ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Papillary lesions of the breast: selected diagnostic and management issues.

The assessment and categorization of papillary lesions remains one of the most challenging areas in breast pathology. In this review, we will focus on several diagnostic and management issues related to papillary breast lesions that are frequently encountered in daily practice. These include: (i) the distinctions among papillomas with atypia (atypical papillomas), papillomas with ductal carcinoma in situ, and papillary ductal carcinoma in situ; (ii) recent developments in our understanding of encapsulated ('intracystic') papillary carcinomas and solid papillary carcinomas; and (iii) the impact of core needle biopsy on management decisions and specimen evaluation. The role of immunohistochemistry in the evaluation of these lesions, particularly the role of myoepithelial cell markers, will be emphasized.

Local control following breast-conserving surgery for invasive cancer: results of clinical trials.

Prospective, randomized clinical trials have demonstrated that the alternatives of mastectomy or conservative surgery plus radiation therapy provide equivalent survival for patients with invasive breast cancer. The identification of a subset of women who could undergo conservative surgery without radiotherapy would avoid the costs, inconvenience, and complications of radiotherapy and is an important research goal. Four randomized trials comparing conservative surgery alone with conservative surgery plus radiotherapy have demonstrated an average reduction in the risk of disease recurrence in the breast of 84% with the use of radiotherapy. No significant differences in survival have been observed, although the available studies lack sufficient numbers of patients to demonstrate a potential small, but clinically important, survival advantage for patients treated with radiotherapy. Subset analysis in the randomized trials and prospective studies of highly selected patients have failed to consistently identify a group of patients who do not benefit from radiation therapy. Any recurrence of breast cancer is psychologically devastating, and fewer than one half of the patients who have had disease recurrence after conservative surgery alone have undergone further breast-conserving treatment. At present, a group of patients who do not require radiotherapy has not been reproducibly identified, and radiotherapy should remain a part of breast-conserving therapy for invasive carcinoma.

Loss of tumor marker-immunostaining intensity on stored paraffin slides of breast cancer.

BACKGROUND: We previously observed decreased p53 immunostaining over time in paraffin-embedded sections of ductal carcinoma in situ of the breast of women; these sections had been stored on slides at room temperature. This observation suggests that slide storage adversely affects p53-immuno-staining intensity and could result in spurious negative staining for p53 in patient samples. PURPOSE: The goals of this study were to determine the time course and factors influencing loss of p53 immunoreactivity and to investigate whether a similar loss of reactivity occurs with other antigens commonly used to study breast cancer. METHODS: Serial sections cut from 12 formalin-fixed, paraffin-embedded, p53-positive invasive ductal carcinomas of the breast were stored on slides at room temperature or at 4 degrees C, with or without an additional paraffin coating, for 2, 4, 8, or 12 weeks. For each case, freshly cut slides from the same block (day 0) and stored slides were simultaneously stained for p53 by use of an automated immunostainer. Slides cut from formalin-fixed, paraffin-embedded breast carcinomas and stored for 12 weeks were also stained for factor VIII-related antigen (n = 12), estrogen receptor (ER) (n = 9), and Bcl-2 protein (n = 9). The staining intensity of all slides was assessed by visual microscopic examination and was also quantified by image analysis. Quantitative results were expressed as a percentage (mean +/- standard error) of the staining intensity on day 0. Data were analyzed by the Friedman Repeated Measures Analysis of Variance on Ranks, with statistical significance set at two-sided P < .05. RESULTS: The intensity of p53 staining decreased over time in nine (75%) of the 12 cases studied. In three (or 25% of all cases studied) of the nine cases that showed decreased p53 staining, slides stored for 12 weeks were scored as p53 negative. Antigen loss on slides stored at 4 degrees C was significantly less than that on slides stored at room temperature at all time points (all P < .05). At 12 weeks, the average staining intensity of slides stored at 4 degrees C was 33.2% +/- 9% of that on day 0 compared with 8.4% +/- 3% of that on day 0 for slides stored at room temperature (P < .001). Paraffin coating of the sections did not significantly diminish antigen loss at either room temperature or 4 degrees C, except for slides stored at room temperature for 12 weeks. The intensity of factor VIII staining decreased in nine of 12 cases (average staining intensity, 37.3% +/- 6% of that on day 0 at 12 weeks; P = .0001). The intensity of ER and Bcl-2 staining decreased in all nine cases studied at 12 weeks (average staining intensity, 14.0% +/- 6% and 21.0% +/- 4% of that on day 0, respectively; P = .0001 for each). CONCLUSIONS AND IMPLICATIONS: Slide storage, particularly at room temperature, results in substantial loss of p53 reactivity, with some p53-positive cases becoming p53 negative after 12 weeks of storage. Substantial loss of immunoreactivity for factor VIII, ER, and Bcl-2 occurs on slides stored at room temperature for 12 weeks. Storage of unstained slides for up to 12 weeks may lead to false-negative immunostaining for p53 and other antigens.

