HER2 Receptor Status Research Articles

Abstract P5-07-07: Prognostic relevance of microRNA-155 and microRNA-21 in breast cancer patients

Abstract Introduction MicroRNAs (miRNAs) are short noncoding RNA sequences that degrade or prevent the translation of their target messenger RNA (mRNA). Altered regulation of miRNAs is implicated in different cellular processes. Some miRNAs, such as miRNA-155 (miR155) and miRNA-21 (miR21), are implicated in both immunity and cancer progression. Previous studies show that both miR155 and -21 are oncogenic, as their overexpression promotes invasion, proliferation and migration of breast cancer cells in vitro. Their overexpression within patient cohorts (n= 40-173 patients) reveals a worse prognosis for miR21 and varying associations with prognosis for miR155. By using the Cancer Genome Atlas (TCGA), which contains data from over a thousand patients, we want to clarify whether high expression of miR155 or -21 is associated with an improved or worse survival within breast tumor samples. Because both miR155 and -21 are described as oncogenic, we hypothesize that high expression of these miRNAs would portend a worse survival. Methods Within the breast cohort, 1052/1097 patients within TCGA contained both clinical and miRNA sequence data, acquired via the Genomic Data Common (GDC) data portal. The patients were separated into a high and low expression group for both miR155 and miR21, and associations with overall survival were obtained using the Cox proportional hazard model. Furthermore, a sub-analysis was conducted based on estrogen, progesterone and Her-2 receptor status (ER, PR, Her-2) as well as TNM staging (AJCC 7th edition). Results General patient characteristics within the breast cancer cohort of TCGA included: 70% Caucasian, 73% >50 years old, 75% with TNM stage I and II breast cancers, 74% ER positive, and 33% Her-2 positive. We unexpectedly found that miR155 and miR21 high expression was associated with an improved survival (p=0.05 and 0.038 respectively). In the sub-analysis, a positive association with survival was seen for miR155 high expression in ER negative, and Stage I-II breast cancers (p=0.025, 0.0013 respectively), but not in Stage III-IV. The sub-analysis for miR21 found an association with improved survival for miR21 high expression in ER negative, and stage I-II patients (p=0.033, 0.0015 respectively), but not in Stage III-IV. Although not statistically significant, a trend towards improved survival was found in ER and PR positive subgroups, for both miR155 and -21. For the Her-2 negative subgroup, there was a trend for improved survival in miR155 high expression, but not in miR21 high expression. Knowing that ER negative tumors can attract more immune cells, and that miR155 and -21 can be expressed in immune cells and tumor associated fibroblasts respectively, we speculate that their high expression was concentrated within cells from the tumor microenvironment rather than the cancer cells. Conclusion Using TCGA as a large validation cohort, we found that high expression of miR155 and miR21 was associated with an improved survival, which was contrary to what we predicted. Future experiments using computational biology to determine the cell type composition within the TCGA tumor samples will be performed in an effort to determine whether the tumor microenvironment influenced the survival patterns we observed in the high expression groups of miR155 and -21. Citation Format: Kim SY, Kawaguchi T, Yan L, Young J, Qi Q, Takabe K. Prognostic relevance of microRNA-155 and microRNA-21 in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-07.

Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa

BackgroundBreast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa.MethodsIn this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases.ResultsThe distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer.ConclusionThe present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.

Abstract PD3-06: Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC)

Abstract Introduction: Previous studies have shown that HER2+ breast cancer is biologically heterogenous and intrinsic subtypes can be identified (luminal A, luminal B, HER2-enriched [HER2-E] and basal-like). HER2-E predominates and is associated with higher response rates following anti-HER2-based chemotherapy or dual HER2 blockade (only with lapatinib and trastuzumab). We explored the ability of intrinsic subtypes to predict pCR in pts treated with anti-HER2 neoadjuvant therapy. Methods: KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC. Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 and hormone receptor (HR) status were centrally assessed. Gene expression (RNA) was assessed by a custom 800-gene codeset on the nCounter platform. Intrinsic subtypes were assessed with the research-based PAM50 classifier. Results: KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P, n=221; T-DM1+P, n=223). PAM50 results were available for 354 pts (79.7% of the intent-to-treat [ITT] population). Baseline characteristics and efficacy in the PAM50 population were similar to that of the ITT population. The HER2-E subtype represented 54.8% of the samples (Table 1). Differences were observed by HR status. Almost all luminal tumors (131/132) were identified within HR+ disease. Of HR+ tumors, 32% were identified as HER2-E. In the TCH+P arm, the pCR rate was 72.1% for HER2-E vs 32.8% in the other subtypes combined (Table 2.) In the T-DM1+P arm, the pCR rate was 62.2% for HER2-E vs 26.9% in the other subtypes combined. No major differences were observed in pCR rates within the HER2-E subtype according to HR status. Further multivariable analyses assessing differences between treatment arms and treatment benefit across subtypes is ongoing. Table 1. Intrinsic subtypesn (%)ITT (n=354)HR- (n=143)*HR+ (%) (n=200)*HER2-E194 (54.8)123 (86.0)64 (32.0)Luminal A60 (16.9)1 (0.7)57 (28.5)Luminal B74 (20.9)074 (37.0)Basal-like26 (7.3)19 (13.3)5 (2.5)*Central HR status unknown for n=11 Table 2. pCR by intrinsic subtype TCH+PT-DM1+P npCR, n (%)npCR, n (%)pCR difference (95% CI)HER2-E10475 (72.1)9056 (62.2)-9.89 (-23.11, 3.32)HER2-E and HR+ *3724 (64.9)2715 (55.6)-9.31 (-33.56, 14.94)HER2-E and HR- *6448 (75.0)5937(62.7)-12.29 (-28.56, 3.98)Other subtypes combined6722 (32.8)9325 (26.9)-5.9 (-20.36, 8.45)Luminal A254 (16.0)3510 (28.6)12.57 (-8.18, 33.32)Luminal B3211 (34.4)4212 (28.6)-5.80 (-27.19, 15.58)Basal-like107 (70.0)163 (18.8)-51.25 (-85.49, -17.01)*Central HR status unknown for n=7 Conclusions: In this analysis from the KRISTINE study, HER2-E was the most common intrinsic subtype and was associated with the highest pCR rate with both regimens. Results are consistent with previous findings. The luminal A and B subtypes were well associated with HR+ status. A sizeable subgroup of the HER2-E subtype was HR+ (32%), and pCR rates within the HER2-E subtype seemed independent of HR status. Citation Format: Prat A, Slamon D, Hurvitz SA, Press MF, Lewis Phillips G, Lopez Valverde V, Kiermaier A, Helms H-J, Martin M, de Haas SL. Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-06.

