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2015 San Antonio Breast Cancer Symposium PDF

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2015 San Antonio Breast Cancer Symposium Publication Number: S1-01 Title: Analysis of molecular prognostic factors associated with tumor immune and stromal microenvironment in BEATRICE, an open-label phase 3 trial in early triple-negative breast cancer (eTNBC) Molinero L, Yu J, Li C, Deurloo R, Dent RA A, Bell R, Brown J, Parmar M, Toi M, Suter T, Steger G, Pivot X, Mackey J, Jackisch C, Hall P, Hegde P, Bais C and Cameron D. Genentech Inc., South San Francisco, CA; F Hoffmann-La Roche Ltd, Basel, Switzerland; National Cancer Center, Singapore, Singapore; Sunnybrook Health Sciences Center, University of Toronto, Toronto, Canada; Deakin University, Geelong, Australia; Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom; Medical Research Council Clinical Trials Unit, London, United Kingdom; Kyoto University, Kyoto, Japan; Swiss Cardiovascular Center, Bern University Hospital, Bern, Switzerland; Medical University of Vienna, Vienna, Austria; University Hospital Jean Minjoz, Besançon, France; Cross Center Institute, Edmonton, Canada; Klinikum Offenbach, Offenbach, Germany; Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom and University of Edinburgh and Cancer Services, NHS Lothian, Edinburgh, United Kingdom. Body: Background: TNBC is a mutationally complex heterogeneous breast cancer subtype. In BEATRICE, adding bevacizumab to standard adjuvant chemotherapy for eTNBC improved neither invasive disease-free survival (IDFS; primary endpoint) nor overall survival (OS) [Cameron 2013; Bell SABCS 2014]. We explored prognostic effects of tumor-associated immune and stromal gene signatures. Methods: Gene expression (RNA) was assessed in pretreatment archival tumor tissue using an 800-gene nanostring platform. Given the low event rates and lack of bevacizumab effect in BEATRICE, treatment arms were pooled. The biomarker-evaluable population (BEP; all patients with an evaluable biomarker sample and ‡1 postbaseline efficacy assessment) was dichotomized using median gene expression level as the cutoff. Prognostic associations between IDFS/OS and prespecified candidate gene sets/de novo identified clusters were assessed using univariate Cox proportional hazards models. Results: Baseline characteristics and efficacy were similar in the BEP (988/2591 randomized pts; 38%) and the overall study population. In hierarchical cluster analysis based exclusively on immune gene expression, immune genes were enriched in 33% of samples, intermediate in 38%, and weak in 28%. Further characterization suggested differential prognostic value of distinct immune and stromal cell gene sets (Table). A significant prognostic effect for IDFS and OS was seen for CD8 effector T cell (T ) eff and regulatory T cell (T ) gene signatures, but not for the T :T ratio. A less pronounced positive prognostic effect was seen reg eff reg for other gene sets representing immune cells, including macrophages, CD4 T cells, and B cells (data not shown). Activated T helper (Th)-1 cell-derived chemokines and negative immune modulators of T cell activity (eg PD-L1) were highly prognostic for IDFS and OS. Both the cytokine IL-8 and ESM1 (target of VEGF-A pathway activation) were associated with worse IDFS and OS. No association was seen between outcome and markers for classic microvasculature (CD31, CD34), cancer-associated fibroblasts (FAP, BGN, DCN), VEGF-A, or VEGF-C. IDFS OS Gene signature HR (95% CI) Interaction p-value HR (95% CI) Interaction p-value T 0.40 (0.28-0.57) 7.2x10-7 0.29 (0.17-0.49) 4.2x10-6 eff T 0.38 (0.26-0.54) 1.6x10-7 0.23 (0.13-0.40) 2.9x10-7 reg T :T ratio 0.80 (0.58-1.12) 0.2 0.89 (0.57-1.39) 0.6 eff reg Th1 0.45 (0.31-0.64) 8.1x10-6 0.43 (0.27-0.70) 5.8x10-4 PD-L1 0.42 (0.29-0.60) 1.8x10-6 0.24 (0.14-0.41) 3.4x10-7 IL-8 1.48 (1.06-2.08) 0.022 1.89 (1.18-3.01) 0.0076 ESM1 1.73 (1.23-2.43) 0.0017 2.22 (1.38-3.58) 0.001 Conclusions: These molecular gene signature analyses in eTNBC confirm that markers of cytotoxic CD8 T cells are associated with good prognosis. This is the first report of a positive prognostic effect of regulatory T cell markers, immune checkpoint modulators, and macrophage-associated markers in the adjuvant TNBC setting. High VEGF-A activity, but not its expression, was associated with worse prognosis. The strong prognostic effect of immune checkpoint modulators suggests equilibrium between cytotoxic T cells and their inhibitors in eTNBC, supporting further exploration of immune checkpoint inhibitors in this therapeutic context. 