Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

Russell W. Madison; Sumati V. Gupta; Yasir Y. Elamin; Douglas I. Lin; Sumanta K. Pal; Andrea Necchi; Vincent A. Miller; Jeffrey S. Ross; Jon H. Chung; Brian M. Alexander; Alexa B. Schrock; John V. Heymach; Prasanth Reddy; Siraj M. Ali

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

Russell W. Madison, Sumati V. Gupta, Yasir Y. Elamin, Douglas I. Lin, Sumanta K. Pal, Andrea Necchi, Vincent A. Miller, Jeffrey S. Ross, Jon H. Chung, Brian M. Alexander, Alexa B. Schrock, John V. Heymach, Prasanth Reddy, Siraj M. Ali

Fondazione IRCCS Istituto Nazionale dei Tumori

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. MATERIALS AND METHODS: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. RESULTS: In 3753 cases of UC, EGFR alterations were detected in 4.1154) and were most commonly amplifications (64 99/154), while exon 20 insertions (EGFR(exon20ins) ) were the second most common alteration (18 27/154). Alterations in ERBB2 were observed in 15552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50; ERBB2(exon20ins) occurred in 3.620/552) of cases. EGFR(exon20ins) and ERBB2(exon20ins) occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.73 P = 4.3E-14 and 208 P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 45 respectively. EGFR(exon20ins) and ERBB2(exon20ins) were present in 0.7.5 but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

Original language	English
Journal	BJU International
Issue number	5
Publication status	Published - May 1 2020

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Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions. / Madison, Russell W.; Gupta, Sumati V.; Elamin, Yasir Y.; Lin, Douglas I.; Pal, Sumanta K.; Necchi, Andrea; Miller, Vincent A.; Ross, Jeffrey S.; Chung, Jon H.; Alexander, Brian M.; Schrock, Alexa B.; Heymach, John V.; Reddy, Prasanth; Ali, Siraj M.

In: BJU International, No. 5, 01.05.2020.

Research output: Contribution to journal › Article › peer-review

Madison, Russell W. ; Gupta, Sumati V. ; Elamin, Yasir Y. ; Lin, Douglas I. ; Pal, Sumanta K. ; Necchi, Andrea ; Miller, Vincent A. ; Ross, Jeffrey S. ; Chung, Jon H. ; Alexander, Brian M. ; Schrock, Alexa B. ; Heymach, John V. ; Reddy, Prasanth ; Ali, Siraj M. / Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions. In: BJU International. 2020 ; No. 5.

@article{e472e7833fc04fb0a0d64f9601366eb7,

title = "Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.",

abstract = "OBJECTIVE: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. MATERIALS AND METHODS: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. RESULTS: In 3753 cases of UC, EGFR alterations were detected in 4.1154) and were most commonly amplifications (64 99/154), while exon 20 insertions (EGFR(exon20ins) ) were the second most common alteration (18 27/154). Alterations in ERBB2 were observed in 15552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50; ERBB2(exon20ins) occurred in 3.620/552) of cases. EGFR(exon20ins) and ERBB2(exon20ins) occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.73 P = 4.3E-14 and 208 P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 45 respectively. EGFR(exon20ins) and ERBB2(exon20ins) were present in 0.7.5 but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.",

author = "Madison, {Russell W.} and Gupta, {Sumati V.} and Elamin, {Yasir Y.} and Lin, {Douglas I.} and Pal, {Sumanta K.} and Andrea Necchi and Miller, {Vincent A.} and Ross, {Jeffrey S.} and Chung, {Jon H.} and Alexander, {Brian M.} and Schrock, {Alexa B.} and Heymach, {John V.} and Prasanth Reddy and Ali, {Siraj M.}",

note = "Place: England",

year = "2020",

month = may,

day = "1",

language = "English",

journal = "BJU International",

issn = "1464-4096",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

TY - JOUR

T1 - Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

AU - Madison, Russell W.

AU - Gupta, Sumati V.

AU - Elamin, Yasir Y.

AU - Lin, Douglas I.

AU - Pal, Sumanta K.

AU - Necchi, Andrea

AU - Miller, Vincent A.

AU - Ross, Jeffrey S.

AU - Chung, Jon H.

AU - Alexander, Brian M.

AU - Schrock, Alexa B.

AU - Heymach, John V.

AU - Reddy, Prasanth

AU - Ali, Siraj M.

N1 - Place: England

PY - 2020/5/1

Y1 - 2020/5/1

N2 - OBJECTIVE: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. MATERIALS AND METHODS: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. RESULTS: In 3753 cases of UC, EGFR alterations were detected in 4.1154) and were most commonly amplifications (64 99/154), while exon 20 insertions (EGFR(exon20ins) ) were the second most common alteration (18 27/154). Alterations in ERBB2 were observed in 15552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50; ERBB2(exon20ins) occurred in 3.620/552) of cases. EGFR(exon20ins) and ERBB2(exon20ins) occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.73 P = 4.3E-14 and 208 P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 45 respectively. EGFR(exon20ins) and ERBB2(exon20ins) were present in 0.7.5 but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

AB - OBJECTIVE: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. MATERIALS AND METHODS: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. RESULTS: In 3753 cases of UC, EGFR alterations were detected in 4.1154) and were most commonly amplifications (64 99/154), while exon 20 insertions (EGFR(exon20ins) ) were the second most common alteration (18 27/154). Alterations in ERBB2 were observed in 15552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50; ERBB2(exon20ins) occurred in 3.620/552) of cases. EGFR(exon20ins) and ERBB2(exon20ins) occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.73 P = 4.3E-14 and 208 P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 45 respectively. EGFR(exon20ins) and ERBB2(exon20ins) were present in 0.7.5 but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

M3 - Article

JO - BJU International

JF - BJU International

SN - 1464-4096

IS - 5

ER -