HER2-neu Status Research Articles

Her-2 neu status in gastric carcinoma in Egyptian patients: The epidemiology and the response to chemotherapy

Background: Gastric cancer is the fourth most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide, affecting one million people per year. Currently, gastric cancer is still the seventh most common cause of cancer-related death in the USA, and the prognosis of advanced gastric cancer remains poor. Objectives: The aim of this study was to assess the frequency of Her-2 overexpression and amplification in Egyptian patients with gastric/gastroesophageal adenocarcinoma, in correlation with tumor histology, grade, size, and location (cardia vs. noncardia). Patients and methods: This study included 39 eligible patients with pathologically proven gastric/gastroesophageal carcinoma presented to Menoufia University Oncology Hospital, Alexandria Military Hospital, from January 2012 until the end of June 2013. Results: It was found that the mean age was 55.3 years. There was slightly higher incidence in the male population (51.3%). All of them had tumors of diffuse histopathological type. Stage at presentation was as follows: localized, one (2.6%); locally advanced, 20 (51.3%); and metastatic, 18 (46.2%). Her-2 was found to be overexpressed in four out of 39 patients (10.3%). Her-2-negative patients had a significantly longer overall survival (9 months in Her-2 negative-patients vs. 4 months in Her-2-positive patients) (P= 0.01). Progression-free survival (PFS) was significantly prolonged in Her-2-negative patients. Her-2-negative patients had a PFS of 8 months, versus only 4 months in Her-2-positive patients (P= 0.01). Median survival and PFS in locally advanced disease were significantly affected by the Her-2 status (P= 0.02). Neither median survival (P= 0.8) nor PFS (P= 0.5) was affected in metastatic disease. Conclusion: Her-2 is a prognostic factor in a small cohort of Egyptian patients with gastric/gastroesophageal carcinoma.

Comparison of the influence of human epidermal growth factor receptor 2/neu on the markers of aggression in gastric adenocarcinomas and ductal carcinoma breast

Background: Human epidermal growth factor receptor 2/neu (HER2/neu) assessment is carried out in gastric adenocarcinomas (GAC) and invasive ductal carcinoma (IDC) breast to decide upon of trastuzumab targeted therapy. The study the only of its kind which has compared the influence of HER2/neu expression to markers of tumor aggression in these two malignancies in similar target population. Material and Methods: HER2/neu evaluation was conducted by immunohistochemistry (IHC) using the guidelines of Trastuzumab for Gastric Cancer trial for GAC and ASCO-CAP 2013 for IDC breast. The study correlated HER2/neu expression with markers of tumor aggression. Aims: The present retrospective study compares the disease influence of HER2/neu over expression on markers of disease aggression like age at presentation, grade of tumor and lymph node metastasis in GAC and IDC. Results: We have compared 82 cases of GAC with 113 cases of IDC. HER2/neu expression was seen in 23.2% and 36.3% of GACs and IDCs respectively. The mean age of HER2/neu positive GACs was found to be 3.47 years greater than their negative counterpart but the pattern was reversed in cases of IDC breast where the mean age of HER2/neu positive tumors was 6.09 years less than their negative counterpart. Though no correlation was found between grade of tumor and HER2neu status in GACs (P = 0.2930), however in IDC breast a significant correlation HER2neu positivity was found with higher grade (P = 0.0002). Similarly though we did not find any correlation of HER2neu status with nodal metastasis in GACs (P 0.0511) but in IDCs a significant correlation was found of nodal metastasis with HER2/neu positivity (P = 0.0001). Conclusion: We conclude that HER2/neu expression is more frequent in IDC breast and is significantly associated with markers of aggression in contrast to its influence on the same markers in GACs.

CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients

Despite consistent pharmacogenetic effects of CYP2D6 on tamoxifen exposure, there is considerable controversy regarding the validity of CYP2D6 as a predictor of tamoxifen outcome. Understanding the current state of evidence in this area and its limitations is important for the care of patients who require endocrine therapy for breast cancer. A total of 101 patients with breast cancer who received tamoxifen therapy for at least 3 years, were genotyped for common alleles of the CYP2D6 gene by nested-PCR and restriction fragment length polymorphism PCR. Patients were classified as extensive or poor metabolizers (PM) based on CYP2D6*4 alleles in 3 different groups according to the menopause, Her2-neu status, and stage 3. The mean age of the patients with the disease recurrence was 50.8±6.4 and in non recurrent patients was 48.2±6.8. In this study 63.3% (n=64) patients were extensive metabolizers and 36.6% (n=37) were poor metabolizers. Sixty four of the 101 patients (63.3%) were Her2-neu positive. For tamoxifen- treated patients, no statistically significant difference in rate of recurrence observed between CYP2D6 metabolic variants in stage 3 and post-menopausal patients. However, there was a significant association between CYP2D6 genotype and recurrence in tamoxifen-treated Her2-neu positive patients. Compared with other women with breast cancer, those with Her2-neu positive breast cancer and extensive metabolizer alleles had a decreased likelihood of recurrence. This study for the first time demonstrated significant effects of CYP2D6 extensive metabolizer alleles on risk of recurrence in Her2-neu positive breast cancer patients receiving adjuvant tamoxifen therapy. Therefore, CYP2D6 metabolism, as measured by genetic variation, can be a predictor of breast cancer outcome in Her2-neu positive women receiving tamoxifen.

