Increased use of partial-breast irradiation has not improved radiotherapy utilization for early-stage breast cancer.

BACKGROUND: Radiotherapy (RT) reduces local recurrence after breast-conserving surgery (BCS) for breast cancer, but under-utilization of RT has been reported. Accelerated partial-breast irradiation (PBI) improves RT accessibility, but it is uncertain if this has improved RT utilization. METHODS: The Surveillance, Epidemiology and End Results registry was used to identify women who underwent BCS for stage 0 or 1 breast cancer from 2000 to 2009. Temporal trends in RT utilization and RT modality were determined. Chi-square analysis and multivariate logistic regression identified predictors of RT utilization and modality. RESULTS: Of 180,219 study patients, 131,343 (73 %) received RT; 123,703 (94 %) of RT recipients received whole-breast irradiation (WBI) and 6,251 (5 %) received PBI. PBI rates increased dramatically during the study period (0.32 % in 2000 vs. 6.5 % in 2009), but overall RT utilization remained relatively stable because of a decline in WBI (69.8 % in 2000 vs. 62.4 % in 2009). RT utilization was unchanged in rural counties, and declined for women <40 and ≥70 years of age, and for Native American, Asian and Hispanic patients. White and Black women used PBI most frequently (4 % each) and were the only race groups with improved RT utilization over time. Predictors of RT usage included age, race, marital status, tumor size, grade, hormone receptor status, lymph node evaluation, geographic region, metropolitan status, education, and employment status. CONCLUSIONS: Women who undergo RT are opting for PBI more frequently, but the increased use of this modality has not improved overall RT utilization for patients with early-stage breast cancer.

Patient age is related to decision-making, treatment selection, and perceived quality of life in breast cancer survivors.

BACKGROUND: Patients with breast cancer must choose among a variety of treatment options when first diagnosed. Patient age, independent of extent of disease, is also related to quality of life. This study examined the impact of patient age on treatment selected, factors influencing this selection, and perceived quality of life. METHODS: A 62-question survey evaluating breast cancer treatment and quality of life was mailed to breast cancer survivors. Responses were stratified by age (<50, 50-65, >65 years) and extent of disease. RESULTS: Of the 1,131 surveys mailed, 402 were included for analysis. There were 104, 179, and 119 women aged <50, 50-65, and >65 years, respectively. The median patient age was 58 years, and the average interval from diagnosis to survey participation was 31.5 months. CONCLUSIONS: Young women were more likely to have undergone aggressive therapies and had better physical functioning than old women. Old patients reported good quality of life and body image. Clinicians should consider patient age when discussing breast cancer treatment options.

Improving size, lymph node metastatic rate, breast conservation, and mortality of invasive breast cancer in Rhode Island women, a well-screened population.

The beneficial impact of screening mammography on breast cancer outcome continues to be debated as demonstrated by guidelines published by the United States Preventive Services Task Force. A previous report from Rhode Island, which has a very high rate of mammographic screening, demonstrated significant improvements in invasive breast cancer presentation and mortality through 2001. This report updates data through 2008 to determine whether previous favorable trends continued. Rhode Island Cancer Registry data regarding invasive breast cancer presentation and mortality in 17,522 female residents diagnosed between 1987 and 2008, inclusive, were analyzed for demographic and pathological factors. Data were analyzed by four time periods: 1987-1992, 1993-1998, 1999-2003, and 2004-2008 and overall. Statistically significant improvements occurred over the four successive time periods, in mean cancer size (23.7, 20.9, 19.6, and 19.3 mm, p < 0.0001), pathologic grade (Grade I: 12, 15, 19, and 17 %; Grade III 57, 41, 36, and 35 %, p < 0.0001), breast conserving surgery (38, 56, 67, and 71 %, p < 0.0001) and mortality (37.3, 31.4, 25.1, and 22.6 per 100,000/year, p < 0.0001). The results showed that high screening rates favorably impacted presentation of and mortality from invasive breast cancer in Rhode Island. From 1987 to 2008, there has been a 39 % decline in breast cancer mortality considering 5 year periods (37.3 vs. 22.6 deaths per 100,000) and 41 % comparing the period from 1990 to 2008, which may exceed the goal of 50 % mortality reduction by 2015 established by the American Cancer Society.

