ERBB2
mutations and association with molecular phenotype in urothelial carcinoma.
Authors: Machaalani Marc , El Zarif Talal , Stockhammer Paul , Semaan Karl , Eid Marc , El Hajj Chehade Razane , Nawfal Rashad , Yekeduz Emre , Nassar Amin , Lee Gwo-Shu Mary , Baca Sylvan C. , CHOUEIRI Toni K. , Grant Michael J , Bellmunt Joaquim 
Published: October 2024

4590

Background:
Activating mutations (mut) in
ERBB2
are present in up to 11% of urothelial carcinoma (UC).
ERBB2
-targeted therapies have demonstrated encouraging results across multiple solid tumors. A better understanding of the mutational landscape of UC tumors harboring
ERBB2
mut is warranted to guide treatment selection.
Methods:
This study included patients (pts) with bladder or upper tract UC who had genomic tumor profiling data in the AACR Project GENIE database.
ERBB2
activating mut were confirmed using
OncoKB
,
PolyPhen-2
, or the available literature. The cohort was then stratified into pts with
ERBB2
mutant

and
ERBB2
wild type tumors. Clinical characteristics and genomic data were compared between groups using Chi-squared and Mann–Whitney U tests. FDR-adjusted q-values were determined by the Benjamini–Hochberg method.
Results:
The cohort included 4,069 pts with UC, and most pts (n=3,475, 85%) had bladder UC. 376 (9.2%) pts had tumors harboring
ERBB2
-mutant UC.
ERBB2
mut were significantly enriched in pts with bladder vs. upper tract UC (9.6% vs. 6.7%, p=0.04) and in males vs. females (10.2% vs. 6.7%, p<0.001).

The most common
ERBB2
mut were S310F/Y (51.4%) and I767M (6.6%) missense mut. A higher enrichment with extracellular domain
ERBB2
mut was observed in
ERBB2
mutant bladder vs. upper tract UC (66.2% vs. 41.5%, p<0.01), particularly for S310F/Y mut (55.5% vs. 36.6%, p=0.03).
ERBB2
mutant tumors had a distinct genomic phenotype characterized by a higher median tumor mutation burden (TMB) (15.6 vs 9.1 mut/Mb, p<0.0001), a lower rate of
FGFR3
co-mut, and a higher rate of co-mut in several genes (Table). Among
ERBB2
mutant tumors, the most common co-occurring amplifications occurred in
E2F3
(14.5%) and
ERBB2
(12.5%).
ERBB2
mutant tumors were more enriched with
ERBB2
amplifications vs.
ERBB2
wild type tumors (12.5% vs 5.2%, p<0.0001). Among
ERBB2
mutant tumors, those with vs. without concomitant
ERBB2
amplifications were associated with a higher frequency of co-occurring amplifications in
CDK12
(61.5% vs. 0%, p<0.0001),
RARA
(20% vs. 0%, p<0.0001), and
SUZ12
(12.5% vs. 0.72%, p<0.0001).
Conclusions:
This study provides deeper insights into the biology of UC tumors that harbor activating
ERBB2
mut. We demonstrate that tumors with activating
ERBB2
mut exhibit distinct molecular phenotypes characterized by higher TMB, lower frequency of
FGFR3
co-mutations, and higher frequency of co-occurring genomic alterations. These findings may help elucidate the patterns of response to
ERBB2
-targeted therapies and guide future combination therapy studies in UC.

Co-Mutation

ERBB2
mutant UC% (n=376)

ERBB2
wild Type UC% (n=3,693)

Q-value

FGFR3

8.8% (33)
22.9% (847)
<0.0001

ARID1A

38.2% (139)
23.7% (839)
<0.0001

KMT2A

21.6% (78)
9.6% (331)
<0.0001

ERCC2

19.6% (70)
9% (304)
<0.0001

ATM

18.6% (69)
10.5% (384)
<0.0001

NF1

15.6% (58)
6.2% (224)
<0.0001

BRCA1

11.1% (41)
4.7% (168)
<0.0001

CDK12

10.5% (35)
3.9% (126)
<0.0001