Jill Dietz

Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial

BACKGROUND Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. METHODS Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II-III (> or = T2 and/or > or = N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m(2)) plus docetaxel (75 mg/m(2)) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. FINDINGS Of the 120 patients initially enrolled, one withdrew after signing consent and one patients baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0.054). The most common grade 3-4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. INTERPRETATION Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. FUNDING Novartis Pharmaceuticals and Pfizer Inc.

Impact of postmastectomy radiation on locoregional recurrence in breast cancer patients with 1-3 positive lymph nodes treated with modern systemic therapy.

PURPOSE Postmastectomy radiation therapy (PMRT) remains controversial for patients with 1-3 positive lymph nodes (LN+). METHODS AND MATERIALS We conducted a retrospective review of all 369 breast cancer patients with 1-3 LN+ who underwent mastectomy without neoadjuvant systemic therapy between 2000 and 2007 at Cleveland Clinic. RESULTS We identified 271 patients with 1-3 LN+ who did not receive PMRT and 98 who did receive PMRT. The median follow-up time was 5.2 years, and the median number of LN dissected was 11. Of those not treated with PMRT, 79% received adjuvant chemotherapy (of whom 70% received a taxane), 79% received hormonal therapy, and 5% had no systemic therapy. Of the Her2/neu amplified tumors, 42% received trastuzumab. The 5-year rate of locoregional recurrence (LRR) was 8.9% without PMRT vs 0% with PMRT (P=.004). For patients who did not receive PMRT, univariate analysis showed 6 risk factors significantly (P<.05) correlated with LRR: estrogen receptor/progesterone receptor negative (hazard ratio [HR] 2.6), lymphovascular invasion (HR 2.4), 2-3 LN+ (HR 2.6), nodal ratio >25% (HR 2.7), extracapsular extension (ECE) (HR 3.7), and Bloom-Richardson grade III (HR 3.1). The 5-year LRR rate was 3.4% (95% confidence interval [CI], 0.1%-6.8%] for patients with 0-1 risk factor vs 14.6% [95% CI, 8.4%-20.9%] for patients with ≥2 risk factors (P=.0006), respectively. On multivariate analysis, ECE (HR 4.3, P=.0006) and grade III (HR 3.6, P=.004) remained significant risk factors for LRR. The 5-year LRR was 4.1% in patients with neither grade III nor ECE, 8.1% with either grade III or ECE, and 50.4% in patients with both grade III and ECE (P<.0001); the corresponding 5-year distant metastasis-free survival rates were 91.8%, 85.4%, and 59.1% (P=.0004), respectively. CONCLUSIONS PMRT offers excellent control for patients with 1-3 LN+, with no locoregional failures to date. Patients with 1-3 LN+ who have grade III disease and/or ECE should be strongly considered for PMRT.

Feasibility and Technical Considerations of Mammary Ductoscopy in Human Mastectomy Specimens

Abstract: Recent advances in endoscopic technology have made visualization of human mammary ducts possible. The purpose of this study was to assess the feasibility and technical factors influencing the ability to successfully visualize the epithelium of the human mammary ductal system. Lacrimal duct probes were used to dilate nipple orifices to 1.2 mm on 42 mastectomy specimens. The Depth of Field Imaging Micro‐Minimally Invasive (DOFI® MMI) system consisting of a 1.2 mm rigid ductoscope with a 350 μm working channel was introduced into mammary ducts under air insufflation or saline irrigation. At least one major duct could be dilated and cannulated in all 42 specimens. Visualization of the proximal duct was accomplished in 34 of 42 (81%) specimens, whereas more extensive navigation through the distal subsegmental ducts was achieved in 22 of 42 (52%) specimens. Ductoscopy into the terminal ducts was accomplished in all patients with a previous history of nipple discharge or discharge at the time of the procedure (10 of 10). In three patients with no history of nipple discharge prior to ductoscopy, incidental papillomas were discovered and confirmed by the pathologist. In conclusion, mammary ductoscopy is technically feasible and may have an application as an additional diagnostic modality for patients with pathologic nipple discharge.

Risk Factors for Complications of Radiation Therapy on Tissue Expander Breast Reconstructions

Abstract:  Radiation therapy has been shown to increase complication rates of tissue expander/implant breast reconstructions. The purpose of this study was to evaluate patient characteristics to assess their impact on complications. A retrospective review of patients who underwent mastectomy plus tissue expander/implant reconstruction from January 2000 to December 2006 was performed. The main outcome of interest was the development of postoperative complications. Analyses were performed to detect risk factors for complications. A total of 560 patients were included in the study. A total of 385 patients underwent unilateral and 174 underwent bilateral tissue expander/implant reconstructions, for a total of 733 reconstructions. A total complication rate of 31.8% and a major complication rate of 24.4% were calculated. The risk factors associated with a significantly increased incidence of complications were age greater than 50 years, body mass index (BMI) greater than 30, and radiation. Women younger than 50 years had a complication rate of 28.4%, whereas women older than 50 years had a complication rate of 37.0%. Women with a BMI less than 30 had a complication rate of 27.5%, whereas women with a BMI greater than 30 had a complication rate of 49%. The major complication rate in nonradiated and radiated patients was 21.2% and 45.4%, respectively. Despite higher complication rates, tissue expander/implant reconstructions were successful in 70.1% of radiated patients. Based on this study, the ideal radiated patient would have a BMI less than 30 and be younger than 50 years of age to maximize the likelihood of a successful tissue expander/implant reconstruction.

