HER2 Overexpression Status Research Articles

A study of human epidermal growth factor receptor 2 overexpression by immunohistochemistry in patients with gastric adenocarcinoma.

Gastric cancer is one of the leading causes of cancer-related deaths across the world and in the Middle East. Human epidermal growth factor receptor 2 (HER2) overexpression has been observed in gastric cancers. Trastuzumab, a recombinant monoclonal antibody targeting HER2 protein, is being used for treatment of metastatic gastric cancer. To study the frequency and association of HER2 overexpression with age, gender, histopathological subtype and grade of differentiation in patients with gastric adenocarcinoma from Basra, Iraq. This cross-sectional single-center study collected demographic (age, gender), histopathological (histological subtype, grade of differentiation) and immunohistochemical (HER2 overexpression status) data from 100 consenting adult patients (male: 56) with histopathologically confirmed gastric adenocarcinoma from samples obtained through endoscopy or surgery. HER2 overexpression (ToGA score 3+) was observed in 6/100 (6%) of patients, with another 6 showing 'equivocal' HER2 expression (2+). Out of 20 patients with moderately differentiated gastric cancer, 4 (20%) showed HER2 overexpression (p=0.008). Other factors considered (age, gender, histological subtype) did not show statistically significant correlation with HER2 overexpression. More females showed HER2 overexpression than males (4 vs. 2), and more patients with intestinal type gastric cancer showed HER2 overexpression than diffuse gastric cancer (5 vs. 1), but the difference was not statistically significant in both variables. HER2 overexpression was 6% in this population; statistically significant correlation was found with histological grade. Statistically non-significant correlations were observed between HER2 overexpression and gender, age, and histological subtype.

Abstract P3-05-51: Patients with low expression of BCL 2 experience more late recurrence than patients who do not, which neutralized the protective effect of low BCL2 expression in patients with estrogen receptor positive breast cancer

Abstract Background) BCL2 is a key factor for the regulation of cellular apoptosis and its overexpression inhibits apoptotic cell death and activates cellular proliferation, resulting tumor progression. Although BCL2 are expected to be associated with an adverse prognosis in breast cancer, previous studies have reported inconsistent results and some reported even favorable features. The aim of this study is to investigate what characteristics of BCL2 yield this discrepant result in patients with breast cancer. Materials and methods) Female patients with breast cancer who completed primary treatment against breast cancer between 2003 and 2018 at Wonju Severance Hospital, Korea, were included. Clinocopathological characteristics including BCL2 expression were collected. Patients were categorized into two groups, BCL2 expression in more or less than 10% of tumor cells. Kaplan-Meier curves were generated to compare recurrence-free interval (RFI) and overall survival (OS). Result) The final cohort included 616 patients with a mean age of 54.79±11.2 (25-86) years. Patients with estrogen receptor positive breast cancer were more frequent in patients with tumor in which BCL2 was expressed in less than 10% of tumor cells (70.7% vs. 57.7%). Patients with tumor in which BCL2 was expressed in less than 10% of tumor cells showed better survival than their counterpart. Subgroup analysis according to the estrogen receptor and HER2 overexpression status was done. In patients with tumor in which HER2 was not overexpressed, patients with tumors in which BCL2 expressed less than 10% of tumor cells showed better survival(p=0.007). Survival difference maintained in patients with triple negative disease(p=0.010). However, in patients with estrogen receptor positive breast cancer, survival of two groups of patients with high and low BCL2 expression become not significant over time as late recurrence occurred (p=0.227). In contrast, patients with HER2 positive disease breast cancer showed worse prognosis than their counterpart when their tumor showed BCL2 expression in less than 10% of tumor cells. Conclusion) BCL2 overexpression showed different contribution to the patients’ survival according to the subtypes. Patients with HER2 overexpression showed better survival when BCL2 was overexpressed and patients with HER2 negative disease does not. First, similar survival was resulted from late recurrence in patients with estrogen receptor positive disease. Second, apoptotic capacity of tumor cells may not be major survival factor if tumor cells are exactly targeted. Citation Format: Hyang Suk Choi, Hany Hany Noh, In-Jeong Cho In-Jeong Cho, Seung Taek Lim, Jong-In Lee, Airi Han. Patients with low expression of BCL 2 experience more late recurrence than patients who do not, which neutralized the protective effect of low BCL2 expression in patients with estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-51.

