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DESTINY-Breast01: Biomarker Analysis (August 1, 2019 DCO Date)

Biomarker Analysis

Biomarker Analysis1

  • Here we examine data from patients in DESTINY-Breast01 for molecular variables predictive of patient outcomes1 
  • Archived tumor tissue samples were collected prior to treatment in order to centrally confirm HER2 status and perform baseline biomarker analyses by RNA sequencing1 
  • Plasma samples for biomarker analysis, including circulating tumor DNA (ctDNA), were collected prior to treatment on day 1 of cycle 1, then on day 1 every 3 cycles thereafter (ie, cycles 4, 7, and 10), and at the end of treatment1 
    • GuardantOMNI (Guardant Health) was used for sequencing to detect single-nucleotide variation/ insertion and deletion, amplification (including the HER2 gene ERBB2), and fusion of approximately 500 genes1 
  • Serum samples for HER2 extracellular domain (HER2 ECD) assessment were collected before dosing on day 1 of cycle 3 and every other cycle thereafter (ie, cycles 5, 7, and 9) as well as at the end of treatment1 

Baseline Biomarkers

Baseline Biomarkers1 

Baseline Biomarkers: ctDNA

  • Blood samples were collected at cycle 1, day 1; passed quality control for ctDNA analysis; and showed detectable ctDNA in 97.7% of patients (171/175). Somatic mutations in the GuardantOMNI report were used1 
  • ERBB2 amplification and gain-of-function mutations were observed in 77% (133/173) and 12% (21/173) of samples, respectively1 
  • High-prevalence somatic mutations included TP53 (75% [130/173]), PIK3CA (57% [98/173]), and NOTCH3 (28% [49/173])1 

Mutational Landscape of ctDNA Patients.1

Mutational Landscape of ctDNA Patients.1

Baseline Biomarkers: ERBB2 and HER2 ECD

Neither baseline-adjusted ERBB2 plasma copy number (pCN)1 in ctDNA nor HER2 ECD levels in patients’ sera were predictive of ORR or PFS (ERBB2, p=0.202; HER2 ECD, p=0.352)1 

Baseline-Adjusted ERBB2 Plasma Copy Number (A)a and HER2 ECD Levels (B) vs Response Rate.1

Baseline-Adjusted ERBB2 Plasma Copy Number (A)a and HER2 ECD Levels (B) vs Response Rate.1

aOnly patients with ERBB2 amplification are included.

 
Covariate
Patients, n
PFS
HR (95% CI)p Value
ERBB2 apCN, log21330.85 (0.67-1.09)0.202
HER2 ECD, log21781.08 (0.92-1.26)0.352

Baseline Biomarkers: Gene Alterations

Several somatic alterations in single genes were correlated with PFS and ORR1 

Univariate Analysis of Gene Alterations in Single Genes for PFS and ORR.1  
Covariate

Type

Status

Patients, n

Median (95% CI)

HR    (95% CI)

p Value FDR Response (CR/PR), n (%) Odds Ratio (95% CI) p Value FDR

PFSa

ORRb


MSH2 

SNV

WT

164

17.6 (12.7-NE)

4.05 


.00134 


0.161

101 (61.6) 3.18


0.158


1

indelmut95.2 (4.1-NE)(1.72-9.54)3 (33.3)(0.71-15.18)


GATA3

SNVWT156

17.6

(17.6-NE)

2.76



.00414


0.167

96 (61.5)1.79


0.3


1

indelmut178.1 (5.7-NE)(1.38-5.51)8 (47.1)(0.63-4.96)


AXL


CNV

WT16017.6 (12.7-NE)3.15

 

.00483


0.167

97 (60.6)1.32


.77


1

amp36.7 (4.1-NE)(1.42-7.01)7 (53.8)(0.41-4.32)


RET


CNV

WT14817.6 (12.7-NE)2.53


.0063


0.167

89 (58.6)0.57


.343


1

amp256.7 (4.3-NE)(1.3-4.94)15 (71.4)(0.21-1.59)


