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Mafalda Oliveira, MD PhD Vall d’Hebron University Hospital
Vall d’Hebron Institute of Oncology, Barcelona
Application of NGS panels in liquid
biopsies to manage breast cancer patients
Disclosures
Grant/Research Support (to the Institution): AstraZeneca, Boehringer-Ingelheim, Cascadian Therapeutics, Celldex, Genentech, GlaxoSmithKline, Immunomedics, Novartis, Seattle Genetics, Philips Healthcare, Piqur, PUMA Biotechnology, Roche, Sanofi
Consultant: GSK, PUMA Biotechnology, Roche
Honoraria: Roche
Travel Grants from: GP Pharma, Grünenthal, Novartis, Pierre-Fabre, Roche
Outline
• Advantages of ctDNA for tumor profiling in MBC
• Some methodological issues: analytical and clinical validity
• Clinical Utility of NGS in ctDNA in MBC
• Ongoing research
• Final remarks
Advantages of ctDNA for tumor profiling in MBC
• Tissue not always available
• Less invasive method compared to tumor biopsy
• Lower cost to obtain
• Captures cancer heterogeneity
• Possibility of monitoring response to treatment
Jankowitz et al., Clin Cancer Res. 2017
Potential Uses of Liquid Biopsy in Breast Cancer
Wan et al. Nat Rev Cancer. 2017 Apr;17(4):223-238
Application of NGS panels in liquid
biopsies to manage breast cancer patients
Keep in mind…
Localized vs Metastatic Disease (n = 223)
Bettegowda et al, Sci Tran Med Feb 2014
Shedding rate
Depends on tumor type, metastasis location, time of plasma collection
Detection of Subclones with or without mutations of interest
Intratumoral heterogeneity
González-Angulo et al., Mol Can Ther.,2011
Some methodological issues
Analytical validity Ability of a test to accurately and reliably detect a variant Includes: accuracy, sensitivity, specificity, and robustness
Clinical validity The test may accurately detect the presence or absence of a pathologic state or predict outcomes for groups of patients whose test results differ
Clinical utility High levels of evidence exist to demonstrate that the use of the test improves patient outcomes compared with not using it
Some methodological issues
1. Which is the concordance between NGS results in ctDNA and tissue in MBC?
2. How do outcomes based in tissue profiling compare to outcomes based on ctDNA profiling?
Analytical validity Ability of a test to accurately and reliably detect a variant Includes: accuracy, sensitivity, specificity, and robustness
Clinical validity The test may accurately detect the presence or absence of a pathologic state or predict outcomes for groups of patients whose test results differ
SOLAR-1: PFS by Tissue or ctDNA-determined
Mutation Status
ALP + FUL PBO + FUL
HR Event n/N
(%) Median
PFS Event n/N
(%) Median
PFS
Patients with PIK3CA
mutation: tissue 103/169 (60.9) 11.0 129/172 (75.0) 5.7 0.65
Patients with PIK3CA
mutation: plasma 57/92 (62.0) 10.9 75/94 (79.8) 3.7 0.55
Patients without PIK3CA
mutation: tissue 49/115 (42.6) 7.4 57/116 (49.1) 5.6 0.85
Patients without PIK3CA
mutation: plasma 92/181 (50.8) 8.8 103/182 (56.6) 7.3 0.80
Number of patients still at risk
92 87 80 77 68 61 54 52 44 43 41 38 34 31 29 24 23 19 18 16 9 8 6 2 2 1 1 1 0
94 90 58 53 42 41 37 34 30 30 26 22 20 19 18 14 14 11 10 9 6 6 5 2 2 1 1 1 0 Placebo + ful
Alpelisib + ful
Time (months)
0
20
40
60
80
100
Alpelisib + fulvestrant
Placebo + fulvestrant
Censoring times
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Ev
en
t-fr
ee p
rob
ab
ilit
y (
%)
PIK3CA mutant patients determined by ctDNA
Juric D, SABCS 2018
Correlation of PIK3CA mutation in Tissue / ctDNA
ALP + FUL PBO + FUL
HR N Event n/N (%)
Median PFS
Event n/N (%)
Median PFS
Patients with PIK3CA
mutation: tissue 103/169 (60.9) 11.0 129/172 (75.0) 5.7 0.65 341
Patients with PIK3CA
mutation: plasma 57/92 (62.0) 10.9 75/94 (79.8) 3.7 0.55 186
Patients without PIK3CA
mutation: tissue 49/115 (42.6) 7.4 57/116 (49.1) 5.6 0.85 231
Patients without PIK3CA
mutation: plasma 92/181 (50.8) 8.8 103/182 (56.6) 7.3 0.80 363
19 missing plasma: N=322
4 missing plasma: N=227
Plasma
Mut WT Total
Tissue Mut 186 136 322
WT 0* 227 227
Total 186 363 549
*Personal assumption
25% discordance between plasma and tissue
Juric D, SABCS 2018
• MiSeq Amplicon-based NGS (panel of 59 cancer-related genes) performed in synchronously acquired tumor biopsy and ctDNA at disease progression
• N=28 patients
Oliveira M et al, ASCO 2018
Some methodological issues
Analytical validity Ability of a test to accurately and reliably detect a variant Includes: accuracy, sensitivity, specificity, and robustness
Clinical validity The test may accurately detect the presence or absence of a pathologic state or predict outcomes for groups of patients whose test results differ
Some methodological issues
Analytical validity Ability of a test to accurately and reliably detect a variant Includes: accuracy, sensitivity, specificity, and robustness
Clinical validity The test may accurately detect the presence or absence of a pathologic state or predict outcomes for groups of patients whose test results differ
Clinical utility High levels of evidence exist to demonstrate that the use of the test improves patient outcomes compared with not using it