Prognostic Significance of Fibrotic Focus and Tumor Infiltrating Lymphocytes in Breast Cancer According to Molecular Subtypes

Purpose: This study aimed to analyze the association between fibrotic focus (FF) and tumor-infiltrating lymphocytes (TILs) and to determine the prognostic significance of FF and TILs in the breast according to its molecular subtypes.Methods: The study included patients who underwent surgical treatment for breast cancer, for whom tissue samples were available. FF within the tumor and TILs in breast cancer tissues were evaluated. Clinicopathological characteristics were reviewed from medical records.Results: FF and TILs were present in 31.3% and 81.7% of the patients, respectively. FF and TILs showed a positive correlation. FF were significantly associated with tumor size, lymphovascular invasion, regional lymph node metastasis, and tumor stage. TILs were significantly associated with menopausal status, histologic grade, tubule formation, nuclear grade, mitosis, human epidermal growth factor receptor 2 (HER2) overexpression, molecular subtype of breast cancer, and the number of cluster of differentiation 8+ T cells. In TIL-positive cases, FF were significantly associated with tumor size, regional lymph node metastasis, extranodal extension, lymphovascular invasion, tumor stage, recurrence-free survival, and overall survival (OS). Based on HER2 overexpression status, TILs were significantly associated with tumor size, tumor necrosis, histologic grade, estrogen receptor status, and epidermal growth factor receptor expression in HER2-negative breast cancer. Further, in HER2-negative breast cancer, OS and recurrence-free survival were significantly associated with FF. The OS of FF-positive patients was significantly shorter than that of FF-negative patients.Conclusion: Our study showed an association between FF and TIL levels in breast cancer, indicating that FF are associated with poor prognostic factors for breast cancer and poor OS, and that TILs are associated with HER2 overexpression. However, further studies are needed to elucidate the interactions between FF and TILs in breast cancer.

Contrast-Enhanced CT Parameters of Gastric Adenocarcinoma: Can Radiomic Features Be Surrogate Biomarkers for HER2 Over-Expression Status?

ObjectiveThe aim of this study was to determine the role of contrast-enhanced computed tomography (CE-CT) parameters in predicting the expression status of HER2 in gastric adenocarcinoma (GAC) patients before radical gastrectomy.Materials and MethodsA total of 460 GAC patients who underwent non-contrast CT (NC-CT) and CE-CT examinations before radical resection were enrolled in this retrospective study. The radiologists reviewed their CT scans and recorded parameters, including CT attenuate value (CAV) and corrected CAV (cCAV). The pathologist identified the postoperative HER2 expression status, and HER2 expression status was evaluated by immunohistochemical staining (IHC). The association between CE-CT parameters and HER2 expression status was analyzed.ResultsAmong the 460 patients, 84 patients had HER2 over-expression status, at a prevalence of 18.3%. The CAVs were significantly different between the 2 different HER2 expression groups in the non-contrast and arterial phases (non-contrast phase: p = 0.005; arterial phase: p < 0.001). Besides, there was a significant difference in the cCAVs between the 2 groups in the arterial phase (arterial phase: p = 0.003). Univariate and multivariate logistic regression analyses identified that the maximum diameter of tumor, differentiation degree, CAV in non-contrast, arterial, and portal phases, and cCAV in the arterial phase were predictive factors of HER2 expression status.ConclusionOur analyses showed that the CE-CT parameters were significantly different between different HER2 expression groups. CE-CT parameters could serve as simple, objective predictive factors of HER2 expression status of GAC patients.

Deep Learning to Estimate Human Epidermal Growth Factor Receptor 2 Status from Hematoxylin and Eosin-Stained Breast Tissue Images

