Positive Estrogen Receptor Status Research Articles

Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis

Accurate determination of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2) status was very important in selecting breast cancer treatment. Discordance of ER, PR, and HER2 status between core needle biopsy (CNB) and open excision biopsy (OEB) varied among reported studies. We performed a meta-analysis to compare the accuracy of CNB with that of OEB for ER, PgR, and HER2 status detection in breast cancer. Medical subject heading (MeSH) terms (Breast Neoplasm) and key words (biopsy OR mammotome) AND (incision OR excision OR surgery) AND (estrogen OR progesterone OR HER2 OR hormone). Patients with HER2 immunohistochemical 3+ or fluorescence in situ hybridization positive were classified into HER2[b] group. A total of 27 studies were eligible in this study. Aggregate positive ER and PgR rate was 80.0 and 69.5% for CNB; and 77.7 and 66.2% for OEB, respectively. The HER2 positive rate difference between CNB and OEB was only 0.2%. The pooled sensitivity of evaluating ER, PgR, and HER2 status in CNB compared with OEB was 0.970, 0.911, and 0.799 (0.813 for HER2[b]), respectively. All of AUC values for these status determination were larger than 0.9. Heterogeneity between studies was introduced by various factors in PgR and HER2[b] analysis. Subgroup analysis showed that the specificity and OR of CNB in studies with ER positive rate >78% was lower than studies with ER positive rate ≤78% (P < 0.05). This meta-analysis indicated that CNB had high diagnostic accuracy in evaluating ER, PgR, and HER2 status compared with OBE in breast cancer patients. In terms of 2-3% positive rate difference, ER and PgR status should be detected both on CNB and OEB samples, especially to retest their expression on CNB in patients with hormonal receptor negative tumors in OEB.

Risk factor for axillary lymph node metastases in microinvasive breast cancer.

17 Background: Sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) was controversial. Usually we didn’t SLNB when we performed conserving operation with small sized DCIS. But sometimes we can find DCIS with microinvasive breast cancer (MIC) after operation. Must do reoperation in all patients? We determined the incidence of positive axillary lymph node (ALN) in patients with MIC and the predictive factors of ALN metastases in these patients. Methods: Between July 1989 and December 2008, 9.635 patients had operation on invasive breast cancer in Asan Medical Center. Among these patients 319 patients had MIC. The research conducted on the 293 patients except who didn’t performed axillary lymph node dissection or SLN biopsy. We retrospectively checked clinical and pathologic variables. Results: There were 22 cases of ALN metastases identified in this group of patients (7.5%). Lymphatic invasion (p&lt;0.001) and positive estrogen receptor status (p=0.03) were independent significant predictors of axillary metastases. Conclusions: Microinvasive breast cancer is associated with a low rate of lymph node metastases. Some breast cancer patients with MIC at low likelihood of lymph node metastases may be spared lymph node evaluation.

Brain metastasis-free survival in patients with HER2-positive metastatic breast cancer.