Abstract OT1-3-02: Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af

Abstract Background This phase III randomized post-neoadjuvant chemotherapy trial will evaluate if chest wall and regional nodal XRT (CWRNRT) after mastectomy or whole breast irradiation (WBI) with RNRT after breast-conserving surgery significantly reduces the rate of events for invasive breast cancer recurrence-free interval (IBCR-FI) in patients who present with histologically positive axillary nodes but become histologically negative axillary nodes after neoadjuvant chemotherapy. Secondary aims are OS, LRR-FI, DRFI, DFS-DCIS, and second primary cancer. HYPOTHESIS: Can We Use Tumor and Nodal Response to Neoadjuvant Chemotherapy in Order to Individualize the Use of L-R XRT? Correlative science will examine the effect of RT by tumor subtype, molecular predictors of outcome for patients with residual disease, and the development of predictors of degree of reduction in loco-regional recurrence. Methods Eligible patients with clinical T1-3, N1 breast cancer with pathologic axillary nodal involvement (positive FNA or core needle biopsy) must complete ≥12 weeks of neoadjuvant chemotherapy (anthracycline and/or taxane-based regimen). HER2-positive patients must receive neoadjuvant trastuzumab or other anti-HER2 therapy. After neoadjuvant chemotherapy either breast-conserving surgery or mastectomy will be performed. At the time of surgery, all removed axillary nodes must be histologically free from cancer. 3 or more histologically negative sentinel nodes are acceptable to determine axillary nodal involvement. ER/PR and HER-2 neu status before neoadjuvant chemotherapy is required. All patients will receive additional required systemic therapy. Site radiation credentialing with a facility questionnaire and case benchmarking is required. Randomization for mastectomy patients will be to no CWRNRT or CWRNRT and for breast-conserving surgery patients to WBI or WBI RNRT. Statistical Considerations 1636 patients will be enrolled over 5 years with definitive analysis at 7.5 years. The study is powered at 80% to test the main hypothesis that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-year cumulative rate of 4.6%. Analysis will be on intent-to-treat with 3 formal interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events. Current accrual is 37. (as of 6-10-14) 736 enrolled patients will be evaluated with targeted patient-reported outcome instruments focusing on the effect of RT. Patient assessments will be prior to randomization and then at 3, 6, 12, and 24 months. Contact Information Study protocol information can be found under the protocol-specific web page on the CTSU member web site https://www.ctsu.org. For protocol-specific questions contact – NRG Oncology Pittsburgh Clinical Coordinating Department. Phone: 1-800-477-7227. Email: ccd@nsabp.org. All investigators will enroll patients by accessing OPEN at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the web site. Support: NCI PHS U10-CA-12027, -69651, -37377, -69974, and -2166. Citation Format: Eleftherios P Mamounas, Hanna Bandos, Julia R White, Thomas B Julian, Atif J Khan, Simona F Shaitelman, Mylin A Torres, Susan A McCloskey, Frank A Vicini, Patricia A Ganz, Soonmyung Paik, Nilendu Gupta, Joseph P Costantino, Walter J Curran Jr, Norman Wolmark. Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-3-02.

Abstract P6-10-12: Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes

Abstract Purpose Metformin use has recently been observed to decrease both the rate and mortality of breast cancer. Our study was aim to determine whether metformin use is associated with survival in diabetic breast cancer patients by breast cancer subtype and systemic treatment Patients and Methods Data from the Asan Medical Center Breast Cancer Database from 1997 to 2007 were analyzed. The study cohort comprised 6,967 nondiabetic patients, 202 diabetic patients treated with metformin, and 184 diabetic patients that did not receive metformin. Patients who were divided into three groups by diabetes status and metformin use were also divided into four subgroups by hormone receptor and HER2-neu status. Results In Kaplan-Meier analysis, the metformin group had a significantly better overall and cancer specific survival outcome compared with non metformin diabetic group (P <0.005 for both). There was no difference in survival between the nondiabetic and metformin groups. In multivariate analysis, Compared with metformin group, patients who did not receive metformin tended to have a higher risk of metastasis with HR 5.37 (95%CI, 1.88 to 15.28) and breast cancer death with HR 6.51 (95% CI, 1.88 to 15.28) on the hormone receptor-positive and Her2-negative breast cancer. The significant survival benefit of metformin observed in diabetic patients who received chemotherapy and endocrine therapy (HR for DFS 2.14; 95% CI 1.14 to 4.04) was not seen in diabetic patients who did not receive these treatments. Conclusion Patients receiving metformin treatment when breast cancer diagnosis show a better prognosis only if they have hormone receptor-positive, HER2-positive tumors. Metformin treatment might provide a survival benefit when added to systemic therapy in diabetic patients. Citation Format: Hee Jeong Kim, Hyun Wook Kwon, Jong Won Lee, Sae Byul Lee, Hee Seung Park, Sei Hyun Ahn, Hae Na Shin. Metformin increases survival in hormone receptor-positive, Her2-positive breast cancer patients with diabetes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-12.