Axillary ultrasound and fine-needle aspiration in the preoperative evaluation of the breast cancer patient: an algorithm based on tumor size and lymph node appearance.

OBJECTIVE: The objective of our study was to evaluate the utility of ultrasound-guided fine-needle aspiration (FNA) of the axillary lymph nodes in breast cancer patients depending on the size of the primary tumor and the appearance of the lymph nodes. SUBJECTS AND METHODS: Data were collected about tumor size, lymph node appearance, and the results of ultrasound-guided FNA and axillary surgery of 224 patients with breast cancer undergoing 226 ultrasound-guided FNA. Lymph nodes were classified as benign if the cortex was even and measured < 3 mm, indeterminate if the cortex was even but measured ≥ 3 mm or measured < 3 mm but was focally thickened, and suspicious if the cortex was focally thickened and measured ≥ 3 mm or the fatty hilum was absent. The results of ultrasound-guided FNAs were analyzed by the sonographic appearance of the axillary lymph nodes and by the size of the primary tumor. The sensitivity and specificity of ultrasound-guided FNA were calculated with axillary surgery as the reference standard. The sensitivity and specificity of axillary ultrasound to predict the ultrasound-guided FNA result were calculated. RESULTS: Of the 224 patients, 51 patients (23%) had a positive ultrasound-guided FNA result, which yields an overall sensitivity of 59% and specificity of 100%. The sensitivity of ultrasound-guided FNA was 29% in patients with primary tumors ≤ 1 cm, 50% in patients with tumors > 1 to ≤ 2 cm, 69% in patients with tumors > 2 to ≤ 5 cm, and 100% in patients with tumors > 5 cm. The sensitivity of ultrasound-guided FNA in patients with normal-appearing lymph nodes was 11%; indeterminate lymph nodes, 44%; and suspicious lymph nodes, 93%. Sonographic characterization of lymph nodes as suspicious or indeterminate was 94% sensitive and 72% specific in predicting positive findings at ultrasound-guided FNA. CONCLUSION: Ultrasound-guided FNA of the axillary lymph nodes is most useful in the preoperative assessment of patients with large tumors (> 2 cm) or lymph nodes that appear abnormal.

FePt nanoparticles as an Fe reservoir for controlled Fe release and tumor inhibition.

Chemically disordered face centered cubic (fcc) FePt nanoparticles (NPs) show the controlled release of Fe in low pH solution. The released Fe catalyzes H(2)O(2) decomposition into reactive oxygen species within cells, causing fast oxidation and deterioration of cellular membranes. Functionalized with luteinizing hormone-releasing hormone (LHRH) peptide via phospholipid, the fcc-FePt NPs can bind preferentially to the human ovarian cancer cell line (A2780) that overexpresses LHRH receptors and exhibit high toxicity to these tumor cells. In contrast, the fcc-FePt NPs pre-etched in the low pH (4.8) buffer solution show nonappreciable cytotoxicity. The work demonstrates that fcc-FePt NPs may function as a new type of agent for controlled cancer therapy.

MUC1 Knockdown With RNA Interference Inhibits Pancreatic Cancer Growth.

MUC1, a tumor associated glycoprotein over-expressed in 95% of pancreatic cancers, has been shown to be associated with a worse prognosis. The objective of this study was to determine the impact of loss of MUC1 expression on pancreatic tumor growth. PANC1 human pancreatic carcinoma cells with stable "knockdown" MUC1 expression were created using a MUC1 specific short interfering RNA (siRNA). PANC1 cells with "knockdown" MUC1 expression had decreased in vitro proliferation compared with PANC1 wild type and control cells. PANC1-MUC1siRNA cells grew significantly slower in severe combined immunodeficient (SCID) mice compared with wild type and negative controls. Our data suggested that decreasing MUC1 tumor expression by RNA interference may be a novel molecular approach for the treatment of pancreatic cancer.

MUC1 intra-cellular trafficking is clathrin, dynamin, and rab5 dependent.

