Citations

Purpose To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. Methods A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective–retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. Results The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective–retrospective studies that evaluated the clinical utility of biomarkers. Recommendations In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient's goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

Abstract Introduction: Triple negative breast cancers (TNBC) are characterized as lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression and TNBC patients have higher rates of recurrence and death compared with other breast cancer subtypes. For TNBC patients who fail standard chemotherapy, there are a lack of novel drug therapies, given the absence of well-defined molecular targets. Recently, a microarray meta-analysis identified 7 triple negative subtypes, including the validation of the luminal androgen receptor (LAR) positive subtype [Lehmann, 2011]. However, microarray technology is dependent on probe-target specificity and the 7 subtypes have yet to be validated using RNA sequencing data, and the presences of recurrent genomic alterations in the 7 subtypes are unknown. METHODS: We obtained 1106 breast cancer RNA-Seq bam files from The Cancer Genome Atlas (TCGA) and aligned with Tophat v1.3. The PAM50 intrinsic gene signature was used to extract a cohort of 128 TNBC samples. Consensus clustering of genes, greater than 75th percentile of variance, was performed using Kmeans clustering in Spearman's correlation space. A nearest centroid prediction model was developed from genes differentially expressed among the clusters. Eighty independent TNBC RNA sequencing samples were obtained (British Colombia; BC) [Shah, 2012] which were calibrated to our TNBC conditional quantile normalized cohort and sub-typed by our model. RESULTS: Using RNA-Seq gene expression count data, we identified 5 clusters, all of which were stable, including the LAR cluster. Signaling pathway impact analysis (SPIA) implicated cytokine-cytokine receptor interaction, leukocyte transendothelial migration, and regulation of actin cytoskeleton pathways commonly altered in the non-LAR TNBC subtypes. In contrast, cell cycle, ECM-receptor interaction, endocrine regulated calcium reabsorption, and insulin signaling pathways were altered in the LAR versus non-LAR subtypes. Neuroactive ligand-receptor interactions were observed to be altered commonly between all sub-types. We then applied our model to the Shah, et al cohort. In this cohort, the LAR subtype was consistent with Shah's classification of ‘other’ TNBC and contained no basal samples by PAM50 intrinsic modeling. Analysis of sub-type specific mutation data from the BC cohort demonstrates an increased mutational load in ECM-related proteins, particularly the myosins, along with increased TP53 clonality in the non-LAR subtypes. CONCLUSIONS: Using TCGA RNASeq data, we have confirmed the presence of 5 major TNBC subtypes, including the LAR; which was negligible in basal composition by PAM50 intrinsic modeling. SPIA pathway analysis indicates a core set of pathways demonstrating altered expression across the TNBC sub-types and the identification of molecular targets within each subtype is ongoing. Citation Format: Kevin J. Thompson, Xiaojia Tang, Zhifu Sun, Jason P. Sinnwell, Hugues Sicotte, Douglas W. Mahoney, Steven Hart, Peter T. Vedell, Poulami Barman, Jeanette E. Eckel Passow, Eric D. Wieben, James N. Ingle, Judy C. Boughey, Liewei Wang, Richard Weinshilboum, Krishna R. Kalari, Matthew P. Goetz. Molecular classification of triple negative breast cancer via RNA-sequencing data. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5592. doi:10.1158/1538-7445.AM2014-5592

Abstract INTRODUCTION Next generation sequencing (NGS) of patients has significantly changed our ways to study cancer genomics as it provides precise estimates of gene expression, fusion transcripts, expressed single nucleotide variants (eSNVs), splice variants and copy number variants. The Breast Cancer Genome Guided Therapy (BEAUTY) is an ongoing clinical study in which RNA sequencing (RNAseq) and whole exome sequencing (WES) are performed prior to, during and after neoadjuvant chemotherapy. Here we report the use of these sequencing technologies to investigate gene expression levels and mutational profiles in a triple negative breast cancer (TNBC) patient enrolled in BEAUTY whose disease did not respond to neoadjuvant paclitaxel and anthracycline/cycphosphamide. METHODS Computational approaches were used to integrate WES and RNAseq data obtained before therapy (V1T), after 12 weekly paclitaxel treatments (V2T) and after anthracycline-based regimen at surgical resection (V3T) to study a single patient with persistent TNBC disease after neoadjuvant chemotherapy. RESULTS