Context: Several therapeutically important mutations in cancers are economically detected using immunohistochemistry (IHC), which highlights the overexpression of specific antigens associated with the mutation. However, IHC panels can be imprecise and relatively expensive in low-income settings. On the other hand, although hematoxylin and eosin (H&E) staining used to visualize the general tissue morphology is a routine and low cost, it does not highlight any specific antigen or mutation. Aims: Using the human epidermal growth factor receptor 2 (HER2) mutation in breast cancer as an example, we strengthen the case for cost-effective detection and screening of overexpression of HER2 protein in H&E-stained tissue. Settings and Design: We use computational methods that reliably detect subtle morphological changes associated with the over-expression of mutation-specific proteins directly from H&E images. Subjects and Methods: We trained a classification pipeline to determine HER2 overexpression status of H&E stained whole slide images. Our training dataset was derived from a single hospital containing 26 (11 HER2+ and 15 HER2–) cases. We tested the classification pipeline on 26 (8 HER2+ and 18 HER2–) held-out cases from the same hospital and 45 independent cases (23 HER2+ and 22 HER2–) from the TCGA-BRCA cohort. The pipeline was composed of a stain separation module and three deep neural network modules in tandem for robustness and interpretability. Statistical Analysis Used: We evaluate our trained model through area under the curve (AUC)-receiver operating characteristic. Results: Our pipeline achieved an AUC of 0.82 (confidence interval [CI]: 0.65–0.98) on held-out cases and an AUC of 0.76 (CI: 0.61–0.89) on the independent dataset from TCGA. We also demonstrate the region-level correspondence of HER2 overexpression between a patient’s IHC and H&E serial sections. Conclusions: Our work strengthens the case for automatically quantifying the overexpression of mutation-specific proteins in H&E-stained digital pathology, and it highlights the importance of multi-stage machine learning pipelines for added robustness and interpretability.

Clinicopathological features of young age breast cancer patients in Bali

Abstract Breast cancer is, in general, a heterogeneous disease with diverse biological characteristics, histopathological types, subtypes and clinical behavior. Breast cancer in young age, although rare, is usually a unique and more aggressive cancer associated with poorer prognosis. The combination of young age and advanced stages of breast cancer would make this particular breast cancer more difficult to manage. Therefore, individually tailored therapies have been the subject of many studies for these patients. The purpose of this study was to determine clinicopathological features of young age breast cancer patients in Bali from 2014-2016. This was a descriptive study of young age (≤40 years) breast cancer patients in Bali from January 2014 until June 2016. The samples were taken from the Perhimpunan Ahli Bedah Onkologi Indonesia Cancer registry in Sanglah General Hospital Bali. There were 90 samples gathered from the cancer registry and 56 samples (62,2%) had complete clinicopathological records. Clinicopathological features included in this study were age group, histopathological type, primary tumor size, regional lymph node involvement, presence of distant metastasis, stage regrouping, tumor grade, hormonal receptor status, Her2 overexpression status, and breast cancer subtype. There were 56 young age breast cancer patients, with a mean age of 33,86±4,193 years old, the youngest patient was 22 years old, and the majority of the samples were in the 31-35 years age group (26 samples, 46,4%). Only 2 samples (3,6%) had special type carcinoma, both of them were invasive lobular carcinoma, the rest of the samples were invasive carcinoma of no special type. The 2 samples with invasive lobular carcinoma were in 31-35 years age group, had stage II (T2N0M0) and III (T4N1M0) breast cancer, both with grade II tumor and Luminal A subtype. The majority of primary tumor size was T4 (30 samples, 53,6%), nodal status was N1 (29 samples, 51,8%), and only 10 samples (17,9%) had distant metastasis. The majority of the stage regrouping was in stage III (35 samples, 62,5%) and had grade III tumor (33 samples, 58,9%). There were 10 samples (17,9%) with Luminal A subtype, 19 samples (33,9%) with Luminal B subtype, 16 samples (28,6%) with Her2 type subtype, and 11 samples (19,6%) with triple negative breast cancer subtype. We concluded that the majority of young age breast cancer patients in Bali were invasive carcinoma of no special type in advanced stage, with high grade tumor, and within Luminal B subtype.

Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease.

Correlation between conductivity and prognostic factors in invasive breast cancer using magnetic resonance electric properties tomography (MREPT).

To investigate the correlation between conductivity and prognostic factors of invasive breast cancer using magnetic resonance electric properties tomography (MREPT). This retrospective study was approved by the Institutional Review Board, and verbal informed consent was obtained prior to breast MRI. This study included 65 women with surgically confirmed invasive breast cancers measuring 1cm or larger on T2-weighted fast spin echo (FSE). Phase-based MREPT and the coil combination technique were used to reconstruct conductivity. Simple and multiple linear regression analysis were used to find an independent factor associated with conductivity. In total tumours, tumours with HER-2 overexpression showed lower conductivity than those without, and HER-2 overexpression was independently associated with conductivity. In 37 tumours 2cm or larger, tumours with high mitosis or PR positivity showed higher conductivity than those without, and high mitosis and PR positivity were independently associated with conductivity. In 28 tumours 1-2cm in size, there were no differences in conductivity according to the prognostic factors. Conductivity values measured using MREPT are associated with the HER-2 overexpression status, and may provide information about mitosis and the PR status of invasive breast cancers 2cm or larger. • In all tumours, HER-2 overexpression was independently associated with conductivity. • In tumours ≥ 2cm, high mitosis and PR positivity were associated with conductivity. • Conductivity is associated with the HER-2 overexpression status of invasive breast cancers.