Do pre-diagnostic drinking habits influence breast cancer survival?

Alcohol consumption increases the risk of developing breast cancer and may also be associated with late diagnosis, recurrence, distant metastases and death. Many studies have examined the role of alcohol as a risk factor for the development of breast cancer, but very few studies have addressed the role of alcohol as a prognostic factor for survival among women diagnosed with breast cancer. The aim of this study was to investigate the survival of women with breast cancer in relation to pre-diagnostic alcohol intake and other factors known to influence prognosis. We analyzed data for 264 women in the EUROCARE and ORDET studies who were diagnosed with breast cancer from 1987 up to 31 December 2001 and for whom information was available on follow-up, stage at diagnosis, HER-2 and hormone receptor status, and pre-diagnostic dietary alcohol intake, categorized as zero (0 g/day, non-drinkers), moderate (up to 13 g/day, about 1 serving) and high (>13 g/day). Ten-year relative survival was estimated using the maximum-likelihood approach. The excess risk of death within 10 years of diagnosis was modeled by level of alcohol intake, adjusting separately for age, stage, body mass index and tumor subtype. Ten-year relative survival was lower in women who drank more than 13 g/day (65%; 95% CI, 47-78) than in non-drinkers (88%; 95% CI, 75-95). The excess risk of death within 10 years was significantly higher in women who drank more than 13 g/day than non-drinkers (relative excess risk, 4.13; 95% CI, 1.69-10.10) and was not altered by adjustment for other prognostic factors. The excess risk within 10 years was higher for women with a body mass index of 25 kg/m2 or higher (relative excess risk, 2.20; 95% CI, 1.01-4.70) and higher for those with more advanced disease. Women who drank more than 13 g alcohol per day had lower survival than non-drinkers. The excess risk of death within 10 years of diagnosis was unaffected by other known risk factors. High alcohol consumption may be an adverse prognostic factor for breast cancer.

Receptor Conversion in Distant Breast Cancer Metastases: A Systematic Review and Meta-analysis.

In metastatic breast cancer, hormone and/or human epidermal growth factor receptor 2 (HER2)-targeted therapy decision-making is still largely based on tissue characteristics of the primary tumor. However, a change of estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 status in distant metastases has frequently been reported. The actual incidence of this phenomenon has been debated. We performed a meta-analysis including 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. We noted the direction of change (positive to negative or vice versa) and performed subgroup analyses for different thresholds for positivity, the type of test used to assess HER2 receptor status, and metastasis location-specific differences (two-sided tests). Overall, the incidence of receptor conversion varied largely between studies. For ERα, PR, and HER2, we found that random effects pooled positive to negative conversion percentages of 22.5% (95% confidence interval [CI] = 16.4% to 30.0%), 49.4% (95% CI = 40.5% to 58.2%), and 21.3% (95% CI = 14.3% to 30.5%), respectively. Negative to positive conversion percentages were 21.5% (95% CI = 18.1% to 25.5%), 15.9% (95% CI = 11.3% to 22.0%), and 9.5% (95% CI = 7.4% to 12.1%). Furthermore, ERα discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8%, 95% CI = 15.0% to 28.0%, and 29.3%, 95% CI = 13.0% to 53.5%, vs 14.3%, 95% CI = 11.3% to 18.1, P = .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%, 95% CI = 35.1% to 50.6%, P < .001) and liver metastases (47.0%, 95% CI = 41.0% to 53.0%, P < .001) compared with central nervous system metastases (23.3%, 95% CI = 16.0% to 32.6%). Receptor conversion for ERα, PR, and HER2 occurs frequently in the course of disease progression in breast cancer. Large prospective studies assessing the impact of receptor conversion on treatment efficacy and survival are needed. Meanwhile, reassessing receptor status in metastases is strongly encouraged.

Lymphoid environment in molecular subtypes ofbreast cancer.

Recently, alarge body ofevidence has shown that themicroenvironment ofinvasive breast carcinoma affects its development and thepatient's outcome, and vice versa - cancer cells express factors that modulate tumour milieu in terms ofits composition and function. We performed animmunohistochemical (IHC) staining of108 formalin-fixed, paraffin-embedded (FFPE) tissue samples to investigate therelationships between T-cell, B-cell, and NK-cell infiltrate, invasive breast carcinomas molecular subtypes, and other prognostic indicators. Themain findings ofour study were as follows: thesignificantly higher infiltrate oftheanalysed immune cell subsets in triple-negative (TNBC), HER2-positive, non-luminal and luminal B/HER2+ breast carcinomas than in luminal Acancers; their higher densities in poorly differentiated lesions; correlations between lymphoid cells and theexpression ofhormonal receptors, HER2 receptor status, and marker ofcancer proliferation. Furthermore, we observed T-cell numbers to be associated with greater tumour diameter. In summary, theresults ofour study indicate associations between tumoural lymphoid infiltration and theunfavourable intrinsic subtypes as well as other detrimental prognostic factors in invasive breast carcinomas.

Should molecular subtype be recommended as one of the selection criteria for accelerated partial breast irradiation? Preliminary results from an Asian cohort.

