Early-stage Invasive Breast Cancer Research Articles

Lifestyle and Breast Cancer Recurrences: The DIANA-5 Trial

The DIANA (Diet and Androgens)-5 study is a multi-institutional randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer events in women with early stage invasive breast cancer at high risk of recurrence because of metabolic or endocrine milieu. The intervention is expected to reduce serum insulin and sex hormones, which were associated with breast prognosis in previous studies. Between 2008 and 2010, the study randomly assigned 1208 patients to an intensive diet and exercise intervention or to a comparison group, to be followed-up through 2015. General lifestyle recommendations for the prevention of cancer are given to both groups, and the intervention group is being offered a comprehensive lifestyle intervention, including cooking classes, conferences, common meals and exercise sessions. Adherence assessments occurred at baseline and at 12 months and are planned at 36 and 60 months. They include food frequency diaries, anthropometric measures, body fat distribution assessed with impedance scale, one week registration of physical activity with a multisensor arm-band monitor, metabolic and endocrine blood parameters. Outcome breast cancer events are assessed through self report at semi annual meetings or telephone interview and are validated through medical record verification. The randomized groups were comparable for age (51.8 years), proportion of ER-negative tumors (22%), axillary node metastasis (42%), reproductive variables, tobacco smoking, blood pressure, anthropometric measurements and hormonal and metabolic parameters. DIANA-5 has the potential to establish whether a Mediterranean-macrobiotic lifestyle may reduce breast cancer recurrences. We will assess evidence of effectiveness, first by comparing the incidence of additional breast cancer events (local or distant recurrence, second ipsilateral or contralateral cancer) in the intervention and in the control group, by an intention-to-treat analysis, and second by analyzing the incidence of breast cancer events in the total study population by compliance assessment score.

Mammographic Findings after Intraoperative Radiotherapy of the Breast

Intraoperative Radiotherapy (IORT) is a form of accelerated partial breast radiation that has been shown to be equivalent to conventional whole breast external beam radiotherapy (EBRT) in terms of local cancer control. However, questions have been raised about the potential of f IORT to produce breast parenchymal changes that could interfere with mammographic surveillance of cancer recurrence. The purpose of this study was to identify, quantify, and compare the mammographic findings of patients who received IORT and EBRT in a prospective, randomized controlled clinical trial of women with early stage invasive breast cancer undergoing breast conserving therapy between July 2005 and December 2009. Treatment groups were compared with regard to the 1, 2 and 4-year incidence of 6 post-operative mammographic findings: architectural distortion, skin thickening, skin retraction, calcifications, fat necrosis, and mass density. Blinded review of 90 sets of mammograms of 15 IORT and 16 EBRT patients demonstrated a higher incidence of fat necrosis among IORT recipients at years 1, 2, and 4. However, none of the subjects were judged to have suspicious mammogram findings and fat necrosis did not interfere with mammographic interpretation.

Association of Occult Metastases in Sentinel Lymph Nodes and Bone Marrow With Survival Among Women With Early-Stage Invasive Breast Cancer

Association of Occult Metastases in Sentinel Lymph Nodes and Bone Marrow With Survival Among Women With Early-Stage Invasive Breast Cancer

Association of Occult Metastases in Sentinel Lymph Nodes and Bone Marrow With Survival Among Women With Early-Stage Invasive Breast Cancer

Association of Occult Metastases in Sentinel Lymph Nodes and Bone Marrow With Survival Among Women With Early-Stage Invasive Breast Cancer

P1-10-01: Utility of Routine Cardiac Ejection Fraction (CEF) Measurement Prior to Anthracycline-Based Chemotherapy (ABC): A Study of 466 Patients with Early-Stage Her2-Negative Invasive Breast Cancer.