Prospective trial of breast MRI versus 2D and 3D ultrasound for evaluation of response to neoadjuvant chemotherapy.

Preoperative imaging to assess response to neoadjuvant chemotherapy in breast cancer is routine but no single imaging modality is standard of practice. Our hypothesis is that ultrasound (US) is comparable to magnetic resonance imaging (MRI) in the prediction of residual disease. A single-institution, Institutional Review Board-approved prospective trial of primary invasive ductal breast cancer patients receiving neoadjuvant chemotherapy enrolled women from 2008 to 2012. Two-dimensional (2D) and three-dimensional (3D) US, as well as MRI images of pre- and post-neoadjuvant tumors were obtained. Skin involvement or inadequate images were excluded. Residual tumor on imaging was compared with surgical pathology. Differences of tumor volume on imaging and pathology were compared using the non-parametric Wilcoxon signed-rank test. US to MRI agreement was determined by the kappa coefficient. Tumor volumes in estrogen receptor (ER), progesterone receptor (PR), and Her2neu subgroups were compared using the Kruskal-Wallis test. ER/PR staining <5 % was considered negative; Her2neu status was determined by in situ hybridization. Forty-two patients were enrolled in the study; 39 had evaluable post-treatment data. Four patients were Her2neu positive, and 17 (46 %) patients had triple-negative tumors. Among 11 (28 %) patients with pathologic complete response (pCR), US correctly predicted pCR in six (54.5 %) patients compared with eight (72.7 %) patients when MRI was used. This is a substantial agreement between US and MRI in predicting pCR (kappa = 0.62). There was no difference between 2D and 3D US modalities. For the 39 patients, US and MRI had no significant difference in volume estimation of pathology, even stratified by receptor status. The estimation of residual breast tumor volume by US and MRI achieves similar results, including prediction of pCR.

A study on estrogen receptor, progesterone receptors, HER-2NEU status in breast cancer cases attending to a tertiary care hospital of Andhra Pradesh

A study on estrogen receptor, progesterone receptors, HER-2NEU status in breast cancer cases attending to a tertiary care hospital of Andhra Pradesh

Increased Likelihood of Mastectomy in Human Epidermal Growth Factor Receptor 2-positive Ductal CarcinomaIn Situ

Patients with human epidermal growth factor receptor 2 (HER2neu)-positive breast invasive cancer are known to have larger, more aggressive tumors. Little research exists on the relationship between HER2neu status and extent of ductal carcinoma In Situ (DCIS). A retrospective review of a single-institution database was performed for patients with DCIS between the years 2002 and 2011. A single blinded breast radiologist reviewed preoperative imaging. Pathology was reviewed for extent of DCIS. Primary outcome was mastectomy. Multivariate logistic regression was used to determine adjusted mastectomy risk. There were 166 cases, 34 HER2neu-positive. HER2neu receptor-positive patients had larger lesions on imaging: 4.0 versus 2.7 cm, by 2.9 versus 1.5 cm (P = 0.0499 and 0.0182). HER2neu-positive patients with DCIS were more likely than HER2neu-negative to undergo mastectomy than lumpectomy (53 vs 28%, P = 0.006). Pathology revealed a trend toward larger lesions in HER2neu-positive patients (2.96 vs 2.22 cm, nonsignificant). Patients with HER2neu-positive disease were three times more likely to undergo mastectomy (odds ratio, 2.9; 95% confidence interval, 1.23 to 6.78). Patients with HER2neu-positive DCIS had greater extent of disease by imaging and were more likely to undergo mastectomy than HER2neu-negative. These findings will help surgeons counsel patients on surgical treatment.

Enhanced down-regulation of ALCAM/CD166 in African-American Breast Cancer.

BackgroundVariation in tumor biology in African-American (AA) and Caucasian (CAU) women with breast cancer is poorly defined. Activated leukocyte cell adhesion molecule (ALCAM) is a bad prognostic factor of breast cancer yet it has never being studied in the AA population. We tested the hypothesis that ALCAM expression would be markedly lower in cases of AA breast cancer when compared to CAU.MethodsCases of breast cancer among AA (n = 78) and CAU (n = 95) women were studied. Immunohistochemical staining was used to semi-quantitatively score ALCAM expression in tumor and adjacent non-tumor breast tissues. Clinico-pathological characteristics including histological type, histological grade, tumor size, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), and HER2-neu status were abstracted, and their association with ALCAM expression tested.ResultsUnivariate analysis revealed that the level of ALCAM expression at intercellular junctions of primary tumors correlates with histological grade (AA; p = 0.04, CUA; p = 0.02), ER status (AA; p = 0.0004, CAU; p = 0.0015), PR status (AA; p = 0.002, CUA p = 0.034) and triple-negative tumor status (AA; p = 0.0002, CAU; p = 0.0006,) in both ethnic groups. Multivariate analysis demonstrated that ethnicity contribute significantly to ALCAM expression after accounting for basal-like subtype, age, histological grade, tumor size, and lymph node status. Compared to CAU tumors, the AA are 4 times more likely to have low ALCAM expression (p = 0.003).ConclusionsMarkedly low expression of ALCAM at sites of cell-cell contact in primary breast cancer tumors regardless of differentiation, size and lymph node involvement may contribute to the more aggressive phenotype of breast cancer among AA women.