MUC1, a transmembrane glycoprotein, is abnormally over-expressed in most human adenocarcinomas. MUC1 association with cytoplasmic cell signal regulators and nuclear accumulation are important for its tumor related activities. Little is known about how MUC1 translocates from the cell membrane to the cytoplasm. In this study, live cell imaging was used to study MUC1 intracellular trafficking. The interaction between EGFR and MUC1 was mapped by FRET analysis and EGF stimulated MUC1 endocytosis was observed directly through live cell imaging. MUC1-CT endocytosis was clathrin and dynamin dependent. Rab5 over-expression resulted in decreased cell membrane localization of MUC1, with accumulation of MUC1 endocytic vesicles in the peri-nuclear region. Conversely, over-expression of a Rab5 dominant negative mutant (S34N) resulted in redistribution of MUC1 from the peri-nuclear region to the cytoplasm. Collectively, these results indicated that MUC1 intra-cellular trafficking occurs through a regulated process that was stimulated by direct EGFR and MUC1 interaction, mediated by clathrin coated pits that were dynamin dependent and regulated by Rab5.

Axillary lymph nodes: US-guided fine-needle aspiration for initial staging of breast cancer--correlation with primary tumor size.

PURPOSE: To retrospectively assess the sensitivity and specificity of ultrasonographic (US)-guided fine-needle aspiration (FNA) of axillary lymph nodes for preoperative staging of breast cancer across a range of primary tumor sizes, by using histologic findings as a reference standard. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study; informed consent was waived. US-guided FNA results in 74 patients with breast cancer (75 axillae) were compared with final pathologic results. Lymph nodes were classified as benign, indeterminate, or suspicious on the basis of US characteristics at retrospective review. US-guided FNA in the most suspicious node at US, or the largest node if all appeared benign, was performed. Final pathologic results (sentinel lymph node biopsy [SNB] or axillary lymph node dissection [ALND]) were compared with US and preoperative US-guided FNA results. Results were assessed according to tumor size. Sensitivity, specificity, and positive predictive value of US and US-guided FNA were calculated. RESULTS: Primary tumor sizes were 0.3-12 cm (mean, 3 cm). Patient age range was 31-81 years (mean age, 51 years). Sensitivity of US-guided FNA for predicting positive results at ALND or SNB was 71%-75%. Specificity was 100%. Sensitivity of US-guided FNA increased with primary tumor size. CONCLUSION: US-guided FNA of axillary lymph nodes in patients with newly diagnosed breast cancer had a sensitivity that increased with increasing size of the primary tumor.

A novel approach to T classification in tumor-node-metastasis staging of breast cancer.

BACKGROUND: The aim of this study was to examine the effect of measurement bias in breast cancer and to create a more rational T-size categorization in tumor-node-metastasis staging in response to smaller, screen-detected cancers and measurement bias. METHODS: From 1987 to 2003, 10,853 invasive nonmetastatic breast cancers enlisted in the Rhode Island Cancer Registry with a known dimension were reviewed. Data analyzed by proposed classifications included the rate of lymph node metastases and the mortality rate from breast cancer. RESULTS: The median diameter was 16 mm. Cancer measurements reflected the bias in pathologists' dimension recording, which is centered strongly about whole- and half-centimeter sizes. A new T classification is proposed with the following sizes and frequencies in the Rhode Island Cancer Registry: 1 to 2 mm = T1 mic (3% of registered cases); 3 to 7 mm = T1a (11%); 8 to 12 mm = T1b (23%); 13 to 17 mm = T1c (18%); 18 to 22 mm = T2a (17%); 23 to 27 mm = T2b (8%); 28 to 32 mm = T2c (8%); 33 to 42 mm = T3a (6%); 43 to 52 mm = T3b (3%), and greater than 52 mm = T3c (4%). The unadjusted odds ratio for the probability of node metastases was 1.43 (confidence interval, 1.40-1.46; P < .001) with each increase in proposed grouping. The range in the lymph node metastatic rate was 5.5% for tumors 1 to 2 mm to 64% for cancers greater than 52 mm. By Cox proportional hazard, the unadjusted hazard ratio for death from breast cancer for each increase in proposed grouping was 1.33 (confidence interval, 1.29-1.37; P < .001). The 10-year survival rate ranged from 98.3% for tumors 1 to 2 mm to 70.3% for cancers greater than 52 mm. CONCLUSIONS: A more rational T category for use in tumor-node-metastasis staging is presented to reflect the much smaller invasive breast cancers encountered by screening and to account for the dimension recording bias of pathologists. This new T category shows a clinically and statistically significant linear relationship for both incidence of lymph node metastases and hazard ratio of death.