Consistent absence of HER2 expression, regardless of HER2 amplification status, in neuroendocrine carcinomas of the stomach

To determine HER2 amplification status and HER2 overexpression status in neuroendocrine carcinomas (NECs) of the stomach. We analysed 51 gastric NECs, including 15 pure NECs and 36 NECs associated with adenocarcinoma and/or dysplasia, for HER2 amplification by dual-colour chromogenic in-situ hybridization, and for HER2 expression by immunohistochemistry. HER2 amplification was observed in three NECs (6%) and in seven (19%) cases of adenocarcinoma/dysplasia associated with NEC. Immunohistochemically, all of the NECs, including those showing HER2 amplification, lacked HER2 expression. On the other hand, positive and equivocal HER2 overexpression was observed in three (8%) and six (17%) cases of adenocarcinoma/dysplasia associated with NEC, respectively. HER2 expression is consistently absent in gastric NECs, regardless of HER2 amplification status or association with HER2-positive adenocarcinoma/dysplasia components. Accordingly, HER2 is unlikely to be a valid therapeutic target in gastric NECs. Also, the absence of HER2 expression in NECs could be one of the causes of intratumoral heterogeneity of HER2 expression in gastric cancers.

Prediction consistency and clinical presentations of breast cancer molecular subtypes for Han Chinese population

BackgroundBreast cancer is a heterogeneous disease in terms of transcriptional aberrations; moreover, microarray gene expression profiles had defined 5 molecular subtypes based on certain intrinsic genes. This study aimed to evaluate the prediction consistency of breast cancer molecular subtypes from 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) as well as clinical presentations of each molecualr subtype in Han Chinese population.MethodsIn all, 169 breast cancer samples (44 from Taiwan and 125 from China) of Han Chinese population were gathered, and the gene expression features corresponding to 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) were retrieved for molecular subtype prediction.ResultsFor Sørlie 500 and Hu 306 intrinsic gene set, mean-centring of genes and distance-weighted discrimination (DWD) remarkably reduced the number of unclassified cases. Regarding pairwise agreement, the highest predictive consistency was found between Hu 306 and PAM50. In all, 150 and 126 samples were assigned into identical subtypes by both Hu 306 and PAM50 genes, under mean-centring and DWD. Luminal B tended to show a higher nuclear grade and have more HER2 over-expression status than luminal A did. No basal-like breast tumours were ER positive, and most HER2-enriched breast tumours showed HER2 over-expression, whereas, only two-thirds of ER negativity/HER2 over-expression tumros were predicted as HER2-enriched molecular subtype. For 44 Taiwanese breast cancers with survival data, a better prognosis of luminal A than luminal B subtype in ER-postive breast cancers and a better prognosis of basal-like than HER2-enriched subtype in ER-negative breast cancers was observed.ConclusionsWe suggest that the intrinsic signature Hu 306 or PAM50 be used for breast cancers in the Han Chinese population during molecular subtyping. For the prognostic value and decision making based on intrinsic subtypes, further prospective study with longer survival data is needed.

Risk factors of brain metastasis in a series of Egyptian breast cancer patients: A single-institution experience.