Using RNA-Seq data, we identified an inter-chromosomal fusion transcript between chromosome 20 and 22 (GNAS-TTC38) that was highly expressed at V1T, V2T and V3T. We also identified intra-chromosomal fusion transcripts that were expressed at two time points, such as fusion transcript (KANSL1-ARL17A) on chromosome 17 for V1T and V2T and fusion transcript (RBM12B-LINC00535) on chromosome 8 for V2T and V3T time points. Several gene expression changes were also observed. Gene expression analysis of V1T, V2T and V3T tumors was performed. Differential temporal gene expression profiles of 9884 genes that were significant and varying at different time points were obtained for pathway analysis. Pathway analysis of 9884 genes identified up regulation and down regulation of several transcription factors with a fold change of 2x or more. When compared to blood, DNA tumor and RNA-Seq data, we identified 81 common somatic eSNVs that were expressed in both V1T and V2T time points and we are in the process of investigating V3T data. We found alterations of key transporter domains (CD225, Coatamer_beta_C, DUF2435, Dynamitin, EI24, GLTP, LMF1, Porin_3, V-ATPase_C) in our V1T and V2T SNV data. Similar to gene expression analysis, we are in the process of obtaining the list of mutations at various time points to identify driver and passenger mutation candidate genes for this specific TNBC patient. CONCLUSIONS Our initial time-series analysis of eSNV, fusion transcripts and gene expression data demonstrate that intensive analysis for individual patients is feasible. Further investigation of drug transporters and transcription regulators may help develop personalized treatment strategies for patients with disease resistant to current regimens. Citation Format: Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Douglas W. Mahoney, Poulami Barman, Jason P. Sinnwell, Hugues Sicotte, Peter Vedell, Steven N. Hart, Travis J. Dockter, Katie N. Jones, Amy L. Conners, Ann M. Moyer, Daniel W. Visscher, Jia Yu, Bowen Gao, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Jean-Pierre A. Kocher, Eric D. Wieben, Gianrico Farrugia, Cloann G. Schultz, James N. Ingle, Richard Weinshilboum, Matthew P. Goetz, Liewei Wang, Judy C. Boughey. Analysis of sequencing data to identify potential drug targets for an individual newly diagnosed with basal breast cancer who failed to respond to current standard neoadjuvant chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4185. doi:10.1158/1538-7445.AM2014-4185

Abstract Background: We have previously shown in animal models that combination anti-HER2 therapy leads to complete tumor regression of HER2+ breast cancer (BC). We translated these findings in a neoadjuvant trial of 12 weeks (wks) of L+T (TBCRC006) that demonstrated a meaningful pathologic complete response (pCR) and near pCR (in ER+ tumors) in patients with locally advanced HER2+ BC. In the present trial, we sought to determine whether longer treatment would lead to a higher rate of pCR without the use of chemotherapy by converting near pCR to pCR especially in the ER+ subset. Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2+ BC measuring 2 cm or larger were eligible and were randomized in a 1:2 ratio to 12 vs. 24 wks of L+T. Letrozole (along with ovarian suppression if premenopausal) was also administered in patients whose tumors were also ER+. Serial tumor biopsies were obtained at baseline, wk 1, wk 12, and at the time of surgery. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Patients did not undergo surgery, withdrew consent, or received additional neoadjuvant therapy were counted as non-responders. Results: Ninety-seven patients were enrolled (33 in 12-wk arm and 64 in 24-wk arm), of whom 95 were evaluable. Seventy seven percent of patients were white and 18% were black. Twenty percent were of Hispanic ethnicity. Median age was 51 and 55% were postmenopausal. Median tumor size was 5 cm and 65% were ER+. Study treatment was well tolerated with grade 1-2 diarrhea (24% in 12-wk arm, 31% in 24-wk arm) and grade 1-2 acneform rash (12% in 12-wk arm, 19% in 24-wk arm) being the most common toxicities. Grade 3 toxicities were uncommon and were mostly in the 24-wk arm (elevated liver function test: 9%, diarrhea 2%, mucositis 2%), while the 12-wk arm had one grade 3 anemia and the study’s only serious adverse event (acute kidney injury). There were no grade 4 toxicities. The experimental arm completed stage 2 accrual and pCR rate was numerically superior to control, entirely due to better results in ER+ (Table 1), but lower than the expected pCR rate of 36% needed in the planned analysis to conclude in favor of enhanced efficacy with extended therapy. pCR rates were also lower in the control arm than in the previous study. Table 1. pCR rates 12-week arm % (n)24-week arm % (n)ER-positive8.7% (2/23)33.2% (13/39)ER-negative20% (2/10)8.7% (2/23)Overall