Clinical outcomes based on multigene profiling in metastatic breast cancer patients.
BACKGROUND
Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes.


METHODS
Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected.


RESULTS
Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients.


CONCLUSIONS
Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Reva K
RK
Basho
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Debora
D
de Melo Gagliato
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Naoto T
NT
Ueno
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Chetna
C
Wathoo
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Huiqin
H
Chen
Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Maryam
M
Shariati
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Pfizer, Inc, New York, NY, USA.
Caimiao
C
Wei
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The Cancer Treatment Centers of America, Chicago, IL, USA.
Ricardo H
RH
Alvarez
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Stacy L
SL
Moulder
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Aysegul A
AA
Sahin
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sinchita
S
Roy-Chowdhuri
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mariana
M
Chavez-MacGregor
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jennifer K
JK
Litton
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Vincent
V
Valero
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Raja
R
Luthra
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jia
J
Zeng
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kenna R
KR
Shaw
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
John
J
Mendelsohn
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gordon B
GB
Mills
Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Debu
D
Tripathy
Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Funda
F
Meric-Bernstam
D000483:Alleles; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D005810:Multigene Family; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis
D014408:Biomarkers, Tumor
PIK3CA; TP53; genomics; metastatic breast cancer