2015 San Antonio Breast Cancer Symposium Publication Number: S1-02 Title: Lymphocytic infiltration in invasive lobular breast cancer Desmedt C, Salgado R, Buisseret L, Zoppoli G, Fornili M, Van den Eynden G, Garaud S, Gundem G, Rothé F, Brown D, Kheddoumi N, Rouas G, Galant C, Bertucci F, Piccart M, Campbell P, Viale G, Larsimont D, Willard-Gallo K, Biganzoli E, Pruneri G and Sotiriou C. Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; University of Genoa, Genoa, Italy; University of Milan and Istituto Nazionale Tumori, Milan, Italy; Universiteit Antwerpen, Antwerp, Belgium; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Université Catholique de Louvain, Brussels, Belgium; Institut Paoli-Calmettes, Marseille, France and European Institute of Oncology, Milan, Italy. Body: Background: The presence and prognostic value of tumor infiltrating lymphocytes (TILs) in invasive breast carcinoma has been demonstrated in several studies, especially in the triple-negative and HER2-positive subtypes. So far, TILs have not been investigated with sufficient detail in invasive lobular breast cancer (ILBC). Here we therefore aimed at: first, assessing the distribution of stromal TILs in ILBC; second, correlating the presence of TILs with standard clinical and pathological markers; third, exploring associations of TILs with recurrent genomic alterations; and, fourth, comparing the lymphocytic composition of ER-positive/HER2-negative lobular to ER-positive/HER2-negative ductal tumors. Material and methods: The percentage of stromal TILs was independently assessed according to Salgado et al. (Ann Oncol 2015) by three pathologists on full-face hematoxylin and eosin slides in a well-annotated retrospective series of 614 primary ILBCs previously characterized at the genomic level. The median value of TILs was used for the analyses. For the association analyses, we focused on the more homogeneous group of ER-positive/HER2-negative ILBC (555/614). Breast cancer-free interval was used as survival endpoint and the analyses were censored at 12 years of follow-up. The comparison of the lymphocytic composition (relative percentage of CD45+ TILs which are CD4+, CD8+ or CD19+) was assessed by FACS in a separate prospective cohort of 51 ER-positive/HER2-negative lobular and 112 ER-positive/HER2-negative ductal tumors. Results: The intraclass correlation coefficient between the three pathologists was 0.71 (95%CI:0.65-0.76). The median percentage of stromal TILs was 5% and the interquartile range 5-10%, with only 9% of the samples having ‡ 20%. Greater numbers of TILs were significantly associated with younger age at diagnosis, axillary lymph node involvement, high proliferative tumors as assessed by Ki67, and with the mixed non-classic ILBC subtypes. Greater numbers of TILs were associated with worse prognosis (HR=1.22; 95%CI:1.07-1.38, p=0.003) only in the unadjusted analysis, as it lost significance after adjustment for standard clinical and pathological variables. Greater numbers of TILs were observed in tumors harboring ARID1A, BRCA2, KMT2C and TP53 mutations, as well as chr3p21.31 and chr8q24.23 (PTK2) loss; whereas lower numbers were observed in tumors with ERBB3 mutations as well as chr7p and chr11q14.1 (PAK1) gains. There were no significant differences in the relative proportion of CD4+, CD8+ or CD19+ lymphocytes between ER-positive/HER2-negative lobular and ductal tumors. Conclusion: In this work, which reports to our knowledge on the largest series of ILBC ever assessed for TILs, we showed that most ILBCs were characterized by low lymphocytic infiltration. Besides the association of TILs with clinical and pathological features of ILBC patients, we found that higher TIL levels were observed in the presence of specific mutations and copy number alterations. Higher numbers of TILs were associated with worse prognosis at the univariate analysis. Finally, based on the assessed markers, we have no evidence of differential lymphocytic composition between ER-positive/HER2-negative lobular and ductal tumors. 