pCR12.2% (4/33)24.2% (15/62) Conclusions: Treatment with L+T (with endocrine therapy in ER+ tumors) for 24 weeks leads to doubling of the pCR rate in women with HER2+ breast cancer without using cytotoxic chemotherapy. This approach is effective and well tolerated and warrants study as part of a de-escalation strategy that may spare some patients the cost and toxicity of chemotherapy. Tissue obtained on this trial will provide a valuable resource to validate correlative findings from our prior studies and discover new biomarkers to help guide proper patient selection for treatment. Citation Format: Mothaffar F Rimawi, Polly A Niravath, Tao Wang, Brent Rexer, Andres Forero, Antonio C Wolff, Rita Nanda, Anna M Storniolo, Ian Krop, Matthew P Goetz, Julie R Nangia, Sao Jiralerspong, Anne C Pavlick, Carolina Gutierrez, Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer [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 S6-02.

Abstract Background Cancer genomic investigations have identified recurrent genomic aberrations critical for cancer initiation, progression, and metastases. However, these investigations are typically performed in isolation, and the effects of treatment on the clonal selection of tumor cells are mostly unknown. We hypothesized that molecular profiling of residual tumors after neoadjuvant chemotherapy (NAC) would identify new drug targets/pathways in patients at high risk for disease recurrence. To better identify clonal populations of resistant breast cancer cells, we utilized DNA content-based flow sorting of nuclei to identify and isolate clonal populations for aCGH and next generation sequencing (NGS) both before and after NAC. Methods The Breast Cancer Genome Guided Therapy Study (BEAUTY) (NCT 02022202) is a prospective study of patients with high-risk breast cancer treated with neoadjuvant 12 weekly paclitaxel (T) +/- trastuzumab followed by 4 cycles of anthracycline based chemotherapy. Tumor tissue from baseline, residual disease from surgery, distant metastases, and patient derived xenografts (PDX) are obtained for cell sorting by DNA ploidy, aCGH, RNA and exome sequencing. Results: 140 patients have been enrolled, 104 have completed surgery and 30 unique PDX have been established corresponding to 26 patients prior to chemotherapy and 4 from residual disease at surgery. Baseline exome and RNA sequencing is complete in 140. Currently, genomic analyses of flow sorted matched baseline, surgical, PDX, and distant disease samples are available in 6 patients. Substantial genomic variation was observed in the surgical sample compared to the primary tumor including gain of oncogenic drivers (EGFR) and loss of negative regulators (ATG5) (Table). The PDX recapitulated these events with excellent fidelity compared to the corresponding human tumor. In patients with TNBC, RNA seq obained from matched samples demonstrated changes in immune related pathways. Evaluation of drug targets/pathways identified in the resistant tumors are ongoing using the PDX and sequencing of the remaining matched baseline/surgical disease will be reported. Clonal changes occurring over time in patients with residual disease or disease recurrence after NACTumor SubtypeResidual Cancer BurdenDisease StatusClonal Aberration Changes (baseline and post NAC)TNBC (AR subtype)3Contralateral lymph node recurrence at 150 days2p25.2 - p25.1 amplicon lost at recurrence; 6p21.32 -p21.31 amplicon lost at recurrenceTNBC (BL 1)3Bone/liver/lymph node recurrence at 135 days5q11.2 amplicon gained at surgery; 12p13.33 - p13.2 amplicon gained at surgeryTNBC (BL 1)3Disease-free at day 1506q21 amplicon lost at sugeryTNBC (BL 2)0Brain recurrence at 390 daysChr 2 chromothripsis at surgeryLuminal B3Progression during chemotherapy7p12.1 - p11.2 amplicon gained at surgeryLuminal HER23Disease-free at day 3609q33.2 amplicon lost at surgery; 15q13.1 - q13.3 amplicon lost at surgery; 15q22.2 - q24.1 amplicon lost at surgery Conclusions: We observed substantial evolutionary changes in residual breast tumors remaining after NAC. Our findings suggest that a comprehensive assessment of the mutational landscape that has evolved during NAC can inform drug development in high risk breast cancer patients. Citation Format: Matthew P Goetz, Michael T Barrett, Krishna R Kalari, Vera J Suman, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Ann M Moyer, Donald W Northfelt, Richard J Gray, Jason Sinnwell, Douglas Mahoney, Poulami Barman, Peter Vedell, Xiaojia Tang, Kevin Thompson, Travis Dockter, Katie Jones, Sara J Felten, Amy Conners, Jeanette Eckel-Passow, Hughes Sicotte, Steven N Hart, Jia Yu, Daniel W Visscher, Eric D Wieben, Cloann Schultz, Minetta C Liu, James N Ingle, Liewei Wang, Richard W Weinshilboum, Judy C Boughey. Impact of neoadjuvant chemotherapy on the clonal composition of breast cancer [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 PD3-3.

