blood biomarkers · - comprehensive tumor profile pca heterogeneity - non-invasive biopsies not...
Post on 22-Aug-2020
1 Views
Preview:
TRANSCRIPT
BLOOD BIOMARKERS
ELENA CASTRO
Hospital V. de la VictoriaSpanish National Cancer Research Centre
ESMO Preceptorship on Prostate cancer.Lugano 17-18 October 2019
Disclosures
Participation in advisory boards: Astra-Zeneca, Astellas, Bayer, JanssenResearch funding: Astra Zeneca, Bayer, JanssenSpeaker fees: Astra Zeneca, Astellas, Bayer, Janssen, PfizerTravel, accomodation, expenses: Astellas, Astra-Zeneca, Bayer, Bristol-Myers,Janssen, Roche
BIOMARKER
A characteristic (clinical or molecular) that can be measured (objectively and reproducibly) to indicate a biologic condition (including normal or pathogenic processess) and also a response to a therapeutic intervention.
Bastos & Antonarakis, Expert Rev Mol Diagn, 2018
Docetaxel
Cabazitaxel
Abiraterone
Enzalutamide
Radium-223
Need for validated predictive biomarkers to guide therapeutic choices
BRCA1/2 alterations predict
response to PARP inhibitors
PROGNOSTIC Biomarkers
LABORATORYbiomarkers
CLINICALbiomarkers
IMAGINGbiomarkers
PATHOLOGIC /MOLECULARbiomarkers
- PSA (baseline and kinetics)
- LDH
- Hemoglobin
- Alkaline phosphatase
- Serum Albumin
- Neutrophil-lymphocyte
ratio (NLR)
- CTC count ≥ 5 vs ≤5- CTC count conversión
(<5) after 12 weeks
- Performance status
- Pain / use of opioids
- Sites of metastasis
- Extent of disease
- Histologic variants
- Gleason score
- Rb1, TP53, PTEN alterations
- AR-V7 detection
- AR copy number
- ctDNA fraction
- DDR genes alterations
Bastos & Antonarakis, Expert Rev Mol Diagn, 2018Terada et al, Ther Adv Med Oncol, 2017
Saad et a, Lancet Oncol, 2016
Alkaline Phosphatase Haemoglobin
ECOG Pain
PROSTATE SPECIFIC ANTIGEN (PSA)
• Definition of Castration Resistance
-Castrate serum levels of testosterone (testosterone <50ng/dl or <2nmol/l)
-Two consecutive rises of PSA, 1 week apart, resulting in a 50% increase over the nadir
-If MAB: Antiandrogen withdrawal for at least 4 weeks (flutamida) or 6 weeks (bicalutamide)
-Radiographic progression (RECIST 1.1 and PCWG3 criteria)
Monitoring PCa
PSA should be assessed by cycle (3 or 4 weeks)
PSA outcomes should be interpreted within the context of a drug’s mechanism of actionand the anticipated timing of a potential favorable/unfavorable effect on PSA should be considered
Recognize that a favourable effect on PSA may be delayed for ≥12 weeks, even for a cytotoxicdrug.
Ignore early rises (before 12 weeks) in determining PSA response Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 weeks unless
other evidence of progression
PSA to monitor CRPC treatments
A. Time to PSA Progression B. Time to Radiographic Progression C. Time to Death
Outcome
Maximal Confirmed PSA Decline From Baseline at Month 3 in the Enzalutamide Arm (N = 795)a
No Decline/ Decline < 30%(n = 94/795)
≥ 30% Decline(n = 701/795)
≥ 50% Decline(n = 639/795)
≥ 90% Decline(n = 307/795)
Best objective soft-tissue response (CR + PR), % (95% CI)
12.0 (4.5-24.3) 70.6 (65.1-75.6)P < .001b
74.8 (69.2-79.9)P < .001b
89.7 (82.8-95.0)P < .001b
Median (95% CI) time to PSA progression, mo 3.7 (3.7-4.6) 13.8 (11.3-14.0) 13.9 (13.8-16.6) 22.5 (16.8-NYR)HR (95% CI) for time to PSA progression 1.0 (ref) 0.17 (0.13-0.22) 0.16 (0.12-0.20) 0.10 (0.08-0.14)
Median (95% CI) rPFS, mo 7.9 (3.7-NYR) NYR (13.8-NYR) NYR (13.8-NYR) NYR (13.8-NYR)HR (95% CI) for rPFS 1.0 (ref) 0.20 (0.13-0.31) 0.17 (0.11-0.27) 0.10 (0.05-0.19)
Median (95% CI) OS, mo 23.1 (17.8-28.0) 32.4 (31.5-NYR) NYR (31.5-NYR) NYR (NYR-NYR)HR (95% CI) for OS 1.0 (ref) 0.31 (0.22-0.42) 0.28 (0.20-0.39) 0.19 (0.12-0.28)
Armstrong, ESMO 2017
ORR = 70.6%*
423.5 25.9
45.3
8
47.1 48.9
44.4
68
27.8 23.79.4
18
1.6 1.5 0.92
0%10%20%30%40%50%60%70%80%90%
100%
No PSA Decline(n = 60)
PSA ≥ 30 Decline(n = 407)
PSA ≥ 50 Decline(n = 367)
PSA ≥ 90 Decline(n = 164)
Patie
nts,
%
Complete Response Partial Response Stable Disease Progressive Disease Not Evaluable
ORR = 89.7%*ORR = 74.8%*
PREVAIL: PSA decline associated with radiographic response
*P < .001 vs no PSA decline/PSA decline < 30% based on Fisher’s exact test. ClinicalTrials.gov identifier: NCT01212991. Abbreviations: ITT, intent to treat; ORR, objective response rate; PSA, prostate-specific antigen.