PurposeThe purpose of this study was to report clinical outcomes in patients treated with accelerated partial breast irradiation (APBI), stratified as per molecular subtype and American Society for Therapeutic Radiology and Oncology/Groupe Européen de Curiethérapie and European Society for Radiotherapy & Oncology (ASTRO/GEC-ESTRO) patient selection criteria in order to determine whether molecular subtype should be recommended as one of the selection criteria for APBI.Material and methods157 early-stage breast cancers patients, treated with APBI using multi-catheter interstitial brachytherapy with ≥ 6 months follow-up were included. Molecular subtype was assigned based on estrogen/progesterone receptor (ER/PR), Her2neu and tumor grade. Patients were stratified into ASTRO and GEC-ESTRO risk groups, as per updated ASTRO consensus statement (CS) and GEC-ESTRO recommendation, respectively. The Kaplan-Meier method was used to calculate the time to event data of clinical outcomes.ResultsWith a median follow-up of 35 months, local control (LC) and locoregional control (LRC) were not significantly different among the different molecular subtypes (p = 0.19, p = 0.41, respectively). None of the APBI guidelines predicted risk of local or locoregional recurrence. Re-analyzing the data by replacing ER status with molecular subtype in the ASTRO-CS did not show any significant difference in LC/LRC across the various categories. Her2neu subtype was associated with significantly lower disease-free survival, cause specific survival, and overall survival than the luminal subtypes.ConclusionsNone of the mentioned APBI guidelines predicted local or locoregional recurrence risk in our study population. Additional follow-up will be needed to recommend inclusion of molecular subtype (or at least HER2 receptor status) in the patient selection criteria for APBI.

Correlation of Serum Levels of Urokinase Activation Plasminogen (uPA) and Its Inhibitor (PAI-1) with Hormonal and HER-2 Status in the Early Invasive Breast Cancer.

Introduction:Breast cancer is the most common malignant tumor in women. On the list of causes of death immediately after lung cancer. It is a heterogeneous disease, considering the differences in morphological, cytogenetic, molecular, clinical and therapeutic aspects, so that the prognosis in a patient with the same histological grade and pathological status may vary.Aim:In this paper we wanted to identify the correlation between the assay of the serum values of uPA-PAI-1 complexes and individual prognostic-predictive parameters, primarily with the status of estrogenic (Er), progesterogenic (PgR) and Her-2 receptors („human epidermal growth factor).Material and methods:The study was conducted at the Clinic for General and Abdominal Surgery, University Clinical Center of Sarajevo (CCUS), from September 2016 to April 2017. The study included 66 patients, ages 18 to 75, in whom by the needle biopsy preoperatively was pathohistologically verified primary invasive breast cancer.Results:Two thirds of the sample were classified as invasive ductal carcinoma, similar to the percentage (68.2%) of pT2 size, and almost half in the grade G3. Lymph node status was negative in 54.5% of respondents, and positive in 31.8% of respondents. Most patients had positive estrogenic (83.3%) and progesterone receptors (62.1%). Almost 80% was Her-2 negative. The blood vessel invasion was present in 56.1%, while the neural invasion was present in less than a third of the sample (30.3%). Median values of uPA-PAI-1 complexes were 1.4 (interquartile range 0.9); almost 70% of the sample was negative for the status analysis of uPA-PAI-1 complex (<1).Discussion:A statistically significant difference was determined in the mean values of uPA-PAI-1 complexes in subgroups according to menopausal status, tumor size, histological grade, histological type (invasive ductal carcinoma vs. invasive lobular cancer versus invasive ductal carcinoma vs. invasive lobular cancer), status axillary lymph nodes, Ki67 status (as binary variables), invasion of the blood vessels and neural invasion, as well as subgroups according to the status of expression of hormonal (estrogen and progesterone) receptors.Conclusion:There is a statistically significant difference in the mean values of the uPA-PAI-1 complex and Her-2 receptor expression. Generally, in perspective, this would be the role played by the uPA/PAI-1 complex in breast cancer, which is that the elevated complex values have a negative prognosis and effect on survival, similar to the negative Her-2 receptor status. Complex uPA/PAI-1 is not a specific serum protein in breast cancer patients and cannot be taken as an individual prognostic-predictive marker for mass pre- or post treatment screening and prediction. Unfortunately, none of the biomarkers are able to independently and fully identify patients of the unknown stage of the disease with better or worse prognosis or to identify cases of more aggressive tumor behavior of the same stage for timely inclusion of adjuvant therapy and reduction of the risk of metastatic disease. The decision on treatment and prognosis should be the result of a combination of all diagnostic, therapeutic, pathohistological and molecular-genetic variables.

High concordance of a closed-system, RT-qPCR breast cancer assay for HER2 mRNA, compared to clinically determined immunohistochemistry, fluorescence in situ hybridization, and quantitative immunofluorescence

Historically, mRNA measurements have been tested on several commercially available platforms, but none have gained broad acceptance for assessment of HER2. An mRNA measurement, as a continuous value, has the potential for use in adjudication of the equivocal category. Here we use a real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay in a closed, single-use cartridge, automated system. Multiple cores (1 mm in diameter) were retrospectively collected from 80 formalin-fixed paraffin-embedded (FFPE) tissue blocks with invasive breast cancer seen by Yale Pathology Labs between 1998 and 2011. Tissue cores were processed with a FFPE lysis kit to create lysates that were tested with the automated RT-qPCR assay. Results for IHC and FISH were extracted from the pathology reports and quantitative immunofluorescence (QIF) for each case was measured as previously described. Quality control testing showed that the GX platform RT-qPCR shows no case to case cross contamination on material from routine histology practices. Concordance between RT-qPCR and IHC/FISH was 91.25% (sensitivity=0.87; specificity=0.94; PPV=0.89; NPV=0.92) using a pre-defined delta Ct cut-off (dCt≥−1) for HER2. Concordance (OPA) between RT-qPCR and QIF was 94% (sensitivity=0.90; specificity=0.96; PPV=0.93; NPV=0.94) using dCt≥−1 and a previously defined cut-point for positivity by QIF. In conclusion, the closed system RT-qPCR assay shows >90% concordance with the ASCO/CAP HER2 IHC/FISH scoring. Additionally, the RT-qPCR assay is highly concordant (94%) with the continuous variable HER2 QIF assay, and may better reflect the true continuum of HER2 receptor status in invasive breast cancer. These initial results suggest that fast, closed system molecular assays may have future value for the adjudication of the ASCO/CAP HER2 equivocal category or possibly routine usage in time constrained or low resource settings.