Abstract Background: Despite the lack of evidence to support its utility, routine CEF measurement prior to ABC is a common practice in the community, required in most US clinical trials, endorsed by the American Heart Association and American College of Cardiology, and appears on Food Drug Administration-approved labeling guidelines. Objectives: We determined the frequency of the following events in newly diagnosed invasive breast cancer patients: a) CEF measurement prior to ABC; b) asymptomatic left ventricular dysfunction; c) modification in initial treatment strategy as a result of CEF measurement; d) development of congestive heart failure (CHF) after ABC. Methods: From our cancer registry, we obtained a list of all female patients with newly diagnosed stage I-III breast cancer who were treated with chemotherapy as part of initial therapy at our institution in 2000–2010 (N=562). We excluded those with prior CHF, ABC, and those who had Her2-positive disease (n=66). CEF <50% was considered low. CHF risk factors including coronary heart disease, cigarette smoking, hypertension, obesity, and diabetes mellitus were collected. Results: We included 496 patients with the following stage distribution: I (22%), II (54%), and III (24%). The mean age was 53 years (SD±11; range 25–88). In 30 (7%) patients, ABC was considered inappropriate by the physician provider due to poor performance status, co-morbidities, and physician or patient preference. Of the 466 patients considered for ABC, CEF was measured in 241 (52%) patients before chemotherapy. In the latter group, only 1 (0.4%) patient was found to have asymptomatic left ventricular dysfunction with CEF of 48%. Among patients considered for ABC, 10 (2%) did not receive ABC for the following reasons: low or borderline CEF (2), patient preference (3), co-morbidities (2), and randomization to non-ABC in clinical trials (3). After a mean follow up 57 months (SD±34), only 3 of 456 (0.7%) patients who received ABC developed CHF. Two had normal CEF prior to treatment while the other did not have CEF measured. The practice of CEF measurement prior to ABC varied among physician providers, ranging from 23% to 67% (mean/SD 47%±15%). Those who had CEF measured before chemotherapy were older (55 vs. 50 years; P <0.001) and had more CHF risk factors (1.3 vs. 0.9; P <0.001). Conclusions: At our institution, routine CEF measurement prior to ABC as initial therapy for early-stage Her2-negative invasive breast cancer patients is a common though not uniform practice. Asymptomatic left ventricular dysfunction is rarely detected and generally mild. Our findings do not support the utility of routine CEF measurement in this population and challenge current practice and guidelines. Potential cost implications to our health care system can be substantial. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-10-01.

Treatment of ductal carcinoma in situ (DCIS) with lumpectomy and accelerated whole breast radiation therapy with concomitant boost (ARTB).

93 Background: The efficacy of accelerated radiation therapy (RT) for treating early stage invasive breast cancer has been established (Whelan T et al: NEJM, February 2010). But the role of accelerated schedules in treating patients with DCIS still needs to be defined. We have previously described the feasibility and low toxicity when using ARTB after lumpectomy (Chadha M et al: Int J Radiat Oncol Biol Phys 2007; 69). The objective of this study is to evaluate early outcomes in patients with DCIS treated with lumpectomy and ARTB, and to compare local recurrence rates of ARTB and conventional fraction (fr) RT with sequential boost (CRT). Methods: This study includes patients diagnosed to have primary DCIS treated with lumpectomy and RT. Patients with DCIS who had history of contralateral synchronous or metachronous invasive cancer were excluded. We identified 215 patients from our breast cancer database as having met this selection criteria; 54 patients received ARTB on an IRB approved protocol, and 161 patients matched by prognostic factors constituted the comparative CRT group. ARTB delivered 40.5Gy in 15fr to the breast, and with concomitant boost 45Gy in15fr was delivered to the lumpectomy boost volume. CRT delivered 46.8Gy in 26fr with sequential boost of 14Gy in 7fr. The patients were well matched with no significant difference in the distribution of known prognostic factors including age, nuclear grade, margin status, receptor status, and Body Mass Index between the groups. Results: The overall median follow up was 3.5 years (0.5 years–11.4 years). Actuarial 5-year local relapse-free survival was 95%. The actuarial 3-year local relapse rate was 2% and 0% for CRT and ARTB groups, respectively (p = 0.22). Local recurrence was observed in 9 patients with a median time to failure of 4.3 years (0.5 years to 8.6 years); 4/9 had grade 3 DCIS; 1 patient with grade 3 had close final margin (<1 mm); 5/9 patients received hormone therapy. Conclusions: With the follow up to date, we observed excellent outcomes in patients with DCIS treated by lumpectomy and RT. These preliminary results suggest comparable local control between ARTB and CRT. Additional studies and longer follow-up are needed.

Toxicity of hypofractionated adjuvant radiation after breast-conserving surgery for DCIS.

