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Correlation of Somatic Genomic Alterations Between Tissue Genomics and Circulating Tumor DNA (ctDNA) Employing Next Generation Sequencing (NGS): Analysis in Lung and Gastrointestinal Cancers.

Toor M, et al.

Supplementary Table 1

Supplementary Table 1. Common genes between Caris, Paradigm and Guardant360 platforms

Paradigm vs Guardant360 Caris vs Guardant360

1. AKT1 1. AKT1A

2. ALK 2. ALK3. BRAF 3. APC4. BRCA1 4. AR5. BRCA2 5. ARAF6. CCND1 6. ARD1A7. CCND2 7. ATM8. CCNE1 8. BRAF9. CDK4 9. BRCA110. CDK6 10. BRCA211. EGFR 11. CCND112. EGFR 12. CCND213. ERBB2 13. CCNE114. ERBB2 14. CDH115. ESR1 15. CDK416. FGFR1 16. CDK617. FGFR2 17. CDKN2A18. FGFR2 18. CTNNB119. FGFR3 19. DDR220. GATA3 20. EGFR21. GNAQ 21. ERBB222. GNAS 22. ESR123. HRAS 23. EZH224. IDH1 24. FBXW725. IDH2 25. FGFR126. KIT 26. FGFR227. KRAS 27. FGFR328. MAP2K1 28. GATA329. MAP2K2 29. GNA1130. MET 30. GNAQ31. MET 31. GNAS32. MTOR 32. HNF1A33. MYC 33. HRAS34. NRAS 34. IDH135. PDGFRA 35. IDH236. PIK3CA 36. JAK237. RET 37. JAK338. ROS1 38. KIT39. SMO 39. KRAS40. TP53 40. MAP2K141. TSC1 41. MAP2K2

42. MET43. MLH144. MPL45. MTOR46. MYC47. NF1

48. NFE2L249. NOTCH150. NPM151. NRAS52. NTRK153. NTRK354. PDGFRA55. PIK3CA56. PTEN57. PTPN1158. RAF159. RB160. RET61. ROS162. SMAD463. SMO64. STK1165. TERT66. TP5367. TSC168. VHL


Supplementary Table 2: Common mutations between Guardant 360 and Caris/Paradigm platforms

Pt

#

Age

(years)

Gender(M/F)

Diagnosis Common mutations

(n =8)

4 78 M Adenocarcinoma of

Lung

EGFR (G719A)

EGFR (S768I)

10 45 M Colorectal

Adenocarcinoma

KRAS (G12D)

TP53 (R248W)

15 67 F Adenocarcinoma of

Lung

EGFR (Exon 19 Insertion)

18 74 M Gastroesophageal

Junction Carcinoma

ERBB2 (Amplification)

24 63 M Intrahepatic

Cholangiocarcinoma

IDH1 (R132C)

27 62 F Colorectal

Adenocarcinoma

KRAS (Q61H)


Supplementary Table 3: Actionable mutations detected both in tissue and blood and FDA approved drugs for these mutations

Pt #

Age

(years)

Gender(M/F)

Diagnosis Number of

metastatic

lesions

Targetable

mutations in tissue

(n=9)

Drugs (FDA

approved and drugs

under clinical trials)

Reference(s)

Targetable

mutations in blood(n=14)

Drugs (FDA

approved and under

clinical trials)

Reference(s)

2 78 F Adenocarcinoma Lung

2 EML4/ALK

Alectinib*Ceritinib*Crizotinib*Brigatinib*

(1)(2)(3)(4)

4 78 M Adenocarcinoma Lung

>3 EGFR (G719A)

EGFR (S768I)

Afatinib*Erlotinib*Gefitinib*

AP32788***


AP32788***

(5)(6)(6)(5)(7)(8)

EGFR (G719A)

EGFR (S768I)


AP32788***


AP32788***

(5)(6)(6)(5)(7)(8)

6 66 M Pancreatic Ductal

Adenocarcinoma

>3 CDKN2A (L78fs)

Palbociclib**

Palbociclib** +

Letrozole**

(9,10) ATM (R3008C)

Olaparib** (11)

11 67 M Small Cell Lung

Carcinoma

>3 NF1 (R816*)

Trametinib**

Binimetinib***

PLX3397***

(12–14)


2 FGFR1 (Amplifica

tion)

AZD4547***

Debio1347***


>3 EGFR (Exon 19 Insertion)


AP32788***

(15)(15)(15)

EGFR (Exon 19 Insertion)

