Assessment of intravitreal anti-VEGF drugs and dexamethasone for retinal diseases in real world setting: A multi-centre prospective study from Southern Italy.

Describe drug utilisation and clinical outcomes of intravitreal anti-VEGF drug and dexamethasone use in the real-world setting in Southern Italy using data from multi-centre study of retinal disease. Clinical data of retinal disease patients treated with anti-VEGF drugs and dexamethasone implant in 6 out-patient ophthalmology centres from Southern Italy were collected by means of an electronic case report form. Patients receiving at least one intravitreal injection/implant of the study drugs were followed for up to two years and described in terms of demographics and clinical characteristics. Drug utilisation patterns were described. A sign-rank test was used to compare clinical data on visual acuity and other ophthalmic parameters from baseline at different follow-up times for each indication. Data from 1327 patients was collected. Most patients were diagnosed with age-related macular degeneration (AMD) (660, 49.7%), followed by diabetic macular oedema (423, 31.9%), retinal vein occlusion (164, 12.3%), and myopic choroidal neovascularization (80, 6.0%). Patients were followed for a median of 10.3 months (interquartile range: 3.6 - 24.7 months). Mean patient age was 69.7 (±10.9) years and 54.2% were males. Ranibizumab (55.4%) and aflibercept (27.5%) were the most commonly used drugs. Baseline visual acuity significantly improved by about 0.05 to 0.1 logMAR at all follow-up times for AMD and RVO but less consistently for the other diseases. Intravitreal ranibizumab use accounted for half of all treatment for retinal diseases in a Southern Italian out-patient setting. Patients treated with anti-VEGF drugs for AMD and RVO in Southern Italy experienced significant improvement in VA.

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010-2016.

PURPOSE: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions. METHODS: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data. RESULTS: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up (N = 30,745), 16.0% (N = 30,745), 16.0% (N = 30,745), 16.0% (. CONCLUSION: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson's Disease: A Case Report.

In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System.

INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear. OBJECTIVE: The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS). METHODS: We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA®) queries (SMQs). RESULTS: Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders). CONCLUSIONS: This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

Tamoxifen and depression: more evidence from the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention (P-1) Randomized Study.

BACKGROUND: Concerns have been raised that tamoxifen may be associated with depression. To investigate this question, we examined the psychological effects of tamoxifen treatment for breast cancer prevention on women at different levels of risk for clinical depression who were enrolled in the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention (P-1) Study. METHODS: A total of 11 064 women were randomly assigned to receive for 5 years daily doses of 20 mg of tamoxifen or placebo in the P-1 study, a multicenter, double-blind, placebo-controlled chemoprevention trial. Each woman was prospectively assessed for depression risk on the basis of medical history items collected at the baseline examination and placed in a high-, medium-, or low-risk group. Every 6 months, for a total of 36 months, the participants were assessed for depressive symptoms by completing the Center for Epidemiological Studies-Depression (CES-D) questionnaire. Scores of 16 or higher were indicative of an episode of affective distress. Differences between the risk groups and treatment arms were analyzed by logistic regression. All statistical tests were two-sided. RESULTS: Women in the higher risk depression groups were more likely to score 16 or higher on the CES-D (percent follow-up examinations with a score of > or = 16: high-risk group = 35.7%, with 95% confidence interval [CI] = 32.5% to 38.9%; medium-risk group = 19.2%, with 95% CI = 18.1% to 20.3%; and low-risk group = 8.7%, with 95% CI = 8.3 to 9.1%) and to have these scores more frequently and for longer periods than women in the lower risk groups. Within each depression risk group, there was no difference in the proportion of women scoring 16 or higher by treatment assignment (tamoxifen versus placebo) (odds ratio = 0.98; 95% CI = 0.93 to 1.02). A post-hoc analysis indicated that the lack of a tamoxifen effect was not a result of differential missing data. CONCLUSIONS: Physicians need not be overly concerned that treatment with tamoxifen will increase the risk for or exacerbate existing depression in women. Nevertheless, physicians should continue to screen for and treat or refer potential cases of depression encountered in routine clinical practice.

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

The reliability of multiple regression and an alternative method for extracting task-specific exposure estimates from time-weighted average data.

