Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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All Patients n = 114 | Patients Receiving Sequencing n = 36 | Patients Not Receiving Sequencing n = 78 | p-Value | |
---|---|---|---|---|
Demographics | ||||
Mean age (years ± SD) (at diagnosis) | 64.5 ± 11.8 | 60.7 (12.9) | 66.3 (10.9) | 0.02 |
Female, n (%) | 51 (44.7) | 17 (47.2) | 34. (43.6) | 0.72 |
Race, n (%) | ||||
Asian | 30 (26.3) | 9 (25.0) | 21 (26.9) | 0.71 |
Black | 0 (0) | 0 (0) | 0 (0) | |
Hispanic | 30 (26.3) | 8 (22.2) | 22 (28.2) | |
Middle Eastern | 0 (0) | 0 (0) | 0 (0) | |
White | 54 (47.4) | 19 (52.3) | 35 (44.9) | |
Cholangiocarcinoma risk factors, n (%) | ||||
Viral hepatitis | 18 (15.8) | 5 (13.9) | 13 (16.7) | 0.71 |
Primary sclerosing cholangitis | 1 (0.9) | 1 (2.8) | 0 (0) | 0.14 |
Alcohol abuse | 5 (4.4) | 2 (5.6) | 3 (3.9) | 0.68 |
Obese (BMI > 30) | 25 (22.1) | 6 (16.7) | 19 (24.7) | 0.34 |
Diabetes | 27 (23.7) | 5 (13.9) | 22 (28.2) | 0.10 |
Clinical characteristics, n (%) | ||||
Obstructive jaundice at diagnosis | 46 (40.4) | 13 (36.1) | 33 (42.3) | 0.53 |
Tumor site | 0.69 | |||
Intrahepatic, n (%) | 61 (53.5) | 21 (58.3) | 40 (51.3) | |
Hilar, n (%) | 17 (14.9) | 4 (11.1) | 13 (16.7) | |
Extrahepatic distal, n (%) | 36 (31.6) | 11 (30.6) | 25 (32.1) | |
Tumor grade, n (%) | 0.73 | |||
Well differentiated | 9 (7.9) | 2 (5.6) | 7 (9.0) | |
Moderately differentiated | 52 (45.6) | 18 (50.0) | 34 (43.6) | |
Poorly differentiated | 53 (46.5) | 16 (44.4) | 37 (47.4) | |
Mean tumor size, cm (SD) | 4.6 (2.5) | 4.5 (2.9) | 4.4 (2.3) | 0.80 |
Multifocal disease | 16 (14.0) | 8 (22.2) | 8 (10.3) | 0.29 |
Bilobar disease | 4 (3.5) | 1 (2.8) | 3 (3.9) | 0.77 |
T-stage | 0.40 | |||
1 | 26 (22.9) | 8 (22.8) | 18 (24.3) | |
2 | 40 (36.7) | 16 (45.7) | 24 (32.4) | |
3 | 40 (36.7) | 11 (31.4) | 29 (39.2) | |
4 | 3 (2.8) | 0 (0) | 3 (4.1) | |
N-stage | 0.34 | |||
0 | 57 (58.2) | 22 (68.8) | 35 (53.0) | |
1 | 37 (37.8) | 9 (28.1) | 28 (42.4) | |
2 | 4 (4.1) | 1 (3.1) | 3 (4.6) | |
AJCC 8th Edition—Pathological Stage | 0.40 | |||
IA | 12 (11.1) | 3 (8.8) | 9 (12.2) | |
IB | 28 (25.9) | 7 (20.6) | 21 (28.4) | |
IIA | 25 (23.2) | 12 (35.3) | 4 (5.4) | |
IIB | 28 (25.9) | 7 (20.6) | 21 (28.4) | |
IIIA | 10 (9.3) | 2 (5.9) | 8 (10.8) | |
IIIB | 21 (19.4) | 7 (20.6) | 14 (18.9) | |
IIIC | 3 (2.8) | 0 (0) | 3 (4.1) | |
IV | 2 (1.9) | 0 (0) | 2 (2.7) |
All Patients n = 114 | Patients Receiving Sequencing n = 36 | Patients Not Receiving Sequencing n = 78 | p-Value | |
---|---|---|---|---|
Systemic chemotherapy | 83 (72.8) | 28 (77.8) | 55 (70.5) | 0.42 |
Radiation therapy | 43 (38.4) | 15 (41.7) | 28 (36.8) | 0.62 |
Surgery | 0.64 | |||
Liver resection without bile duct resection | 61 (53.5) | 21 (58.3) | 40 (51.3) | |
Resection requiring bile duct resection/reconstruction | 21 (18.4) | 7 (19.4) | 14 (18.0) | |
Pancreaticoduodenectomy | 32 (28.1) | 8 (22.2) | 24 (30.8) | |
Margin status | 0.32 | |||
R0 | 86 (75.4) | 26 (72.2) | 60 (76.9) | |
R1 | 25 (21.9) | 10 (27.8) | 15 (19.2) | |
R2 | 3 (2.6) | 0 (0) | 3 (3.9) | |