Development and preclinical evaluation of a Bacillus Calmette-Guérin-MUC1-based novel breast cancer vaccine.

Due to the high incidence of breast cancer and associated mortality rate,the development of an effective vaccine may be beneficial for the prevention or adjuvant treatment of this malignancy. We have constructed a novel breast cancer vaccine, Bacillus Calmette-Guérin (BCG)-hIL2MUC1, that consists of BCG and expresses a truncated form of MUC1 and human interleukin (IL)-2. In vitro analysis of the BCG-hIL2MUC1 construct confirmed coexpression of MUC1 and human IL-2. The ability of BCG-hIL2MUC1 to inhibit breast cancer growth was evaluated in hu-PBL-SCID mice (severe combined immunodeficient mice reconstituted with 50 x 10(6) human peripheral blood lymphocytes) that received three biweekly injections of BCG-hIL2MUC1 (0.5 colony-forming unit). Control animals received PBS, MUC1 peptide (100 microg), or empty vector BCG-261 (0.5 colony-forming unit) vaccination. After immunization, hu-PBL-SCID mice (n = 8 in each group) were xenografted with 4 x 10(6) ZR75-1 human breast cancer cells. Whereas mice receiving the control vaccines developed a tumor, only 87% of BCG-hIL2MUC1-immunized animals developed a palpable tumor with a slower rate of tumor growth (P < 0.001). Histological analysis of the primary tumors in BCG-hIL2MUC1-immunized animals revealed areas of reduced MUC1 expression. CD8-positive human lymphocytes were detected only in tumors grown in BCG-hIL2MUC1-immunized animals. These results imply a critical role of coexpressed IL-2 and MUC1 in eliciting tumor-specific immune response. To our knowledge, this is the first report of BCG engineered to express a tumor-associated antigen. Our results suggest that BCG-hIL2MUC1 immunization inhibited breast cancer growth in hu-PBL-SCID mice. Therefore, BCG-hIL2MUC1 may be a promising candidate as a breast cancer vaccine.

Preliminary results of a phase I/II study of HDR brachytherapy alone for T1/T2 breast cancer.

PURPOSE: To investigate the feasibility, toxicity, cosmetic outcome, and local control of high-dose-rate (HDR) brachytherapy alone without whole breast external beam irradiation for early-stage breast carcinoma. METHODS AND MATERIALS: Between June 1997 and August 1999, 32 women diagnosed with a total of 33 AJCC Stage I/II breast carcinomas underwent surgical breast excision and postoperative irradiation using HDR brachytherapy interstitial implantation as part of a multi-institutional clinical Phase I/II protocol. Eligible patients included those with T1, T2, N0, N1 (< or =3 nodes positive), and M0 tumors of nonlobular histologic features with negative surgical margins, no extracapsular lymph node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, reexcision, or either sentinel or full-axillary sampling. Direct visualization, surgical clips, and ultrasound and/or CT scan assisted in the delineation of the target volume, defined as the excision cavity plus a 2-cm margin. High-activity 192Ir (3-10 Ci) was used to deliver 340 cGy/fraction, 2 fractions/d, for 5 consecutive days, to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. RESULTS: The median follow-up of all patients was 33 months, and the mean patient age was 63 years. The mean tumor size was 1.3 cm, and 55% had an extensive intraductal component. Three patients had positive axillary nodes. Two patients experienced moderate perioperative pain that required narcotic analgesics. No peri- or postoperative infections occurred. No wound healing problems and no significant skin reactions related to the implant developed. The Radiation Therapy Oncology Group late radiation morbidity scoring scheme was applied to the entire 33-case cohort. In the assessment of the skin, 30 cases were Grade 0-1 and 3 cases were Grade 2. Subcutaneous toxicity was scored as 11 patients with Grade 0, 3 with Grade 1, 8 with Grade 2, 3 with Grade 3, and 8 with Grade 4. Clinically evident fat necrosis occurred in 8 patients at a median of 7.5 months after HDR brachytherapy completion. The only variables significantly associated with Grade 3-4 toxicity were the number of source dwell positions and the volume of tissue encompassed by the prescription isodose shell. The global cosmetic scores after a minimum of 18 months' follow-up were 0 cases with poor, 4 with fair, 5 with good, and 24 with excellent scores. One case of ipsilateral breast tumor recurrence was diagnosed 23 months after HDR brachytherapy, for a 4-year actuarial recurrence rate of 3%. This failure appeared to be a new primary tumor, because it was histologically distinct from the initial tumor and was located 9 cm from the initial tumor bed and 3 cm from the edge of the implant volume. CONCLUSION: Radiotherapy of the tumor bed alone with HDR interstitial brachytherapy is associated with a 33% incidence of Grade 3-4 s.c. toxicity, but with generally favorable overall cosmetic results. The risk of toxicity appears to be primarily related to the implant volume. With limited follow-up, the incidence of ipsilateral breast tumor recurrence was low.