41 Background: Brain metastases (BM) are diagnosed in up to 40% of patients with HER2-positive metastatic breast cancer (MBC). Since the introduction of trastuzumab in 1999, a rising incidence of BM was reported. We aimed to identify factors that prolong BM free survival (BMFS) in all HER2-positive patients (pts) treated for MBC at the Medical University of Vienna from 1999-2009. Methods: BMFS was defined as primary study endpoint and measured as the interval from diagnosis of metastatic disease until diagnosis of brain metastases. 201 pts with HER2-positive MBC were identified from a breast cancer database. 82 pts (40.8%) were diagnosed with BM; 13 pts were excluded from this analysis as brain was the first site of disease progression. Complete data sets of 69 pts with pathologically verified HER2-positive MBC were available. HER2 status was analyzed by immunohistochemistry and reanalyzed by FISH if a score of 2= was gained. BMFS was estimated by using the Kaplan-Meier product-limit method; factors significantly associated with BMFS in the univariate analysis were included into a Cox proportional hazard model. Results: Median BMFS was 25 months (m; 95%CI 13.37-36.63 m). Trastuzumab-based treatment significantly prolonged median BMFS (29 vs. 11 m; p&lt;0.01); BMFS was further improved by trastuzumab treatment in multiple lines (30 vs. 17 m; p=0.045). Co-positivity for estrogen receptor (ER) and HER2 predicted for longer BMFS (30 vs. 15 m; p&lt;0.05). Further variables such as prior exposure to capecitabine, presence of visceral metastasis, presence of lung metastasis, stage IV disease at primary diagnosis, as well as disease free interval from adjuvant therapy were not significantly associated with BMFS. In the Cox regression model, positive ER status (HR 2.03; 95%CI 1.22-3.36; p&lt;0.05) and trastuzumab-based treatment (HR 2.72; 95%CI 1.20-6.17; p=0.017) remained independent predictors for longer BMFS. Conclusions: Trastuzumab-based therapy significantly prolongs BMFS in HER2-positive pts with MBC, probably due to improved systemic disease control. In line with known better survival outcome, ER/HER2 co-positive disease appears to be a less aggressive subtype of HER2-positive breast cancer associated with longer BMFS.

Accelerated partial breast irradiation using brachytherapy (APBIb) for breast cancer (bca): Predictors of use and guideline concordance.

84 Background: APBIb is a novel alternative to whole breast irradiation (WBI). The American Society for Radiation Oncology Guidelines (ASTRO-G) established appropriateness for APBIb use off protocol. Methods: 138,815 bca patients from the Surveillance, Epidemiology, and End Results database underwent WBI or APBIb after lumpectomy from 2000 to 2007. Patients were classified as suitable, cautionary, or unsuitable for APBIb according to ASTRO-G. Logistic regression was applied to study APBIb use overall and within each guideline category. Results: Overall, 2.6% received APBIb and use varied by ASTRO-G: 5% in suitable, 3.4% in cautionary, and 1.6% in unsuitable patients (p&lt;0.0001). APBIb use increased with time (2000: 0.3%, 2007: 7%) and varied widely with region (0% Alaska; 7% Atlanta, Georgia). Independent predictors of APBIb among suitable patients included white (OR 2.0, p&lt;0.001) race, region (OR 2.6-8.6, p&lt;0.0001), later year (2006-7 v 2000-2 OR 20.3, p&lt;0.0001), and lower grade (OR 1.3, p=0.01). Among cautionary patients, white race (OR 1.8, p&lt;0.001), non-Hispanic ethnicity (OR 1.3, p&lt;0.04), region (OR 3.1-10.2, p&lt;0.0001), metropolitan location (OR 1.9, p=0.01), later year (2006-2007 OR 17.6, p&lt;0.0001), and lower grade (OR 1.4, p&lt;0.0001) predicted for APBIb. Among unsuitable patients, race (p&lt;0.0001), region (OR 3.3-21.6, p&lt;0.0001), later year (2006-7 OR 12.7, p&lt;0.0001), estrogen receptor-positive status (OR 1.3, p=0.002), lower grade (OR 1.3, p&lt;0.01), and negative lymph nodes (OR 2.0, p&lt;0.0001) predicted for use. In several regions, odds of APBIb increased as appropriateness decreased (see Table). Conclusions: APBIb has been rapidly adopted in the US. Its use varied by race, ethnicity, and region, especially among patients who may not be suitable candidates for this technique. [Table: see text]

PIK3CA mutation is an independent indicator of malignant phenotype and prognosis in breast cancer