Machine learning approaches to decipher hormone and HER2 receptor status phenotypes in breast cancer

Breast cancer prognosis and administration of therapies are aided by knowledge of hormonal and HER2 receptor status. Breast cancer lacking estrogen receptors, progesterone receptors and HER2 receptors are difficult to treat. Regarding large data repositories such as The Cancer Genome Atlas, available wet-lab methods for establishing the presence of these receptors do not always conclusively cover all available samples. To this end, we introduce median-supplement methods to identify hormonal and HER2 receptor status phenotypes of breast cancer patients using gene expression profiles. In these approaches, supplementary instances based on median patient gene expression are introduced to balance a training set from which we build simple models to identify the receptor expression status of patients. In addition, for the purpose of benchmarking, we examine major machine learning approaches that are also applicable to the problem of finding receptor status in breast cancer. We show that our methods are robust and have high sensitivity with extremely low false-positive rates compared with the well-established methods. A successful application of these methods will permit the simultaneous study of large collections of samples of breast cancer patients as well as save time and cost while standardizing interpretation of outcomes of such studies.

The Effect of Receptor Status on Mastectomy and Contralateral Prophylactic Mastectomy Rates in Early Stage Invasive Breast Carcinoma

BackgroundThere is an established relationship between hormone receptor (HR; estrogen and/or progesterone receptors) status, HER2 status, and locoregional recurrence. The purpose of this study was to analyze how HR and HER2 receptor status have influenced the surgical management trends among patients with early stage breast cancer. Patients and MethodsThe National Cancer Database was queried for patients with cT1 to cT3, cN0, and cM0 breast carcinoma from 2004 to 2012. Patients were grouped on the basis of receptor status and surgical management (mastectomy or breast-conserving surgery [BCS]). Multivariable analyses were performed to investigate factors associated with increased odds of receiving mastectomy over BCS. Among a subgroup of patients who underwent ipsilateral mastectomy, analyses were performed to determine any association between contralateral prophylactic mastectomy (CPM) and receptor status. ResultsWe found 280,241 patients who met inclusion criteria for analyzing mastectomy or BCS surgical decision. Patients with HER2-positive (HER2+) tumors (HR+/HER+ and HR−/HER2+) were the most likely to undergo mastectomy (odds ratio [OR], 1.212 and 1.499 respectively, compared with HR+/HER2− patients, each P < .001). HR status alone did not affect ipsilateral surgical management as patients with HR+/HER2− and HR−/HER2− tumors demonstrated similar mastectomy rates (P = .391). Among the 108,018 who underwent mastectomy, 20% underwent CPM. After adjustment, patients with HR+/HER2+, HR−/HER2+, and HR−/HER2− were all more likely to undergo CPM (OR 1.356, 1.608, and 1.358, respectively compared with HR+/HER2− patients, each P < .001). ConclusionThis analysis indicates that patients with early stage breast cancer are more likely to undergo a mastectomy and CPM if they have HER2+ tumors.

Survival by HER2 receptor status in stage IV breast cancer: SEER 2010-2012.

1032 Background: Therapeutic advances have altered the course of once highly lethal HER2+ breast cancer (BC). We report survival in a recent population-based cohort by HER2 status, overall, and within hormone receptor(HR)+ BC. Methods: Surveillance, Epidemiology, and End Results Program data were queried to identify women diagnosed 2010-2012 with Stage IV BC as first cancer. Patients were grouped by HER2 and HR status. Kaplan Meier estimates of 3-yr observed survival (OS) were compared with log-rank tests. A multivariate cox model was fitted for the HER2+ cohort. Results: 3-yr OS for HER2+(any HR), HR+/HER- and triple-negative (TN) BC was 52.3%, 48.4% and 16.0% respectively (p&lt;0.01 HER2+(any HR) vs TNBC; p=0.20 HER2+(any HR) vs HR+/HER2-). Across registries, OS for HER2+(any HR) BC ranged from 29.2% to 61.7% (p=0.05). On Cox model, survival in HER2+(any HR) BC was associated with age 50+ (Hazard ratio (HR) 1.84, 95% CI 1.45-2.34), HR+ status (HR 0.70, 0.58-0.84), high histologic grade (HR 1.30, 0.58-0.84), surgery (HR 0.40, 0.33-0.49), separated marital status (HR 1.72, 1.4-2.13), year 2012 (HR 0.81, 0.64-1.04), and registry (varies by reference group). For HR+ BC, OS also differed by HER2 status: 55.3% for HR+/HER+ and 48.4% for HR+/HER2- (p&lt;0.01). 3-yr OS by HER2 status for women presenting with HR+ BC is shown (Table). Conclusions: Survival in de novo Stage IV HER2+ BC in the United States exceeds that in HER2- BC, with median survival &gt;3 yrs. Survival was significantly better for HR+/HER+ BC than HR+/HER- BC. Disparate OS in HER2+ BC suggest opportunities may remain to fully realize advances in HER2-directed therapy. Given recent therapeutic advances, the trend of HER2+ survival gains from 2010 to 2012 will likely continue. [Table: see text]

Measuring functional HER2-driven signaling status ex vivo to predict response to HER2 therapy: Results from a mouse breast tumor xenograft study.

