Update Breast Cancer 2018 (Part 4) – Genomics, Individualized Medicine and Immune Therapies – in the Middle of a New Era: Treatment Strategies for Advanced Breast Cancer

Volkmar Müller; Achim Wöckel; Michael P. Lux; Wolfgang Janni; Andreas D. Hartkopf; Naiba Nabieva; Florin-Andrei Taran; Peyman Hadji; Hans Tesch; Johannes Ettl; Diana Lüftner; Manfred Welslau; Erik Belleville; Sara Y. Brucker; Florian Schütz; Peter A. Fasching; Tanja N. Fehm; Hans-Christian Kolberg; Andreas Schneeweiss; Friedrich Overkamp

doi:10.1055/a-0715-2899

Geburtshilfe und Frauenheilkunde, Table of Contents

CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2018; 78(11): 1119-1128
DOI: 10.1055/a-0715-2899

GebFra Science

Review/Übersicht

Georg Thieme Verlag KG Stuttgart · New York

Update Mammakarzinom 2018 (Teil 4) – Genomforschung, individualisierte Medizin und Immuntherapien – mitten in einer neuen Ära: Therapie des fortgeschrittenen Mammakarzinoms

Article in several languages: English | deutsch

Authors

Volkmar Müller

¹Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany
Achim Wöckel

²Department of Gynecology and Obstetrics, University Hospital Würzburg, Germany
Michael P. Lux

³Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
Wolfgang Janni

⁴Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
Andreas D. Hartkopf

⁵Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
Naiba Nabieva

³Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
Florin-Andrei Taran

⁵Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
Peyman Hadji

⁶Department of Bone Oncology, Nordwest Hospital, Frankfurt, Germany
Hans Tesch

⁷Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany
Johannes Ettl

⁸Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
Diana Lüftner

⁹Charité University Hospital, Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology and Tumour Immunology, Berlin, Germany
Manfred Welslau

¹⁰Onkologie Aschaffenburg, Hämatolo-Onkologische Schwerpunktpraxis am Klinikum Aschaffenburg, Aschaffenburg, Germany
Erik Belleville

¹¹ClinSol GmbH & Co. KG, Würzburg, Germany
Sara Y. Brucker

⁵Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany
Florian Schütz

¹²Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
Peter A. Fasching

³Erlangen University Hospital, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
Tanja N. Fehm

¹³Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany
Hans-Christian Kolberg

¹⁴Department of Gynecology and Obstetrics, Marienhospital Bottrop, Bottrop, Germany
Andreas Schneeweiss

¹²Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany

¹⁵National Center for Tumor Diseases, Division Gynecologic Oncology, University Hospital Heidelberg, Heidelberg, Germany
Friedrich Overkamp

¹⁶OncoConsult Hamburg GmbH, Hamburg, Germany

Abstract

Zusammenfassung

Neue Therapieentwicklungen zur Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom konzentrieren sich zurzeit sowohl auf die Identifikation von Patientinnen für zielgerichtete Therapieansätze als auch auf die Weiterentwicklung von immuntherapeutischen Ansätzen. Die Datenlage zu den CDK4/6-Inhibitoren konnte vervollständigt werden und ist konsistent in dieser Klasse von Substanzen (Palbociclib, Ribociclib und Abemaciclib). Weitere Signalwege, die untersucht werden, sind der PI3K-und der AKT-Signalweg sowie verschiedene Ansatzpunkte zu deren Hemmung. Für beide Wirkmechanismen liegen auch erste Studienergebnisse vor, die vor Kurzem vorgestellt wurden. Außerdem wachsen die Erkenntnisse zu den PARP-Inhibitoren, für die auch untersucht wird, in welcher Population sie am effektivsten eingesetzt werden können. Dieser Review-Artikel soll die aktuellen Studien zusammenfassen und einen Ausblick der neuesten Entwicklungen geben.

