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

cortega@aslcn2.it