Prognostic factors for survival in metastatic breast cancer by hormone receptor status.

Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003-2006 treated with curative intent who developed MBC within 5years of follow-up were selected from the Netherlands cancer registry (N=2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR-) tumours was 8months, compared to 19months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR- patients, but not in HR+patients. HER2-Neu positive status was associated with better survival in both HR+ and HR- patients, although the association was stronger in HR- patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR- patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients.

Abstract P6-12-04: Risk factors for inflammatory breast cancer

Abstract Background: The 5-year survival rates for inflammatory breast cancer (IBC) are significantly lower than non-IBC, highlighting the importance of cancer prevention in IBC. We investigated the risk factors for IBC subtypes based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2neu) status to determine distinct etiological pathways. The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at University of Texas MD Anderson Cancer Center (UTMDACC) treats the largest number of IBC patients in a single center. The center maintains a prospective, comprehensive epidemiology registry, through which we were able to conduct the largest single center case-control study on IBC. Methods: We identified 246 patients diagnosed with IBC using strict consensus criteria and 397 cancer free patients seen at the UTMDACC Dan L. Duncan Cancer prevention clinic. We used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between breast cancer reproductive and lifestyle risk factors and IBC tumor subtypes. The tumor subtypes of IBC patients were classified as ER-positive (ER+/PR+/Her2neu-), Her2neu-positive (Her2neu+) and triple negative (ER-/PR-/Her2neu-). Results: In age-adjusted univariate analysis, body mass index (BMI), history of smoking, number of children, age at first pregnancy, breastfeeding, menopausal status, and first degree family history of breast cancer were statistically significant associated with risk of IBC (p&amp;lt;0.05). In multivariable analysis of IBC tumor subtypes, compared to cancer free controls, patients with triple negative (OR = 3.73, 95% CI = 1.52 – 9.13) and Her2neu-positive (OR = 19.27, CI = 4.14 – 89.62) tumors were significantly more likely to have ≥ 2 vs 0-1 children. Patients with triple negative (OR = 0.19, 95% CI = 0.09 – 0.45) and ER-positive (OR = 0.42, CI = 0.19 – 0.88) tumors were significantly less likely to have a history of breastfeeding. Patients with ER-positive (OR = 5.02, CI = 2.29 – 10.99) tumors were also significantly more likely to have a history of smoking. Patients with triple negative (OR = 6.07, CI = 2.62 – 17.07), ER-positive (OR = 7.22, CI = 2.94 – 17.78) and Her2neu-positive (OR = 12.81, CI = 4.59 – 35.78) were more likely to be overweight or obese (BMI ≥ 25kg/m2). Conclusion: The associations identified suggest that overweight or obese status is an important modifiable risk factor for all IBC subtypes. Triple negative IBC share similar risk factors as non-IBC triple negative tumors with increasing number of children and lack of breastfeeding associated with increased risk. Interestingly lack of breastfeeding was also associated with ER-positive IBC tumors, and Her2neu-positive IBC tumors were associated with increasing number of children; two associations that have not been previously reported. Impact: These results highlight the importance of evaluating epidemiologic risk factors of IBC, which could lead to the identification of subtype specific prevention strategies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-04.

Breast cancer patients with diabetes mellitus: Defining the population and assessing outcomes.

137 Background: Diabetes has been associated with an increased risk of mortality among patients with many types of cancers. Methods: We performed a case-control study of 109 breast cancer patients to determine the impact of diabetes on disease recurrence and survival. These 109 patients diagnosed with invasive breast cancer during 2007-2011 with diabetes were identified from the institutional Cancer Registry and matched to 109 breast cancer patients without diabetes according to age, race/ethnicity and year of diagnosis. Statistical tests included paired t-tests, McNemar’s tests, and stratified Cox regression. Results: The median ages of those with and without diabetes were 68 years, and 91% in both groups were white (both matched). Patients with and without diabetes were not significantly different in terms of tumor grade, cancer stage, estrogen or progesterone receptor status, HER2 neu status, marital and employment status, smoking use, use of adjuvant chemotherapy, and steroid treatment (all P &gt;.4). Patients with diabetes reported less use of alcohol (50% vs 64%, P=.04), and had greater BMI (79% overweight/obese vs 58%, P= .002). Survival analysis demonstrated no differences in survival from initial breast cancer diagnosis (HR=1.25, 95% CI 0.49-3.17) with median follow-up of 2.2 years (range 0.1-4.9), and no differences in recurrence-free survival (HR=1.00, 95% CI 0.14-7.10) though very few deaths and recurrences were observed. Within the diabetes group, 96 (88%) had type 2 diabetes and 97/106 (92%, 3 unknown) had diabetes pre-existing to cancer diagnosis. Initial diabetes therapy included diet (33, 30%), oral therapy (48, 44%), insulin (21, 19%), or oral+insulin (6, 6%). 7 patients required a change in diabetes therapy within 1 year of cancer diagnosis with 3 patients starting insulin. 32/70 (46%) with available lab data had 1 or more A1C &gt;/=7 within 1 year of cancer diagnosis. Conclusions: In this retrospective, carefully matched case-control study, we developed a comprehensive profile of the patient population with newly diagnosed breast cancer and diabetes. Diabetes did not appear to impact mortality or recurrence-free survival based on descriptive estimates in this small breast cancer cohort.