Schlüsselwörter

Mammakarzinom - Behandlung - Metastasen - CDK4/6 - PD1/PDL1

Full Text

References

References/Literatur
1 Schneeweiss A, Lux MP, Janni W. et al. Update Breast Cancer 2018 (Part 2) – Advanced Breast Cancer, Quality of Life and Prevention. Geburtsh Frauenheilk 2018; 78: 246-259
2 Taran FA, Fasching PA, Volz B. et al. Overall survival of metastatic breast cancer patients – data from the PRAEGNANT breast cancer registry. Cancer Res 2018; 78
3 Slamon DJ, Leyland-Jones B, Shak S. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-792
4 Swain SM, Baselga J, Kim SB. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724-734
5 Verma S, Miles D, Gianni L. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-1791
6 Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res 2016; 18: 17
7 OʼLeary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 2016; 13: 417-430
8 Baselga J, Campone M, Piccart M. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366: 520-529
9 Tesch H, Stoetzer O, Decker T. et al. Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. Int J Cancer 2018;
10 Robson M, Im SA, Senkus E. et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017; 377: 523-533
11 Litton J, Rugo HS, Ettl J. et al. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physicianʼs choice of therapy in patients with advanced breast cancer and a germline BRCA mutation [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: Abstr.. GS6-07
12 Telli ML, Turner NC, Mailliez A. et al. ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial [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: Abstr.. P1-14-03
13 Turner NC, Telli ML, Rugo HS. et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 35 (Suppl.) Abstr.. 1007
14 Polasik A, Tzschaschel M, Schochter F. et al. Circulating Tumour Cells, Circulating Tumour DNA and Circulating MicroRNA in Metastatic Breast Carcinoma – What is the Role of Liquid Biopsy in Breast Cancer?. Geburtsh Frauenheilk 2017; 77: 1291-1298
15 Normanno N, Cervantes A, Ciardiello F. et al. The liquid biopsy in the management of colorectal cancer patients: Current applications and future scenarios. Cancer Treat Rev 2018; 70: 1-8
16 Baselga J, Cortes J, Kim SB. et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012; 366: 109-119
17 Urruticoechea A, Rizwanullah M, Im SA. et al. Final overall survival (OS) analysis of PHEREXA: A randomized phase III trial of trastuzumab (H) + capecitabine (X) ± pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) who experienced disease progression during or after H-based therapy. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1013
18 von Minckwitz G, Timms K, Untch M. et al. Homologous repair deficiency (HRD) as measure to predict the effect of carboplatin on survival in the neoadjuvant phase II trial GeparSixto in triple-negative early breast cancer. Cancer Res 2017; 77: P1-09-02
19 Guo W, Lin L, He X. et al. Biomarkers of DNA Repair and Related Pathways: Significance of Treatment in Triple-Negative Breast Cancer. Crit Rev Oncog 2017; 22: 427-437
20 Zhao EY, Shen Y, Pleasance E. et al. Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. Clin Cancer Res 2017; 23: 7521-7530
21 Telli ML, Hellyer J, Audeh W. et al. Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast Cancer Res Treat 2018; 168: 625-630
22 Tutt A, Tovey H, Cheang MCU. et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 2018; 24: 628-637
23 Fasching PA, Loibl S, Hu C. et al. BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study. J Clin Oncol 2018; 36: 2281-2287
24 Hahnen E, Lederer B, Hauke J. et al. Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol 2017; 3: 1378-1385
25 Wunderle M, Gass P, Haberle L. et al. BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat 2018; 171: 85-94
26 Byrski T, Gronwald J, Huzarski T. et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010; 28: 375-379
27 Loibl S, OʼShaughnessy J, Untch M. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol 2018; 19: 497-509
28 Telli ML, Metzger O, Timms K. et al. Evaluation of homologous recombination deficiency (HRD) status with pathological response to carboplatin ± veliparib in BrighTNess, a randomized phase 3 study in early stage TNBC. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 519
29 Couch FJ, Hart SN, Sharma P. et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015; 33: 304-311
30 Haberle L, Hein A, Rubner M. et al. Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods. Geburtsh Frauenheilk 2017; 77: 667-678
31 Purrington KS, Slager S, Eccles D. et al. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. Carcinogenesis 2014; 35: 1012-1019
32 Stevens KN, Fredericksen Z, Vachon CM. et al. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus. Cancer Res 2012; 72: 1795-1803
33 Stevens KN, Vachon CM, Lee AM. et al. Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 2011; 71: 6240-6249
34 Wunderle M, Olmes G, Nabieva N. et al. Risk, Prediction and Prevention of Hereditary Breast Cancer – Large-Scale Genomic Studies in Times of Big and Smart Data. Geburtsh Frauenheilk 2018; 78: 481-492
35 Davies H, Glodzik D, Morganella S. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017; 23: 517-525
36 Litton JK, Scoggins M, Hess KR. et al. Neoadjuvant talazoparib (TALA) for operable breast cancer patients with a BRCA mutation (BRCA+). J Clin Oncol 2018; 36 (Suppl.) Abstr.. 508
37 Fasching PA, Hu C, Hart SN. et al. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [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: Abstr.. PD1-02
38 Kommission Mamma der Arbeitsgemeinschaft Gynäkologische Onkologie e.V. in der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e.V. sowie in der Deutschen Krebsgesellschaft e.V.. Diagnostik und Therapie von Patientinnen mit primärem und metastasiertem Brustkrebs. Online: https://wwwago-onlinede/fileadmin/downloads/leitlinien/mamma/2017-03/AGO_deutsch/PDF_Gesamtdatei_deutsch/Alle_aktuellen_Empfehlungen_2018pdf last access: 07.07.2018