128 Background: Traditional fractionation for whole breast radiation therapy after breast-conserving surgery has been 50Gy in 25 fractions over a 5-week period, with or without a 10 Gy boost. Hypofractionation has recently been adapted for early-stage invasive breast cancer, typically treating with 42.5 Gy in 16 daily fractions. This approach has been shown to have equivalent efficacy as the more traditional schedule. Its application to patients with DCIS has been an extrapolation of these data, and warrants further examination. This retrospective analysis reviews toxicity outcomes in women with DCIS treated with hypofractionation at our institution. Methods: 59 women with DCIS treated with lumpectomy and hypofractionated radiotherapy with or without boost between 2006 and 2010 at the Einstein-Montefiore Cancer Center were identified. Median age was 65 (39-85). Median follow-up was 13.7 months (2–37.6). Surgical margin status was negative in 55, positive in 1, and unknown in 3. Thirteen patients had high-grade DCIS, 17 intermediate-grade, and 13 low-grade nuclear features, and 16 did not have grade delineation. 68% of patients (40 women) had disease that was positive both for ER and PR receptors, 2 women were simultaneously positive for ER and PR, 5 women had ER-only positive disease, 2 women had HER2-neu-only positive disease, 1 woman was positive for both ER and HER2-neu receptors, 1 woman was positive only for PR receptors, and 6 women were negative for all receptors; receptor status of specimens from 2 patients is not known. All women were treated with whole-breast hypofractionated therapy (42.4 Gy, in 16 fractions of 2.65 Gy each). 49 women received a boost to the lumpectomy cavity consisting of 10Gy in 5 fractions or 9.6 Gy in 4 fractions at the physician’s discretion. Results: With this regimen, no patient experienced acute RTOG grade 3 or higher skin, or other toxicity. No treatment breaks were required due to toxicity. The most common side effects were grade 1 dermatitis, followed by grade 2 dermatitis with mild edema of the treated breast. Conclusions: Our results suggest that postoperative hypofractionated radiation to the breast is well tolerated by women with DCIS and does not result in untoward acute toxicity.

Baseline diastolic dysfunction as a predictive factor of trastuzumab-mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer

To evaluate the interest in assessing left ventricular diastolic function at baseline for prediction of trastuzumab-mediated cardiotoxicity (TMC) in the setting of adjuvant treatment for breast cancer. The study included 118 women presenting with HER2-positive early-stage invasive breast cancer. Patients received trastuzumab therapy over 1 year, concurrent with six cycles of docetaxel (n = 53), or following anthracycline-based chemotherapy with a cumulative dose of 300 mg/m(2) (n = 45) or 600 mg/m(2) (n = 20) of epirubicine. RNA was performed before anthracycline-based chemotherapy, before trastuzumab treatment (baseline), and every 3 months during treatment. Left ventricular ejection fraction (LVEF) and peak ejection rate (PER) were calculated to evaluate LV systolic function; peak filling rate (PFR), and time to peak filling rate (TPFR) were also calculated to evaluate LV diastolic function. Eighteen patients (15%) developed grade 1 or 2 TMC during follow-up. No significant difference was observed for age, cardiovascular risk factors, fasting blood glucose level, heart rate, systolic blood pressure, baseline LVEF, PER, and PFR between patients with and without TMC. In contrast, patients with TMC showed a longer TPFR at baseline (median [Q1-Q3]: 165 ms [149-190] vs. 142 ms [130-162]; P < 0.001). Furthermore, by logistic regression analysis, baseline TPFR >180 ms and the cumulative dose of epirubicin remained independent predictors of TMC. Patients receiving 600 mg/m(2) of epirubicin before trastuzumab showed a higher incidence of TMC (35%) than did both patients who previously received 300 mg/m(2) of epirubicin (13%) and those who received only docetaxel associated with trastuzumab (9%). Impaired left ventricular diastolic function before treatment is an independent predictor of trastuzumab-mediated cardiotoxicity. The evaluation of diastolic function could allow optimal risk stratification before the introduction of trastuzumab.