50 Background: Incidence of cerebral metastasis is increasing among breast cancer patients. Many factors have been reported associated with increased risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in breast cancer patients. Methods: We retrospectively analyzed histologically proven breast cancer patients who presented to Cairo Oncology Center (COC) in the period from 1999 till 2008, with follow up period of 6 months at least for those in adjuvant setting. The following factors were analyzed: age, tumor size and grade, nodal status, ER, PgR and HER2 over-expression status. Results: Our study included 2,338 patients. 96 patients (4.1%) experienced brain metastasis during the course of their disease. 3 patients had brain metastasis among other sites of distant spread at first presentation to COC. 30 out of 96 patients (31.25%) with localized breast cancer had brain metastasis at first relapse with 13 (13.5%) of them had isolated brain metastasis. In a median follow-up of 37.1 months (6-277) the median time to develop brain metastasis was 26.5 months (0-144). Based on univariate analysis, the following variables were associated with shorter time to develop brain metastasis: tumor size more than 5 cm (HR = 2.1, 95% CI 1.14-3.87), lymph node involvement at diagnosis (HR = 1.57, 95%CI 1.17-2.10), ER negativity (HR = 1.58, 95%CI 1.33-1.73), PgR negativity (HR = 1.55, 95%CI 1.29-1.72) and HER2-neu over-expression (HR = 2.68, 95%CI 1.51-4.75). On multivariate analysis, only patients with lymph node involvement at diagnosis and those with HER2-neu positive breast cancer were associated with shorter time to develop brain metastasis. Conclusions: We concluded that HER2 over-expression as well as lymph node involvement are the 2 main factors associated with shorter time to develop brain metastasis. These patients could be good candidates for trials investigating the role of any prophylactic intervention to decrease their risk to develop brain metastases.

Prolonged clinical benefit with the maintenance hormone therapy in patients with metastatic breast cancer.

e11051 Background: The maintenance hormone therapy (MHT) after cytotoxic chemotherapy is widely used by many clinicians in metastatic breast cancer patients with hormone-senstive tumors, although there are insufficient evidences in the literature to support this practice. We evaluated the efficacy of MHT and identify those who benefit most from maintenance hormone therapy. Methods: Metastatic breast cancer patients who had been treated with MHT from 2006 to 2010 in a single institute were retrospectively reviewed. Progression free survival (PFS) was a primary endpoint and predictive factors for PFS were analyzed. Results: A total of 91 patients were reviewed with a median age of 53 (range, 33-70). Aromatase inhibitors were most frequently used drugs (74.2%)for MHT. The median PFS was 12.0 months (range, 1-66). Prolonged PFS was found in patients with less previous palliative chemotherapy (one vs. two vs. more than two, 16.0 vs. 11.0 vs. 6.0 months, respectively; p=0.02), less metastatic sites (one or two vs. more than two, 15.0 vs. 6.0; p=0.04), and minimal residual disease (minimal residual disease vs. Intolerance of chemotherapy, 15.0 vs. 6.0; p=0.05). Multivariate analysis showed that HER2 overexpression status (HR 1. 89, 95% CI 1.06-3.33; p=0.03) and the minimal residual disease (HR 0.44, 95% CI 0.26-0.75; p=0.003) remained as significant variables. Conclusions: Evidence from this study showed that MHT with aromatase inhibitor siginificantly improved PFS and was well tolerated. MHT is a good therapeutic option for patients with metastatic breast cancer who have not progressed on first-line chemotherapy, especially whose hormone receptor positive, HER2-negative and minimal residual disease after cytotoxic chemotherapy.

Abstract 2392: Primary cultures established from estrogen receptor negative breast tumors: Method and characterization