The predictive value of serum soluble E-cadherin levels in breast cancer patients undergoing preoperative systemic chemotherapy

ObjectivesTo date, no reliable markers are available to predict response to or to assess prognosis after preoperative systemic chemotherapy (PST) in patients with locally advanced breast cancer. Previous studies demonstrated that elevated levels of soluble E-cadherin (sE-cadherin), a product of proteolytic cleavage of cell surface E-cadherin, are associated with higher risk for metastatic disease and poor prognosis in various tumor types. We, therefore, hypothesized that serum sE-cadherin levels measured before PST may correlate with pathological response. Design and methodsIn a retrospective analysis, sE-cadherin levels were measured in sera of 108 female patients with histologically proven breast cancer before initiation of PST by using a commercially available quantitative sandwich enzyme immunoassay technique. Patients received a median number of 4 (range 3–6) cycles of anthracyline-based chemotherapy. The median patient age was 51.5 (range 21–71) years. Tumor size was measured clinically and translated into the tumor–node–metastasis (TNM)-system before the start of chemotherapy. Histopathological response in surgically removed specimens was evaluated using a modified Sinn regression score. In univariate analyses the correlations between levels of sE-cadherin and pathological response to PST were calculated. ResultsThe histopathological regression scores correlated significantly with tumor grading (p=0.045), clinical lymph node status before PST (p=0.031) and sE-cadherin levels (p=0.039). No correlation was seen between histopathological regression scores and hormone receptor and menopausal status as well as Her2-neu status. ConclusionsE-cadherin may be a marker predicting response to PST for patients with breast cancer. Our findings warrant further evaluation of sE-cadherin in a prospective trial.

Comparison of [99mTc] tilmanocept and [99mTc] sulfur colloid for identification of sentinel lymph nodes in clinically node-negative breast cancer patients.

11098 Background: Receptor-targeted (CD206) [99mTc] tilmanocept is a radiopharmaceutical specifically engineered for sentinel lymph node (SLN) identification that has recently completed phase III clinical trials. The agent has been compared to vital blue dye in prior studies, but has not yet been compared to radio-labeled sulfur colloid. We compared the performance of [99mTc]tilmanocept vs. filtered [99mTc]sulfur colloid (fTcSC) in two cohorts of clinically node-negative breast cancer patients (BCP) who underwent SLN mapping at a single institution. Outcomes were degree of SLN localization and % positive nodes among those removed. Methods: The [99mTc]tilmanocept cohort was composed of UCSD-specific patients pooled from two phase III clinical trials (Jun 2008-Jun 2009, Jul 2010-Apr 2011); the fTcSC cohort was composed of consecutive BCP undergoing SLN mapping at UCSD (Mar 2011-Feb 2012). Demographic, lymph node-specific, and cancer characteristics were compared between groups. A zero-inflated binomial model compared %-positive nodes among nodes removed. Results: There were 85 vs.120 patients in the [99mTc]tilmanocept and fTcSC cohorts, respectively. The groups did not differ in demographic or clinicopathologic factors predictive of axillary metastatic disease (age, race, cancer stage, histologic subtype and grade, hormone and HER2-Neu status or presence of lymphovascular invasion). The [99mTc]tilmanocept group had significantly fewer SLNs removed (mean 1.9 vs. 3.9, p&lt;0.001), achieved higher gamma counts/node (28 vs. 1.6 kcps, p&lt;0.001), and detected a significantly higher percent of tumor-positive SLNs (73% vs. 49%, p=0.016) while identifying the same rate of node-positive patients (24% vs. 18%, p=0.4). Conclusions: [99mTc]Tilmanocept identified the same rate of node positive patients and removed fewer SLNs compared to fTcSC among BCP with similar risk of axillary metastatic disease. These data suggest that [99mTc]tilmanocept more precisely targets true SLNs and may minimize morbidity while maintaining or improving the accuracy of axillary staging in clinically node-negative breast cancer patients.

Abstract 4023: Comparison of transcriptional signatures in US African American and Kenyan TNBC samples identifies differential expression in key oncogenic pathways.