39 Sledge jr. GW, Toi M, Neven P. et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol 2017; 35: 2875-2884
40 Neven P, Rugo HS, Tolaney SM. et al. Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1002
41 Tripathy D, Im SA, Colleoni M. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018;
42 Slamon DJ, Neven P, Chia S. et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 2018; 36: 2465-2472
43 Turner NC, OʼLeary B, Cutts R. et al. Genetic landscape of resistance to CDK4/6 inhibition in circulating tumor DNA (ctDNA) analysis of the PALOMA3 trial of palbociclib and fulvestrant versus placebo and fulvestrant. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1001
44 Bardia A, Diamond JR, Vahdat LT. et al. Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2– metastatic breast cancer (mBC). J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1004
45 Saura C, Thistlethwaite F, Banerji U. et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1014
46 Iwata H, Tamura K, Doi T. et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: Long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 2501
47 Modi S, Tsurutani J, Takahashi S. et al. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Cancer Res 2018; 78: Abstr.. PD3-07
48 Li X, Dai D, Chen B. et al. Efficacy of PI3K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: A literature-based meta-analysis of 46 randomised control trials. PLoS One 2018; 13: e0192464
49 Lux MP, Fasching PA, Schrauder MG. et al. The PI3K Pathway: Background and Treatment Approaches. Breast Care (Basel) 2016; 11: 398-404
50 Schettini F, Buono G, Trivedi MV. et al. PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom?. Breast Care (Basel) 2017; 12: 290-294
51 Baselga J, Dent SF, Cortés J. et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. J Clin Oncol 2018; 36 (Suppl.) Abstr.. LBA1006
52 Schmid P, Abraham J, Chan S. et al. AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1007
53 Kim SB, Dent R, Im SA. et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2017; 18: 1360-1372
54 Dent R, Im SA, Espie M. et al. Overall survival (OS) update of the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for locally advanced/metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1008
55 Bettegowda C, Sausen M, Leary RJ. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6: 224ra224
56 Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett 2007; 253: 180-204
57 Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-437
58 Vidula N, Juric D, Niemierko A. et al. Comparison of tissue genotyping (TG) vs. circulating tumor DNA (ctDNA) for selection of matched therapy and impact on clinical outcomes among patients with metastatic breast cancer (MBC). J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1020
59 Medford A, Niemierko A, Moy B. et al. Molecular alterations in the Ras-Raf-Erk (MAPK) pathway in metastatic hormone receptor positive (HR+)/HER2- breast cancer: Incidence and impact on clinical outcomes. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1021
60 Budd GT, Cristofanilli M, Ellis MJ. et al. Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12: 6403-6409
61 Cristofanilli M, Budd GT, Ellis MJ. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-791
62 Huebner H, Fasching PA, Gumbrecht W. et al. Filtration based assessment of CTCs and CellSearch(R) based assessment are both powerful predictors of prognosis for metastatic breast cancer patients. BMC Cancer 2018; 18: 204
63 Muller V, Riethdorf S, Rack B. et al. Prognostic impact of circulating tumor cells assessed with the CellSearch System and AdnaTest Breast in metastatic breast cancer patients: the DETECT study. Breast Cancer Res 2012; 14: R118
64 Janni WJ, Rack B, Terstappen LW. et al. Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer. Clin Cancer Res 2016; 22: 2583-2593
65 Janni W, Rack BK, Fasching PA. et al. Persistence of circulating tumor cells in high risk early breast cancer patients five years after adjuvant chemotherapy and late recurrence: Results from the adjuvant SUCCESS A trial. J Clin Oncol 2018; 36 (Suppl.) Abstr.. 515
66 Davis AA, Pierga JY, Dirix LY. et al. The impact of circulating tumor cells (CTCs) detection in metastatic breast cancer (MBC): Implications of “indolent” stage IV disease (Stage IV_indolent). J Clin Oncol 2018; 36 (Suppl.) Abstr.. 1019
67 Fasching PA, Brucker SY, Fehm TN. et al. Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. Geburtsh Frauenheilk 2015; 75: 41-50
68 Hartkopf AD, Graf J, Simoes E. et al. Electronic-Based Patient-Reported Outcomes: Willingness, Needs, and Barriers in Adjuvant and Metastatic Breast Cancer Patients. JMIR Cancer 2017; 3: e11
69 Hartkopf AD, Huober J, Volz B. et al. Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors – Data from the German PRAEGNANT breast cancer registry. Breast 2018; 37: 42-51
70 Hein A, Gass P, Walter CB. et al. Computerized patient identification for the EMBRACA clinical trial using real-time data from the PRAEGNANT network for metastatic breast cancer patients. Breast Cancer Res Treat 2016; 158: 59-65
71 Muller V, Nabieva N, Haberle L. et al. Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. Breast 2018; 37: 154-160
72 Wallwiener M, Heindl F, Brucker SY. et al. Implementation and Feasibility of Electronic Patient-Reported Outcome (ePRO) Data Entry in the PRAEGNANT Real-Time Advanced and Metastatic Breast Cancer Registry. Geburtsh Frauenheilk 2017; 77: 870-878
73 Wallwiener M, Matthies L, Simoes E. et al. Reliability of an e-PRO Tool of EORTC QLQ-C30 for Measurement of Health-Related Quality of Life in Patients With Breast Cancer: Prospective Randomized Trial. J Med Internet Res 2017; 19: e322
74 Wallwiener M, Simoes E, Sokolov AN. et al. Health-related Quality of Life in Metastatic and Adjuvant Breast Cancer Patients. Geburtsh Frauenheilk 2016; 76: 1065-1073
75 Basch EM, Deal AM, Dueck AC. et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. J Clin Oncol 2017; 35 (Suppl.) Abstr.. LBA2