Microvessel density and distribution in ductal carcinoma in situ of the breast.

BACKGROUND: Prior studies have suggested that microvessel density is an important prognostic factor in invasive breast cancer. However, the extent and distribution of microvessels in association with ductal carcinoma in situ (DCIS) have not been well defined. PURPOSE: Our goal was to determine the density and distribution of stromal microvessels in DCIS and to investigate the relationships among microvessel density, histopathologic features, HER2/neu oncogene expression, and tumor proliferation rate. METHODS: Of 61 consecutive cases of DCIS identified from hospital pathology reports, 55 cases were evaluated. Breast biopsy specimens had been preserved in paraffin blocks for each DCIS case. Histologic sections of formalin-fixed, paraffin-embedded tissue were stained with hematoxylin-eosin and immunostained for factor VIII-related antigen, the HER2/neu oncoprotein, and the proliferative-associated antigen detected by the Ki-S1 antibody. Factor VIII-stained sections from each case were independently examined by two pathologists and overall tumor-associated stromal microvessel density was scored semiquantitatively on a 1+ to 3+ scale by each observer. Quantitative microvessel counts of DCIS-associated stromal microvessel density were performed. The presence or absence of a cuff of microvessels in immediate apposition to the basement membrane of involved spaces was also evaluated. RESULTS: A variable number of microvessels were found to be present in a diffuse pattern surrounding spaces involved with DCIS. Semiquantitative microvessel scores were 2+ in the majority of cases (53%); 22% of cases were 1+, and 25% were 3+. Quantitative microvessel counts ranged from 17 to 80 vessels per 100x field (0.45 mm2), with a mean +/- SD of 42.9 +/- 16.6. Comedo-type lesions were significantly (P = .004) more often associated with 3+ microvessel density than non-comedo-type lesions by semiquantitative assessment. As determined by both semiquantitative and quantitative analysis, respectively, the presence of prominent microvessel density was significantly associated with marked stromal desmoplasia (P = .05 and P = .04), HER2/neu expression (P = .03 and P = .0002), and high Ki-S1 proliferation index (P = .05 and P = .01). Vascular cuffing around involved spaces was identified in 21 of the 55 cases (38%) and was not significantly associated with histologic features, HER2/neu expression, or Ki-S1 proliferation index. CONCLUSIONS: DCIS of the breast is characterized by two patterns of stromal microvessels. The first pattern is a diffuse increase in stromal microvessels surrounding involved spaces. This pattern is particularly prominent in comedo-type lesions with marked stromal desmoplasia. The second pattern is microvessel cuffing of involved spaces that is present in only a minority of cases and appears unrelated to histologic features evaluated, including DCIS subtype.

Clinical-pathologic study of early breast cancer treated by primary radiation therapy.

