Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-ß2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for ⩽2.5 v. 2.6-2.9 kg); higher adult height with RAR-ß2 methylation (OR = 3.34, 95% CI, 1.19-9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

Is MUGA scan necessary in patients with low-risk breast cancer before doxorubicin-based adjuvant therapy? Multiple gated acquisition.

Doxorubicin-based chemotherapy in the adjuvant treatment of breast cancer has become standard. Use of doxorubicin is limited by cardiac dysfunction; however, the incidence is dramatically reduced by limiting the dose to less than 550 mg/m(2). Although the cumulative dose in breast cancer is typically 240 mg/m(2), multiple gated acquisition (MUGA) scans are still recommended for determining cardiac functional status in these patients. To examine the need for this practice, we reviewed 296 patients who underwent surgery for breast cancer at Roswell Park Cancer Institute between July 1997 and December 1998. Fifty-nine of 95 (62%) patients receiving doxorubicin-based regimens, and 3 of 39 (7%) receiving nondoxorubicin regimens had pretreatment MUGA scans. The MUGA scans showed normal results in 58 patients and low-normal in 4 (6.5%), with no wall motion abnormalities encountered. There were no cases where doxorubicin was not used because of an abnormal MUGA scan. There were no cardiac complications in the 59 women who received doxorubicin-based chemotherapy. MUGA will screen out few, if any, women under consideration for doxorubicin-based adjuvant therapy; the decision to avoid doxorubicin can be made based on age and preexisting comorbidity. Guidelines recommending routine use of MUGA before the administration of doxorubicin for adjuvant therapy for breast cancer should be reconsidered.

Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma.

BACKGROUND AND OBJECTIVES: While sentinel lymph node biopsy is considered by many to have replaced axillary node dissection in the management of breast cancer, concerns remain regarding false-negative results. METHODS: To investigate the accuracy of sentinel node biopsy, we reexamined all sentinel and nonsentinel nodes with multilevel sectioning and immunohistochemical staining in 42 consecutive cases of breast cancer in which sentinel node biopsy was performed and followed by axillary dissection. RESULTS: By routine hematoxylin and eosin (H&E) staining, 34% of patients were found to be node positive, with no cases of false-negative sentinel node biopsy. Reevaluation of 775 negative sentinel and nonsentinel nodes with an additional two levels and immunohistochemistry identified three "node-negative" patients who had micrometastases in the sentinel node, increasing detection in 8% of cases. More important, is the fact however, that there were no cases where additional sections and immunohistochemistry identified metastases in nonsentinel nodes that had bypassed the sentinel node. The accuracy of the sentinel node in predicting the nodal status was 100%. CONCLUSIONS: Cytokeratin immunohistochemistry will identify more patients with nodal micrometastases; however, it was unable to identify any cases where micrometastases were present in nonsentinel nodes when the sentinel node was negative. The status of the sentinel node accurately identifies the status of the axillary basin.

Intraoperative pathologic evaluation of a breast cancer sentinel lymph node biopsy as a determinant for synchronous axillary lymph node dissection.

BACKGROUND: Intraoperative pathologic evaluation of a breast cancer sentinel lymph node (SLN) biopsy permits synchronous axillary lymph node dissection (ALND), but frozen section is time consuming and potentially inaccurate. This study evaluated intraoperative gross examination and touch prep analysis (TPA) of a breast cancer SLN biopsy as determinants for synchronous ALND. METHODS: Intraoperative gross examination/TPA were performed on the SLN of consecutive breast cancer patients from 1997 to 2000. Patients with an intraoperative "positive" SLN underwent synchronous ALND. Intraoperative results were compared with the final pathology. RESULTS: Thirty-seven of 150 patients had a positive SLN on final pathology. Intraoperative gross examination/TPA identified 54% (20 of 37) of these patients. All intraoperative "positive" patients underwent synchronous ALND. Of 17 "false-negative" findings, 53% (9 of 17) had micrometastatic disease. There were no "false-positive" results. Overall sensitivity and specificity were 54% and 100%, respectively. CONCLUSIONS: Gross examination/TPA are simple, rapid techniques for the intraoperative evaluation of a breast cancer SLN. As there were no false-positive results, the rationale behind SLN biopsy was preserved. These techniques permitted synchronous ALND in over half of all patients with a positive SLN. This represents a potential benefit to the patient by eliminating a second hospitalization for delayed ALND.