Abstract Purpose: Tamoxifen and raloxifene, are primary prevention strategies for women at high risk of breast cancer (Visvanathan, 2013). Recent advances in genetic studies of breast cancer risk have identified common susceptibility loci that explain 14% of familial risk for breast cancer in the general population (Michailidou, 2013). However, it is not known if these loci are risk factors for breast cancer among high-risk women treated with SERMs for breast cancer prevention. We hypothesized that the large risk reduction associated with SERMs, coupled with the fact that several breast cancer loci correlate with family history, may limit the contribution of these common genetic loci to breast cancer in this high risk population. We present the first report to evaluate 75 established breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), as a risk factor for breast cancer among high risk women taking raloxifene and tamoxifen for breast cancer prevention. Methods: We conducted a matched case-control study of 594 cases (i.e., participants who developed breast cancer while on SERM therapy) and 1,171 matched controls selected from the 33,000 participants enrolled in the NSABP P-1 and P-2 breast cancer prevention trials. Genotypes of 75 single nucleotide polymorphisms (SNPs) were available from a genome-wide association study conducted at the RIKEN Center for Genomic Medicine. We formed a quantitative PRS from reported per-SNP odds ratios (OR) for the 75 susceptibility loci. Conditional logistic regression was used to examine the PRS as a risk factor for breast cancer and to assess whether the PRS and breast cancer association differed by treatment type, family history, or other clinical characteristics. Analyses also examined associations of PRS with invasive vs. in situ cancer and ER-positive vs. ER-negative cancer. Results: The PRS ranged from 3.98 to 7.74, and a one unit change in PRS was associated with a 42% increase in breast cancer (OR=1.42; 95% CI: 1.18-1.70; P = 0.0002). There was evidence of a stronger association of PRS with breast cancer among women with no first-degree family history (OR=1.62, 95% CI: 1.18-2.21) compared to those with a positive family history (OR=1.32, 95% CI: 1.06-1.66) (Pintx<0.05). The PRS also appeared a stronger risk factor for ER-positive (OR=1.59, 95% CI: 1.25-2.02, P < 0.0002) vs. ER-negative (OR=1.05, 95% CI: 0.68-1.62, P=0.84) breast cancer, although differences did not reach statistical significance (Pintx=0.10). PRS and breast cancer associations were similar across tamoxifen and raloxifene treatments, age at trial entry, 5-year predicted Gail model risk, hysterectomy status, BMI, presence of atypical hyperplasia and invasive vs. in situ cancer. Conclusion: A polygenic risk score composed of 75 loci was a risk factor for ER-positive breast cancer, especially in the absence of a first-degree family history of breast cancer. Further, the PRS associations with breast cancer were similar for women taking tamoxifen or raloxifene for prevention. These data suggest that common genetic variation adds information on risk of ER-positive breast cancer in a high-risk population receiving SERMs. Citation Format: Celine M Vachon, Daniel J Schaid, James N Ingle, Matthew P Goetz, Donald L Wickerham, Michiaki Kubo, Erin E Carlson, Soonmyung Paik, Norman Wolmark, Yusuke Nakamura, Liewei Wang, Richard M Weinshilboum, Fergus J Couch. The contribution of common genetic variation to breast cancer risk among women receiving tamoxifen or raloxifene within the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 trials [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 P6-10-03.