Abstract Strong epidemiological data supports breast cancer (BC) as the second leading cause of cancer death among US African American (AA) women, with a 20% greater mortality rate than that in Caucasians (Cauc). Collection of similar BC incidence and mortality data for Eastern Africa is limited, however, it is known that BC presents as advanced-stage disease, comprised mainly of poorly differentiated cancers that are less likely to be hormone responsive. Our combined investigative team continues to analyze a cohort of indigenous Kenyan BC patients, in order to begin to understand biological similarities and differences between BC in native African and AA patients. Previous related gene expression studies conducted in a Triple Negative Breast Cancer (TNBC) stage-matched multi-ethnic US cohort suggested differential expression patterns across ethnicities. We are extending this focus to similar studies involving native African samples. Archived BC pathology samples (FFPE) were either obtained from University of Miami or from a native African tumor bank (Kenya). Forty-seven BC samples were contributed from Kenya, and re-analyzed (in Miami) for ER/PR/ Her2Neu status, resulting in confirmation of 29 Kenyan TNBC cases. 10 um sections were cut from each tumor FFPE block, and following RNA isolation and cDNA preparation, hybridized to the Almac breast-enriched gene expression array (Breast Cancer DSA Research Tool). After quality control assessment of array data, a total of 60,856 gene/probes were analyzed by RMA; normalized, log transformed to the median, and compared on GeneSpring® analytical software. Data sets were separated by further analysis based on node status [(N0-Kenyan-7, AA-10); (Mixed Node-Kenyan-16, AA-7)]. Unpaired student's T-test was performed on all subsets and the resulting p-values were corrected for Multiple Testing using Benjamin-Hochberg. Differentially expressed genes/probes were extracted for each subset using p-value &amp;lt; 0.01 and fold change of &amp;gt; 1.5. These probe/gene lists were further analyzed using GeneGo pathway analysis and enriched pathways were identified. Comparisons of transcriptional differences between Kenyan and AA TNBC, regardless of node status, suggest expression alterations in several key pathways, including EMT Transition, Cytoskeleton Remodeling, Immune Response and Epigenetic Control. These preliminary results are being validated by QPCR and other methodologies. In conclusion, we have demonstrated that high quality RNA can be extracted from archived FFPE tumor samples, including samples from East Africa. This observation raises the possibility of future genomic analyses using archived samples. We are intrigued by our study observations, which suggest that inherent gene expression differences exist between Kenyan and AA TNBC samples in previously-recognized pathways important in onocogenesis. Citation Format: Lisa L. Baumbach-Reardon, Julie Getz, Mary Ellen Ahearn, Carmen Gomez, Peter Bird, John Carpten, Mark Pegram. Comparison of transcriptional signatures in US African American and Kenyan TNBC samples identifies differential expression in key oncogenic pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2013-4023

Abstract PD03-09: Statins and breast cancer risk: A follow-up analysis of the Women's Health Initiative Cohort

Abstract Introduction: Statins (HMG CoA reductase inhibitors) are a class of cholesterol lowering drugs that affect many intracellular pathways and have implications for chemopreventive activity against cancer. Epidemiological data on statins and breast cancer risk are conflicting. We analyzed updated data from the Women's Health Initiative (WHI) to assess the relationship between statins and breast cancer risk. Methods: This analysis included 154,587 post-menopausal women ages 50–79 years at baseline, in which 7,430 incident cases of invasive breast cancer were identified over an average of 10.8 (SD 3.3) years of follow-up. All cases of breast cancer were confirmed by review of medical records and pathology reports. Participants were asked to bring all current medications to their baseline visits and information on statin use was recorded. Statins were classified as lipophilic (lovastatin, simvastatin, fluvastatin) or hydrophilic (pravastatin and atorvastatin). Self and interviewer-administered questionnaires were used to collect information on other breast cancer risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use as well as, type of statin (lipophilic vs. hydrophilic), statin potency, and duration of use with breast cancer. To evaluate the effect of change in statin use over time, statin use was examined as a time-dependent exposure using updated information on statin use gathered during follow-up visits. Separate analyses were conducted by hormone receptor and HER2neu status, other tumor characteristics and use of postmenopausal hormone therapy. All statistical tests were two-sided. Results: Statins were used at baseline by 11,584 (7.5%) women in the cohort of whom 7,840 used lipophilic statins. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for statin users compared with non-users was 0.93 (95% C.I. 0.83–1.05), however for women using lipophilic statins the HR was 0.86 (95% CI, 0.74–1.00). Statin use for &amp;lt; 1 year was associated with a reduction in risk (HR 0.79, 95% C.I. 0.63–0.99) however there was no trend for overall duration of use. In the stratified analysis by tumor size, there was a marginal reduction in risk for tumors between 10 and 30 mm but not in smaller or larger tumors. There were no effect modifications by tumor stage, hormone receptor or HER2neu status, hormone therapy use, family history of breast cancer or body mass index. In the multivariable adjusted time-dependent model, the HR for simvastatin was 0.80 (95% CI, 0.64–0.99). Conclusion: Simvastatin was associated with a reduced risk of invasive breast cancer, and as a class, lipophilic statins were associated with a marginal benefit. This provides further evidence for possible class differences in statins with regard to chemo-preventive effects in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-09.