e23203 Background: Clinical trials indicate a weak correlation between HER2 expression levels and HER2 targeted therapy benefit. Other biological factors, such as HER2 signaling activity, may be important to measure when identifying patients for treatment with HER2 therapies. To measure the HER2 signaling activity of a patient’s live tumor cells, a new assay using an impedance biosensor, the CELx HER2 Signaling Function (CELx HSF) Test, was developed. In this study, we evaluated whether functional HER2 signaling status was more predictive of response to a dual-HER2 kinase inhibitor than HER2 receptor or gene amplification status, using breast tumor xenograft in vivo models. Methods: Two breast cancer cell lines were studied: HCC1954, a HER2+ cell line with normal HER2 signaling according to the CELx HSF Test, and BT483, a HER2- cell line with abnormally high HER2 signaling according to the CELx HSF Test. Thus, the HER2 receptor status of each cell line was opposite its HER2 signaling status. For each cell line, twenty 4-5 week old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or a treatment group that received lapatinib at a dose of 20mg/kg daily for 16 days. Results: There was no significant difference in tumor volume between the control and lapatinib-treated groups in the mice injected with the HCC1954 (HER2+, normal HER2 signaling) cells. Average tumor sizes reached 1028.7 ± 166.9 mm3 for the control group and 893.8 ± 111.5 mm3 for the lapatinib-treated group (P = 0.285) by the end of the study. With the BT483 (HER2-, abnormal HER2 signaling) cells, lapatinib treatment significantly slowed down the increase in tumor size. Average tumor sizes reached 328.3 ± 54.9 mm3 for the control group and 192.4 ± 19.4 mm3 for the lapatinib-treated group (P = 0.0049). Conclusions: The results demonstrate that functional HER2-driven signaling status in live tumor cells is more correlative to response to lapatinib in mouse xenograft tumors than HER2 expression level. These findings provide strong evidence that HER2- breast cancer patients with abnormal HER2 signaling may respond to anti-HER2 therapies.

THE IMPACT OF LOCOREGIONAL TREATMENT ON SURVIVAL OF PATIENTS WITH PRIMARY METASTATIC BREAST CANCER

This retrospective study included 295 wo-men aged from 23 to 76 years with PMBC. Among the 295 patients, the effect of locoregional treatment of primary tumor on survival outcomes was evaluated in 177 women with distant metastases at diagnosis of breast cancer. 35 patient received breast surgery (group 1), 95 patients with PMBC - radiotherapy (group 2) and 47 patients - combination of breast surgery and radiation (group 3). The remaining 118 patients didn't receive surgery or/and radiotherapy (group 4). All patients received systemic cytotoxic chemotherapy. The groups of patients with PMBC did not differ significantly by age, menstrual function, ER status, Her2 receptor status, site of metastasis and number of metastatic lesions. 2- and 5-year overall survival in patients of group 1 was 54 and 32%, group 2 - 47 and 8%, group 3 - 73 and 18%, whereas in patients from group 4 - 26 and 9%, respectively. The median survival of patients who underwent surgery was 36 months, patients with PMBC who received radiotherapy - 24 months, patients who obtained combination of breast surgery and radiation - 30 months vs 18 months in patients who did not undergo primary tumor locoregional treatment. The results of this study showed a favourable effect of locoregional treatment in patients with PMBC.

Abstract P1-03-07: High concordance of a closed system, near point of care, RT-qPCR breast cancer assay for HER2 (ERBB2) mRNA compared to both IHC/FISH and quantitative immunofluorescence

Abstract Background Reliable assessment of HER2 receptor status in breast cancer by either IHC or FISH does not unequivocally define receptor expression, due to their semi-quantitative nature, and as many as 10-15% of cases fall into the ASCO/CAP “equivocal” category. Historically, RNA measurements by PCR, including using several commercially available platforms, have been tested, but have not gained broad acceptance for assessment of HER2. However, RNA measurement, as a continuous value, has potential for use for adjudication of the equivocal category. In the current study, we used a real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay (GeneXpert® Breast Cancer Stratifier RUO Assay, Cepheid, Sunnyvale, CA, USA) for ERBB2 (HER2) mRNA on the GeneXpert® (GX) platform (Cepheid), which utilizes a closed-system, single-use cartridge, automated system. The RT-qPCR results from GX were then compared with results from clinical HER2 IHC/FISH assays following ASCO/CAP 2013 HER2 testing guidelines (Wolff et al JCO 2013) and quantitative immunofluorescence (QIF). Methods Multiple cores (1mm in diameter) were retrospectively collected from 80 formalin-fixed paraffin-embedded (FFPE) tissue blocks with invasive breast cancer seen by Yale Pathology Labs between 1998 and 2011. Tissue cores were processed as lysates for testing at Yale in the automated GX assay. Briefly, gene-specific reverse transcription was performed, followed by RT-qPCR (TaqMan) and ERBB2 mRNA results were expressed as the difference in cycle threshold values (delta Ct) between the endogenous control transcript (CYFIP1) and the ERBB2 mRNA transcript. Results from IHC and FISH were extracted from the pathology reports for the Yale CLIA lab and QIF for each case was measured as previously described (Carvajal et al, JNCI 2015). Results Quality control testing showed that the GX platform shows no case to case cross contamination on material from routine histology practices. Concordance between RT-qPCR and IHC/FISH was 91.25% (sensitivity = 0.87; specificity = 0.94; PPV = 0.89; NPV = 0.92) using a pre-defined delta Ct cut-off (dCt ≥ -1) for HER2 (+) based on prior concordance studies with HER2 IHC/FISH. Concordance between RT-qPCR and QIF was 99% (sensitivity = 0.97; specificity = 1.0; PPV = 1.0; NPV = 0.98) using dCt ≥ -1 and the pre-defined cut-point for positivity by QIF. Conclusions The GX closed system RT-qPCR assay shows greater than 90% concordance with the ASCO/CAP 2013 HER2 IHC/FISH scoring. Additionally, the GX RT-qPCR assay is highly concordant (99%) with the continuous variable HER2 QIF assay, and may better reflect the true continuum of HER2 receptor status in invasive breast cancer. These initial results suggest that rapid, closed system molecular assays may have future value for the adjudication of the ASCO/CAP HER2 equivocal category. This pilot study did not include ASCO/CAP 2013 “equivocal” cases, but that effort is underway. Citation Format: Wasserman B, Carvajal-Hausdorf D, Ho K, Wong W, Wu N, Chu VC, Lai EW, Weidler JM, Bates M, Neumenister V, Rimm DL. High concordance of a closed system, near point of care, RT-qPCR breast cancer assay for HER2 (ERBB2) mRNA compared to both IHC/FISH and quantitative immunofluorescence [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-07.