Abstract Background: While the biological functions and clinical importance of ERα are well understood in breast cancer, much less is known about its most closely related family member, ERβ, particularly in the setting of triple negative disease. Additionally, the ability to therapeutically target ERβ in triple negative breast cancer (TNBC) has not been fully explored. Methods: Expression of ERβ protein was determined using a well characterized and validated ERβ specific monoclonal antibody that only recognizes the full-length form of this receptor (PPG5/10) in a cohort of 71 TNBCs. To further define the biological functions of ERβ in TNBC, novel ERβ expressing triple negative cell lines (MDA-MB-231 and Hs578T) were developed and comprehensively characterized at the level of global gene expression profiling, modulation of important biological pathways, cellular proliferation and response to targeted therapies. Results: In TNBCs from 71 patients, nuclear and cytoplasmic ERβ was detected at moderate to high levels in 24% and 32% of cases respectively. This moderate to high expression of both nuclear and cytoplasmic ERβ was associated with higher levels of Ki67. Of the 17 tumors expressing ERβ, 13 (76%) were negative for androgen receptor expression. In the triple negative MDA-MB-231-ERβ and Hs578T-ERβ cell lines, expression of ERβ led to inhibition of proliferation in response to both estrogen and multiple ERβ specific agonists. Microarray analysis and RT-PCR profiling of these cells revealed that estrogen and ERβ agonists highly induced the expression of multiple cystatins, a family of small secreted cysteine protease inhibitors, while suppressing the expression of many interleukins. Conditioned media isolated from estrogen or ERβ agonist treated MDA-MB-231-ERβ cells inhibited the proliferation rates and blocked TGFβ signaling in non-ERβ expressing TNBC cells, effects that were completely reversed following depletion of cystatins from the conditioned media. Conclusions: ERβ is expressed in a substantial proportion of TNBCs, and most do not express the androgen receptor. In TNBC, where targeted therapies are lacking, our data suggest that estrogen or ERβ specific agonists would be expected to elicit anti-tumor effects when ERβ is expressed. These tumor suppressive effects of ERβ appear to be mediated in part through the actions of cystatins, and their inhibition of TGFβ signaling, suggesting that this family of secreted proteins may represent novel biomarkers for monitoring ERβ specific drug responsiveness and/or patient outcomes. Citation Format: Jordan M Reese, Malayannan Subramaniam, Vera J Suman, Xianglin Wu, Vivian Negron, Anne Gingery, Kevin S Pitel, Sejal S Shah, Heather E Cunliffe, Ann E McCullough, Barbara A Pockaj, Thomas C Spelsberg, Matthew P Goetz, James N Ingle, John R Hawse. Therapeutic targeting of ERβ in triple negative breast cancer [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 P6-03-06.