American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guideline on Adjuvant Ovarian Ablation in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer

The American Society of Clinical Oncology (ASCO) has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. The Cancer Care Ontario (CCO) Guideline on Adjuvant Ovarian Ablation (OA) in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer was reviewed for developmental rigor by methodologists. An ad hoc review panel of experts reviewed the content. The ASCO ad hoc OA guideline review panel concurred that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. According to the CCO guideline: one, OA should not be routinely added to systemic therapy with chemotherapy, tamoxifen, or the combination of tamoxifen and chemotherapy; two, OA alone is not recommended as an alternative to any other form of systemic therapy, except in the specific case of patients who are candidates for other forms of systemic therapy but who, for some reason, will not receive any other systemic therapy (eg, patients who cannot tolerate other forms of systemic therapy or patients who choose no other form of systemic therapy); and three, when chemical suppression using luteinizing hormone-releasing hormone agonists is the chosen method of OA, in the opinion of the Breast Cancer Disease Site Group, monthly injection is the recommended mode of administration. The mode of administration in nearly all of the available trials has been monthly administration. The ASCO review panel agrees with the recommendations as stated in the CCO guideline, with the qualification that ongoing research studies may alter the recommendations of the panel.

Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer.

Immunochemical staining of sentinel lymph nodes (SLNs) and bone marrow identifies breast cancer metastases not seen with routine pathological or clinical examination. To determine the association between survival and metastases detected by immunochemical staining of SLNs and bone marrow specimens from patients with early-stage breast cancer. From May 1999 to May 2003, 126 sites in the American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study. All 5210 patients underwent breast-conserving surgery and SLN dissection. Bone marrow aspiration at the time of operation was initially optional and subsequently mandatory (March 2001). Sentinel lymph node specimens (hematoxylin-eosin negative) and bone marrow specimens were sent to a central laboratory for immunochemical staining; treating clinicians were blinded to results. Overall survival (primary end point) and disease-free survival (a secondary end point). Of 5119 SLN specimens (98.3%), 3904 (76.3%) were tumor-negative by hematoxylin-eosin staining. Of 3326 SLN specimens examined by immunohistochemistry, 349 (10.5%) were positive for tumor. Of 3413 bone marrow specimens examined by immunocytochemistry, 104 (3.0%) were positive for tumors. At a median follow-up of 6.3 years (through April 2010), 435 patients had died and 376 had disease recurrence. Immunohistochemical evidence of SLN metastases was not significantly associated with overall survival (5-year rates: 95.7%; 95% confidence interval [CI], 95.0%-96.5% for immunohistochemical negative and 95.1%; 95% CI, 92.7%-97.5% for immunohistochemical positive disease; P = .64; unadjusted hazard ratio [HR], 0.90; 95% CI, 0.59-1.39; P = .64). Bone marrow metastases were associated with decreased overall survival (unadjusted HR for mortality, 1.94; 95% CI, 1.02-3.67; P = .04), but neither immunohistochemical evidence of tumor in SLNs (adjusted HR, 0.88; 95% CI, 0.45-1.71; P = .70) nor immunocytochemical evidence of tumor in bone marrow (adjusted HR, 1.83; 95% CI, 0.79-4.26; P = .15) was statistically significant on multivariable analysis. Among women receiving breast-conserving therapy and SLN dissection, immunohistochemical evidence of SLN metastasis was not associated with overall survival over a median of 6.3 years, whereas occult bone marrow metastasis, although rare, was associated with decreased survival. clinicaltrials.gov Identifier: NCT00003854.

Analysis of Margin Index as a Method for Predicting Residual Disease After Breast-Conserving Surgery in a European Cancer Center

Breast-conserving surgery (BCS), followed by appropriate adjuvant therapies is established as a standard treatment option for women with early-stage invasive breast cancers. A number of factors have been shown to correlate with local and regional disease recurrence. Although margin status is a strong predictor of disease recurrence, consensus is yet to be established on the optimum margin necessary. Margenthaler et al. recently proposed the use of a "margin index," combining tumor size and margin status as a predictor of residual disease after BCS. We applied this new predictive tool to a population of patients with primary breast cancer who presented to a symptomatic breast unit to determine its suitability in predicting those who require reexcision surgery. Retrospective analysis of our breast cancer database from January 1, 2000 to June 30, 2010 was performed, including all patients who underwent BCS. Of 531 patients who underwent BCS, 27.1% (144/531) required further reexcision procedures, and 55 were eligible for inclusion in the study. Margin index was calculated as: margin index=closest margin (mm)/tumor size (mm)×100, with index >5 considered optimum. Of the 55 patients included, 31% (17/55) had residual disease. Fisher's exact test showed margin index not to be a significant predictor of residual disease on reexcision specimen (P=0.57). Of note, a significantly higher proportion of our patients presented with T2/3 tumors (60% vs. 38%). Although an apparently elegant tool for predicting residual disease after BCS, we have shown that it is not applicable to a symptomatic breast unit in Ireland.

