Prostata: Castration resistant HIGHLIGHTS -...
Transcript of Prostata: Castration resistant HIGHLIGHTS -...
Prostata: Castration resistant
HIGHLIGHTS General Sessions
Cinzia Ortega
Oncologia
ASLCN2
Disclosures
• Advisory Boards, Consultant, Honoraria for:
• JANSSEN
• ASTELLAS
• NOVARTIS
• PFIZER
Slide 6
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium
outline
• MOLECULAR DRIVERS IN mCRPC • Genomic alterations • Genomic evolution in PC • Significantly mutated genes in mCRPC
• Liquid biopsies
• AR indifferent disease
• Biomarkers
outline
• MOLECULAR DRIVERS IN mCRPC • Genomic alterations • Genomic evolution in PC • Significantly mutated genes in mCRPC
• Liquid biopsies
• AR indifferent disease
• Biomarkers
MOLECULAR DRIVERS IN mCRPC Genomic alterations
Robinson et al, Cell 2015
Systematic and multi-institutional study of mCRPC tumors obtained from
men previously treated with abi or enza.
•determine the landscape of somatic genomic alterations
•genomic differences between primary prostate cancer and mCRPC
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium (modified)
Robinson et al , Cell 2015
The most frequently aberrant genes in mCRPC included AR (62.7%), ETS
family (56.7%), TP53 (53.3%) and PTEN (40.7%)
Different aberrations seen in mCRPC
Robinson et al, Cell 2015
Aberrations in the AR pathway
Robinson et al, Cell 2015
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium (modified)
Key genes altered
Point mutations
Presented By Joshua Lang at 2017 Genitourinary Cancers Symposium
Challenges
Presented By Eliezer Van Allen at 2017 Genitourinary Cancers Symposium (modified)
outline
• MOLECULAR DRIVERS IN mCRPC • Genomic alterations • Genomic evolution in PC • Significantly mutated genes in mCRPC
• Liquid biopsies
• AR indifferent disease
• Biomarkers
Liquid biopsies: using clues from studies of genomic evolution to develop clinically applicable biomarkers
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
Liquid biopsies
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
Plasma AR status and clinical outcome
Evaluation of plasma AR by next generation
sequencing could identify cancers with
primary resistance to abiraterone.
www.ScienceTranslationalMedicine.org 4 November 2015 Vol 7 Issue 312
Detection of plasma AR amplification,
heavily mutated AR (>2 mutations) and
RB1 loss were associated with worse PFS.
Detection of plasma AR amplification,
heavily mutated AR (>2 mutations) and
RB1 loss were associated with worse PFS.
Plasma AR is associated with worse outcome in PREMIERE trial
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium 98 mCRPC treated with enza in 16 spanish hospitals (pretreatment collection)
Conclusions
Presented By Gerhardt Attard at 2017 Genitourinary Cancers Symposium
Slide 1
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
Slide 5
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
Hormone regulated gene
In BC this gene is frequently
deleted or has loss of function
mutations
In BC this gene is associated
with the resistance to TAM
In PC truncating mutations
Enriched in M1 PC
More clonal in M1
Slide 11
Presented By Joshua Armenia at 2017 Genitourinary Cancers Symposium
outline
• MOLECULAR DRIVERS IN mCRPC • Genomic alterations • Genomic evolution in PC • Significantly mutated genes in mCRPC
• Liquid biopsies
• AR indifferent disease
• Biomarkers
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
AR indifferent disease can emerge during progression
Wyatt et al, EMBO Molecular Medicine Vol 7 | No 7 | 2015
Small cell carcinoma • Morphological diagnosis
• Therapeutic implications • high response to CDDP-based CT • Poor response to AR directed therapies
• Neuroendocrine markers (synaptophysin and cromogranin) • Not specific for small cell • Not predictive for response to therapy
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Small Cell Prostate Carcinomas: <br />Molecularly Distinct from Typical Adenocarcinomas
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Tp53, RB1 and PTEN loss promote
androgen indifference
Cabazitaxel +/- Carboplatin in mCRPC
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Presented By Ana Aparicio at 2017 Genitourinary Cancers Symposium
Conclusions
outline
• MOLECULAR DRIVERS IN mCRPC • Genomic alterations • Genomic evolution in PC • Significantly mutated genes in mCRPC
• Liquid biopsies
• AR indifferent disease
• Biomarkers
Clinical significance of AR mRNA quantification from CTCs in men with metastatic castrate-resistant prostate cancer treated with abiraterone or enzalutamide
Presented By John Silberstein at 2017 Genitourinary Cancers Symposium
Abstracts of interest • Abs 140: Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy
response and applicability of circulating tumor DNA. Werner J. Struss, Matti Annala, Evan W Warner, Kevin Beja, Gillian Vandekerkhove, Amanda Wong, Martin Gleave, Kim N. Chi, Alexander William Wyatt
• Abs 141: Association of changes in circulating cell-free plasma DNA (cfDNA) and circulating tumor cells (CTC) during treatment with clinical outcome from olaparib in castration-resistant prostate cancer (CRPC): Exploratory analyses from the TOPARP-A trial. Joaquin Mateo, Helen Mossop, Jane Goodall, David Lorente, Nuria Porta, Suzanne Carreira, Susana Miranda, Zafeiris Zafeiriou, Christy Ralph, Suneil Jain, Robert J. Jones, Syed A. Hussain, Tony Elliott, Andrew Protheroe, Berni Ebbs, Lorna Leonard, Diletta Bianchini, Penelope Flohr, Emma Hall, Johann S. De Bono
• Abs 149: Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy. Guru Sonpavde, Rebecca J Nagy, A. Oliver Sartor, Gregory Russell Pond, Theodore Stewart Gourdin, Lakshminarayanan Nandagopal, Elisa M. Ledet, Neeraj Agarwal, Emma Carroll, Gurudatta Naik, Jue Wang, Mehmet Asim Bilen, Petros Grivas, Richard B. Lanman, AmirAli Talasaz, Michael B.
• Abs 152: Circulating tumor cells (CTCs) and plasma cell free DNA (cfDNA) androgen receptor amplification (ARamp)-based prognosis in metastatic castration-resistant prostate cancer (mCRPC). Manish Kohli, Jian Li, Meijun Du, David W. Hillman, Winston Tan, Rachel Carlson, Liguo Wang, Liewei Wang, Minetta C. Liu, Huijuan Zhang, Peng Zhang, Liang Wang
• Abs 160: Circulating androgen receptor and serum chromogranin A in castration-resistant prostate cancers (CRPC) patients treated with abiraterone and enzalutamide. Vincenza Conteduca, Samanta Salvi, Valentina Casadio, Cristian Lolli, Giorgia Gurioli, Giuseppe Schepisi, Filippo Martignano, Cecilia Menna, Salvatore Luca Burgio, Sara Testoni, Gerhardt Attard, Ugo De Giorgi
• Abs 186:Circulating tumor DNA (ctDNA) and correlations with clinical prognostic factors in patients with metastatic castration-resistant prostate cancer (mCRPC). Daniel Khalaf, Matti Annala, Kevin Beja, Gillian Vandekerkhove, Muhammad Zulfiqar, Daygen L. Finch, Conrad D. Oja, Joanna Vergidis, Martin Gleave, Alexander William Wyatt, Kim N. Chi