Endoscopic approach for benign tumor ablation of the forehead and brow.

Resection of benign tumors of the forehead and brow raises aesthetic concerns. An endoscopic subperiosteal approach to benign bony and soft-tissue tumors in the supraorbital and frontotemporal regions permits extirpation of these masses without producing visible facial scars. Therefore, this technique was used for tumor resection in 4 patients. This procedure demonstrated magnified visualization of the masses, and safe access for excisional biopsy and bony contouring. In addition to more acceptable surgical scars, patients experienced no significant postoperative morbidity and a reduced incidence of swelling, discomfort, and scalp anesthesia. Therefore, we conclude that the endoscopic subperiosteal approach is a favorable alternative for resection of suitable tumors.

Mammary ductoscopy and ductal washings for the evaluation of patients with pathologic nipple discharge.

Abstract:  The majority of breast diseases result from lesions of the ductal epithelium. Mammary ductoscopy allows for visualization of intraductal abnormalities, and ductoscopic lavage provides thousands of cells for analysis. We reviewed our experience of 89 cases of patients with pathologic nipple discharge (PND) undergoing ductoscopy‐directed duct excision and collection of ductal washings. Patients undergoing ductoscopy‐directed duct excision with ductal washings had an 88% abnormal pathology rate. Most abnormalities were benign (71% papillomas), but the atypia rate for this group was 62%. The combination of visualization and pathologic analysis of washings provided the highest predictive value for the diagnosis of papilloma. Cellular yields for this technique were excellent with most specimens yielding >5,000 epithelial cells per high powered field and with evaluable ductal cells in 82% of specimens. Mammary ductoscopy offers the advantage of a high lesion localization rates with intraoperative guidance. The most accurate tool was the combination of ductal washings and ductoscopic visualization, but preoperative use of these techniques is not helpful in most cases. Greater than 90% of patients with PND are found to have a lesion on pathologic examination when using this technique for directed duct excision. Of interest, ductal washings obtained from symptomatic patients with benign diseases are often atypical.

False‐positive Extra‐Mammary Findings in Breast MRI: Another Cause for Concern

Breast magnetic resonance imaging (MRI) has been repeatedly shown to have a high false‐positive rate for additional findings in the breast resulting in additional breast imaging and biopsies. We hypothesize that breast MRI is also associated with a high rate of false‐positive findings outside of the breast requiring additional evaluation, interventions, and delays in treatment. We performed a retrospective review of all breast MRIs performed on breast cancer patients in 2010 at a single institution. MRI reports were analyzed for extra‐mammary findings. The timing and yield of the additional procedures was also analyzed. Three hundred and twenty‐seven breast cancer patients (average age = 53.53 ± 11.08 years) had a breast MRI. Incidental, extra‐mammary findings were reported in 35/327 patients (10.7%) with a total of 38 incidental findings. The extra‐mammary findings were located in the liver (n = 21, 60.0%), thoracic cavity (n = 12, 34.3%), kidneys (n = 1, 2.9%), musculoskeletal system (n = 3, 8.6%), and neck (n = 1, 2.9%). Eighteen of the 35 patients (51.4%) received additional radiographic imaging, 3 (8.6%) received additional laboratory testing, 2 (5.7%) received additional physician referrals and 2 (5.7%) received a biopsy of the finding. The average time to additional procedures in these patients was 14.5 days. None of the incidental, extra‐mammary findings were associated with breast cancer or other malignancy. Breast MRI was associated with a high rate (10.7%) of extra‐mammary findings, which led to costly additional imaging studies, referrals, and tests. These findings were not associated with breast cancer or other malignancies. Extra‐mammary findings highlight an unrecognized adverse consequence of breast MRI.

Idiopathic Systemic Capillary Leak Syndrome Preceding Diagnosis of Infiltrating Lobular Carcinoma of the Breast With Quiescence During Neoadjuvant Chemotherapy