We performed a clinical-pathologic review of 231 patients with early breast cancer treated by primary radiation therapy. There were 27 patients with infiltrating ductal carcinoma treated with excisional biopsy whose tumors showed a constellation of histologic features: moderate or marked intraductal carcinoma in the tumor, intraductal carcinoma in the adjacent tissue, and high nuclear grade. These patients had a 5-yr local tumor control rate of 61% compared to 96% for similar patients whose tumors did not show all three features. Radiation dose to the primary tumor area influenced the likelihood of local recurrence in these 27 patients: 15 of these patients received 6000 rads or more to the primary tumor area and had a 5-yr local tumor control rate of 84%, compared to 48% for the 12 patients who received less than 6000 rads. These results indicate that a subgroup of breast cancer patients can be identified that has a high risk of local recurrence when an insufficient radiation dose (i.e., less than 6000 rads) is delivered to the primary tumor area.

Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer.

PURPOSE: To compare fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in the determination of HER-2/neu status of breast cancers. MATERIALS AND METHODS: FISH and IHC for HER-2/neu were performed on formalin-fixed paraffin sections of 100 consecutive invasive breast cancers. FISH was performed at Beth Israel Deaconess Medical Center, Boston, MA, using the Oncor/Ventana INFORM kit (Ventana Medical Systems, Tucson, AZ; formerly sold by Oncor, Inc, Gaithersburg, MD) in a laboratory certified as proficient in this procedure. IHC was performed at PhenoPath Laboratories, Seattle, WA, using a polyclonal antibody to the HER-2/neu protein. FISH and IHC were analyzed in a blinded fashion, and the results were then compared. Procedure and interpretation times and reagent costs for FISH and IHC were also compared. RESULTS: HER-2/neu was amplified by FISH in 26% of cases, and 23% were HER-2/neu-positive by IHC. FISH and IHC were both assessable in 90 cases. Concordance between FISH and IHC results was seen in 82 of these cases (91%, P <.001). The FISH procedure required more technologist time and more interpretation time per case for the pathologist than IHC. Reagent costs were substantially higher for FISH than for IHC. CONCLUSION: There is a high level of correlation between FISH and IHC in the evaluation of HER-2/neu status of breast cancers using formalin-fixed paraffin-embedded specimens. Although the choice of which assay to use should be left for individual laboratories to make based on technical and economic considerations, our results may make it difficult to justify the routine use of FISH for determination of HER-2/neu status in breast cancer.

Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system.

PURPOSE: To evaluate the specificity of the HercepTest for Immunoenzymatic Staining (Dako Corp, Carpinteria, CA) for determining HER-2/neu protein expression in breast cancer. MATERIALS AND METHODS: Forty-eight invasive breast cancers previously found to be HER-2/neu-negative by two different immunohistochemical (IHC) assays and not amplified for the HER-2/neu gene by fluorescence in situ hybridization were studied using the HercepTest kit. HercepTest was performed according to the manufacturer's guidelines, and the results were scored on a 0 to 3+ scale using the United States Food and Drug Administration (FDA)-approved grading system. In this system, cases scored as 2+ or 3+ are considered HER-2/neu-positive. RESULTS: Among these 48 cases, the IHC score using the FDA-approved scoring system was 0 in four cases (8.3%), 1+ in 16 (33.3%), 2+ in 21 (43.8%), and 3+ in seven (14.6%). Therefore, 58.4% of these cases were categorized as HER-2/neu-positive, and the specificity of the HercepTest kit for HER-2/neu expression was 41.6%. However, with the use of a modified scoring system that took into account the level of staining of nonneoplastic epithelium, the specificity increased to 93.2%. CONCLUSION: Our results indicate that the HercepTest kit, when used in accordance with the manufacturer's guidelines and the FDA-approved scoring system, results in a large proportion of breast cancers being categorized as positive for HER-2/neu protein expression and that many of these seem to be false-positives. Consideration of the level of staining of nonneoplastic epithelium resulted in improved specificity. The current FDA-approved scoring system for HercepTest results should be reevaluated before its widespread use in clinical practice.