The reliability of multiple regression analysis as a method for determining task-specific exposures from multi-task time-weighted average data was evaluated in comparison with the alternative P-screen method. The performances of the two methods were tested using simulated sample data that were calculated as averages over six tasks, where task-specific concentrations drawn randomly from lognormal distributions were weighted by randomly generated task time-weights. Data sets consisted of 20 or 100 simulated samples. The simulated data sets conformed to requirements inherent in the P-screen method that at least one task be absent from each sample and each task be absent from at least one sample. In thousands of Monte Carlo trials under various conditions, the two methods were found to perform equally well when dichotomous task measures (occurrence/ nonoccurrence) were used. Combining the two methods did not improve reliability appreciably, suggesting that the methods are effectively equivalent when dichotomous task measures are used. When task durations were used as the regressors or time-weights, multiple regression was found to be more reliable than P-screen. It is well recognized that incidental or fundamental collinearities between regressors may undermine multiple regression analyses. The P-screen-related restrictions on the task structure of data sets reduces the potential for problems arising from such collinearities. However, the use of multivariate analysis of multiple-task samples will always be an imperfect substitute for single-task sampling.

Tamoxifen and cardiac risk factors in healthy women: Suggestion of an anti-inflammatory effect.

-Tamoxifen reduces the incidence of breast cancer in women at risk for that disease. Because heart disease is the leading cause of death in women and because tamoxifen is also associated with venous thrombosis, an improved understanding of the association of tamoxifen with cardiovascular disease risk factors is required. In 111 healthy women at a single center, who were participating in a randomized double-blind breast cancer prevention trial, the 6-month effects of oral tamoxifen (20 mg/d) compared with placebo on factors related to inflammation, hemostasis, and lipids were studied. Tamoxifen was associated with reductions of 26% in median C-reactive protein, 22% in median fibrinogen, and 9% in cholesterol (all P:<0.01 compared with placebo). There were no differences in treatment effects on factor VII coagulant activity, fragment 1-2, and triglycerides. In secondary analyses, the effect of tamoxifen on C-reactive protein was larger in postmenopausal women and in women with higher waist-to-hip ratios. The effect on fibrinogen was larger in women with higher baseline cholesterol. Tamoxifen demonstrated effects on inflammatory markers that were consistent with reduced cardiovascular risk. These findings are in contrast to recent reports of increased C-reactive protein associated with postmenopausal estrogen. The potential for beneficial cardiovascular effects of tamoxifen in healthy women is suggested.

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.

Results and implications of the Royal Marsden and other tamoxifen chemoprevention trials: an alternative view.

At the time of the release of the findings of the Breast Cancer Prevention Trial (BCPT), early interim results from two smaller European studies were also released. These smaller studies included one from the Royal Marsden (RM) Hospital in London, England, and another from the Italian National Cancer Institute. Since then, there has been much discussion about the relevance of the interim findings from the European studies and the likely reason for the failure of these studies to find a treatment effect. In some instances, the discussion has been incomplete or inconsistent with the observations from the trial. This has caused some confusion regarding the likely differences among the three studies of breast cancer prevention with tamoxifen. Recently, investigators from the RM study have published their interpretation of the reasons for the negative findings from the European studies. The discussions of the RM investigators are reviewed and used as a basis to illustrate some misconceptions regarding key differences in trial design and implementation among the BCPT and the European trials. The investigator discussions are also used to illustrate the significance of performing an appropriate benefit/risk assessment to identify women who would likely have a net beneficial effect when using tamoxifen to reduce the risk of breast cancer occurrence. Differences in terms of the characteristics of the study populations resulting in inadequate statistical power is the most likely reason for the failure to detect treatment differences in the European trials. Possible confounding due to the use of hormone replacement therapy is another reason that must be considered. Also, benefit/risk analysis indicates that tamoxifen has substantial public health potential as an approach to reduce breast cancer incidence and the physical and mental morbidity associated with this disease. The drug cannot be used indiscriminately due to the potential side effects, but benefit/risk assessment methodology can be used to identify substantial numbers of women in whom treatment would provide a net beneficial effect.

Benefit/risk assessment of SERM therapy: clinical trial versus clinical practice settings.