Period of treatment | 0.06 | |||
Early (2010–2013) | 25 (21.9) | 3 (8.3) | 22 (28.2) | |
Mid (2014–2016) | 41 (36.0) | 16 (44.4) | 25 (32.1) | |
Late (2017–2020) | 48 (42.1) | 17 (47.2) | 31 (39.7) | |
Median overall survival—months (25%, 75%) | 59 (25, NR) | 42 (25, NR) | NR (26, NR) | 0.16 |
Genes Assessed (WE: Whole Exome) | Actionable Mutations Identified | Tumor Mutational Burden (per MBP) | Identified Mutations/Alterations | Drugs Associated with Identified Mutations | Trials Identified | Therapy Received | Survival (Months) * AWD, † NED at Last Follow-up | |
---|---|---|---|---|---|---|---|---|
1. | 324 | 2 | - | KRAS G12S LRP1B D478N | KRAS Cobimetinib Trametinib | 8 | Gemcitabine/Cisplatinum 5-FU FOLFOX Pembrolizumab | 53 |
2. | 48 | 0 | - | - | 0 | 0 | Gemcitabine/Cisplatinum | 68 |
3. | 324 | 2 | - | KRAS G12V TP53 R248Q | KRAS Trametinib | 6 | Gemcitabine/Cisplatinum Capecitabine | 21 |
4. | WE | 1 | 1 | NRAS Q61R | 0 | 11 | Gemcitabine/Cisplatinum FOLFOX | 76 * |
5. | 324 | 2 | - | BRAF V600E CDKN2A/B | BRAF Dabrafenib Regorafenib Trametinib Vemurafenib | 10 | Gemcitabine/Cisplatinum Capecitabine Dabrafenib/Trametinib | 31 |
6. | 50 | 2 | - | TP53 R213 NRAS G12D | MEK Trametinib mTOR Everolimus Temsirolimus | 5 | Gemcitabine/Cisplatinum | 13 |
7. | 324 | 6 | - | ARID1A E1763 & Q372 NF2 447 PTPN11 G503V CDKN2A EP300 | NF2 Everolimus Lapatinib Temsirolimus Trametinib PTPN11 Trametinib | 10 | Sorafenib Pembrolizumab | 45 |
8. | WE | 4 | 1 | KRAS G12V TP53 S125G CDK6 amplification CDKN2A L16 | CDK6 Abemaciclib Palbociclib Ribociclib | 28 | - | 68 * |
9. | 324 | 2 | - | BRAF V600E CDKN2A loss | BRAF Cobimetinib Dabrafenib Regorafenib Trametinib Vemurafenib | 4 | Gemcitabine/Cisplatinum | 59 * |
10. | 324 | 5 | - | ARID1A Y1719 IDH2 R172W TP53 Y220C BAP1 123-1 LRP1B R295 | None | 1 | - | 8 * |
11. | 324 | 6 | - | PIK3CA M1004I TP53 C141W ATRX A419V GATA6 amplification MCL1 amplification U2AF1 S34F | PIK3CA Everolimus Temsirolimus | 4 | Gemcitabine/Cisplatinum Pembrolizumab | 53 * |
12. | 324 | 7 | 5 | ERBB2 amplification KRAS amplification MET amplification CDKN2A p16INK4a & p14ARF TET2 R1572W | ERBB2 Afatinib Lapatinib Neratinib Pertuzumab Traztuzumab Ado-traztuzumab Traztuzumab-dkst KRAS Cobimetinib Trametinib MET Cabozantinib Crizotinib | 19 | Gemcitabine/Cisplatinum FOFOX Capecitabine | 35 * |
13. | 324 | 1 | - | IDH1 | None | 0 | Gemcitabine/Cisplatinum CAPOX | 36 |
14. | - | 2 | - | KRAS TP53 | None | 0 | Gemcitabine/Cisplatinum FOLFOX Atezolizumab Cobimetinib | 42 |
15. | 49 | 1 | - | PIK3CA E542K | None | 0 | - | 10 * |
16. | 48 | 1 | - | KRAS G12V | None | 0 | Gemcitabine/Cisplatinum FOLFIRI Capecitabine | 25 |
17. | WE | 0 | <1 | - | None | 0 | Gemcitabine/Cisplatinum FOLFOX 5-FU | 41 * |
18. | 324 & 48 | 5 | 3 | EGFR A289V BAP1 V616 TP53 V173M MET amplification | MET Crizotinib Cabozantinib EGFR Pantitumumab Osimertinib Lapatinib Gefitinib Erlotinib Cetuximab Afatinib | 10 | Gemcitabine/Cisplatinum FOLFOX FOLFIRI | 11 |
19. | 159 | 1 | 5 | IDH1 R132L | RRM1 positive Gemcitabine | 4 | Gemcitabine/Cisplatinum Capecitabine | 43 * |