Abstract Background: Triple negative breast cancer (TNBC) represents 15% of all breast cancers, and is characterized by an aggressive clinical course. While efforts are ongoing to characterize the molecular basis for variation in TNBC, there are conflicting data regarding the impact of prognostic factors such as age and Ki-67 typically used for treatment decisions in other breast cancer subtypes. We identified a retrospective cohort of women with ER- breast cancer with long term follow-up, and performed central confirmation of ER, PR, HER2, Ki-67 and histological classification to assess the association of Ki-67 and histologic subtype on clinical outcome in TNBC pateints (pts). Methods: 9,836 women who underwent breast cancer surgery at Mayo Clinic Rochester from 1985-2005 were identified. Pts were excluded due to: ER+ disease (7363); prior cancer (553); non-invasive disease (465); bilateral breast cancer (167); metastatic disease [at diagnosis or within 60 days of surgery (110)]; ER- disease treated with neoadjuvant chemotherapy (121) or adjuvant hormonal therapy (112); or tumor block exhausted (94). For all others, centralized ER/PR/HER2 identified the following for exclusion, >1% ER staining (n=76), > 1% PR (n=14) and HER2+ (n=144) by IHC (3+) or FISH amplification. 225 cases are still undergoing review. For the centrally confirmed pts with TNBC (n=392), Ki-67 and histological characterization (WHO subtypes) were assessed. Results: Patient characteristics are listed in the table. The median age for all TNBC’s was 45 (range 29-88) and nearly all tumors were grade 3 (91%) with high proliferation (63% with Ki-67 > 30%). The median follow-up was >10 years, where 139 pts had a disease event: progression (86) or second primary (53) and 53 died without a disease event. The 10 yr DFS rate was 55.8% (95%CI: 48.8-63.9%) among the 238 pts who did not receive adjuvant chemotherapy (AdjCT) and 58.9% (95% CI: 48.9-70.9%) among the 102 pts administered AdjCT. In pts without adjCT, DFS was found to differ with respect to number of positive LNs (0 vs. 1-4 vs. 4+; log rank p=0.003) and medullary histology (log rank p=0.015) but not with age (< 50 vs. ≥ 50), tumor size (< 2.0 vs. 2-5 vs. ≥ 5.0 cm) or Ki-67 (0-15% vs. 15.1-30% vs. >30 %). Conclusions: Our findings confirm the poor prognosis of TNBC. The medullary histological subtype is associated with significantly better prognosis than other TNBC subtypes (10 year DFS rate of 78.5%; 95%CI: 59.1-99.9% in pts not treated with adjCT). After central confirmation, neither age nor Ki-67 provide additional prognostic information. Patient characteristicsMedian Age (range)45(29-88) n%Histology Apocrine287.1Carcinoma, anaplastic or undiffrentiated9323.7Central scar/necrotizing348.7Clear Cell297.4Infiltrating ductal ca7118.1Large Cell neuroendocrine143.6Medullary and atypical medullary4311.0Metaplastic ca246.1Trabecular ca338.4other histologies235.9Grade 130.82317.9335891.3Tumor Size 0.1-2 cm19650> 2.0 cm19549.6not stated10.3Nodal status 0251641-38220.94-9338.410+225.6not evaluated41.0Ki-67 0-157719.615.1-306516.6>30%24763.3not done20.5Adjuvant Chemotherapy Yes10226.0No23860.7unknown5213.3 Citation Format: Ahmed Elkhanany, Vera J Suman, Victoria Cafourek, Judith A Gilbert, James N Ingle, Fergus Couch, Daniel W Vissscher, Matthew P Goetz. Triple negative breast cancer: The role of classic histological and prognostic factors on disease free survival [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 P5-02-11.

Abstract [Background] Patient advocates bring a unique, valuable perspective and presence to SPOREs. However, although patient advocates are recommended members of SPORE grants, guidelines are not given on the role of advocates or on measurement of the performance of advocates. [Methods] The Mayo Clinic Breast Cancer SPORE Patient Advocate Advisory Committee has developed a participation measurement tool. This tool will underpin and augment evaluations of the individual advocate contributions by the program PI and the SPORE project leaders. The Advocate Advisory Committee Chair will review the evaluations with the individual advocates. Annually, the advocate committee will review the performance of the group by the standard of the metrics. [Results] Advocates kept a log of their SPORE activities for four months then worked with a statistician to discern patterns of measurable, evaluable behaviors. The determined evaluable areas are training, scientific activity, meeting attendance, communication. Currently, those metrics are being tracked. Advocates developed the metrics together and report activities at the monthly advocate meetings. Currently, activities are simply tracked and categorized. No minimum standards are set. This will be the third step in the development of the metrics. [Conclusions] This approach is the first step in the development of meaningful evaluation of advocate SPORE activities. It quantifies the participation of advocates in the SPORE and provides the basis for developing a qualitative performance evaluation. The SPORE PI and the Committee Chair will use the evaluations to interpret the involvement of advocates in SPORE research and activities and to plan interventions to strengthen the advocate contributions to the SPORE. Citation Format: Cynthia Chauhan, Wayland Eppard, Lori Denison, Debra Gearhart, Lawanna Holmes, Ruth Kraft, Linda Miller, Mary A Sitta, Mary L Smith, James Ingle, Matthew Goetz. Measurements of advocate participation in and contributions to the Mayo Clinic breast cancer SPORE [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 P2-09-04.