Benefit/risk assessment (B/rA) can be used in a variety of circumstances encompassing clinical practice and research settings. Subsequent to the reporting of the results from the Breast Cancer Prevention Trial (BCPT), methodology was developed to perform B/rA for the use of the selected estrogen receptor modulator (SERM), tamoxifen. Although the methodology was specifically developed and applied to the use of tamoxifen, it is a generalized procedure that can be readily modified and applied to other forms of therapy including other SERMs. Recently, the methodology has been incorporated into the Study of Tamoxifen and Raloxifene (STAR) trial, a randomized clinical trial designed to compare the chemopreventive effects of two SERMs--tamoxifen and raloxifene. The B/rA of SERMs is complex because SERMs are known to exhibit properties that can reduce or increase the incidence of several health outcomes. This paper summarizes the uses of B/rA in the clinical practice and clinical trial settings and describes the constraints of the methodology as it is being applied to the assessment of therapy with SERMs.

Conclusions: Considerations regarding SERMs.

The "considerations" addressed in this section consist of a number of thought-provoking issues and unresolved questions that emerge from the papers in this volume. The evidence for tamoxifen carcinogenicity in animal models and, to a more restricted extent, in humans has led some investigators to question whether SERMs are ready or appropriate for clinical testing--specifically, in a disease prevention setting involving healthy but high-risk individuals. There is, however, inconsistency in both efficacy and toxicity--specifically, carcinogenicity--between animal models and humans, leading others to question the value of basing the decision to proceed with clinical studies on preclinical results in animals. Although the molecular basis for SERM action is rapidly being clarified, the cellular activity of these agents is still elusive. We discuss the view that the efficacy of tamoxifen in breast cancer is based on its treatment of "occult cancers," or small collections of cancer cells that are not clinically apparent, not only in the context of prevention but also in the treatment setting. As part of our approach that assumes estrogen activity to be the foundation upon which SERM development is being modeled, we discuss the inconsistency between the epidemiologic data and prospective randomized data with respect to the relationship between estrogen use and cardiovascular disease. The need to validate surrogate markers of SERM action is discussed in relation to bone but is clearly relevant to all disease sites. The semantics used in describing SERM action as agonistic or antagonistic in relation to estrogen at various target sites has been inconsistent, especially in the clinical context. We attempt to dissect out some of the inconsistencies in semantics in the hope that this will contribute to improved communication of data resulting from SERM research. In the clinical arena, we begin with the premise that the large, simple randomized trial offers the optimal design for the testing of SERMs. In view of limited resources, however, we counter this position with alternative, if less desirable, approaches to the clinical format for SERM testing. Finally, we explore the process by which statistically meaningful results from clinical trials are extrapolated into the specific drug indications that apply to clinical practice.

A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure.

We compared noninvasive positive-pressure ventilation (NPPV), using bilevel positive airway pressure, with usual medical care (UMC) in the therapy of patients with acute respiratory failure (ARF) in a prospective, randomized trial. Patients were subgrouped according to the disease leading to ARF (chronic obstructive pulmonary disease [COPD], a non-COPD-related pulmonary process, neuromuscular disease, and status postextubation), and were then randomized to NPPV or UMC. Thirty-two patients were evaluated in the NPPV group and 29 in the UMC group. The rate of endotracheal intubation (ETI) was significantly lower in the NPPV than in the UMC group (6.38 intubations versus 21.25 intubations per 100 ICU days, p = 0.002). Mortality rates in the intensive care unit (ICU) were similar for the two treatment groups (2.39 deaths versus 4.27 deaths per 100 ICU days, p = 0.21, NPPV versus UMC, respectively). Patients with hypoxemic ARF in the NPPV group had a significantly lower ETI rate than those in the UMC group (7.46 intubations versus 22.64 intubations per 100 ICU days, p = 0.026); a similar trend was noted for patients with hypercapnic ARF (5.41 intubations versus 18.52 intubations per 100 ICU days, p = 0.064, NPPV versus UMC, respectively). Patients with ARF in the non-COPD category had a lower rate of ETI with NPPV than with UMC (8.45 intubations versus 30.30 intubations per 100 ICU days, p = 0.01). Although the rate of ETI was lower among COPD patients receiving NPPV, this trend did not reach statistical significance (5.26 intubations versus 15.63 intubations per 100 ICU days, p = 0.12, NPPV versus UMC, respectively). In conclusion, NPPV with bilevel positive airway pressure reduces the rate of ETI in patients with ARF of various etiologies.

Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer.