The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is considered to play an important role in tumorigenesis. Frequent somatic mutations in the PI3K subunit p110a (PIK3CA) occur in a variety of cancer types. The purpose of this study was to determine the relationship between PIK3CA mutation in breast cancer and pathological features and outcome of patients. The PIK3CA mutations in exons 7, 9, 20 were screened in 250 primary breast cancers using PCR and fluorescent (F)-SSCP, and the results were analyzed according to their cliniopathological data. The frequency of PIK3CA mutations among the 250 cases was 35.2% (88/250), point mutations in exon 7 were found in 8 (3.2%) cases,40 (16.0%) cases in exon 9 and 47 (18.8%) cases in exon 20. No significant correlation between PIK3CA mutation and age, histological type, differentiation, and lymph node metastasis was observed. Mutations were associated with larger tumor size (P = 0.004) and positive estrogen receptor status (P = 0.008). Patients with PIK3CA mutations showed a significantly worse survival (P = 0.004), particularly in those with positive estrogen receptor expression or non-amplified HER-2 (both P = 0.002). PIK3CA mutations may play an important role in the carcinogenesis and development of breast cancer. The association with large tumor size, ER+ and poor survival indicates that PIK3CA mutation could be an independent factor for tumor malignant phenotype and prognosis.

Risk Factor for Axillary Lymph Node Metastases in Microinvasive Breast Cancer

Sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) was controversial. Usually we did not do a SLN biopsy when we performed conserving operations with small-sized DCIS. However, sometimes we find DCIS with microinvasive breast cancer (MIC) after the operation. Must reoperations be performed in all patients? The incidence of axillary metastases in microinvasive breast cancer (MIC) has not been extensively studied. We determined the incidence of positive axillary lymph node (ALN) in patients with MIC and the predictive factors of ALN metastases in these patients. Between July 1989 and December 2008, 9635 patients had operation on invasive breast cancer in Asan Medical Center. Among these patients, 319 patients had MIC. The research conducted on the 293 patients (excluded were 26 who did not receive axillary lymph node dissection or SLN biopsy). We retrospectively checked clinical and pathologic variables. There were 22 cases of ALN metastases identified in this group of patients (7.5%). Lymphatic invasion (P<.001) and positive estrogen receptor status (P=03) were independent significant predictors of axillary metastases. Microinvasive breast cancer is associated with a low rate of lymph node metastases. Some breast cancer patients with MIC at low likelihood of lymph node metastases may be spared lymph node evaluation.

Accelerated partial-breast irradiation using brachytherapy (APBIb) for breast cancer (BCA): Predictors of use and guideline concordance.

6080 Background: APBIb is an alternative to whole breast irradiation (WBI) after breast conserving surgery (BCS). We evaluated patterns of APBIb use with respect to treatment suitability criteria defined by 2009 American Society for Radiation Oncology consensus guidelines (ASTRO-G) in a population based cohort. Methods: 138,815 patients diagnosed from 2000-2007 with non-metastatic bca who underwent WBI or APBIb after BCS were identified from the Surveillance, Epidemiology and End Results database. Patients were classified as “suitable,” “cautionary,” or “unsuitable” for APBIb according to ASTRO-G. Multivariable logistic regression analysis was applied to study APBIb use in the overall cohort and in each guideline category. Results: Overall, 2.6% of the cohort received APBIb, and use varied by ASTRO-G category: 5% of suitable patients, 3.4% of cautionary patients, and 1.6% of unsuitable patients (p<0.0001). APBIb use increased from 0.3% in 2000-2 to 5.5% in 2006-7 and varied widely with U.S. region (0% in Alaska, 7% in Atlanta, Georgia). Independent predictors of APBIb among suitable patients included white (odds ratio (OR) 2.0, p<0.001) and black (OR 1.9, p<0.01) race, region (OR 2.6-8.6, p<0.0001), later treatment year (2006-7 v 2000-2 OR 20.3, p<0.0001), lower grade disease (OR 1.3, p=0.01), and sentinel lymph node biopsy (SLNB) (OR 1.3, p<0.0001). Among cautionary patients, white race (OR 1.8, p<0.001), non-Hispanic ethnicity (OR 1.3, p<0.04), region (OR 2.6-10.2, p<0.0001), metropolitan location (OR 1.9, p=0.01), later treatment year (2006-7 OR 17.6, p<0.0001), lower grade disease (OR 1.4, p<0.0001), and SLNB (OR 1.6, p<0.0001) predicted for APBIb. Among unsuitable patients, race (p<0.0001), region (OR 3.3-21.5, p<0.0001), later treatment year (2006-7 OR 12.6, p<0.0001), estrogen receptor positive status (OR 1.3, p=0.002), lower grade disease (OR 1.3, p<0.01), type of nodal surgery (p<0.0001), and negative lymph nodes (OR 2.0, p<0.0001) predicted for use. Conclusions: APBIb after BCS has been rapidly adopted in the U.S. Its use varied by race, ethnicity, and widely by region especially among patients who may not be suitable candidates for this radiation technique.