Casting-type calcifications with invasion and high-grade ductal carcinoma in situ: a more aggressive disease?

HYPOTHESIS: Women with breast cancer who have casting-type microcalcifications associated with multifocal invasion and extensive ductal carcinoma in situ (DCIS) form a subset of patients with a poor prognosis. Our study aims to identify the mammographic and pathologic features of this group. DESIGN: Women with casting-type microcalcifications, multifocal invasion, and extensive DCIS were identified from our tumor board registry. Mammographic features, tumor characteristics, treatment, and survival rates were evaluated. Invasive tumors were limited to 14 mm or smaller. SETTING: University medical teaching hospital and breast cancer specialty clinic. RESULTS: Of the 984 patients with breast cancer treated at our center, 15 patients were identified who had extensive casting-type calcifications and DCIS. Twelve of these patients also had multifocal invasive breast cancer. All had casting-type microcalcifications occupying more than 1 breast quadrant. All but 1 of the patients were treated using mastectomy with sentinel node biopsy or axillary node dissection. All but 1 patient had extensive grade 3 DCIS. Invasive tumors were negative for estrogen receptor and progesterone receptor expression in half of the patients, and 60% were positive for the HER-2-neu receptor. Positive axillary lymph nodes were found in 33% of patients, and 75% received adjuvant chemotherapy. After a median follow-up period of 20.5 months (range, 6-72 months), 1 patient had died and 1 had distant metastases. Of the 3 patients who had DCIS without invasion, 1 experienced a recurrence with infiltrating ductal carcinoma. CONCLUSIONS: In women with small multifocal breast cancers with extensive casting calcifications and DCIS, the incidence of positive lymph nodes was 33%, with a tendency for poor tumor markers. These women appear to be at substantial risk for systemic disease; lymph node sampling and adjuvant systemic therapy are recommended.

Decreased breast cancer tumor size, stage, and mortality in Rhode Island: an example of a well-screened population.

BACKGROUND: Since the 1980s, Rhode Island has achieved one of the highest mammography screening rates in the nation. The objective of this study was to determine the effect of high mammography rates on breast cancer presentation and outcomes. METHODS: Using the Rhode Island Cancer Registry, the incidence of DCIS and invasive cancer, tumor size, stage, rate of BCS and mortality from breast cancer were determined from 1987 to 2001. RESULTS: Over 80% of Rhode Island women report routine mammography. From 1987 to 2001, there were 1,660 cases of DCIS and 11,301 cases of invasive breast cancer. Although the overall incidence of invasive cancer was stable, the median diameter decreased from 2 cm to 1.5 cm with a significant decrease in the incidence of stage III and IV cancers. There was an increase in BCS for women 50 to 64 years of age with stage I and II disease and for women older than 65 years with stage I disease. Disease-specific mortality decreased by 25%. CONCLUSIONS: High mammography rates in Rhode Island are associated with smaller and earlier-stage breast cancers. This largely accounts for the decreased mortality from breast cancer and the increased rate of BCS.