To the Editor: A 43-year-old woman presented with 3 episodes of shock within a 6-month period (Table); all episodes occurred after symptoms of nonspecific abdominal pain. During the second episode of shock, an infiltrating lobular carcinoma of the breast (estrogen receptive–positive, progesterone receptor–negative, human epidermal growth factor 2–positive [T3,N1,M0]) was diagnosed. After resolution of the third episode of shock, a standard regimen consisting of paclitaxel, carboplatin, and trastuzumab was instituted; the patient had no further episodes of shock for the next 9 months. TABLE. Laboratory Values at Patient Presentation of Each Episode of Shocka Three months after the patient underwent a modified radical mastectomy and completed chemotherapy, she experienced 4 episodes of hypotension within a 3-week period, the last of which resulted in refractory shock. On the basis of her history of unexplained shock with prodromal symptoms and an IgG κ monoclonal gammopathy, idiopathic systemic capillary leak syndrome (SCLS) was diagnosed. Prophylactic therapy with terbutaline and theophylline was initiated. Eighteen months later, the patient experienced 1 episode of shock, with a concurrently low level of serum theophylline (7.7 μg/mL). In addition to resuscitation with 10 L of normal saline in the first 24 hours, she was given increasing doses of theophylline and treated with albumin infusion and montelukast; symptoms resolved after 1 day of this therapeutic regimen. Idiopathic SCLS is a rare and life-threatening disorder, with only 100 to 125 cases published worldwide since the first report in 1960.1-6 The shock that patients with SCLS experience, with associated hemoconcentration and hypoalbuminemia, is caused by sudden, massive leakage of proteins and serum into the extravascular space.1,7 Plasma proteins up to 200 kDa or, in some cases, 900 kDa escape the capillary bed, resulting in an intravascular loss of up to 70% of plasma volume.2,8,9 Most patients have an associated IgG κ or λ monoclonal gammopathy,1,10 although its importance remains unknown. Idiopathic SCLS has been reported preceding hematologic malignancy11 but not in association with a solid tumor; it should be distinguished from drug-induced SCLS that may occur after treatment of other malignancies. In addition to the classic findings, our patient had neutrophilia at the outset of each attack, which lasted 24 to 48 hours and was as high as 40 × 109/L during one episode. Given that neutrophilia has been observed in patients with SCLS, it is notable that no episodes of SCLS occurred in our patient while receiving chemotherapy, and routine laboratory testing during that time revealed low or normal white blood cell counts. Demargination due to endothelial damage could be responsible for the neutrophilia, but a pathologic role of the neutrophils is also a possibility. Although the mechanism behind capillary leak in idiopathic SCLS is unknown, evidence supports endothelial apoptosis, rather than endothelial contraction or widened cell-cell junctions, as the cause.1,13,14 Use of numerous investigational drugs has been reported with variable outcomes.6,15-20 Traditional prophylactic therapies, theophylline/aminophylline and terbutaline, have been reported to achieve durable success,3,6,9,21 despite a lack of understanding of their mode of action. Spironolactone, hydrocortisone, progesterone, and dexamethasone all appear to protect against endothelial cell apoptosis in response to serum deprivation,22 whereas albumin inhibits endothelial cell apoptosis when there is intact endothelial cell adhesion,23 suggesting that these therapies have potential benefit. Neutrophil-mediated endothelial apoptosis has been described in patients with other inflammatory disorders.24,25 Given the neutrophilia seen in SCLS and the quiescence of SCLS in our patient while receiving neoadjuvant chemotherapy, one area of interest may involve neutrophil regulation. Although the chemotherapeutic benefit may have been due to general immunosuppression, there may be mechanism-specific similarities between theophylline, paclitaxel, and carboplatin. In addition to decreasing endothelial permeability through elevation of intracellular cyclic adenosine monophosphate5,26 and offering immune-modulatory effects,26 theophylline may affect neutrophil life span. Theophylline causes granulocyte apoptosis in vitro, even in the presence of granulocyte-macrophage colony-stimulating factor,27 with B-cell lymphoma 2 (bcl-2) down-regulation involved in theophylline-induced apoptosis of eosinophilic granulocytes.28 Granulocyte life span is determined by a balance of proapoptotic and antiapoptotic gene expression, with down-regulation of the inducible and short-lived anti-apoptotic bcl-2 family member expression sufficient for neutrophil apoptosis.29,30 Both paclitaxel and carboplatin also affect bcl-2 down-regulation in other settings.31,32 Given these observations, future studies should investigate whether neutrophils obtained during acute attacks are sufficient to cause endothelial apoptosis, whether bcl-2 or its family members are aberrantly expressed, and whether the aforementioned drugs alter bcl-2 family member expression. We offer special thanks to all the physicians and nurses involved in the diagnosis and treatment of the patient.

High Risk Lesions

There is a remarkably varied spectrum of noncancerous breast lesions that can be identified by screening mammography since the advent of improved imaging techniques. The variety and volume of such lesions has increased dramatically over the last decade. The physicians who are responsible for the care of these patients are challenged with the interpretation of the results with minute amounts of tissue from minimally invasive biopsies. It is essential for the multidisciplinary breast team to evaluate the concordance of each biopsy in relation to histology, imaging, history and physical examination. This is most easily accomplished with a concordance conference attended by all of the involved specialists including pathologists, breast imagers, as well as surgeons. In some institutions, this is done by whoever performs the biopsy, which is usually the radiologist or surgeon.

Endoscopic Diagnosis and Treatment of Breast Diseases

In the last 3 decades breast conservation has shown survival rates comparable to more extensive surgical treatments for breast cancer. Over this period sentinel node has replaced axillary dissection for staging, minimally invasive percutaneous biopsy has replaced excisional biopsy for diagnosis, and the trend continues with the investigation of percutaneous ablative therapies for small breast cancers. Minimally invasive approaches have changed the practice of breast surgery and steered us toward endoscopic techniques, which are the future of breast surgery.