Impact of HER2-targeted therapy on overall survival (OS) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC).

572 Background: Trastuzumab (T) prolongs OS over chemotherapy alone in pts with HER2+ MBC. Upon disease progression, pts may switch to lapatinib (L) or continue on T. We aimed at assessing the impact of both strategies on OS in all pts treated for HER2+ MBC at the Department of Medicine 1, Medical University of Vienna, from 1999-2009. Methods: 201 pts were identified from a BC databank. 115 pts (572%) received multiple lines of T, whereas 58 (28.9%) were treated with a single line of T-based palliative therapy. A control group of 28 pts (13.9%) had never received T as they were treated before 1999, when T was introduced. HER2 was determined by immunohistochemistry and reanalyzed by FISH if a score of 2+ was gained. OS from diagnosis of metastatic disease was defined as primary study endpoint and estimated using the Kaplan-Meier method. A Cox proportional hazards model was applied to correct for other factors associated with OS. Results: T significantly prolonged OS in HER2+ MBC (41 vs. 13 months; p<0.001). T in multiple lines further numerically improved OS (47 vs. 28 months; p=0.069), which however did not reach statistical significance. In the Cox regression model, brain metastases (BM) (HR 0.67; 95% CI 0.47-0.96) predicted for shorter OS, while positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13-2.27) was significantly associated with better outcome. Addition of L did not further improve OS in patients receiving multiple lines of T (62 vs. 47 months; p=n.s.), while in pts with BM, L improved OS in an univariate model (6 pts; 22 vs. 5 months; p=0.022). Furthermore, numerically less pts treated with L developed BM (30.8% vs. 39.6%; p=n.s.). Incidence of BM in the total sample was 39% and was independent of ER-status (44% vs. 37%; p=n.s.). Conclusions: Introduction of T improved OS in pts with HER2+ MBC, with a further numerical improvement when administered in multiple lines. As in HER2-negative tumours, ER-negative disease was associated with worse outcome, although no higher risk for BM was observed. In this homogenous sample of pts treated with T in multiple lines, L did not further improve OS; however, L might reduce the risk for developing BM and improve OS in pts with BM.

Syndecan-1 and Syndecan-4 Are Independent Indicators in Breast Carcinoma

Syndecan proteoglycans may be key regulators of tumor invasion and metastasis because this four-member family of transmembrane receptors regulates cell adhesion, proliferation, and differentiation. Their expression can also serve as prognostic markers. In breast carcinomas, syndecan-1 overexpression correlates with poor prognosis and aggressive phenotype. Syndecan-4 is expressed in most breast carcinoma cell lines, but its role in malignancy is unclear. A possible relationship between syndecan-1 and syndecan-4 expression and established prognostic factors in breast carcinomas was examined. Duplicate samples of 114 benign and malignant breast disease cases were stained for the two syndecans. Clinicopathological information was available for all cases. Syndecan-1 was detected in 72.8% of cases, with significant association between its expression and histological tumor type (p<0.05) and high grade tumors (p<0.05). Syndecan-4 was expressed in 66.7% of cases; expression correlated significantly with positive estrogen (p<0.01) and progesterone (p<0.01) receptor status. Independent expression of the two syndecans was noted from an analysis of single and double positive cases. There was a statistical relationship between syndecan-1 presence in high-grade tumors and absence of syndecan-4, whereas syndecan-4 presence in cases positive for estrogen and progesterone receptor associated with syndecan-1 absence. These syndecans may, therefore, have distinct roles in regulating breast carcinoma cell behavior.