Contralateral breast cancer: clinical characteristics and impact on prognosis.

PURPOSE: To determine the characteristics of patients with unilateral breast cancer who subsequently develop contralateral breast cancer (CBC), to assess their prognosis relative to patients who do not develop a CBC, and to assess the feasibility of using conservative surgery (CS) and radiotherapy (RT) to treat CBC. MATERIALS AND METHODS: Of 1,624 women treated with CS and RT for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, 77 developed an invasive CBC. Sixty-two CBCs were treated with CS and RT. The median follow-up duration was 95 months from the time of initial breast cancer diagnosis, and 63 months from CBC diagnosis. RESULTS: The cumulative actuarial rate of CBC was 7.0% at 10 years, and the annual incidence rate for CBC was relatively constant. Young age predicted for CBC. When age was analyzed by decade the relative risk (RR) for older patients compared with younger patients was 0.79 (95% confidence interval [CI], 0.62 to 1.01). The presence of lobular carcinoma in situ (LCIS), higher tumor stage, and lack of adjuvant systemic therapy also predicted for CBC with borderline significance. Multivariate analyses showed that CBC was associated with a statistically significant greater likelihood of local recurrence (LR) or distant recurrence (RR, 1.68; 95% CI, 1.03 to 2.71), and distant-only recurrence (RR, 2.17; 95% CI, 1.28 to 3.69). Among assessable patients treated with bilateral RT, 28 of 31 ipsilateral and 11 of 11 contralateral breasts had an excellent or good overall cosmetic outcome at 5 years, and treatment-related complications were minimal. CONCLUSION: We conclude that (1) young age is associated with a greater likelihood of CBC, (2) patients who develop a CBC have a greater subsequent risk of distant relapse as compared with patients without CBC, and (3) it is feasible to deliver sequential nonoverlapping bilateral RT without compromising the cosmetic outcome or increasing complications.

Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer.

PURPOSE: The prognosis and factors that influence prognosis following salvage mastectomy in patients with recurrence in the treated breast after conservative surgery (CS) and radiation therapy (RT) were investigated. MATERIALS AND METHODS: A total of 1,593 patients with stage I or II invasive breast cancer were treated following gross total excision of the tumor at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. One hundred sixty-six of the 1,593 (10%) had subsequent recurrence in the breast. Of these, 123 had salvage mastectomy and constitute the study population. The recurrent tumor was predominantly invasive in 99 patients, noninvasive in 14, and focally invasive in 10. Following mastectomy, chemotherapy or hormonal therapy was administered to 29 patients. The median follow-up time was 39 months after salvage mastectomy. RESULTS: The 5-year actuarial rate of further local or distant relapse for the entire group was 41%. None of the 24 patients with focally invasive or noninvasive tumors had a subsequent relapse. In comparison, the 5-year actuarial rate of further relapse in the 99 patients with a predominantly invasive recurrence was 52% (P = .001). The method of detection of the recurrence, the age of the patient at initial diagnosis, the disease-free interval, and the location of the recurrence in the breast were not found to have a statistically significant association with the risk of further relapse. CONCLUSION: We conclude that the histology of the recurrent tumor is an important prognostic factor for the risk of further relapse. Patients with purely noninvasive or focally invasive tumors have an excellent prognosis following salvage mastectomy. In contrast, patients with predominantly invasive tumors are at substantial risk for further relapse.

Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence.

PURPOSE: To examine the relationship between pathologic margin status and outcome at 8 years after breast-conserving surgery and radiation therapy. PATIENTS AND METHODS: The study population comprised 533 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II breast cancer who had assessable margins, who received at least 60 Gy to the primary tumor bed, and who had more than 8 years of potential follow-up. Each margin was scored (according to the presence of invasive or in situ disease that touched the inked surgical margin) as one of the following: negative, close, focally positive, or extensively positive. Outcome at 8 years was calculated using crude rates of first site of failure. A polychotomous logistic regression analysis was performed. Median follow-up time was 127 months. RESULTS: At 8 years, patients with close margins and those with negative margins both had a rate of local recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate of 27%, whereas patients with focally positive margins had an intermediate rate of LR of 14%. In the polychotomous logistic regression model, margin status and the use of systemic therapy were the only two variables that had significant effects on the risk ratio of LR to remaining alive and free of disease. Among the 45 patients with focally positive margins who received systemic therapy, the crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%). CONCLUSION: Pathologic margin status and the use of adjuvant systemic therapy are the most important factors associated with LR among patients treated with breast-conserving surgery and radiation therapy.