Armstrong, ESMO 2017
LATITUDE study: PSA response associated with better outcomesin mHSPC receiving ADT + AA + P or PBO
Matsubara N, et al. Ann Oncol 2018;29(Suppl 8):797PD.
Risk reduction AAP + ADT
Risk reduction PBO + ADT
50% PSA response ~56% (RR=0.44) ~41% (RR=0.59)
90% PSA response ~89% (RR=0.107) ~72% (RR=0.283)
Reduction in risk of death in PSA responders vs nonresponders
Time to PSA progression strongly correlated with rPFS (Kendall’s tau=0.9211) and OS (Kendall’s tau=0.666)
• Rising PSA is typically the first sign of tumour regrowth, preceding clinical and radiographic progression
Halabi et al , JCO, 2014
Halabi et al , JCO, 2014
Patient 1 Patient 2
ECOG 0 2
PSA 17.3 207
Disease site Lymphs only Visceral
Opioids use No Yes
LDH Normal >1ULN
Hemoglobin 14 10.8
Alkaline Phosphatase 119 247
- Comprehensive tumor profilePCa heterogeneity
- Non-invasiveBiopsies not always feasible
- Easily obtainedRepeatableMonitoring
CIRCULATING biomarkers
de Bono, Clin Cancer Res, 2008
CIRCULATING TUMOR CELLS
CTCs enumeration in mCRPC has been correlated with survival (prognostic biomarker)
CTC count ≥ 5 at baseline have worse survival
de Bono et al, Clin Cancer Res, 2008Olmos et al, Ann Oncol, 2009
CIRCULATING TUMOR CELLS
CTCs conversión associated with better outcomes
CTC conversión (from ≥ 5 to ≤ 5) after 12 weeks of therapy have better outcomes
CTC conversión (30% decrease) after 12 weeks of therapy have better outcomes
TOPARP-B
Bi-allelic BRCA (n=46)
Composite response rate 29/46 (63%)
Objective response rate 12/29 (41%)
PSA50 23/46 (50%)
CTC Conversion 18/38 (47%)
GALAHAD
CTCs to measure response in clinical trials
Mateo et al, NEJM, 2015; Mateo et al, ASCO 2019, Smith et al, ESMO 2019
Molecular characterization of CTCs
Attard et al, Cancer Res, 2009
AR splicing variants
Lallous et al, Int J Mol Sci, 2013
AR-V7 Adna test
Antonarakis et al. N Engl J Med 2014
Treatment1Baseline AR-V7+
Response
AR-V7 status PSA50 P- value rPFS P- value OS (95% CI) P value
Abiraterone(N=31) 19% (6/31)
+ 0% (0/6).004
2.3 mos<.001
10.6 mos (8.5–NR).002
– 68% (17/25) >6.3 mos >11.9 mos (11.9–NR)
Enzalutamide(N=31) 39% (12/31)
+ 0% (0/12).004
2.1 mos<.001
5.5 mos (3.9–NR).006
– 53% (10/19) 6.1 mos NR (NR–NR)
Adna-test
Epic test
Armstrong et al, JCO, 2019
Scher, JAMA Oncol, 2016
ARSi:PSA decline ≥50: 0% AR-V7+PSA decline <50%: 20%AR-V7+
No association between AR-V7 and response to taxanes
AR-V7 prevalence increases with disease progression
Response to taxanes independent of AR-V7
Annala et al, Cancer Discov, 2018
CIRCULATING TUMOR DNA (ctDNA)
Normal DNA
Tumour DNA
Annala et al, Cancer Discov, 2018
Annala et al, Cancer Discov, 2018
AR amplification and mutation do not preclude therapy response
Conteduca , Ann Oncol, 2017
Annala et al, Cancer Discov, 2018
AR gain associates with por OS and PFS
Annala et al, Cancer Discov, 2018Conteduca et al, Ann Oncol, 2017
Romanel et al, Sci Trans Med, 2015
Annala et al, Cancer Discov, 2018
Concordance of genome copy number between liquid and solid
biopsiesConcordance of mutation calls between solid and liquid biopsies
Wyatt et al, JNCI, 2017
Relationship between observed copy number and ctDNA fraction
Jayaram et al, Cancer Discov, 2018
A low ctDNA fraction limits the detection of less abundant subclonal aberrations and accurate estimation of copy-number changes, especially monoallelic mutations
top related