1. Does the use of matched therapies based on ctDNA analysis improve clinical outcomes of MBC patients?
2. Which is the clinical impact of switching treatment if ctDNA analysis identifies the emergence of a resistance allele in MBC?
Selection of matched therapy
Actionable alteration Frequency Class of drug Examples
PIK3CA mutation Luminal 30-40% HER2+ 20-25%
TNBC ~10%
PI3K alpha-isoform inhibitors
Alpelisib GDC-0077
AKT1 mutation ~5% AKT inhibitors Ipatasertib
Capivasertib
ERBB2 mutation ~2-4% HER2-negative HER2 TKI inhibitors Neratinib TAS-0728
ESR1 alterations 30-40% ER+/HER2- Oral SERDs
SERCAs GDC-9545, AZD9833
H3B-6545
NTRK fusions Secretory breast cancer TRK inhibitors Entrectinib
Larotrectinib
High TMB 1-5% all breast cancers Immune checkpoint
inhibitors
Pembrolizumab, Atezolizumab,
Durvalumab, Avelumab MMR <1% all breast cancers
Several panels of NGS for ctDNA
Guardant 360
Foundation ACT
Oncomine Breast Panel
In-House Panels VHIO-Card: 59 genes
ctDNA mutations and efficacy of targeted agents
Number of patients still at risk
92 87 80 77 68 61 54 52 44 43 41 38 34 31 29 24 23 19 18 16 9 8 6 2 2 1 1 1 0 94 90 58 53 42 41 37 34 30 30 26 22 20 19 18 14 14 11 10 9 6 6 5 2 2 1 1 1 0 Placebo + ful
Alpelisib + ful
Time (months)
0
20
40
60
80
100
Alpelisib + fulvestrant
Placebo + fulvestrant
Censoring times
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Ev
en
t-fr
ee p
rob
ab
ilit
y (
%)
SOLAR-1 - Alpelisib
Smyth L, Oliveira M et al, SABCS 2017 Juric D, SABCS 2018
Capivasertib plus Fulvestrant in AKT1-mut ER+ MBCS
Primary objective: to assess the safety and activity profile (ORR) of targeted therapies in patients with targetable mutations identified by ctDNA screening
ESR1 mutations predict AI resistance in HR+ MBC
Turner N et al. SABCS 2018
Interaction test p=0.02
ESR1 mut HR=0.59, 95%CI: 0.39, 0.89
p=0.01
ESR1 wild type HR=1.05, 95%CI: 0.81, 1.37
p=0.69
PADA-1 Study
NCT03079011
ESR1 mutations in ctDNA are tracked by ddPCR (E380, L536, Y537 and D538 ER)
Some methodological issues
Analytical validity Ability of a test to accurately and reliably detect a variant Includes: accuracy, sensitivity, specificity, and robustness
Clinical validity The test may accurately detect the presence or absence of a pathologic state or predict outcomes for groups of patients whose test results differ
Clinical utility High levels of evidence exist to demonstrate that the use of the test improves patient outcomes compared with not using it
ASCO/CAP Guidelines
Merker JD et al. J Clin Oncol. 2018 Jun 1;36(16):1631-1641
Final remarks
• Use of NGS panels in the management of MBC patients remains mainly investigational
• Discordance between ctDNA assays and tumor tissue is around 30%
• This supports value of tumor tissue genotyping to confirm undetected ctDNA findings
• Test patients at the time of disease progression
• Prospective studies are needed to provide additional evidence of clinical validity and clinical utility of ctDNA testing for the management of MBC patients