ZNF217


CNV

WT14817.6 (12.7-NE)2.37


.00695


0.167

92 (62.2)1.77


193


1

amp256.7 (4.3-NE)(1.27-4.43)12 (48)(0.74-4.4)


DEPDC5

SNVWT15817.6 (17.6-NE)2.48


.019


0.355

94 (59.5)0.74


.784


1

indelmut157.1 (5.7-NE)(1.16-5.3)10 (66.7)(0.23-2.43)


ROBO1

SNVWT16417.6 (12.7-NE)2.98


.0207


0.355

101 (61.6)3.18


.158


1

indelmut95.7 (3-NE)(1.18-7.5)3 (33.3)(0.71-15.18)


TSC2


CNV

WT15217.6 (12.7-NE)2.18


.0271



0.406


93 (61.2)1.43


.481



1


amp217.1 (5.4-NE)(1.09-4.34)11 (52.4)(0.56-3.61)


FGF3


CNV

WT14417.6 (12.7-NE)1.95


.0314



0.419


88 (61.1)1.27


.678



1


amp297.1 (6-NE)(1.06-3.59)16 (55.2)(0.57-2.99)


FGF19




CNV


WT14917.6 (12.7-NE)1.99


.0366



0.439


91 (61.1)1.33


.654



1

amp247.1 (6.2-NE)(1.04-3.79)13 (54.2)(0.53-3.26)


IGF1R



SNV

WT16117.6 (12.7-NE)2.43


.0418



0.454


98 (60.9)1.55


.546



1


indel

mut126.7 (4.2-NE)(1.03-5.7)6 (50)(0.46-5.24)


CARD 11


SNV

WT16417.6 (12.7-NE)2.86


.0454



0.454


100 (61)1.96


.486



1


indel

mut96.7 (4.2-NE)(1.02-8)4 (44.4)(0.5-7.94)


RUNX1




CNV


WT16317.6 (12.7-NE)1.34


.575



0.877


94 (57.7)0


.00637



0.764


amp10NE (6.7-NE)(0.48-3.71)10 (100)(0-0.6)

SETD2



SNV

WT16417.6 (12.7-NE)1.18


.778


0.929

102 (62.2)5.7


.0305


1

indel

mut9NE (4.1-NE)(0.37-3.79)2 (22.2)(1.21-39.18)
aCox proportional hazards model; bFisher exact test.

Baseline Biomarkers: Not Associated With Clinical Outcomes

PIK3CA mutations and ERBB2 gain-of-function mutations were not associated with clinical outcomes1 

PIK3CA (A) and ERBB2 Gain-of-Function Mutations (B) and PFS.1

PIK3CA (A) and ERBB2 Gain-of-Function Mutations (B) and PFS.1


Covariate 

Type 

Status 

Patients, n 
Median (95% CI) 

HR (95% CI) 

p Value Response (CR/PR), n (%)

Odds Ratio (95% CI) 

p Value

PFS

ORR


ERBB2a

SNVno GOF mut15217.6 (12.7-NE)1.13


0.747

89 (58.6) 0.57 


0.343

Indel

(GOF)

mut21NE (9.9-NE)(0.53–2.4)15 (71.4)(0.21-1.6)


PIK3CAb

SNVno GOF mut10118.1 (12.7-NE) 1.4


0.215

56 (55.4) 0.62 


0.158

Indel

(GOF)

mut7217.6 (9.6-NE)(0.82–2.36)48 (66.7)(0.33–1.2)
aERBB2 gain-of-function mutations were selected based on OncoKB; bPIK3CA SNVs were selected according to the EMILIA study (R88Q, N345K, C420R, E542K, E545A, E545D, E545G, E545K, Q546E, Q546K, Q546L, Q546R, M1043I, H1047L, H1047R, H1047Y, G1049R).