CDK4


AP32788***

(15)(15)(15)

(16)

(Amplifica

tion)

BRCA2

(R2842H)

Palbociclib**

Abemaciclib***

Rucaparib**Niraparib**Olaparib**

(17)

(18)(19)


3 EGFR

(L858R)

PIK3CA (e542k)


Taselisib**

AZD5363*** GDC-0077***

(20)(21,22)

(23)

(24)

KIT (T670I)

Sorafenib (25)

18 74 M Gastroesophageal Junction

Carcinoma

2 ERBB2 (Amplifica

tion)

Trastuzumab*

Lapatinib**+ Trastuzumab*

Pertuzumab** +

Trastuzumab*

Ado-trastuzuma

b emtansine*

*

Lapatinib**

Neratinib**

Afatinib**

(26)

(27,28)

(26)

(29)

(26)

(30)

(27,28)

(31)

(32)

ERBB2 (Amplifica

tion)

ERBB2(D769Y)

Trastuzumab*

Lapatinib**+

Trastuzumab*

Pertuzumab** +

Trastuzumab*

Ado-trastuzuma

b emtansine*

*

Lapatinib**

Neratinib**

Afatinib**

Neratinib*

(26)

(27,28)

(26)

(29)

(26)

(30)

(27,28)

(31)

(32)

(33)

MET (Amplifica

tion)

Crizotinib**

Cabozantinib**

(34,35)

(36)

24 63 M Intrahepatic

Cholangiocarcinoma

> 3 IDH1 (R132C)

AG-120***BAY14360

32***CB-839***

BRAF (D594N)

IDH1 (R132C)

Sorafenib

AG-120***BAY14360

32***CB-839***

(37)

* FDA approved drugs** FDA approved drugs for malignancies other than GI and lung*** Drugs under clinical trials, www.clinicaltrials.gov

Supplementary Figure 1

Supplementary Figure 1a.

Supplementary Figure 1b.

Supplementary Figure 1c

Supplementary Figure 1d

Figure legends:

Supplementary figure 1a shows case 1 with metastatic pancreatic adenocarcinoma to

the liver treated with mFOLFIRINOX. ctDNA analysis shows that on day 77 of treatment

both KRAS (G12D) and TP53 (A159D) mutations become undetectable. In parallel,

CT scans show a significant decrease in the liver lesions. On day 196 ctDNA NGS

demonstrates emergence of new TP53 splice site mutations, although the clinical

relevance of these alterations is not clear.

Supplementary figure 1b shows a patient with metastatic pancreatic adenocarcinoma to

the liver. Day 0 represents the initiation of gemcitabine and nab-paclitaxel

chemotherapy. On day 63 persistence of KRAS (G12V), APC (K1310fs) and GNAS

(R201H) mutations was noted on ctDNA analysis but a mutation within SMAD4

(H132P), which is a bad prognostic marker, also emerged at this time point.

Interestingly, the patient was deteriorating clinically, and imaging showed worsening of

disease.

Supplementary figure 1c represents a patient with cholangiocarcinoma who developed

recurrent disease on imaging studies before the onset of clinical symptoms. Originally,

the patient had undergone surgical resection followed by chemotherapy and radiation.

On day 634 post resection the patient was doing well clinically, and imaging reported no

recurrence. However, on day 753 ctDNA analysis showed mutations within KRAS

(A146T), SMAD4 (S357P), FGFR3 (S408F), and APC (S2028R) as shown above;

although the patient was asymptomatic, PET scan showed recurrence of the tumor

within the liver which was also confirmed by biopsy.

Supplementary figure 1d shows the clonal evolution of an EGFR exon 19 deletion

positive lung adenocarcinoma. The patient benefited from treatment with afatinib until

day 367 when progression was demonstrated on imaging studies. ctDNA analysis

identified both exon 19 deletion and T790M mutation in the tyrosine kinase (TK) domain

of the EGFR gene on day 375. The patient started on treatment with osimertinib on day

431 which resulted in an excellent response. ctDNA analysis on day 825 detected MET

and CCNE1 gene amplifications. There was a clonal expansion of the EGFR TK exon

19 deletion, TP53 R248W, and PDGFRA E459* mutations; also, a new RB1 K122*

clone was detected, indicating possible disease progression. Disease progression was

confirmed by CT scans on day 885. The patient started treatment with a combination of

osimertinib and crizotinib on day 910. Treatment benefit lasted for approximately 6

months until confirmed radiologic progression occurred on day 1071.

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