Skin recurrences after breast-conserving therapy for early-stage breast cancer.

PURPOSE: To assess the frequency and prognosis of skin recurrences after breast-conserving therapy (BCT) compared with other breast recurrences. MATERIALS AND METHODS: From 1968 to 1986, 1,624 patients with unilateral stage I or II breast cancer treated with BCT at the Joint Center for Radiation Therapy (Boston, MA) underwent gross tumor excision and received a dose of > or = 60 Gy to the tumor bed. Skin recurrences (SR) were defined as breast recurrences without associated parenchymal disease. An invasive breast recurrence with any parenchymal disease noted clinically or radiographically was scored as an other breast recurrence (OBR). Median follow-up for survivors was 137 months. RESULTS: SR represented 8% (18 of 229) of all breast recurrences and occurred in 1.1% of all patients. The outcome after local recurrence was different for patients with SR and invasive OBR. Patients with SR more frequently had uncontrolled local failure (50%; 9 of 18) than did patients with OBR (14%; 26 of 188) (P = .0007). Forty-four percent (8 of 18) of patients with SR had distant metastasis simultaneously or within 2 months of the recurrence compared with 5% (9 of 188) of invasive OBR patients (P < .0001). For patients without distant metastasis at the time of recurrence, the 5-year actuarial rate of development of distant metastasis was 60% for SR patients compared with 39% for invasive OBR patients (P = .07), and the corresponding 5-year actuarial survival rates beyond the time of local failure were 51% and 79%, respectively (P = .06). CONCLUSION: In contrast to other types of invasive breast recurrence after breast-conserving therapy, skin recurrences are rare and are associated with a significantly higher rate of distant metastasis and uncontrolled local disease as well as a lower rate of survival.

The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast.

Previous studies of patients with infiltrating ductal breast cancer treated with conservative surgery (ie, limited excision) and radiotherapy have indicated that the presence of an extensive intraductal component (EIC) in the excision specimen is highly associated with subsequent breast recurrence. The reason for this association is not clear, but possible explanations include the presence of more extensive disease in the breast or increased radiation resistance among tumors with an EIC (EIC+) compared with those without (EIC-) tumors. To investigate this association further, we related the presence or absence of an EIC in the primary tumors of 214 women who underwent mastectomy to the likelihood of finding additional foci of cancer in their mastectomy specimens using a correlated pathologic-radiologic mapping technique. Primary tumors that were EIC+ were significantly more likely to have carcinoma in the remainder of the breast than those which were EIC--(74% v 42%; P = .00001). This difference was primarily due to the presence of residual intraductal carcinoma. Seventy-one percent of EIC+ patients had residual intraductal carcinoma compared with 28% of EIC-patients (P less than .00001). In particular, 44% of EIC+ patients had "prominent" residual intraductal carcinoma compared with 3% of EIC-patients (P less than .00001). We conclude that patients whose tumors contain an EIC more frequently have a large subclinical tumor burden in the remainder of the breast compared with patients whose tumors do not contain an EIC. This observation may explain the association between EIC and subsequent breast recurrence when patients are treated with a limited excision before radiotherapy.

Laser balloon angioplasty: clinical, angiographic and histologic results.