Abstract P1-03-04: Concordance of local immunohistochemistry with TargetPrint microarray based assessment of ER, PR and Her2 and BluePrint molecular subtyping in the Symphony Triple A study

Abstract PURPOSE: A decade ago intrinsic biological breast cancer subtypes have been identified which have proven to be of clinical importance in terms of outcome and response to systemic treatment. The aim of the current study is to assess concordance between breast cancer subtypes determined by local immunohistochemistry (IHC) assessment of estrogen receptor (ER), progesterone receptor (PR) and Her2-receptor status and microarray based molecular subtyping in a subset of ER+ early stage breast cancer patients. PATIENTS AND METHODS: In this prospective observational multicenter study information on local pathology assessment and BluePrint/TargetPrint results were obtained in ER+ Dutch early stage breast cancer patients in whom a 70-gene profile (MammaPrint) was used as they were enrolled in clinical trial based on the existence of controversy regarding the additional value of adjuvant CT. Local IHC assessment of ER, PR and Her2 status were compared with microarray based assessment (TargetPrint/BluePrint) of these characteristics. Reclassification of ER and PR overexpression was assessed by a McNemars test and by Spearman correlation. Furthermore, concordance between the clinical subtypes based on local pathology (Luminal-type: ER+/PR+/Her2-; Her2-type: Her2+ disease) and molecular subtyping was assessed. RESULTS: Between January 2013 And December 2015 660 patients, treated in 31 hospitals, were enrolled. In 564 (85%) BluePrint and/or TargetPrint was performed in addition to the 70-GS. The majority of patients had ER+/Her2- disease and TargetPrint reclassified 1% (n = 7) of patients as ER-negative (r = 0,250, p &amp;lt;0,001). TargetPrint reclassified 7% (n = 40) and 2% (n = 11) of patients for PR and Her2 status respectively (table 1, r = 0,580, p &amp;lt;0,001 for PR Table 1. Concordance between immunohistochemistry and TargetPrint. TargetPrint result (ER, PR and Her2 resp.) ImmunohistochemistryPositiveNegativeOverall discordance (%)p-value*Estrogenreceptor status Positive557 (99%)6 (1%) Negativen.a.n.a.1%n.a.Progesterone receptor status Positive474 (96%)18 (4%) Negative22 (31%)49 (69%)7%0,636Her2 receptor status Positive3 (30%)7 (70%) Negative4 (3%)546 (97%)2%0,549Equivocal0 (0%)3 (1%) * P-value represents results of the McNemar test.). Based on IHC 545 (98%) patients were regarded as luminal-type and the remaining 2% as Her2-type. BluePrint reclassified 2% of the clinical luminal-type patients: 4 (1%) patients were reclassified as basal-type and 3 (0%) patients as Her2-type. Of the clinical Her2-type patients 80% (n=8) was reclassified by BluePrint as molecular luminal-type. Table 2. Concordance between clinical subtyping and molecular subtyping according to BluePrint. BluePrint resultClinical SubtypeNo. ptsLuminalBasalHer2Luminal545539 (99%)4 (1%)3 (0%)Her2108 (80%)02 (20%)Note. Overall discordance 3%. Conclusion: In the current study we observe a high concordance between microarray-based assessment of ER, PR and Her2 and local pathology in Dutch ER+ early stage breast cancer patients. In the small subset of ER+ patients who are considered candidates for 70 GS use and who have HER2+ tumors by IHC molecular typing of HER2 status is of additional value. Citation Format: Kuijer A, Straver M, Elias S, Smorenburg C, Wesseling J, Linn S, Rutgers E, Siesling S, van Dalen T. Concordance of local immunohistochemistry with TargetPrint microarray based assessment of ER, PR and Her2 and BluePrint molecular subtyping in the Symphony Triple A study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-04.

Abstract P1-10-12: Radiation therapy in 1-3 node positive mastectomy patients: Who benefits?

Abstract Introduction A recent meta-analysis on radiation therapy (XRT) demonstrated improved outcomes and recommended its use. However, these data were derived from the 1960's-1980's and might not reflect the effects of XRT when used in modern oncology practice [1]. Consequentially, XRT benefits for mastectomy patients with 1–3 positive nodes at the time of surgery (SX) remain uncertain. In this retrospective study we examined XRT effects in a modern cohort of mastectomy patients with 1–3 positive nodes at SX, across multiple outcomes: loco-regional recurrence (LRR), distant recurrence (DR), total recurrence (TR), breast cancer (BCa mortality) and all-cause mortality (ACM). Subjects The Swedish Cancer Institute's breast cancer patient registry was used to identify mastectomy patients who had 1-3 positive lymph nodes at SX and known HER-2 receptor status. HER-2 positive patients who did not receive Herceptin were excluded. Methods Clinical, pathological, treatment and outcomes data were extracted from our registry. Logistic multiple regressions were used to identify clinical and pathology elements available at the time of SX that correlated with LRR, DR, TR, BCaM and ACM. Regression model elements included: tumor receptor status - estrogen (ER), progesterone (PR) and HER-2, presence or absence of lymphovascular invasion (LVI), extension of LVI, number of LN+, node positivity ratio (positive/examined), surgical margins (SxM); patient age, chemotherapy, XRT and hormonal treatment. Results The application of these filters to our breast cancer registry yielded 935 patients with a mean follow up time of 7 years. Our sample was “modern”: 95% of our patients were diagnosed after 1999, 80% after 2004. Logistic regression indicated that across all patients, XRT was associated with improved LRR (Nagelkerke R2=5%, p&amp;lt;.01), and ACM (Nagelkerke R2=1%, p&amp;lt;.05). The four clinical and pathologic elements that most strongly correlated with outcomes were LVI (+), LN+&amp;gt;1, PR (-) and SxM (+) and we stratified the population into risk groups based on the number of factors present; low-risk = no factors, medium-risk = 1 factor, High-risk = 2+ factors. We also stratified by treatments, comparing the effects of chemotherapy alone vs. chemotherapy plus XRT across the major patient outcomes and risk groups (see Table 1). This comparison only showed XRT effects for LRR in the higher risk groups. XRT effects by Risk Groups TREATMENTN=LRRDRTRBCa Mort.ACMLow RiskCH+, No XRT1080%4.6%4.6%2.9%3.7%GroupCH+, XRT+410%2.5%2.5%2.4%2.5%Medium RiskCH+, No XRT2152.8%10.2%12.1%5.6%10.7%GroupCH+, XRT+1880% *8.5%8.5%4.3%6.4%Highest RiskCH+, No XRT834.8%8.4%13.3%8.4%16.9%GroupCH+, XRT+122.8% +13.1%13.9%8.2%13.1%* =p&amp;lt;.05, + =p&amp;lt;.07 Discussion XRT improved LRR in the medium and high risk groups, but lacked benefit in the low-risk group and did not provide statistically significant improvements in BCa survival. These results suggest caution in using XRT in low-risk patients, but it has some value in reducing LRR in medium and high-risk populations, without survival benefits. 1. Lancet Volume 383, No. 9935, p2127–2135, 21 June 2014. Citation Format: Ellis ED, Scanlan JM, Kaplan HG, Kieper DA, Morris AD, Atwood M. Radiation therapy in 1-3 node positive mastectomy patients: Who benefits? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-12.