Clinical axillary recurrence in breast cancer patients after a negative sentinel node biopsy.

BACKGROUND: The purpose of this study was to determine the axillary recurrence rate in breast cancer patients with a negative sentinel lymph node who did not have an axillary node dissection. METHODS: Sentinel lymphadenectomy for breast cancer patients, without axillary node dissection if the node was negative, was introduced in 1998 at our institution. This study includes those women with a negative sentinel lymph node. Adjuvant chemotherapy was administered based on primary tumor characteristics. If breast radiotherapy was used, no attempt was made to include the axilla. RESULTS: From January 1998 to December 2001, 206 patients (208 breast cancers) had a negative sentinel lymph node. The median age at diagnosis was 56 years and median tumor size was 1.2 cm. With a median follow-up of 26 months, there have been 3 axillary recurrences with a clinical sentinel lymph node false negative rate of 1.4%. CONCLUSIONS: In this study, the clinical false negative rate of a sentinel lymph node biopsy is 1.4%. Our study provides further evidence supporting the use of sentinel lymphadenectomy in women with breast cancer.

Axillary staging using ultrasound-guided fine needle aspiration biopsy in locally advanced breast cancer.

BACKGROUND: Axillary lymph node status is important for staging and planning therapy prior to neoadjuvant chemotherapy in patients with locally advanced breast cancers (LABC). The objective of this study was to evaluate the use of axillary ultrasonography coupled with fine needle aspiration biopsy (US-FNAB) to determine lymph node status prior to initiation of neoadjuvant chemotherapy. METHODS: Patients with a LABC, defined as a breast cancer clinically larger than 3.0 cm or a cytology positive axillary lymph node, were evaluated by clinical examination followed by ultrasonographic evaluation. Lymph nodes were categorized as suspicious for malignancy based on size >1.0 cm, decrease in the fatty hilum, or parenchymal echogenicity. US-FNAB was performed on all patients. Most patients received neoadjuvant chemotherapy followed by definitive surgery. Axillary surgery consisted of axillary lymph node dissection. Axillary status by clinical examination and US-FNAB was compared with that obtained by axillary node dissection. RESULTS: From January 1998 to May 2001, 26 patients (27 axillae) presented with LABC to our institution. The median age of these patients was 48 years. The sensitivity and specificity of US-FNAB for evaluating axillary metastatic disease in patients with LABC were 100% and 100%, respectively. CONCLUSIONS: In patients with locally advanced breast cancer, axillary ultrasonography coupled with fine needle aspiration biopsy can accurately stage the axilla. It is particularly useful and should be used more frequently in patients undergoing neoadjuvant chemotherapy. The use of ultrasonography to stage the axilla in patients who present with small breast cancers should be explored.

The effect of neoadjuvant chemotherapy on estrogen and progesterone receptor expression and hormone receptor status in breast cancer.

BACKGROUND: Neoadjuvant chemotherapy may decrease tumor volume to allow breast conservation surgery. Its effect on estrogen and progesterone receptor (ER/PR) expression and hormone receptor (HR) status is controversial. METHODS: From February 2001 to July 2002, 56 breast cancer patients treated with neoadjuvant chemotherapy and 56 non-neoadjuvant therapy (control) patients with adequate tissue samples were identified. Quantitative ER/PR expression was analyzed in preneoadjuvant or preoperative core biopsies and final surgical specimens. Changes between the two groups were compared to determine if alterations were due to neoadjuvant chemotherapy or tissue sampling. RESULTS: The ER/PR expression changed in 34 (61%) neoadjuvant chemotherapy patients and 27 (48%) control patients. These expression changes resulted in HR status (positive/negative) alterations in 3 patients (5%) in both groups. Age, histology, chemotherapy regimen, and neoadjuvant response did not predict change. CONCLUSIONS: Hormone receptor status changed in 5% of neoadjuvant chemotherapy and control groups due to tissue sampling. As these changes may impact treatment, HR expression reanalysis in final surgical specimens is recommended.