Changing paradigm of breast cancer.

[1] Cancer of the Breast has emerged as a leading site of cancer in most urban population of India. It is estimated that 90,000 new cases of breast cancer are detected annually. National cancer registry programme has shown a statistical rising trend in the incidence rate of Breast cancer. In the hospital cancer registries Breast cancer constitutes 14.32% to 30% of all cancers in women [2]. The variation noticed after development of Atlas of cancer in India, showed higher microscopic incidence of breast cancer in peripheral parts of India [3]. The debate continues regarding screening programme of breast cancer in India how feasible & what methodology one should adopt in implementing the different programme. The articles related to problem of breast cancer and its variation has been published in this issue. There is cultural variation in women in different parts of India. The incidence of receptor status varies from western to developing world. This has been published by Suraj et al. on Estrogen receptor negative breast cancer in India do we have higher burden of this type. This clearly depicts their higher triple negative cancer and the facilities available for evaluating these patients for standard of care treatment. Inamdar et al. publishing the Correlation Between Obesity and High Density Lipoprotein Cholesterol (HDL-C) in Breast Cancer Patients of Southern Rajasthan, a variant observed in that population which leads to future thinking on preventive surgery for cancer in relation to obesity and breast cancer. Maji et al.—Onco plastic surgery- our experience in the breast clinic, from Eastern part of the country. Indicating that breast conservative surgery with or without reconstruction is a demand by the patients one has to learn the newer techniques to give a quality of life for the women suffering of Breast cancer. This issue also highlights complications of axillary dissection both after mastectomy and BCS, by Brar et al. To complete Tripuraneni et al. as given a overview on Radiation therapy in early stage invasive breast cancer. Sameer Damle et al. bringing out the issue of Prophylatic mastectomy in Contralateral Breast cancer. The other articles in this issue a review by Raghunandan et al on Imaging in staging and Management of Pancreatic ductal adeno carcinomas, and Chamberlain and his colleagues have reviewed the significance of CA 19-A as Bio marker in Pancreatic cancer. The simple and a day to day problem of FNAC of Thyroid Nodules an article on inadequate cytology in thyroid nodules: should we repeat Aspiration or Follow-Up? By Yoon et al. has extend a curiosity and thinking on this subject what to do. The breast cancer remains a challenge and changing paradigm has been observed in various aspects of Breast cancer in Indian subcontinent.

The influence of travel time on breast cancer characteristics, receipt of primary therapy, and surveillance mammography

Travel time has been shown to influence some aspects of cancer characteristics at diagnosis and care for women with breast cancer, but important gaps remain in our understanding of its impact. We examined the influence of travel time to the nearest radiology facility on breast cancer characteristics, treatment, and surveillance for women with early-stage invasive breast cancer. We included 1,012 women with invasive breast cancer (stages I and II) who had access to care within an integrated health care delivery system in western Washington State. The travel times to the nearest radiology facility were calculated for all the U.S. Census blocks within the study area and assigned to women based on residence at diagnosis. We collected cancer characteristics, primary and adjuvant therapies, and surveillance mammography for at least 2.5 years post diagnosis and used multivariable analyses to test the associations of travel time. The majority of women (68.6%) lived within 20 min of the nearest radiology facility, had stage I disease (72.7%), received breast conserving therapy (68.7%), and had annual surveillance mammography the first 2 years after treatment (73.7%). The travel time was not significantly associated with the stage or surveillance mammography after adjusting for covariates. Primary therapy was significantly related to travel time, with greater travel time (>30 min vs. ≤ 10 min) associated with a higher likelihood of mastectomy compared to breast conserving surgery (RR = 1.53; 95% CI, 1.16-2.01). The travel time was not associated with the stage at diagnosis or surveillance mammography receipt. The travel time does seem to influence the type of primary therapy among women with breast cancer, suggesting that women may prefer low frequency services, such as mastectomy, if geographic access to a radiology facility is limited.