Abstract P5-08-24: How do real-world treatment patterns compare to guideline recommendations for first-line metastatic breast cancer patients in US community clinics?

Abstract Background: Treatment (txt) guidelines are based on trial data from a small minority of patients (pts). Linked electronic health records (EHRs) are a novel approach to examine txt patterns and outcomes in larger and more generalizable populations. Given the increasing importance of real world data and real world outcomes, we utilized linked EHRs from a network of US community clinics to examine how real world txt patterns compare to metastatic breast cancer (mBC) txt guideline recommendations. Methods: The Flatiron database provides real world clinical data collected from EHRs used by US cancer care providers. The Flatiron network comprises ~15% of US cancer pts and is geographically and demographically diverse. Using EHR from Jan 2016 mBC database, we evaluated first-line (1L) txt patterns in mBC by molecular subtype. Pts were selected if they received mBC txt within 60 days of mBC diagnosis between 01Jan2011-31Dec2015, had ≥2 visits within the Flatiron Network on or after 01Jan2013, and were ≥18 years (yrs). Analyses were conducted to describe pt and clinical characteristics and 1L txt by HER2 and/or hormone receptor (HR) status. Results: Among 2509 mBC pts identified, 58.9% were HR+/HER2-, 17.7% HER2+, 11.6% HR-/HER2- (triple negative, TNBC), 7.4% HER2 equivocal, and 4.3% 'not done/unknown HER2 status'. Txt patterns in the latter two groups were not analyzed. Selected pt and disease characteristics by subtype are shown in Table 1. Median follow-up since mBC diagnosis was 1.1 yrs (range 0-5 yrs). The 1L mBC txts by subtype are shown in Table 2. Pts with HR+/HER2- subtype were treated primarily with hormonal therapy (68%) and/or chemotherapy (chemo) (35%). Among HER2+ pts, the 1L mBC txt patterns include trastuzumab+pertuzumab with chemo (31%), trastuzumab with chemo (22%), trastuzumab with hormonal therapy (9%), ado-trastuzumab (4%), lapatinib with chemo (3%), and lapatinib with hormonal therapy (1%). For TNBC, the majority received chemo (95%), such as paclitaxel (21%), nab-paclitaxel (13%) and docetaxel (12%). Conclusion: This study advances our current understanding of real world 1L patterns of care by molecular subtype among mBC pts and how these compare to guideline recommendations. While the majority of pts are receiving therapy per guidelines, up to 22% of HER2+ of pts are not receiving targeted therapy in 1L mBC Table 1. Patient and disease characteristics by subtypeN (%)HR+/HER2- (N=1479)HER2+ (N=445)TNBC (N=291)Age at mBC diagnosis (yrs), median (range)66 (24-85)60 (27-85)60 (33-85)Sex Female1459 (99)441 (99)289 (99)Race White995 (67)274 (62)168 (58)Black112 (8)44 (10)42 (14)Asian19 (1)14 (3)5 (2)Other179 (12)50 (11)36 (12)Missing173 (12)63 (14)40 (14)MBC type De novo418 (28)172 (39)94 (32)Recurrent881 (60)225 (51)178 (61)Unknown180 (12)48 (11)19 (7)HR Status Positive1479 (100)300 (67)--Negative--145 (33)291 (100) Table 2. 1L mBC treatments by subtypeN (%)HR+/HER2- (N=1479)HER2+ (N=445)TNBC (N=291)Any Targeted Therapy*77 (5)346 (78)12 (4)Any Chemotherapy521 (35)283 (64)276 (95)Any Hormonal Therapy1010 (68)115 (26)16 (6)*Targeted therapy includes trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib and bevacizumab Citation Format: Chu L, Yoo B, Carrigan G, Lai C, Beattie M, Reyes C. How do real-world treatment patterns compare to guideline recommendations for first-line metastatic breast cancer patients in US community clinics? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-24.

