Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies.
Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified.



DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements.



Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein.



Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2654-2662. © 2016 American Cancer Society.
Foundation Medicine Inc, Cambridge, Massachusetts.|Department of Pathology, Albany Medical College, Albany, New York.
Jeffrey S
JS
Ross
Foundation Medicine Inc, Cambridge, Massachusetts.
Laurie M
0000-0003-2022-6130
LM
Gay
Foundation Medicine Inc, Cambridge, Massachusetts.|Department of Computational Biology, Zhejiang Cancer Hospital, Hangzhou, China.
Kai
K
Wang
Foundation Medicine Inc, Cambridge, Massachusetts.
Siraj M
SM
Ali
Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
Saranya
S
Chumsri
Foundation Medicine Inc, Cambridge, Massachusetts.
Julia A
JA
Elvin
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Ron
R
Bose
Foundation Medicine Inc, Cambridge, Massachusetts.
Jo-Anne
JA
Vergilio
Foundation Medicine Inc, Cambridge, Massachusetts.
James
J
Suh
Foundation Medicine Inc, Cambridge, Massachusetts.
Roman
R
Yelensky
Foundation Medicine Inc, Cambridge, Massachusetts.
Doron
D
Lipson
Foundation Medicine Inc, Cambridge, Massachusetts.
Juliann
J
Chmielecki
Department of Breast Oncology, Hackensack University Medical Center, Hackensack, New Jersey.
Stanley
S
Waintraub
Department of Hematology/Oncology, Avera Health, Sioux Falls, South Dakota.
Brian
B
Leyland-Jones
Foundation Medicine Inc, Cambridge, Massachusetts.
Vincent A
VA
Miller
Foundation Medicine Inc, Cambridge, Massachusetts.
Philip J
PJ
Stephens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008207:Lymphatic Metastasis; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
ERBB2; breast cancer; comprehensive genomic profiling; human epidermal growth factor receptor 2 [HER2]/neu; next-generation sequencing; short variants