Biomarkers Over Time

Biomarkers Over Time1

Biomarkers Over Time: ERBB21

  • ERBB2 pCN that was amplified at cycle 1, day 1 had decreased to nonamplified levels by cycle 4, day 1 in 88% of patients (100/114) who had available samples1 
  • Samples from almost all responders demonstrated a decrease to nonamplified levels1 
  • Patients whose ERBB2 pCN dropped to nonamplified levels at cycle 4, day 1 had longer PFS1 
  • ERBB2 amplification status at cycle 4, day 1 predicted clinical outcomes
    • In the multivariate analysis for PFS with HER2 IHC/ISH status, the covariate ERBB2 amplification status at cycle 4, day 1 remained significant (data not shown)
  • Paired ctDNA data from 40 patients who discontinued T-DXd treatment due to disease progression were analyzed
  • Oncogenic/likely oncogenic alterations were selected based on OncoKB2
  • Acquired mutations were observed in several genes

ERBB2 Plasma Copy Number Over Time by Patient Response.1

ERBB2 Plasma Copy Number Over Time by Patient Response.1

PFS by ERBB2 Amplification Status at Cycle 4, Day 1.1

PFS by ERBB2 Amplification Status at Cycle 4, Day 1.1

PFS and ORR by ERBB2 Amplification Status at Cycle 4, Day 1.1
Covariate 
Status 
Patients, n 
Median (95% CI) 

      HR       (95% CI) 

p Value Response (CR/PR), n (%) Odds Ratio (95% CI) p Value

PFS

ORR
ERBB2 amp at C4D1Nonamp 10018.1 (17.6–NE) 3.55 


0.00309

71 (71)6


0.00466

Amp146.2 (4.1-NE)(1.53–8.24)4 (28.6)(1.8-22)

ERBB2 pCN values less than the threshold of amplification determined by Guardant Health were represented by a value of 2.


Biomarkers Over Time: Gene Alteration1 

  • Paired ctDNA data from 40 patients who discontinued T-DXd treatment due to disease progression were analyzed
  • Oncogenic/likely oncogenic alterations were selected based on OncoKB1 
  • Acquired mutations were observed in several genes1 
Oncogenic/Likely Oncogenic Acquired Mutations Detected at Disease Progression.1
GenePatients, nMutation 
TP53 3C275Y, R248W, E271K, N239_C242del
BRCA1 2D695fs, 1641_K652del, P674fs, N665fs, E1849
ARID1A 1H688fs 
ATM 1Q1015 
EPHA3 11486fs 
KDM5C 1R198 
MED12 1R1549fs
NFE2L2 1E79K 
NOTCH4 1C744 
POLE1L424V
PTEN1Q214 
TOP11M644_M645del

Mutational Landscape in Patients With Progression of Disease.1

Mutational Landscape in Patients With Progression of Disease.1

Acquired: a mutation detected only at disease progression; lose: a mutation detected only at cycle 1, day 1 (C1D1); mixed: different/the same variants in the same gene at C1D1 and at disease progression.

Abbreviations

Amp = amplification

;

apCN = adjusted plasma copy number

;

CR = complete response

;

ctDNA = circulating tumor DNA

;

DCO = data cut-off

;

DNA = deoxyribonucleic acid 

;

ECD = extracellular domain

;

FDR = false discovery rate

;

GOF = gain-of-function

;

HER2 = human epidermal growth factor receptor 2

;

HR = hazard ratio

;

IHC = immunohistochemistry

;

ISH = in situ hybridization

;

mut = mutation

;

nonamp = nonamplified

;

ORR = objective response rate

;

PD = progressive disease

;

PFS = progression-free survival 

;

PR = partial response 

;

RNA = ribonucleic acid

;

SD = stable disease

;

SNV = single nucleotide variant

;

T-DXd = trastuzumab deruxtecan

References

1. Modi S, Andre F, Krop IE, et al. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis [poster and abstract]. Poster presented at: 2020 Americam Society of Clinical Oncology (ASCO) Virtual Scientific Program. J Clin Oncol. 2020; 38(suppl 15): Abs 1036.
2. Chakravarty D, Gao J, Philips SM, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017;1:PO.17.00011.

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