Abstract P1-01-13: Patterns of definitive axillary management in the era prior to reporting ACOSOG Z0011: comparison between NCCN Centers and hospitals in Michigan

Abstract Background: The results of the ACOSOG- Z0011 trial have had potential practice changing implications for the management of patients with positive sentinel lymph node (SLN) undergoing lumpectomy and radiation for breast cancer. However, some evidence suggests a shift in axillary management even prior to the initial report of data supporting sentinel lymph node biopsy (SLNB) alone in mid-2010. We analyzed data in the National Comprehensive Cancer Network (NCCN) outcomes database from NCCN centers and the Michigan Breast Oncology Quality Initiative (MiBOQI) hospitals to examine institutional practice patterns with respect to use of completion axillary dissection (CALND) for SLN positive breast cancer in the years leading up to publication of these trial results. We hypothesized that CALND would be omitted more frequently in women treated at NCCN centers compared to those treated at MiBOQI programs. Methods: We identified 2,172 women with clinical T1/T2 N0 breast cancer who underwent breast surgery and SLNB and had a positive SLN from 2007 through 2010 at one of 12 participating NCCN centers or 12 MiBOQI sites. Patient and tumor characteristics, definitive breast procedure, year of diagnosis, and institutional affiliation were analyzed as predictors of use of SLNB alone in univariate Chi-Square and multivariable logistic regression models. Results: CALND was omitted in 314 (14.5%) of the 2,172 patients. Over time, there was a dramatic increase in the use of SLNB alone (12% in 2007 to 23% in 2010). In the univariate analyses, increased patient age, later year of diagnosis, lower T stage, and lower pathologic N stage were significant predictors of use of SLNB alone (all p &amp;lt; .0001). There was no association between definitive breast surgery type, hormone receptor status, Her-2 Neu status, or institutional affiliation and use of SLNB alone. In the multivariable model, older age at diagnosis, later year of diagnosis, and lower pathologic N stage remained significant independent predictors of SLNB alone. There were no significant differences in rates of omission of CALND between NCCN and MIBOQI sites. Conclusions: Omission of CALND occurred frequently in women with SLN positive breast cancer cared for in both NCCN and MiBOQI institutions in advance of reporting results of ACOSOG-Z0011. This shift was seen in management of patients undergoing lumpectomy as well as mastectomy. Further study is warranted to determine the extent of durable practice changes as well as any impact on survival and local-regional control. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-13.

Abstract P3-07-13: Importance of socioeconomic status in relation to breast cancer risk and prognostic factors in Argentina.

Abstract In Argentina, there are no studies evaluating neither breast cancer screening nor risk and prognostic factors in relation to socioeconomic status among women in metropolitan areas. Taking into account that Argentina presents social and economical disparities and that there is a mixture of features of both developed and developing societies, it is interesting to compare prognostic and risk factors in disadvantaged and advantaged women as it would clarify the influence of socioeconomic factors in breast cancer biology. The purpose of this study was to compare risk and prognostic factors of invasive breast cancer in two different Argentine populations. Study participants and data collection. A total of 625 women who had a histologically confirmed diagnosis of invasive primary breast cancer were included; 270 patients belonged to a private clinic of the city of La Plata (province of Buenos Aires) belonging to an Advantaged Population (AP) and 355 patients belonged to a public hospital of the city of Neuquén (province of Neuquén, Patagonia) belonging to a Disadvantaged Population (DP). Women of these geographical regions and first diagnosed with invasive primary breast carcinoma from 2002 until 2007 were eligible as cases. There were no racial or ethnic differences between the two groups of women; all of them were born in Argentina. Risk factors included age at diagnosis, menarche and menopause status, breastfeeding and parity, while prognostic factors were: disease stage, number of metastatic lymph nodes, tumor size, histological and nuclear grade, vascular invasion, ER, PR, and Her2neu statuses. Methods: Statistical analysis included frequency analysis and ANOVA (p &amp;lt; 0.05). Results: A remarkable difference between the two populations was found: the age at diagnosis was significantly lower in DP than in AP: 63% of DP versus 44% of AP was &amp;lt;55 years old. AP stage III was observed at X = 49 years old versus DP at X = 54 years old; cutaneous and/or thoracic wall invasion was found at diagnosis in 15.4% of DP, while it was absent in all APs. Both groups showed advanced stages in younger patients. In general, tumor size versus age showed a negative relationship (p &amp;lt; 0.04); this observation was only significant for AP (p &amp;lt; 0.02). ER, PR expression, and Her2neu status presented differences between the two populations. Percentage of AP patients with positive ER were 78.8%, positive PR: 79.5%; while Her2-neu positive status was found in 5.3%. In the case of DP patients, positive percentages were: ER: 66.3%, PR: 51.2%; and finally Her2-neu: 38.8%. Histological and nuclear grade DP compared to AP were significantly higher, while vascular and lymphatic invasion showed the inverse DP: 30% versus AP: 18%, p &amp;lt; 0.01. Taking into account the number of children, significant differences between groups were found: DP, 2.8+/−0.11 while AP, 1.9+/−0.13 (media +/− standard error). In general, it was observed that patients who had breastfed presented lower number of metastatic lymph nodes than those who had not. Conclusions: Patients belonging to these two different geographical regions constitute two different populations. Breastfeeding and number of children, considered in relation to socio-economic features, are important risk factors of invasive breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-13.