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Downregulation of gelsolin correlates with the progression to breast carcinoma.

The actin cytoskeleton underlies several normal cellular functions and is deranged during carcinogenesis. Gelsolin, a multifunctional actin-binding protein, is downregulated in several types of tumors and its abnormal expression is one of the most common defects noted in invasive breast carcinoma (ICA). This study utilizes immunohistochemistry to examine the expression of gelsolin in 95 ICA, 59 ductal carcinoma in situ (DCIS) and 36 benign lesions, including 17 atypical ductal hyperplasia (ADH). Cytoplasmic staining was scored as positive, reduced or negative. Gelsolin expression was then correlated with patient's age, tumor size, histologic grade and lymph node status. All unremarkable breast biopsies, 88% of ADH, 44% of DCIS and 28% of ICA were positive for gelsolin. This represents a significant difference among the groups (p = < 0.0001) and the trend towards reduced gelsolin with the progression to ICA is significantly linear (p = < 0.0001). For invasive carcinoma, patients older than 44 years were significantly more likely to have decreased expression of gelsolin than patients 44 years old and younger (p = 0.007). Bivariate analysis showed no correlation of gelsolin expression with lymph node status (p = 0.62), tumor size (p = 0.10), histologic grade (p = 0.42), estrogen receptor status (p = 1.0) or other clinicopathologic parameters. In clinical follow-up, there were 18 breast tumor related deaths within a median follow-up time of 4.2 years. Survival analysis indicated that the level of gelsolin expression may be associated with survival (p = 0.06). In summary, the frequency of gelsolin deficiency increases significantly with progression from ADH to DCIS to ICA. Additionally, gelsolin expression may be an independent marker of prognosis.

Measuring and predicting surgeons' practice styles for breast cancer treatment in older women.

BACKGROUND: Few measures exist to assess physicians' practice style, and there are few data on physicians' practice styles and patterns of care. OBJECTIVES: To use clinical vignettes to measure surgeons' "propensity" for local treatments for early-stage breast cancer and to describe factors associated with propensity. RESEARCH DESIGN AND SUBJECTS: A cross-sectional mailed survey with telephone follow-up of a random sample of 1,000 surgeons treating Medicare beneficiaries in fee-for-service settings. MEASURES: Outcome measures include treatment propensity, self-reported practice, and actual treatment received by the surgeons' patients. RESULTS: Propensities were significantly associated with actual treatment, controlling for covariates. Area Medicare fees were the strongest predictor of propensity, followed by region, attitudes, volume, and gender. For instance, after other factors were considered, surgeons practicing in areas with the highest breast-conserving surgery (BCS) fees were 8.61 (95% CI 2.26-32.73) times more likely to have a BCS propensity than surgeons in areas with the lowest fees. Surgeons with the strongest beliefs in patient participation in treatment decisions were nearly 6 times (95% CI 1.67-20.84) more likely to have a BCS propensity than surgeons with the lowest such beliefs, controlling for covariates. Male surgeons were also independently more likely to have a mastectomy propensity than female surgeons. CONCLUSIONS: Surgeons' propensities explain some of the observed variations in breast cancer treatment patterns among older women. Standardized scenarios provide a practical method to measure practice style and could be used to evaluate physician contributions to shared decision making, practice patterns, costs and outcomes, and adherence to guidelines.

In-situ ablation of breast cancer.

Recent trends in the management of early breast cancer have moved toward breast conservation, without a loss in disease-free intervals or overall survival. The in situ ablation of breast tumors without the need for lumpectomy is the next logical extension of this trend. Advances in stereotactic guided localization, ultrasound and magnetic resonance imaging (MRI) technology has markedly improved our ability to visualize, biopsy and possibly treat breast tumors. With these technologies, probes for delivery of energy for ablating tumors and for monitoring the effect can be placed precisely within breast tumors. Several methods are available to destroy tumors in situ, based on thermal destruction of tumor with either heat or cold. Cryoablation is performed using a liquid-nitrogen cooled needle. Heating techniques include delivery of the heat through probes placed in the lesion to conduct radiofrequency irradiation or laser light energy. Two techniques, focused ultrasound and focused microwave thermotherapy, are truly non-invasive in that they do not involve any skin puncture. In addition to the incentive of eliminating lumpectomy from the treatment paradigm for early stage breast cancer, and the potential cosmetic advantages, in situ ablation may also provide an immunological benefit by providing a source of antigens for the development of a systemic anti-tumor immune response. The augmentation of this response may provide an advantage to in situ ablation in terms of recurrence and survival rates.