Abstract Approximately 35% of breast cancers lack expression of estrogen receptor (ER) protein. ER-negative (ER-) breast cancer carries a worse prognosis than ER positive (ER+) breast cancer, but more importantly, it precludes use of less toxic endocrine therapies. Our objective was to establish primary cultures from dissociation of ER- breast tumors in order to provide an alternative cellular model that can be used as a valuable tool for both in vitro and in vivo studies of ER- breast cancer. A total of eight ER- tumors were successfully dissociated into primary cultures: four from ER-/PR-/H2N- and four from ER-/PR-/H2N+ primary breast tumors with a 100% success rate. The epithelial-enriched cell pellet was placed in culture and for experiments carried for a maximum of 30 passages. These cells will be hereafter referred to as “dissociated tumor” (DT) cultures. Cells were grown in 2D culture and their in vitro morphology, proliferation rates, mammosphere and soft agar colony formation ability, and CD44/CD24 surface marker expression (tumor initiating cell (TIC) content) are determined. In addition we have performed gene expression profiling and established their tumorigenic potential in NOD/SCID female mice. Each culture exhibited its own relatively unique morphology; two of the eight cultures grew mainly as suspensions while the remaining six DT cultures grew with a higher percentage of attached, mesenchymal phenotype cells. Proliferation rates ranged from 38 to 60 hours, and while all of the DT cultures had the ability to form mammospheres, five of the eight DTs (DT13, DT16, DT22, DT25 and DT28) formed colonies in soft agar. Analysis of CD44 and CD24 surface markers expression showed that while all DT cultures were CD44 positive, expression of CD24 varied among DTs. Of the eight DT cultures, we found five of them to have a high (&amp;gt;85%) CD44+/CD24-/lo cell content, one the CD44+/CD24high phenotype and two of eight have populations with increasing levels of CD24 expression ranging from -/lo to medium. This CD44+/CD24-/lo phenotype is stable when examined over several passages. Microarray analysis comparing the DT cultures to cancer cell lines showed that they clustered with each other and with several breast cancer cell lines of known ER- status and EGFR or Her2 overexpression status. In agreement with the soft agar assay, DT16, DT22, DT25 and DT28 had the ability to form tumors when injected into the mammary fat pad of female NOD/SCID mice. In summary, our study describes primary cultures of dissociated ER negative breast cancer cells that provide an alternative, primary cell based model that allows both in vitro as well as in vivo experimental approaches. The use of these types of cellular models may lead to a better understanding of ER- breast cancer biology as well as being a valuable tool for screening potential therapeutic options for ER- breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2392. doi:10.1158/1538-7445.AM2011-2392

Abstract B57: Breast cancer subtypes and survival in a hospital-based sample in Puerto Rico

Abstract Introduction: Breast cancer is the most common female malignancy in Puerto Rico and the United States. Breast cancer is a multifaceted disease comprised of distinct biological subtypes with diverse etiology, therapeutic indications and clinical outcomes. Information on the impact of hormone receptor status sub-types in disease prognosis is still limited for Hispanics. To overcome this limitation, we aimed to evaluate the association of breast cancer subtypes and other clinical factors with breast cancer survival in a hospital-based female population of breast cancer cases. Methods: We analyzed data from female patients with invasive breast cancer diagnosed between 2000-2005, at the I. Gonzalez Martinez Hospital and the Auxilio Mutuo Hospital (n=974). Information on Her2/neu (Her2) overexpression, Estrogen receptor (ER) and Progesterone receptor (PR) status and other clinical characteristics was retrieved from the hospitals’ cancer registries, the Puerto Rico Central Cancer Registry and from medical and pathology record review. Survival by covariates of interest was estimated using the Kaplan-Meier method, and survival curves were compared using the Wilcoxon test. Multivariate Cox proportional hazards models were employed to assess factors associated to breast cancer survival. Results: Overall, 22.5% of breast cancer cases were Her2+, 16.6% were triple negative (ER-/PR-/Her2-) and 60.9% were Her2-/ER+ or PR+. Factors associated to breast cancer death in bivariate analyses included younger age at diagnosis (&amp;lt; 50 years) (HR=1.70, 95% CI: 1.17-2.49), ER- (HR=1.91, 95% CI: 1.38-2.64), PR- (HR=1.10, 95% CI: 1.51 −2.07) and triple negative status (HR=2.45, 95% CI: 1.72-3.48); no differences were observed by Her2 status (p&amp;gt;0.05). Meanwhile, women with regional (HR=1.83, 95% CI: 1.29-2.61) and distant (HR=9.21, 95% CI:4.94-17.17) disease at time of diagnosis had higher risk of death as compared to those with localized disease. In multivariate analysis, Her2 positivity was still not associated with breast cancer mortality after adjusting for age and stage at diagnosis (HR=1.22, 95% CI:0.83-1.78). Meanwhile, women with triple-negative breast cancer had higher risk of breast cancer death after adjusting for age and stage at diagnosis (HR=2.65, 95% CI:1.80-3.88). Conclusions: This is the most comprehensive epidemiological study to date on the impact of hormone receptor expression sub-types in breast cancer survival in Puerto Rico. The clinical correlates of breast cancer survival in this population follow the same trends described previously in US populations. Even though no significant differences in survival were observed by Her2 overexpression status, consistent to results in other populations, the triple negative subtype was associated with decreased survival. The results of this study are useful for the development of breast cancer control strategies in Puerto Rico. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B57.

Hyperactivation of the PI3K-AKT Pathway Commonly Underlies Resistance to Trastuzumab in HER2 Amplified Breast Cancer.