An Assessment of the Collective Efforts of Clinical Trials to Provide Evidence-based Practice Guidelines in Cancer Care

Materials/Methods: The NCCN Breast Outcomes Database was used to identify women 70 and over with T1, cN0, hormone receptor positive breast cancers from 2000-2009 receiving care at 13 participating NCCN cancer centers. Factors considered to be potentially associated with use of RT a priori were evaluated in univariate and multivariable models, including year of diagnosis, tumor size, grade, histology, multicentric/ multifocal disease, Her2neu status, triggering event, patient age, race/ ethnicity, body mass index (BMI), Charlson/Katz co-morbidity score, type of biopsy, use of axillary surgery, and treating institution. Date of diagnosis was classified as 2000-2004 versus 2005-2009, reflecting the date of guideline change. Results: One thousand, five hundred forty-three women met study criteria; overall 1292 women (84%) had BCS. Among these, 1,005 (78%) received adjuvant breast RT; standard whole breast RT technique was used in 98.5%. ET without or with chemotherapy was used in 83% of all women. In a multivariable analysis, diagnosis year prior to 2005 (p Z 0.0003), younger age (p < 0.0001), lower co-morbidity score (p Z 0.0006), and larger tumor sizes (p Z 0.0146) were all significant predictors of use of RT. For example, 94% of women ages 70-74 received RT in 2000, compared with 88% in 2009; for the same time intervals in the 80 or above age group, usage was 80% versus 38%. Women who had axillary surgery as well were significantly more likely to receive RT (p < 0.0001). In addition, treating institution was a statistically significant factor associated with use of RT (p < 0.0001). Conclusions: Following the change in the NCCN guideline recommendations for elderly women with Stage I, estrogen receptor positive BC, the use of RT with BCS decreased over time in NCCN centers; however most women still received RT. Patient characteristics such as age and comorbidity impacted the use of RT. In addition, a key factor significantly affecting treatment use of RT was the institution where a woman received her treatment. Author Disclosure: B. McCormick: K. Stock; Varian. R. Ottesen: None. M. Hughes: None. S. Javid: None. S. Khan: None. J. Mortimer: None. J. Niland: None. J. Weeks: None. S. Edge: None.

Abstract PR03: Investigation of transcriptome differences in breast cancer tissues from African American and East African patients with triple-negative breast cancer.

Abstract Introduction: Strong epidemiological data supports breast cancer (BC) as the second leading cause of cancer death among African-American (AA) women, with a 20% greater mortality rate than that in Caucasians (Cauc). Collection of similar BC incidence and mortality data for Eastern Africa is limited, with the Nairobi Cancer Registry serving as the primary data collection source. However, it is known that in this African region, BC presents as an advanced-stage disease, comprised mainly of poorly differentiated cancers that are less likely to be hormone responsive. Objectives: Our combined investigative team is studying a cohort of indigenous Kenyan breast cancer patients, in order to begin to understand biological similarities and differences between BC in native African and US African patients. Recent gene expression studies conducted by our group suggest differential expression patterns in Triple Negative Breast Cancer (TNBC) across a stage-matched multi-ethnic US cohort. We are extending this focus to similar studies involving native African samples. Methods: Archived BC pathology samples (FFPE) were either obtained from University of Miami (C. Gomez; M. Jorda) or from a native African tumor bank (P. A. Bird, Kijabe). Forty-seven BC samples were contributed from Kenya, and re-analyzed (in Miami) for ER/PR/ Her2Neu status, resulting in confirmation of 29 Kenyan TNBC cases. As expected, a high percentage of the Kenyan tumors were advanced stage and high grade. These Kenyan TNBC cases, as well as US AA TNBC cases from Miami, were analyzed by gene expression studies. 10 um sections were cut from each tumor FFPE block, and following RNA isolation and cDNA preparation, hybridized to the Almac breast-enriched gene expression array (Breast Cancer DSA Research Tool). After quality control assessment of array data, unpaired student's T-test was performed between Kenyan and AA samples, and resulting p-values were corrected for Multiple Testing using Benjamin-Hochberg. Results: Three sets of differentially expressed genes/probes were extracted using different thresholds: Stringent (P-value ≤ 0.01 &amp; Fold Change ≥ 2.0; 1013 probes); Less Stringent (P-value ≤ 0.02 &amp; Fold Change ≥ 2.0; 1669 probes); and Most Significant (P-value ≤ 0.001 &amp; Fold Change ≥ 1.5,136 probes), the latter of which generated hierarchical clustering of the most significant differentially expressed genes. These probe/gene lists were further analyzed using GeneGo pathway analysis. Initial analyses point to possible gene expression differences within several key pathways, including signal transduction in the AKT signaling pathway. Further data set analyses are being performed, including consideration of additional tumor characteristics. The latest data interpretations will be presented. Conclusions: This study represents the first direct comparison of gene expression in TNBC specimens across US AA and Kenyan East Africans. These results will be compared with data from our previous ethnic cohort studies. We will strive to correlate all experimental data with available clinical data, and determine possible correlations between genomic signatures, clinical tumor characteristics, and demographic information among and across ethnic groups. Ultimately, this work will contribute to our further biologic understanding of BC across different ethnicities, and thus, development of new preventive, predictive and therapeutic measures. This abstract is also presented as Poster B67. Citation Format: Lisa Baumbach, Mark Pegram, Carmen Gomez, Biju Issac, Jennifer Clarke, Merce Jorda, Mary Ellen Ahearn, John Carpten, Peter Bird. Investigation of transcriptome differences in breast cancer tissues from African American and East African patients with triple-negative breast cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr PR03.