Transcription factors zeb1, twist and snai1 in breast carcinoma

BackgroundEpitheliomesenchymal transition (EMT) is the process where cancer cells attain fibroblastic features and are thus able to invade neighboring tissues. Transcriptional factors zeb1, snai1 and twist regulate EMT.MethodsWe used immunohistochemistry to investigate the expression of zeb1, twist and snai1 in tumor and stromal compartments by in a large set of breast carcinomas. The results were compared with estrogen and progesterone receptor status, HER2 amplification, grade, histology, TNM status and survival of the patients.ResultsNuclear expression for twist was seen in the epithelial tumor cell compartment in 3.6% and for snai1 in 3.1% of the cases while zeb1 was not detected at all in these areas. In contrast, the tumor stromal compartment showed nuclear zeb1 and twist expression in 75% and 52.4% of the cases, respectively. Although rare, nuclear expression of twist in the epithelial tumor cell compartment was associated with a poor outcome of the patients (p = 0.054 log rank, p = 0.013, Breslow, p = 0.025 Tarone-Ware). Expression of snai1, or expression of zeb1 or twist in the stromal compartment did not have any prognostic significance. Furthermore, none of these factors associated with the size of the tumors, nor with the presence of axillary or distant metastases. Expression of zeb1 and twist in the stromal compartment was positively associated with a positive estrogen or progesterone receptor status of the tumors. Stromal zeb1 expression was significantly lower in ductal in situ carcinomas than in invasive carcinomas (p = 0.020). Medullary carcinomas (p = 0.017) and mucinous carcinomas (p = 0.009) had a lower stromal expression of zeb1 than ductal carcinomas. Stromal twist expression was also lower in mucinous (p = 0.017) than in ductal carcinomas.ConclusionsExpression of transcriptional factors zeb1 and twist mainly occur in the stromal compartment of breast carcinomas, possibly representing two populations of cells; EMT transformed neoplastic cells and stromal fibroblastic cells undergoing activation of zeb1 and twist due to growth factors produced by the tumor. However, epithelial expression of twist was associated with a poor prognosis, hinting at its importance in the spread of breast carcinoma.

Association Between Patient and Tumor Characteristics With Clinical Outcomes in Women With Ductal Carcinoma In Situ

We synthesized the evidence of the association between patient and tumor characteristics with clinical outcomes in women with ductal carcinoma in situ of the breast. We identified five randomized controlled clinical trials and 64 observational studies that were published in English from January 1970 to January 2009. Younger women with clinically presented ductal carcinoma in situ had higher risk of ipsilateral recurrent cancer. African Americans had higher mortality and greater rates of advanced recurrent cancer. Women with larger tumor size, comedo necrosis, worse pathological grading, positive surgical margins, and at a higher risk category, using a composite prognostic index, had worse outcomes. Inconsistent evidence suggested that positive HER2 receptor and negative estrogen receptor status were associated with worse outcomes. Synthesis of evidence was hampered by low statistical power to detect significant differences in predictor categories and inconsistent adjustment practices across the studies. Future research should address composite prediction indices among race groups for all outcomes.

Population‐based analysis of occult primary breast cancer with axillary lymph node metastasis