20. | 159 | 1 | 5 | BAP1 E278 | None | 0 | Gemcitabine/Paclitaxel FOLFOX FOLFIRI Sorafenib | 30 |
21. | 48 | 3 | - | KRAS G12D TP53 H193R SMAD4 R361C | None | 0 | - | 11 |
22. | WE | 1 | <1 | TP53 V216G | None | 1 | Gemcitabine/Cisplatinum | 33 * |
23. | 324 | 3 | - | KRAS G12V TP53 A276D KDM6A P334 | KRAS Cobimetinib Trametinib | 0 | - | 18 * |
24. | 324 | 9 | 4 | PIK3CA E545K AKT1 W80R FGFR2 C382R CDKN2A/B loss SMAD4 R361C & R361H TP53 R213 | AKT1 & PIK3CA Everolimus Temsirolimus FGFR2 Pazopanib Ponatinib | 19 | Gemcitabine/Cisplatinum Capecitabine | 12 |
25. | 324 | 2 | - | BRAF V600E TBX3 942-1G | BRAF Cobimetinib Dabrafenib Trametinib Regorafenib Vemurafenib | 9 | Gemcitabine Capecitabine Pembrolizumab Dabrafenib/Trametinib Lenvatinib | 25 |
26. | WE | 3 | 2 | CCND1 amplification TERT C124C4 TSC1 Y48 | CCND1 Abemaciclib Palbociclib Ribociclib TSC1 Everolimus Temsirolimus | 17 | Pembrolizumab | 14 * |
27. | 49 | 2 | - | KRAS G13D GNAS R201H | None | 36 | Gemcitabine/Cisplatinum Capecitabine CAPOX | 25 * |
28. | WE | 2 | 1 | KRAS G12D PIK3CA H1047R | PIK3CA Copanlisib Everolimus Temsirolimus | 10 | Gemcitabine/Cisplatinum Capecitabine | 22 * |
29. | WE | 1 | <1 | BAP1 F15_T16 | 0 | 4 | Gemcitabine/Cisplatinum | 17 |
30. | 168 | 0 | 0 | MDM4 amplification NOTCH2 amplification FAM48C amplification PDGFRA amplification KIT amplification HIST2H3D amplification HIST2H3C amplification MCL1 amplification IL10 amplification FGFR3 amplification WHSC1 gain FGFR2 loss NFKB1A loss FGFR3 TACC3 | 0 | 0 | Gemcitabine Floxuridine | 49 |
31. | WE | 3 | 1 | CDKN2A H83N FGF3 amplification FGF4 amplification | FGF3 Sorafenib FGF4 Pazopanib Sorafenib | 10 | Gemcitabine/Cisplatinum Capecitabine | 15 † |
32. | WE | 1 | <1 | GNAS R844C | None | 6 | - | 7 † |
33. | WE | 1 | 1 | IDH1 R132C | IDH1 Ivosidinib | 0 | Capecitabine | 3 * |
34. | 48 | 4 | - | TP53 P152 ARID2 F1537 GNAS amplification ZNF217 amplificaiton | None | 6 | Gemcitabine/Cisplatinum 5-FU Pembrolizumab | 36 |
35. | WE | 0 | <1 | - | None | 0 | Gemcitabine/Cisplatinum | 22 † |
36. | WE | 4 | <1 | KRAS G12D IDH1 R132L KDM5C G1452 MDM2 amplification | IDH1 Ivosidinib KDM5C Sunitinib | 15 | Gemcitabine/Cisplatinum Ivosidinib | 26 * |
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Thornblade, L.W.; Wong, P.; Li, D.; Warner, S.G.; Chang, S.; Raoof, M.; Kessler, J.; Amini, A.; Lin, J.; Chung, V.; et al. Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma. Cancers 2021, 13, 4062. https://doi.org/10.3390/cancers13164062
Thornblade LW, Wong P, Li D, Warner SG, Chang S, Raoof M, Kessler J, Amini A, Lin J, Chung V, et al. Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma. Cancers. 2021; 13(16):4062. https://doi.org/10.3390/cancers13164062
Chicago/Turabian StyleThornblade, Lucas W., Paul Wong, Daneng Li, Susanne G. Warner, Sue Chang, Mustafa Raoof, Jonathan Kessler, Arya Amini, James Lin, Vincent Chung, and et al. 2021. "Patterns of Whole Exome Sequencing in Resected Cholangiocarcinoma" Cancers 13, no. 16: 4062. https://doi.org/10.3390/cancers13164062