2015 San Antonio Breast Cancer Symposium Publication Number: S1-03 Title: Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy Loi S, Drubay D, Adams S, Francis PA A, Joensuu H, Dieci MV Vittoria, Badve S, Demaria S, Gray R, Piccart MJ J, Kellokumpa-Lehtinen P-L, Andre F, Dufaure-Gare I, Denkert C, Salgado R and Michiels S. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Gustave Roussy, Villejuif, France; New York University School of Medicine, NY; Helsinki University Central Hospital, Helsinki, Finland; University of Padova, Padova, Italy; Indiana University, Indianapolis, IN; Dana-Farber Cancer Institute, Boston, MA; Institut Jules Bordet, Brussels, Belgium; Tampere University Hospital, Tampere, Finland and Charite Universite Hospital, Berlin, Germany. Body: Background: Retrospective analyses from individual clinical trials have suggested that host anti-tumor immunity as measured by stromal tumor infiltrating lymphocytes (TILs) is important for the outcomes of the primary triple negative breast cancer (TNBC) subgroup, but the clinical utility of TILs in day-to-day management of primary TNBC is still limited. Our objective was to conduct a pooled analysis of the clinical trials that have investigated TILs in TNBC patients treated by anthracyclines-based (A) chemotherapy regimens in order to gain a robust understanding of the prognostic value of TILs in this setting. Material and methods: Methods were predefined in a protocol. Eligible studies were randomized clinical trials that have evaluated the prognostic associations of TILs (evaluated in the same manner) in patients diagnosed with early stage TNBC treated with A or A plus taxanes (A+T). Cox regression models stratified by trial for invasive disease-free survival (IDFS, primary endpoint) and overall survival (OS), fitting stromal TILs as a continuous variable. Results: We collected individual data from 991 TNBC patients included in 6 randomized clinical trials (ECOG2197, ECOG1199, BIG2-98, FinHER, 2 from Gustave Roussy): 62% of patients were treated by A+T and 38% by A alone; 32% of patients had no nodal involvement, 43% of patients had 1-3 nodes and 25% patients more than 3 nodes involved. The average age was 49 years (range 22.6-85 yrs) and the average tumor size 3.0 cm (sd 1.7). Across the entire data set, the average value of stromal TILs was 20% (sd 17%); 90% of patients had at least 1% stromal TILs. After adjusting for trial, stromal TILs were significantly lower with increasing tumor size (linear model, p<0.0001) but not significantly associated with nodal status categories (p=0.52 and p=0.37) nor age (p=0.25). With a median follow-up of 6.6 years for IDFS and 7.3 years for OS, a total of 363 IDFS events and 273 deaths were observed. Each 10% increase in stromal TILs was associated with a 14% relative reduction in IDFS events (HR=0.86, 95% 0.80 to 0.93, p<0.0001) and a 17% relative reduction in deaths (HR=0.83, 95% CI 0.76 to 0.91, p=0.0001). There was no significant evidence for heterogeneity between trials for IDFS (chi2=4.55, p=0.34) nor for OS (chi2=4.45, p=0.34). In a multivariable analysis adjusted for age, nodal status, tumor size and chemotherapy regimen, stromal TILs added significant independent prognostic information for both IDFS and OS (likelihood chi2=17.9 for IDFS, p<0.0001 and chi2=16.7 for OS, p<0.0001). The adjusted hazard ratio for each 10% increase in stromal TILs was HR=0.86 (0.76-0.92) for IDFS events and HR=0.84 (0.76-0.92) for death. Conclusion: This large pooled individual patient data analysis confirms the strong prognostic role of stromal TILS in primary TNBC treated with A or A+T. TILs should now be strongly considered for incorporation as a stratification factor in future clinical trials enrolling TNBC patients. Given the important prognostic role of pre-existing immunity, patients with TNBC are rational candidates for immunotherapy clinical trials. Funding:Ligue Nationale Contre le Cancer. 