Single-institution data suggest that treatment with radiation and axillary lymph node dissection (ALND) may be an appropriate alternative to mastectomy for T0N+ breast cancer. Population-based multi-institutional data supporting this approach are lacking. The cause-specific survival (CSS) and overall survival (OS) of women with T0N+M0 ductal, lobular, or mixed breast cancer in the Surveillance, Epidemiology, and End Results database from 1983 to 2006 were analyzed. Groups were defined as: 1) no ALND, mastectomy, or RT (observation); 2) ALND only; 3) mastectomy plus ALND with or without postmastectomy radiation (Mast); and 4) breast-conserving therapy (BCT) with ALND and radiation (BCT). In total, 750 of 770,030 patients with breast cancer had T0N+M0 disease (incidence, 0.10%), and 596 of those patients underwent ALND (79.5%). Patients who underwent Mast or BCT (n = 470) had a 10-year OS rate of 64.9% compared with 58.5% for patients who underwent ALND only (n = 126; P = .02) and 47.5% for patients who underwent observation only (n = 94; P = .04). The 10-year CSS rate was 75.7% for patients who underwent BCT versus 73.9% for patients who underwent Mast (P = .55). In multivariate analysis of CSS for patients who underwent Mast or BCT, the following factors were correlated with an unfavorable outcome: positive estrogen receptor status (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.24-0.96; P = .04), >/=10 positive lymph nodes (HR, 5.7; 95%CI, 2.4-13.4; P </= .01), and <10 resected lymph nodes (HR, 42.9; 95%CI, 1.2-7.1; P = .02). Mast did not improve CSS compared with BCT (HR, 1.09; 95%CI, 0.57-2.1; P = .79). Definitive locoregional treatment with either Mast or BCT improved the outcome of patients with T0N+breast cancer, and no difference in survival was observed between the treatments. Cancer 2010. (c) 2010 American Cancer Society.

Inflammatory breast cancer—The Royal Marsden Hospital experience

Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered. Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS. The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation. Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook.

High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer.

IntroductionHER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group, needed to be further characterized in large sample sets.MethodsGenome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail.ResultsThe HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors.ConclusionsWe have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.

Detection of minimal residual disease in blood and bone marrow in early stage breast cancer

The significance of circulating tumor cells (CTCs) in blood and of disseminated tumor cells (DTCs) in bone marrow (BM) in patients with early stage breast cancer is unclear. In this study, the authors investigated the occurrence of CTCs and DTCs in women with early stage breast cancer and evaluated the correlation of their presence with other prognostic markers. Blood and BM aspirations were collected at the time of primary breast surgery. CTCs were detected by using the CellSearch assay, and DTCs were detected by immunostaining BM aspirates for pancytokeratin. The presence of CTCs and DTCs was correlated with tumor classification (T1 vs T2), tumor histologic grade, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, and lymph node (LN) status. Of 92 patients who were included in the study, 49 had T1 tumors, and 43 had T2 tumors. CTCs were detected in 31% of patients, and DTCs were detected in 27% of patients. There was no correlation between the occurrence of CTCs and DTCs with the tumor classification (T1 vs T2) or histologic grade. CTCs were detected in 33% of patients with ER-positive disease versus 26% of patients with ER-negative disease, in 32% of patients with PR-positive disease versus 30% of patients with PR-negative disease, and in 25% of patients with HER2-positive disease versus 31% of patients with HER2-negative disease. DTCs were observed in 23% of patients with ER-positive disease versus 37% of patients with ER-negative disease, in 22% of patients with PR-positive disease versus 32% of patients with PR-negative disease, and in 0% of patients with HER2-positive disease versus 29% of patients with HER2-negative disease. CTCs and DTCs were nearly equally prevalent in both LN-positive women and LN-negative women. There was no significant correlation between the occurrence of CTCs or DTCs with tumor classification (T1 vs T2), tumor histologic grade, positive ER status, positive PR status, or positive HER2 status, and axillary LN status. CTCs and DTCs in women with early stage breast cancer did not correlate with the standard prognostic indicators that were considered. The implications of their occurrence in patients with early stage disease will require further large-scale studies.