Radiation Therapy in Early-Stage Invasive Breast Cancer

The treatment of breast cancer involves a multi-disciplinary approach with radiation therapy playing a key role. Breast-conserving surgery has been an option for women with early-stage breast cancer for over two decades now. Multiple randomized trials now have demonstrated the efficacy of breast-conserving surgery followed by radiation therapy. With the advancements in breast imaging and the successful campaign for early detection of breast cancer, more women today are found to have early-stage small breast cancers. Patient factors (breast size, tumor location, history of prior radiation therapy, preexisting conditions such as collagen vascular disease, age, having prosthetically augmented breasts), pathological factors (margin status, tumor size, presence of extensive intraductal component requiring multiple surgical excisions), as well as patient preference are all taken into consideration prior to surgical management of breast cancer. Whole-breast fractionated radiation therapy between 5 and 7 weeks is considered as the standard of care treatment following breast-conserving surgery. However, new radiation treatment strategies have been developed in recent years to provide alternatives to the conventional 5-7 week whole-breast radiation therapy for some patients. Accelerated partial breast radiation therapy (APBI) was introduced because the frequency of breast recurrences outside of the surgical cavity has been shown to be low. This technique allows treatments to be delivered quicker (usually 1 week, twice daily) to a limited volume. Often times, this treatment involves the use of a brachytherapy applicator to be placed into the surgical cavity following breast-conserving surgery. Accelerated hypofractionated whole-breast irradiation may be another faster way to deliver radiation therapy following breast-conserving surgery. This journal article reviews the role of radiation therapy in women with early-stage breast cancer addressing patient selection in breast-conserving therapy, a review of pertinent trials in breast-conserving therapy, as well as the different treatment techniques available to women following breast-conserving surgery.

Axillary lymph node dissection in early-stage invasive breast cancer: is it still standard today?

Evaluation of axillary lymph node status by sentinel lymph node biopsy (SLNB) and complete axillary lymph node dissection (ALND) are an inherent part of breast cancer treatment. Increased understanding of tumor biology has changed the prognostic and therapeutic impact of lymph node status. Non-invasive imaging techniques like axillary ultrasound, FDG-PET, or MRI revealed moderate sensitivity and high specificity in evaluation of lymph node status. Therefore, they are not sufficient for lymph node staging. Otherwise, the impact of remaining micrometastases and even macrometastases for prognosis and treatment decisions is overestimated. Considering tumor biology, the distinction of axillary metastases in isolated tumor cells (ITC, pN0(i+)); micrometastases (pN1mi), and macrometastases (pN1a) is not comprehensible. Increasing data support the thesis that remaining axillary metastases neither increase the axillary recurrence rate nor decrease overall survival. It is doubtful that axillary tumor cells are capable to complete the complex multistep metastatic process. If applied, axillary metastases are sensitive to systemic treatment and are targeted by postoperative tangential breast irradiation. Therefore, the controversy about the clinical relevance of tumor cell clusters or micrometastases in SLN is a sophisticated but not contemporary discussion. Currently, there is no indication for axillary surgery in elderly patients with favorable tumors and clinically tumor-free lymph nodes. Nonetheless, a rational and evidence-based approach to the management of clinically and sonographically N0 patients with planned breast-conserving surgery and limited tumor size is needed now.

Redox Protein Expression Predicts Radiotherapeutic Response in Early-Stage Invasive Breast Cancer Patients