BACKGROUND: In response to findings from the Breast Cancer Prevention Trial that tamoxifen treatment produced a 49% reduction in the risk of invasive breast cancer in a population of women at elevated risk, the National Cancer Institute sponsored a workshop on July 7 and 8, 1998, to develop information to assist in counseling and in weighing the risks and benefits of tamoxifen. Our study was undertaken to develop tools to identify women for whom the benefits outweigh the risks. METHODS: Information was reviewed on the incidence of invasive breast cancer and of in situ lesions, as well as on several other health outcomes, in the absence of tamoxifen treatment. Data on the effects of tamoxifen on these outcomes were also reviewed, and methods were developed to compare the risks and benefits of tamoxifen. RESULTS: The risks and benefits of tamoxifen depend on age and race, as well as on a woman's specific risk factors for breast cancer. In particular, the absolute risks from tamoxifen of endometrial cancer, stroke, pulmonary embolism, and deep vein thrombosis increase with age, and these absolute risks differ between white and black women, as does the protective effect of tamoxifen on fractures. Tables and aids are developed to describe the risks and benefits of tamoxifen and to identify classes of women for whom the benefits outweigh the risks. CONCLUSIONS: Tamoxifen is most beneficial for younger women with an elevated risk of breast cancer. The quantitative analyses presented can assist health care providers and women in weighing the risks and benefits of tamoxifen for reducing breast cancer risk.

Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

PURPOSE: This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. PATIENTS AND METHODS: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies-Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. RESULTS: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. CONCLUSION: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.

Validation studies for models projecting the risk of invasive and total breast cancer incidence.

BACKGROUND: In 1989, Gail and colleagues developed a model for estimating the risk of breast cancer in women participating in a program of annual mammographic screening (designated herein as model 1). A modification of this model to project the absolute risk of developing only invasive breast cancer is referred to herein as model 2. We assessed the validity of both models by employing data from women enrolled in the Breast Cancer Prevention Trial. METHODS: We used data from 5969 white women who were at least 35 years of age and without a history of breast cancer. These women were in the placebo arm of the trial and were screened annually. The average follow-up period was 48.4 months. We compared the observed number of breast cancers with the predicted numbers from the models. RESULTS: In terms of absolute risk, the ratios of total expected to observed numbers of cancers (95% confidence intervals [CIs]) were 0.84 (0. 73-0.97) for model 1 and 1.03 (0.88-1.21) for model 2, respectively. Within the age groups of 49 years or less, 50-59 years, and 60 years or more, the ratios of expected to observed numbers of breast cancers (95% CIs) for model 1 were 0.91 (0.73-1.14), 0.96 (0.73-1. 28), and 0.66 (0.52-0.86), respectively. Thus, model 1 underestimated breast cancer risk in women more than 59 years of age. For model 2, the risk ratios (95% CIs) were 0.93 (0.72-1.22), 1.13 (0.83-1.55), and 1.05 (0.80-1.41), respectively. Both models exhibited a tendency to overestimate risk for women classified in the higher quintiles of predicted 5-year risk and to underestimate risk for those in the lower quintiles of the same. CONCLUSION: Despite some limitations, these methods provide useful information on breast cancer risk for women who plan to participate in an annual mammographic screening program.

Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma.

BACKGROUND: This report is an 8-year update of the authors' previous findings from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which relates to the influence of pathologic characteristics on the natural history and treatment of intraductal carcinoma (DCIS). METHODS: Nine pathologic features observed in a pathologic subset of 623 of 814 evaluable women enrolled in this randomized clinical trial were assessed for their role in the prediction of second ipsilateral breast tumors (IBT), other events, and selection of breast irradiation (XRT) following lumpectomy. RESULTS: The frequency of subsequent IBT was reduced from 31% to 13% (P = 0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for all pathologic features examined. Four characteristics were individually noted to be significantly related to IBT, but only moderate-to-marked and absent-to-slight comedo necrosis were found to be independent high and low risk predictors, respectively, for such an event in patients of both treatment groups. XRT effected a 7% absolute reduction at 8 years in the low risk group. Despite a relatively high incidence (approximately 40%) of IBT consisting of invasive cancer, mortality due to breast carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years. CONCLUSIONS: The degree of comedo necrosis in patients with DCIS appears to be sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to have only a slight or borderline influence on the frequency of IBT at 8 years, excision of DCIS with free margins is advised. The low risk group exhibits a statistically significant reduction of IBT from XRT. The decision to forgo XRT in the treatment of this singular subset of patients would appear to depend on clinical considerations and the input of informed patients rather than being standard practice. [See editorial on pages 375-7, this issue.]