Ultrasound-Guided Bipolar Radiofrequency Ablation of Breast Cancer in Inoperable Patients: a Pilot Study

Radiofrequency ablation (RFA) is a promising minimal invasive modality to treat small breast cancer (BCA). In most studies cancers were surgically excised shortly after RFA. We present six patients inoperable when diagnosed with BCA, and performed RFA instead of surgery. Ultrasound-guided bipolar RFA was performed under local anesthesia in six women aged 63 - 85 years. They had core-biopsy proven T 1 - 2N0 M0, grade I or II, 1.0 - 2.7 cm sized invasive ductal cancers, with positive estrogen receptor status. Four tumors measured > 2 cm, and three 1.0 - 1.2 cm in diameter. Patients were at high-risk for general anesthesia and surgery because of severely impaired cardiac function, advanced age, or associated diseases (acute myeloid leukaemia (AML), diabetes, hypertension, depression) and/or refused surgery. Six tumors in five patients were completely ablated, without recurrence during follow-up (range: 9 - 49 months). One superficially located cancer was partially ablated; the patient died two months later from myocardial infarction. The Patient with AML and BCA had an infection of the treated breast after 4 months and postponed mastectomy to an AML remission status. There were no signs of malignancy in histopathology; the patient finally died of leukemia 42 months after RFA. The remaining four patients are well, without complications. Ultrasound-guided percutaneous RFA under local anesthesia is an effective alternative to surgery for BCA < 3 cm in patients with a high-risk for surgery.

Microarray-Based Determination of Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Status in Breast Cancer

The level of estrogen receptor (ER), progesterone receptor (PR), and HER2 aids in the determination of prognosis and treatment of breast cancer. Immunohistochemistry is currently the predominant method for assessment, but differences in methods and interpretation can substantially affect the accuracy, resulting in misclassification. Here, we investigated the association of microarray-based mRNA expression levels compared with immunohistochemistry. Microarray mRNA quantification of ER, PR, and HER2 was done by the developed TargetPrint test and compared with immunohistochemical assessment for breast tumors from 636 patients. Immunohistochemistry was done in a central laboratory and in an independent reference laboratory according to American Society of Clinical Oncology/College of American Pathologists guidelines for 100 cases. For HER2 immunohistochemistry 2+ cases, additional chromogenic in situ hybridization (CISH) was used to determine the final status. ER concordance between microarray and central immunohistochemistry was 93% [95% confidence interval (95% CI), 91-95%]. Only 4% of immunohistochemistry-positive samples were classified negative using microarray, whereas 18% of immunohistochemistry-negative samples showed a positive microarray ER status. Concordance for PR was 83% (95% CI, 80-86%) and 96% of all samples showed an identical classification of HER2 status by microarray and immunohistochemistry/CISH (95% CI, 94-98%). Nine percent of immunohistochemistry HER2-positive samples showed a negative microarray classification. Detailed review of 11 cases with discordant classifications by American Society of Clinical Oncology/College of American Pathologists and central immunohistochemistry indicated that microarray assessment was likely to add additional information in 5 cases. Microarray-based readout of ER, PR, and HER2 shows a high concordance with immunohistochemistry/CISH and provides an additional, objective, and quantitative assessment of tumor receptor status in breast cancer.

Correlation of levels of Akt phosphorylation at Ser473 with benefit from paclitaxel chemotherapy in NSABP B-28 patients with node-positive breast cancer

537 Background: We investigated the levels of tumor phospho-Akt(Ser473) (pAkt) and treatment outcome of patients with node-positive breast cancer after adjuvant treatment with doxorubicin/cyclophosphamide (AC) followed by four cycles of paclitaxel (PTX) (AC→PTX) compared with AC chemotherapy alone in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial. Methods: The primary tumors on B-28 tissue microarray were available from 1581 of 3060 patients enrolled. pAkt status was examined by immunohistochemistry with the antibody to pAkt(Ser473) (Cell Signaling Technology) at the National Cancer Institute. Levels of pAkt were quantitatively scored with the assistance of an Automated Digital Imaging System blinded to clinical outcome, and categorized by the staining index (intensity X % of staining /100) of &gt; 2 (high) and ≤ 2 (low). The association between tumor pAkt level and clinical outcome at 10 years was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor and HER2 status. Results: Among patients with low tumor pAkt levels (n = 975), there was no DFS difference between those treated with or without PTX (adjusted HR = 1.02, p = 0.81). However, among patients with high tumor pAkt levels (n = 606), those treated with AC→PTX had a 26% reduction in DFS event rate compared to those treated with AC only (adjusted HR = 0.74, p = 0.02). There was no OS difference between treatment groups for those with low pAkt cancer (HR = 0.97, p = 0.80). In patients with high pAkt cancer, those treated with AC→PTX had a 20% reduction in death rate compared to those treated with AC only but this difference did not reach statistical significance (adjusted HR = 0.80, p = 0.17). Conclusions: High levels of Akt phosphorylation at Ser473 independently predict a DFS benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide in node-positive breast cancer. Patients with low levels of pAkt breast cancer may not benefit from the sequential addition of PTX to doxorubicin plus cyclophosphamide. [Table: see text]