2015 San Antonio Breast Cancer Symposium Publication Number: S1-04 Title: Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial Dirix LY Y, Takacs I, Nikolinakos P, Jerusalem G, Arkenau H-T, Hamilton EP P, von Heydebreck A, Grote H-J, Chin K and Lippman ME E. Sint Augustinus - University of Antwerp, Antwerp, Belgium; Semmelweis University, Budapest, Hungary; University Cancer & Blood Center, LLC, Athens, GA; CHU Sart Tilman Liege and Liege University, Liege, Belgium; Sarah Cannon Research Institute, London, United Kingdom; Sarah Cannon Research Institute, North Nashville, TN; Merck KGaA, Darmstadt, Germany; EMD Serono, Billerica, MA and University of Miami Miller School of Medicine, Miami, FL. Body: Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report clinical activity of avelumab in a cohort of patients (pts) with locally advanced (LA) or metastatic breast cancer (MBC) refractory to or progressing after standard-of-care therapy (NCT01772004). Methods: Pts received avelumab at 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response was evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Biopsy or surgical specimens were collected within 90 days prior to 1st dose of avelumab for biomarker analyses. Tumor PD-L1 expression was assessed by immunohistochemistry using various cutoff criteria. Results: As of 27 Feb 2015, 168 pts (167 female, 1 male) with MBC, including ductal (56.5%), carcinoma NOS (9.5%), lobular (3.6%), or other (30.4%), were treated with avelumab and followed for a median of 10 mo (range 6-15). Median age was 55y (range 31-81), ECOG performance status was 0 (49.4%) or 1 (50.6%), and pts had received a median of 3 prior therapies for LA/M disease (range 0-10; pts must have received prior treatment with taxane and anthracycline, unless contraindicated). Pts were HER2–/ER+ or PR+ (69 [41.1%]), triple negative (TNBC = HER2–/ER–/PR–; 57 [33.9%]), HER2+ (26 [15.5%]), or had unknown biomarker status (16 [9.5%]). Median duration of treatment was 8 wks (range 2-50), and 9 pts (5.4%) remained on avelumab. Any grade treatment-related treatment-emergent AEs (TEAEs) occurred in 120 pts (71.4%); the most common (>10%) were fatigue (33 [19.6%]), nausea (24 [14.3%]), and infusion-related reactions (20 [11.9%]). Treatment-related grade ‡3 TEAEs occurred in 24 pts (14.3%) and included (‡1%) fatigue, anemia, increased GGT, and autoimmune hepatitis (each 3 [1.8%]), and arthralgia (2 [1.2%]). There were 2 treatment-related deaths (acute liver failure, respiratory distress). Unconfirmed objective response rate (ORR) in the entire cohort was 5.4% (9 pts; 95% CI: 2.5, 9.9), with 1 CR and 8 PRs. Five of 9 responses were ongoing at time of cutoff. Stable disease was observed in additional 40 pts (23.8%), for an overall disease control rate of 29.2%. Evidence of tumor reduction by ‡30% was seen in 15 pts (8.9%). There were responders in all biomarker subgroups, including 5 PRs in TNBC (n=57 [8.8%; 95% CI: 2.9, 19.3]). PD-L1 expression was evaluable in 136 pts. Among all pts with PD-L1 expressing immune cells within the tumor, 33.3% (4 of 12) had PRs. In pts with TNBC who had PD-L1+ immune cells within the tumor, 44.4% (4 of 9) had PRs, compared with 2.6% (1 of 39) for TNBC and PD-L1– immune cells. Conclusions: Avelumab showed an acceptable safety profile and had clinical activity in a subset of pts with MBC. In pts with TNBC, presence of PD-L1 expressing immune cells within the tumor may be associated with clinical responses to avelumab. Further analyses of PD-L1 expression and clinical activity of avelumab in MBC are ongoing. *Proposed INN. 2015 San Antonio Breast Cancer Symposium Publication Number: S1-05 Title: Moved to S1-05 Pituskin E, Mackey JR R, Koshman S, Jassal D, Pitz M, Haykowsky MJ J, Thompson R, Oudit G, Ezekowitz J and Paterson I. University of Alberta, Edmonton, AB, Canada; University of Manitoba, Winnipeg, MB, Canada; Mazankowski Alberta Heart Institute, Edmonton, AB, Canada; Cross Cancer Institute, Edmonton, AB, Canada; Bergen Cardiac Care Centre, Winnipeg, MB, Canada and Cancer Care Manitoba, Winnipeg, MB, Canada. Body: 2015 San Antonio Breast Cancer Symposium Publication Number: S1-05 Title: Abstract Withdrawn Body: 2015 San Antonio Breast Cancer Symposium Publication Number: S1-06 Title: The miR-424/503 cluster is a breast cancer tumor suppressor with a role in chemoresistance Silva J, Llobet-Navas D, Rodriguez-Barrueco R, Sanchez-Garcia F and Pe'er D. Mount Sinai School of Medicine, NYC, NY and Columbia University, NYC, NY. Body: Recently, we have identified the miR-424(322)/503 cluster as an important regulator of mammary epithelial homeostasis. The miR-424(322)/503 cluster was identified as one of the few miRNAs significantly upregulated during involution after pregnancy. By generating a