Breast cancer risk factors and HER2 over-expression in tumors.

Few epidemiologic studies have investigated the potential role of HER2 in the etiology of breast cancer. We conducted a case-case study of 156 women with incident, invasive ductal carcinoma. Multivariate unconditional logistic regression was used to estimate the odds ratios for a HER2 positive tumor in relation to known and putative risk factors of breast cancer. HER2 status was detected by immunohistochemistry on archival tissue. HER2 positive breast cancers tended to be larger and were less likely to express estrogen receptors, and the incidence rate was higher in patients less than 40 years old. We observed an association between a self-reported history of benign breast disease and the occurrence of HER2 positive breast cancer (OR, 2.1;95% CI, 1.1-4.1). We did not detect associations between HER2 over-expression and family history of breast cancer, parity, late age at first birth, ever having breast fed an infant, or oral contraceptive use. Our findings merit consideration in light of recent evidence of HER2 amplification or over-expression in benign breast disease. Should the link to breast cancer be established, HER2 positive benign breast disease could potentially serve as an early marker for preventive intervention.

NCCN: Breast cancer.

The 2001 NCCN Breast Cancer Guidelines reflect the results of 5 generations of NCCN Breast Cancer Guidelines. Evidence-based guidelines, such as the NNCN Breast Cancer Guidelines, are possible only because of the availability of high-level evidence at multiple decision points in treatment. The continued performance of high quality clinical trials is central to our ability to further improve the treatment of breast cancer. The panel believes that participation in high quality clinical trials is the preferred treatment at all points in breast cancer therapy.

Postexcision mammography is indicated after resection of ductal carcinoma-in-situ of the breast.

BACKGROUND: The adequacy of excision of ductal carcinoma-in-situ (DCIS) usually is confirmed with specimen mammography and histopathological assessment of specimen margins. Postexcision mammography of the involved breast is used at some centers. The objective of this study was to evaluate the impact of postexcision mammography in DCIS. METHODS: We conducted a retrospective chart review of all patients treated for DCIS at our institution from 1995 to 1998. RESULTS: Sixty-seven patients had postexcision mammography performed. Residual microcalcifications were identified in 16 patients (24%). Further surgery was precluded by precise mammographic-pathological correlation by using sliced-specimen mammography in two patients. Twelve patients had repeat wide excision, and two patients underwent mastectomy. Residual DCIS was identified at re-excision in 9 of 14 patients (64%). The margin status of the initial resection was negative in three of nine patients (33%) and positive or unknown in six of nine patients (67%). CONCLUSIONS: Postexcision mammography is a valuable technique that complements specimen mammography and histopathological margin assessment in confirming that an adequate excision of DCIS has been performed. Postexcision mammography should be performed in all patients with DCIS associated with mammographic calcifications who are treated with breast-conserving therapy.

Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND: Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in breast cancer and stratified them into categories reflecting the strength of published evidence. MATERIALS AND METHODS: Factors were ranked according to previously established College of American Pathologists categorical rankings: category I, factors proven to be of prognostic import and useful in clinical patient management; category II, factors that had been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected about existing prognostic factors, and (3) improving patient care. RESULTS AND CONCLUSIONS: Factors ranked in category I included TNM staging information, histologic grade, histologic type, mitotic figure counts, and hormone receptor status. Category II factors included c-erbB-2 (Her2-neu), proliferation markers, lymphatic and vascular channel invasion, and p53. Factors in category III included DNA ploidy analysis, microvessel density, epidermal growth factor receptor, transforming growth factor-alpha, bcl-2, pS2, and cathepsin D. This report constitutes a detailed outline of the findings and recommendations of the consensus conference group, organized according to structural guidelines as defined.