Abstract P4-21-28: Trastuzumab improves outcomes of New Zealand women with HER2+ stage I-III breast cancer

Abstract Introduction HER2 status has been routinely ascertained for stage I-III breast cancer since late 2005. Trastuzumab was first funded in New Zealand for use in HER2+ breast cancer in July 2007. This observational study aims to compare the difference in outcome between women with HER2+ stage I-III breast cancer who received trastuzumab as adjuvant therapy versus those who did not. Differences in presentation, treatment and outcomes between Māori and NZ European were studied. Methods The combined Waikato and Auckland Breast Cancer Registries have clinical details of 12377 women diagnosed with breast cancer between June 2000 and May 2013. 9506 women with breast cancer were tested for HER2 receptor status. Proportion of women with HER2+ (FISH amplified or IHC 3+), stage I-III breast cancer were examined by age, ethnicity and stage. Differences in use of trastuzumab for women with stage I-III breast cancer with a tumour size equal or larger than 1 cm and aged less than 75 years were assessed by ethnicity and year of diagnosis. Patients who had inflammatory breast cancer or developed metastatic disease or local recurrence within 3 months after diagnosis were excluded. Kaplan-Meier method and Cox proportional hazards model were used to examine the breast cancer-specific survival between women treated with trastuzumab and chemotherapy and those treated with chemotherapy without trastuzumab. Results 1454 patients with early invasive breast cancer were HER2+. The proportion of cases with HER2+, stage I-III breast cancer increased with stage (stage I-III: 11.5%-26.9%), but decreased with age (&amp;lt;40 years to 80+ years: 28.8%-9.7%). Māori women were more likely to have HER2+ cancers than NZ European (17.8% versus 14.9%; p=0.02). Among the eligible patients, 605 women received trastuzumab and chemotherapy within 12 months for stage I-III breast cancer, and 275 had chemotherapy without trastuzumab. A small proportion (10.2%, 34/333) of women diagnosed in 2000-2005 received trastuzumab as part of a clinical trial. The proportion of women who received trastuzumab increased to 60.3% in 2006-2009 and to 87.1% in 2010-2013. 46.2% of Māori women were treated with trastuzumab compared to 55.9% of NZ European (p=0.040). The cancer-specific survival estimated with Kaplan-Meier method is shown in Table 1. Women treated with chemotherapy without trastuzumab were 2.7 times (95% CI: 1.9-3.9) more likely to die of breast cancer compared to those treated with trastuzumab and chemotherapy, after adjustment for stage, tumour size and hormone therapy. Table 1. Breast cancer-specific survival between women with HER2+ stage I-III breast cancer who received trastuzumab as adjuvant therapy versus those who did notTreatmentNumber of patientsMedian follow-up time (months)5-year survival10-year survivalTrastuzumab+chemotherapy6055389.6%84.3%Chemotherapy without trastuzumab27510775.6%69.1% Conclusions Trastuzumab improved the breast cancer-specific survival of women with HER2+ stage I-III breast cancer. Māori women were more likely to have HER2+ cancer and less likely to be treated with trastuzumab. Rates of treatment with trastuzumab and the adjusted survival between Māori women and NZ European women were not significantly different. Citation Format: Lawrenson R, Lao C, Harvey V, Campbell I, Brown C, Seneviratne S, Edwards M, Scott N, Elwood M, Sarfati D, Kuper-Hommel M. Trastuzumab improves outcomes of New Zealand women with HER2+ stage I-III breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-28.

Abstract P2-05-17: Development of a recurrence risk stratification schema to inform treatment decisions in breast cancer patients undergoing mastectomy with 1-3 positive nodes

Abstract Introduction Controversies exist regarding the appropriateness of radiation therapy (XRT) in mastectomy patients who have 1 – 3 positive nodes (LN+). We sought to create a straightforward recurrence and survival prediction model derived from clinical and pathologic parameters common in the community cancer center setting at the time of surgery (SX) that may help determine the patients most likely to benefit from XRT. Subjects In this retrospective observational study, we examined our institution's breast cancer patient registry to identify mastectomy patients with one to three LN+ at the time of diagnosis and tumor pathology results including Her-2 receptor status. Consistent with current treatment standards, Her-2 positive tumors that were not treated with Herceptin were excluded. Methods Breast cancer registry data elements including clinical, pathology, treatment and outcomes data were extracted. Logistic multiple regressions were used to predict loco-regional recurrence (LRR), distant recurrence (DR) and total recurrence (TR) as well as breast cancer mortality (BCa mortality) and all-cause mortality (ACM) based on clinical and pathologic parameters available at SX. The parameters included in the regression model were: tumor receptor status - estrogen (ER), progesterone (PR) and HER-2, the number of nodes examined, presence or absence of lymphovascular invasion (LVI), extension of LVI, number of LN+, node positivity ratio (positive/examined), surgical margins or “tumor on ink”, (SxM); and patient age. Results The application of these filters to our breast cancer registry yielded 935 patients with a mean follow up time of 7 years. Our sample was “modern”: 95% of our patients were diagnosed after 1999, 80% after 2004. Across multiple analyses, the four most consistent risk indicators were PR(-),LVI (+), LN+&amp;gt;1 and SxM (+). In our model, patients with none of the four factors were designated low-risk, those with only one factor were medium-risk, those with 2+ were high-risk (see Table 1). Risk model Validation: All patients N =LRRDRTRBCa Mort.ACMLow Risk2160%3.7%3.7%2.8%8.8%Medium Risk4912.4%9.6%11.2%5.7%12%High Risk2284.4%12.7%16.7%11.8%18.9%3 grp. p-value .01.001.001.001.01 From this complete group, we extracted the relatively small number of patients (N = 137) who, due to a variety of factors, received no chemotherapy or radiation therapy and which showed stronger contrasts between risk groups (see Table 2). Risk model Validation: No chemotherapy or XRT N=LRRDRTRBCa Mort.ACMLow Risk511.9%3.9%3.9%3.9%23.5%Medium Risk708.6%10%18.7%8.6%27.1%High Risk1625%31.3%50%50%68.8%3 grp. p-value .01.001.001.001.01 Discussion We believe this risk group concept is straightforward, feasible and clinically useful in all clinical settings. Our future work seeks to validate this concept in another independent cancer registry. In our analyses we noted that while both PR- and ER- were predictive of patient outcomes in simple correlations, PR- was more predictive in all multivariate equations. Citation Format: Scanlan JM, Ellis ED, Kaplan HG, Kieper DA, Morris AD, Atwood M. Development of a recurrence risk stratification schema to inform treatment decisions in breast cancer patients undergoing mastectomy with 1-3 positive nodes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-17.