knock-out mouse model, we found that regression of the mammary epithelium after pregnancy was compromised in the absence of miR-424(322)/503. Mechanistically, our studies unveiled that miR-424(322)/503 is induced by the canonical TGF-b-SMAD pathway, and that it orchestrates changes in the mammary epithelium by downregulating the expression of key components of signal transduction (IGF1R) and apoptosis (BCL2) Llobet et al. Genes&Development 2014). Remarkably, our new studies have revealed that miR-424(322)/503-/- female mice develop hyperplasia and mammary tumors that are promoted by pregnancy. Thus, we investigated the status of this cluster in human breast cancers. For this we analyzed the METABRIC dataset. These studies revealed that the miR-424(322)503 cluster was heterozygously deleted in ~16% of breast cancers and that its deletion correlates with lower expression levels of the mature miRNA forms. Importantly, miR-424(322)/503 is located on the X-chromosome and we have confirmed that is monoallelically expressed due to X-chromosome inactivation. Thus, the mutation of the active allele strongly impacts the expression of the miR-cluster. Deletions of the miR-424(322)/503 locus were more frequent in molecular subtypes with aggressive behavior (Luminal B, HER2+ and Basal) and both deletions and low expression of the cluster were associated with poor prognosis and reduced survival. Some of the miR-424(322)/503 targets that we have previously validated (BCL2 and IGF1R) are involved in resistance to chemotherapy. Thus, we investigated in vivo, utilizing our knock-out mouse model, if loss of miR-424(322)/503 induces resistance to chemotherapeutic drugs. For this we crossed our miR-424(322)/503-/- animals with the HER2+ model FVB/N-Tg(MMTVneu)202Mul/J. Tumors emerging in HER2+/miR-424(322)/503-/- animals presented higher levels of BCL2 and hyperactivation of the IGF1R-AKT signaling compared to HER2+/miR-424(322)/503+/+ counterparts. Furthermore, these tumors were resistant to standard chemotherapy. Importantly, inhibition of BCL2 with ABT-199 and IGF1R with BMS-754807, two compounds currently in clinical trial, completely reverted chemotherapy resistance. Overall, our data present evidence supporting a tumor suppressor role for miR-424(322)/503 cluster and its implication in resistance to chemotherapy. 2015 San Antonio Breast Cancer Symposium Publication Number: S1-07 Title: A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04) Toi M, Lee S-J, Lee ES, Ohtani S, Im Y-H, Im S-A, Park B-W, Kim S-B, Yanagita Y, Takao S, Ohno S, Aogi K, Iwata H, Kim A, Sasano H, Yokota I, Ohashi Y and Masuda N. Yeungnam University Hospital, Daegu, Korea; Kyoto University Hospital, Kyoto, Japan; National Cancer Center, Seoul, Korea; Hiroshima City Hospital, Hiroshima City, Hiroshima, Japan; Samsung Medical Center, Seoul, Korea; Seoul National University Hospital, Seoul, Korea; Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; Asan Medical Center, Seoul, Korea; Gunma Prefectural Cancer Center, Ota, Gunma, Japan; Hyogo Cancer Center, Akashi, Hyogo, Japan; National Kyusyu Cancer Center, Fukuoka, Japan; NHO Shikoku Cancer Center, Matsuyama, Ehime, Japan; Aichi Cancer Center, Nagoya, Aichi, Japan; Korea University Guro Hospital, Seoul, Korea; Tohoku University, Sendai, Miyagi, Japan; Kyoto Prefectural University of Medicine, Kyoto, Japan; Chuo University, Tokyo, Japan and NHO Osaka National Hospital, Osaka, Japan. WITHELD PENDING PRESS CONFERENCE 2015 San Antonio Breast Cancer Symposium Publication Number: S1-08 Title: High risk premenopausal luminal A breast cancer patients derive no benefit from adjuvant chemotherapy: Results from DBCG77B randomized trial Nielsen TO O, Jensen ‎ M-B, Gao D, Leung S, Burugu S, Liu S, Tykjær Jørgensen CL L, Balslev E and Ejlertsen B. Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Danish Breast Cancer Cooperative Group, Copenhagen, Denmark; Genetic Pathology Evaluation Centre, Vancouver, BC, Canada; Canadian Immunohistochemistry Quality Control, Vancouver, BC, Canada and University of Ottawa, Ottawa, ON, Canada. WITHELD PENDING PRESS CONFERENCE

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infiltrating lymphocytes (TILs) is important for the outcomes of the primary triple negative breast cancer (TNBC) subgroup, but the
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