Early-stage invasive breast cancer patients have commonly undergone breast-conserving surgery and radiotherapy. In a large majority of these patients, the treatment is effective; however, a proportion will develop local recurrence. Deregulated redox systems provide cancer cells protection from increased oxidative stress, such as that induced by ionizing radiation. Therefore, the expression of redox proteins was examined in tumor specimens from this defined cohort to determine whether such expression could predict response. The nuclear and cytoplasmic expression of nine redox proteins (glutathione, glutathione reductase, glutaredoxin, glutathione peroxidase 1, 3, and 4, and glutathione S-transferase-θ, -π, and -α) was assessed using conventional immunohistochemistry on a tissue microarray of 224 tumors. A high cytoplasmic expression of glutathione S-transferase-θ significantly correlated with a greater risk of local recurrence (p = .008) and, when combined with a low nuclear expression (p = .009), became an independent predictive factor (p = .002) for local recurrence. High cytoplasmic expression of glutathione S-transferase-θ also correlated with a worse overall survival (p = .009). Low nuclear and cytoplasmic expression of glutathione peroxidase 3 (p = .002) correlated with a greater risk of local recurrence and was an independent predictive factor (p = .005). These proteins did not correlate with tumor grade, suggesting their function might be specific to the regulation of oxidative stress rather than alterations of tumor phenotype. Only nuclear (p = .005) and cytoplasmic (p = .001) expression of glutathione peroxidase 4 correlated with the tumor grade. Our results support the use of redox protein expression, namely glutathione S-transferase-θ and glutathione peroxidase 3, to predict the response to radiotherapy in early-stage breast cancer patients. If incorporated into routine diagnostic tests, they have the potential to aid clinicians in their stratification of patients into more tailored treatment regimens. Future targeted therapies to these systems might improve the efficacy of reactive oxygen species-inducing therapies, such as radiotherapy.

Factors associated with the misdiagnosis of sentinel lymph nodes using touch imprint cytology for early stage breast cancer

Accurate intraoperative diagnosis of sentinel node metastasis enables the surgeon to make an immediate decision to proceed to axillary lymph node dissection (ALND), thereby avoiding the economic and psychological costs of a second operation. The present study aimed to evaluate the clinical value of touch imprint cytology (TIC) and investigate the potential factors associated with misdiagnosis. A total of 366 patients with Tis-T2 breast carcinoma were included after undergoing successful sentinel lymph node biopsy (SLNB). TIC was routinely performed intraoperatively, and the results were compared with definitive histological assessments of serial sections (SS) with hematoxylin and eosin (H&E) staining. A total of 992 SLNs from 366 patients were used in the study. Based on the final histological diagnosis, the sensitivity, specificity and overall accuracy of TIC was 76.6, 98.8 and 92.3%, respectively, on a per patient basis, and 79.9, 98.9 and 96.1%, respectively, on a per node basis. TIC was significantly more sensitive for macrometastasis than micrometastasis (80.0 vs. 28.6%, P<0.01). Of 9 total 'false positives', 3 were due to micrometastasis which were not identified by serial section with H&E staining, 4 were actual false-positives which were due to interpretation error, and 2 were due to sampling error. The majority of the false-negatives (28 of 30 SLNs) were due to micrometastasis in the SLNs (sampling error). In conclusion, TIC is feasible for clinical use and is able to detect macrometastasis in the SLNs of early stage invasive breast cancer patients with an acceptable accuracy while its ability to detect micrometastasis is limited.

Abstract PD06-02: Are Outcomes Really Similar after Lumpectomy and Mastectomy for Early Stage Invasive Breast Cancer? Evidence from Population-Based Data

Abstract Background: Randomized clinical trials have established equivalent survival for patients undergoing breast conserving therapy and radiation (BCT) compared to those undergoing mastectomy (M). However, these studies were conducted over two decades ago prior to the era of widespread systemic therapy and improved locoregional therapy and did not assess separately effects by age and tumor type types. We examined survival in a contemporary and representative series of women undergoing BCT or M without radiation for early stage (I-II) breast cancer to assess observationally whether survival varied by surgical treatment among age groups and tumor types. Methods: We used the population-based California Cancer Registry supported by the NCI's Surveillance, Epidemiology and End Results (SEER) Program. We included women diagnosed with stage I and II breast cancer between 1990 and 2003, treated with either BCT or M, and followed for vital status for through the end of 2008. Overall survival (OS) and disease-specific survival (DSS) were compared between BCT and M groups using the Cox proportional hazards model, adjusting for tumor stage at diagnosis, tumor size, grade, number of positive nodes and race. Analysis was stratified by age group (&amp;lt;50 years and ≥50 years) and tumor estrogen receptor (ER) status. Results: 139,430 women fulfilling eligibility criteria and 15,917deaths were identified in the cohort between 1990 and 2003; overall 5-year survival was 93.7% (95% CI 93.6-93.9%). 26% of the total cohort were &amp;lt;50 years of age at diagnosis; 62% were ER-positive. Stage at diagnosis, tumor size, grade, number of positive nodes and race differed significantly among the BCT and M groups. Adjusting for all of these factors, women undergoing BCT had a significantly lower hazard of mortality when compared to women who had M (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.79 - 0.89), with a more pronounced survival difference among women &amp;gt;50 (HR 0.76, 95% CI 0.73 — 0.79). This effect did not differ by ER status among women aged &amp;lt;50. However, among women aged ≥50, this effect was significantly stronger among ER(+) (HR 0.76, 95% CI 0.71-0.80) than ER(-) tumors (HR 0.81, 95% CI 0.75-0.89). Conclusion: In a large, representative series of patients with early stage breast cancer, irrespective of age group or ER status, BCT was independently associated with a significant 19-32% improvement in OS. Although it is highly likely that at least some of this difference relates to unmeasured tumor characteristics or baseline health characteristics influencing treatment choice or overall survival, these findings are provocative and should be further explored in data resources with greater clinical detail. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-02.