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Down-regulation of gelsolin expression in human breast ductal carcinoma in situ with and without invasion.

Expression of gelsolin, an actin filament regulatory protein, in human breast ductal carcinoma in situ (DCIS) was analyzed by immunohistochemistry using a monoclonal antibody. Formalin-fixed paraffin-embedded tissues from 59 pure DCIS specimens and 33 DCIS specimens with associated invasive components were evaluated for gelsolin reactivity and compared to eight normal breast cases and 76 invasive breast cancers. The proportion of cases exhibiting negative/low expression of gelsolin in the epithelium was as follows -- normal, 0%; pure DCIS, 56%; DCIS associated with invasion, 58% in the DCIS component and 66% in the invasive component; invasive carcinoma, 70%. These data demonstrate that down-regulation of gelsolin expression in breast epithelium frequently parallels progression to malignancy. Testing gelsolin expression (normal vs. negative/low levels) in the DCIS lesions for associations with patient age or any of the following histopathologic parameters revealed no significant (95% probability level) correlations -- tumor size; pathologic (Van Nuys system) grade; nuclear grade; necrosis; presence of histologic calcifications; presence or type of adjacent benign lesions; architectural histologic pattern; and mammographic extent. Gelsolin loss was more commonly associated with mammographic soft tissue lesions as compared to calcified lesions (P = 0.009). A positive trend of borderline significance (P = 0.06) found in the DCIS with invasion group was a correlation between down-regulated gelsolin expression in the DCIS component and size (< versus > or = 15 mm) of the invasive tumor. In conclusion, reduced gelsolin protein is detectable in at least half of breast lesions which have progressed to DCIS. The trend between increasing gelsolin loss and malignant progression from normal epithelium to DCIS to invasive breast cancer (P < 0.0001) suggests additional investigation is needed to determine the potential of altered gelsolin expression as a marker for prognosis and for therapeutic interventions in breast cancer.

Laparoscopic cholecystectomy and unsuspected gallbladder carcinoma.

Gallbladder cancer is a relatively uncommon malignancy in the United States. Its presentation is similar to that of lithic disease of the gallbladder. Laparoscopic cholecystectomy has become the method of choice for removing the gallbladder in most benign conditions. Occasionally, unsuspected gallbladder carcinoma is encountered in association with laparoscopic cholecystectomy. Overall, gallbladder cancer portends a poor prognosis. However, in select cases, a favorable outcome can be expected and the less favorable predicted expected outcome can be improved. Management of patients with gallbladder cancer in different situations is discussed: gallbladder cancer noted postoperatively on final pathology, gallbladder cancer noted after removal of the gallbladder and opening of the specimen at the time of surgery, difficulty encountered at the time of dissection and resultant suspicion of gallbladder cancer, and diagnosis of extensive disease at initial placement of the laparoscope. The technique of extended cholecystectomy is outlined.

Breast cancer imaging.

The role of the surgeon in the diagnosis and management of breast cancer continues to evolve as office based diagnostic procedures gain more prominence. This article outlines the basic clinical and technical aspects of mammography and ultrasound. The evaluation and management of several challenging breast problems are discussed.

Sarcoma of the breast: implications of the extent of local therapy.

Although the majority of breast neoplasms will be of epithelial origin, tumors of the stromal elements of the breast may occur. A retrospective review of the medical records and tumor registry data of 25 patients with breast sarcoma treated at Roswell Park Cancer Institute from 1964 to 1995 was performed. There were 24 females and 1 male, with a median age of 55 years. Delay in seeking medical attention was common. Angiosarcoma was the most common histologic type of breast sarcoma (n = 10). Mastectomy was the predominant form of local therapy (21 patients). Overall survival was 61 per cent at 5 years and 36 per cent at 10 years. There was no difference in survival or local control rates for those patients treated with local excision when compared with patients treated with mastectomy. Sarcoma is an unusual form of breast tumor. Survival and local control are similar when comparing local excision and mastectomy. When local excision is performed, attention must be directed to achieving clear margins of resection. The benefit of adjuvant therapy remains undefined.