Effect of endocrine therapy with tamoxifen on hormone receptor status in patients with breast cancer

e11598 Background: Endocrine therapy (ET) of patients with hormone receptor (HR)-positive breast cancer (BC) is thought to adversely affect the HR status of the tumor with time. In order to evaluate this, a study was undertaken comparing the HR status of patients with estrogen receptor (ER)-positive BC prior to adjuvant tamoxifen (Tam) therapy and after progression. Methods: A retrospective analysis of all BC patients presented to the unit between 1999 to 2004 with an initial stage I-III ER-positive BC, who received Tam between 6 and 60 month and went on to develop progressive disease in the form of local recurrence or distant metastasis. Progression was confirmed by tumor biopsy and analysis of the HR status. All patients were evaluated for ER and progesterone receptor (PR) status using immunohistochemistry as well as tumor grading prior to Tam therapy and after relapse. Results: 67 eligible patients with ER-positive BC were recorded. All patient and tumor characteristics, including age, tumor size, histology and adjuvant therapy were similar as published elsewhere. 82% were initially PR-positive. The mean duration of Tam administration of 20mg po was 40.7±19.9 month. The mean duration to progression was calculated at 54.9±34.6 month. After relapse, 70.1% of tumors retained a positive ER status and only 53% showed positive PR expression. Using the nonparametric McNemar's test, a highly significant reduction (p&lt; 0.001) of both HR was the result of Tam administration. Conclusions: our data suggests that progression under ET shows a trend towards loss of HR status (ER as well as PR). Therefore, this data is a useful tool for the clinician in evaluating the effectiveness of further ET in patients with progressive BC without having been able to confirm the present HR status through biopsy. Furthermore, as opposed to common belief, the reduction in positive ER tumors showed no correlation with tumor grading. No significant financial relationships to disclose.

Time-Varying Effects of Prognostic Factors Associated With Disease-Free Survival in Breast Cancer

Early detection and effective treatments have dramatically improved breast cancer survivorship, yet the risk of relapse persists even 15 years after the initial diagnosis. It is important to identify prognostic factors for late breast cancer events. The authors investigated time-varying effects of tumor characteristics on breast-cancer-free survival using data on 3,088 breast cancer survivors from 4 US states who participated in a randomized dietary intervention trial in 1995-2006, with maximum follow-up through 15 years (median, 9 years). A piecewise constant penalized spline approach incorporating time-varying coefficients was adopted, allowing for deviations from the proportional hazards assumption. This method is more flexible than standard approaches, provides direct estimates of hazard ratios across time intervals, and is computationally tractable. Having a stage II or III tumor was associated with a 3-fold higher hazard of breast cancer than having a stage I tumor during the first 2.5 years after diagnosis; this hazard ratio decreased to 2.1 after 7.7 years, but higher tumor stage remained a significant risk factor. Similar diminishing effects were found for poorly differentiated tumors. Interestingly, having a positive estrogen receptor status was protective up to 4 years after diagnosis but detrimental after 7.7 years (hazard ratio = 1.5). These results emphasize the importance of careful statistical modeling allowing for possibly time-dependent effects in long-term survivorship studies.