A biologically competitive 21 days hypofractionation scheme with weekly concomitant boost in breast cancer radiotherapy feasibility acute sub-acute and short term late effects

BackgroundRadiation therapy after lumpectomy is a standard part of breast conserving therapy for invasive breast carcinoma. The most frequently used schedule worldwide is 60 Gy in 30 fractions in 6 weeks, a time commitment that sporadically may dissuade some otherwise eligible women from undertaking treatment. The purpose and primary endpoint of this perspective study is to evaluate feasibility and short-term late toxicity in a hypofractionated whole breast irradiation schedule.MethodsBetween February and October 2008 we treated 65 consecutive patients with operable invasive early-stage breast cancer with a hypofractionated schedule of external beam radiation therapy. All patients were assigned to 39 Gy in 13 fractions in 3 weeks to the whole breast plus a concomitant weekly boost dose to the lumpectomy cavity of 3 Gy in 3 fractions.ResultsAll the patients had achieved a median follow up of 24 months (range 21-29 months). At the end of treatment 52% presented grade 0 acute toxicity 39% had grade 1 and 9% had grade 2. At 6 months with all the patients assessed there were 34% case of grade 1 subacute toxicity and 6% of grade 2. At 12 months 43% and 3% of patients presented with clinical grade 1 and grade 2 fibrosis respectively and 5% presented grade 1 hyperpigmentation. The remaining patients were free of side effects. At 24 months, with 56 assessed, just 2 patients (3%) showed grade 2 of late fibrosis.ConclusionsThe clinical results observed showed a reasonably good feasibility of the accelerated hypofractionated schedule in terms of acute, subacute and short-term late toxicity. This useful 13 fractions with a concomitant boost schedule seems, in selected patients, a biologically acceptable alternative to the traditional 30 days regime.

Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen

The purpose of this study is to compare immunohistochemistry (IHC) and cytosol-based assays for determination of estrogen receptor (ER) and prediction of response to adjuvant tamoxifen treatment in postmenopausal women with early-stage invasive breast cancer. The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. The patients were stratified according to tumor size and lymph node status in high-risk and low-risk groups. In this study we evaluated 683 patients with "low risk" breast cancer (size ≤30 mm, lymph node-negative) for whom ER status had been determined by both the cytosol assays and IHC at one pathology laboratory. The median follow-up was 17 years. Six hundred eighty-three patients had tumors with ER determined by both methods, 536 (78.5%) were ER-positive by cytosol assays using the cutoff level at ≥0.05 fmol/μg DNA and 539 patients were ER-positive (79%) by IHC using the cutoff level at ≥10% cell stained. Thirty-nine tumors (5.7%) were ER-positive by cytosol but not by IHC, whereas the opposite pattern was found for 42 cases (6.1%). Only seven tumors had stained cells between 0 and 9% by IHC. The concordance between IHC and cytosol assays was high (88%). The kappa statistic was 0.65, 95% CI 0.58-0.72. Among patients classified as ER-negative no therapeutic benefit from tamoxifen was observed. Among patients with ER-expressing tumors, tamoxifen resulted in significantly better recurrence-free survival irrespective of the method (IHC: HR, 0.53, P < 0.001; cytosol: HR, 0.53, P < 0.001). The effect on overall survival was not statistically significant probably due to the limited sample size. Both IHC and cytosol assay accurately predict long-term response to adjuvant tamoxifen.