an EIC-negative tumor, the 5-year rate of TR/MM was less than 10% in all margin groups. Among the 30 patients with an EIC-positive tumor, the 5-year rate of TR/MM was 0% when margins were negative or close but 50% when margins were more than focally positive. CONCLUSIONS. These results provide support for the use of breast-conserving surgery and breast irradiation in all patients with uninvolved margins, whether the tumor is EIC-positive or EIC-negative. This study suggests that breast-conserving therapy (including a radiation boost to the primary site) also may be a reasonable option for some patients with an EIC-negative tumor and margin involvement.