Abstract BACKGROUND: Targeted therapy of HER2 amplified breast cancers with Trastuzumab has resulted in a survival benefit for patients with this disease. However, de novo and acquired resistance to Trastuzumab is commonly encountered. Many laboratory models of Trastuzumab resistant cancer have been developed and suggest that hyperactivation of the HER3-PI3K-AKT pathway downstream of HER2 may enable resistance. It has also been suggested that changes to HER2 itself, such as through loss of HER2 amplification or induction of p95-HER2 expression, may mediate resistance. A comprehensive in vivo assessment of multiple mechanisms of resistance has yet to be reported. Moreover, it is not known if these lesions are always present in pretreatment tumor samples or can be acquired over time. The aim of this study was to identify which mechanisms of resistance are present in human tumor samples after progression of disease on a Trastuzumab containing regimen. METHODS: Patients with HER2 amplified breast cancer with progression of disease by RECIST criteria on a Trastuzumab containing regimen were enrolled on an IRB approved protocol to obtain biopsies of progressive tumors. One tumor biopsy was flash frozen for nucleic acid studies and one biopsy preserved in formalin. For the pre-Trastuzumab comparison, archival formalin-fixed paraffin embedded (FFPE) blocks were obtained. Manual microdissection was performed on the frozen blocks to isolate tumor-containing sections for DNA isolation. PIK3CA hotspot mutations were identified using the Sequenom MassARRAY system. Following antibody optimization, IHC staining for HER3, PTEN and P-AKT (S473) was performed on freshly cut sections. Stained sections were scored by two, independent reviewing pathologists. HER3, PTEN and P-AKT expression were scored relative to staining in adjacent normal ductal epithelium. Staining and scoring for ER, PR, and HER2 was performed in CLIA-certified clinical laboratory. RESULTS: 19 patients have been enrolled and completed biopsy on protocol. Changes in HER2 overexpression status from the pretreatment biopsy to the post-progression biopsy were noted in 2/15 evaluated samples, with the remaining cases demonstrating stability. PTEN expression was diminished or absent in four cases. Activating mutations in hotspot regions of PIK3CA were identified in 3/10 cases. Enhanced expression of the HER3 receptor was identified in 4/11 cases with 2 of the cases showing an increase in expression compared to the pretreatment sample. CONCLUSIONS: HER2 overexpression status infrequently changed from the pre-Trastuzumab to post-Trastuzumab biopsy. Abnormalities in HER3, PI3K, and PTEN were not coexistent (e.g. PTEN loss and PI3K mutation were not seen in the same samples) in most cases. In some instances, the pretreatment tumor sample did not demonstrate lesions that were found on the post-progression sample, suggesting the possibility that molecular lesions may arise in response to therapy. Finally, in most cases, an abnormality in HER3, PI3K, or PTEN was identified implying a critical role for this pathway in mediating resistance to Trastuzumab. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 709.

Triple negative breast carcinoma is a prognostic factor in Taiwanese women

BackgroundCurrently, there is a debate as to whether triple negative breast carcinoma (TNBC) has a worse prognosis than non-TNBC. Our aim was to determine whether TNBC is a prognostic factor for survival.MethodsWe identified 1,048 Taiwanese breast carcinoma patients, of whom 167 (15.9%) had TNBC. Data used for analysis were derived from our cancer registry database for women with breast cancer who were diagnosed between 2002 January and 2006 December.ResultsIn the Kaplan-Meier analysis, tumor subgroup (TNBC vs. non-TNBC) was a prognosis factor related to 5-year overall survival. In the univariate analysis, tumor subgroup (TNBC vs. non-TNBC) was a significant factor related to 5-year overall survival, in addition to age, tumor size, lymph node, metastasis, grade, stage, estrogen receptor status, progesterone receptor status, and HER2 overexpression status. In the multivariate analysis, tumor subgroup was not a significant factor related to 5-year disease-free survival (DFS). In node-positive patients, tumor subgroup was a significant factor related to 5-year overall survival, in addition to age, tumor size, metastasis, and grade. In node-negative patients, tumor subgroup was not a significant factor related to 5-year disease-free survival and 5-year overall survival.ConclusionOur results indicated that TNBC patients in Taiwan have worse 5-year overall survival than non-TNBC patients. Notably, in node-positive patients, TNBC played a prognostic role in 5-year overall survival.