Laser balloon angioplasty combines conventional coronary angioplasty with laser energy to transiently heat vascular tissue. Laser balloon angioplasty, was performed in 21 patients (aged 56 +/- 13 years), including 10 patients treated urgently after acute failure of conventional angioplasty and 11 patients treated with elective laser balloon angioplasty. Immediately after conventional angioplasty, laser doses (1 to 10 doses of 205 to 380 J each) were delivered during inflation of the laser balloon to a pressure of 4 atm. Seven (70%) of 10 patients with acute failure of conventional angioplasty were successfully treated with laser balloon angioplasty, but 3 (30%) were unsuccessfully treated with the laser procedure and required emergency coronary artery bypass surgery. In all three failures, the 3 mm laser balloon angioplasty catheter was not the optimal size for the vessel. In the 11 patients treated with elective laser balloon angioplasty (reference diameter 2.94 +/- 0.22 mm), the minimal luminal diameter increased from 0.45 +/- 0.25 to 1.85 +/- 0.46 mm after conventional angioplasty and to 2.44 +/- 0.29 mm after laser balloon angioplasty (p less than 0.001). This corresponded to a decrease in diameter stenosis from 84 +/- 9% before to 35 +/- 16% after conventional angioplasty and to 15 +/- 10% after laser balloon angioplasty (p less than 0.001). There were no instances of myocardial infarction, emergency coronary artery bypass surgery or death and no acute complications related to delivery of laser energy in this group. Follow-up coronary angiography was performed 5.5 +/- 1.1 months after laser balloon angioplasty in 18 patients discharged from the hospital after a successful procedure. Ten patients (56%) had angiographic restenosis, defined as recurrent diameter stenosis greater than 50%. Six patients were subsequently treated by directional coronary atherectomy, which revealed intimal proliferation indistinguishable from that in patients with restenosis after conventional angioplasty. In conclusion, laser balloon angioplasty may be effective in sealing severe coronary dissections and reversing abrupt closure associated with failed conventional angioplasty. After uncomplicated conventional angioplasty, laser balloon angioplasty improves immediate luminal dimensions, but restenosis appears to be mediated by intimal hyperplasia, similar to that seen after conventional angioplasty.

Postmortem and intraoperative balloon valvuloplasty of calcific aortic stenosis in elderly patients: mechanisms of successful dilation.

Percutaneous balloon dilation of the aortic valve has recently been proposed as a palliative procedure for treating nonsurgical candidates with calcific aortic stenosis. To assess the safety, efficacy and mechanisms of successful balloon valvuloplasty, postmortem (n = 33) and intraoperative (n = 6) balloon aortic valvuloplasty was performed in the hearts of 39 elderly patients with calcific aortic stenosis. The cause of aortic stenosis was degenerative nodular calcification in 28 cases, calcific bicuspid aortic stenosis in 8 cases and rheumatic heart disease in 3 cases. Balloon dilation was performed with 15 to 25 mm balloons in the postmortem specimens, and with 18 to 20 mm balloons in the operating room immediately before aortic valve replacement. After balloon dilation, valve orifice dimensions and leaflet mobility increased in all patients. The mechanisms of successful dilation included fracture of calcified nodules in 16 aortic valves, separation of fused commissures in 5 valves, both in 6 valves and grossly inapparent microfractures in 12 valves. Valve leaflet avulsion occurred in one heart after inflation with a clearly oversized balloon. Liberation of calcific debris, valve ring disruption or midleaflet tears did not occur in any heart. In conclusion, there are at least three mechanisms of successful aortic valvuloplasty, depending on the origin of valvular stenosis. Embolic phenomena and acute valvular regurgitation do not appear to be likely events associated with this procedure.

Long-term results of directional coronary atherectomy: predictors of restenosis.

OBJECTIVES: This study was performed to obtain better understanding of the long-term clinical efficacy of directional coronary atherectomy. BACKGROUND: Although this procedure yields favorable acute results, its acceptance has been limited by the perception that late results (that is, freedom from restenosis) are no better than those of conventional angioplasty. METHODS: A total of 225 atherectomies performed in 190 patients between August 1988 and July 1991 were examined. Minimal lumen diameter of the treated segments was measured on angiograms obtained before, after and 6 months after intervention. RESULTS: Although most lesions (97%) had one or more characteristics predictive of unfavorable short- or long-term results after conventional angioplasty, atherectomy was successful in 205 lesions (91%) with a mean residual stenosis of 7 +/- 16%. After subsequent balloon angioplasty in 16 unsuccessful atherectomy attempts, procedural success was 98%. There were no deaths or Q wave myocardial infarctions, and one patient (0.5%) underwent emergency bypass surgery. Six-month angiographic follow-up was obtained in 77% of the eligible patients. The overall angiographic restenosis rate was 32%. Predictors of a lower restenosis rate included a postprocedure lumen diameter > 3 mm (24% vs. 39%, p = 0.047), serum cholesterol < or = 200 mg/dl (18% vs. 40%, p = 0.018) and recent myocardial infarction (16% vs. 37%, p = 0.034). Life-table analysis showed a 2% mortality rate and a 26% incidence of other events (myocardial infarction, repeat revascularization) within the 1st year. The annual 5% mortality rate and 7% incidence of other events during years 2 and 3 were related in large part to the existence or progression of disease at other locations. CONCLUSIONS: Six-month angiographic follow-up of patients who underwent directional coronary atherectomy during the 1st 3 years of our experience shows an overall restenosis rate of 32%, with lower rates in patients with a postatherectomy lumen diameter > or = 3 mm, cholesterol level < or = 200 mg/dl or a recent myocardial infarction. Few if any events relating to the site of atherectomy developed after the 1st year of follow-up.

Benign breast disease and breast cancer risk: potential role for antiestrogens.

Evidence from clinical follow-up studies has indicated that there is a relationship between the presence of histologically proven benign breast disease and breast cancer risk, and that the risk varies according to the histological category of benign breast disease and hormonal status. The risk associated with these histological factors appears to be equal in both breasts, suggesting that these factors are best considered markers of generalized increased breast cancer risk rather than direct precursor lesions. A number of interesting observations gleaned from the Nashville Study, the Breast Cancer Detection Demonstration Project and the Nurses' Health Study, among other studies, provide evidence of an interaction between these histological risk factors and estrogen in determining the level of breast cancer risk. In the National Surgical Adjuvant Breast Project P-1 trial, tamoxifen was associated with an 86% reduction in breast cancer risk among a small subset of women with biopsy-proven atypical hyperplasia. Taken together, these observations strongly suggest that there is an interaction between estrogen and histological factors in determining breast cancer risk, and that it may be possible to reduce the risk associated with these histological risk factors using antiestrogen therapy.

Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.

The generation of vascular stroma is essential for solid tumor growth and involves stimulatory and inhibiting factors as well as stromal components that regulate functions such as cellular adhesion, migration, and gene expression. In an effort to obtain a more integrated understanding of vascular stroma formation in breast carcinoma, we examined expression of the angiogenic factor vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow. We conclude that a distinct pattern of mRNA expression characterizes the generation of vascular stroma in breast cancer and that the formation of vascular stroma may play a role not only in growth of the primary tumor but also in invasion and metastasis.

Traditional and newer pathologic factors.

There has long been a pressing clinical need to identify prognostic and predictive factors for patients with breast cancer. Although numerous candidate biological and molecular markers have been identified during the last two decades, traditional factors such as lymph node status, tumor size, histologic type, histologic grade, and hormone receptor status remain the most useful indicators of prognosis and therapeutic response. A major obstacle to the translation of research advances into clinically useful prognostic and predictive markers has been the considerable methodologic variability used in the evaluation of the newer markers. It is now generally accepted that, to be useful in patient management, a putative prognostic or predictive marker must have clinical importance, independence, significance, and standardization with regard to methods, interpretation, and reporting. It is hoped that recognition and adoption of these criteria will serve to clarify the value of newer biologic and molecular markers.