Next generation sequencing demonstrates association between tumor suppressor gene aberrations and poor outcome in patients with cancer.
Next generation sequencing is transforming patient care by allowing physicians to customize and match treatment to their patients' tumor alterations. Our goal was to study the association between key molecular alterations and outcome parameters. We evaluated the characteristics and outcomes (overall survival (OS), time to metastasis/recurrence, and best progression-free survival (PFS)) of 392 patients for whom next generation sequencing (182 or 236 genes) had been performed. The Kaplan-Meier method and Cox regression models were used for our analysis, and results were subjected to internal validation using a resampling method (bootstrap analysis). In a multivariable analysis (Cox regression model), the parameters that were statistically associated with a poorer overall survival were the presence of metastases at diagnosis (P = 0.014), gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDKN2A alterations (P = 0.0001). The variables associated with a shorter time to metastases/recurrence were gastrointestinal histology (P = 0.004), APC (P = 0.008), PTEN (P = 0.026) and TP53 (P = 0.044) alterations. TP53 (P = 0.003) and PTEN (P = 0.034) alterations were independent predictors of a shorter best PFS. A personalized treatment approach (matching the molecular aberration with a cognate targeted drug) also correlated with a longer best PFS (P = 0.046). Our study demonstrated that, across diverse cancers, anomalies in specific tumor suppressor genes (PTEN, CDKN2A, APC, and/or TP53) were independently associated with a worse outcome, as reflected by time to metastases/recurrence, best PFS on treatment, and/or overall survival. These observations suggest that molecular diagnostic tests may provide important prognostic information in patients with cancer.
a Center for Personalized Cancer Therapy, and Division of Hematology and Oncology; UCSD Moores Cancer Center ; La Jolla , CA , USA.
Maria
M
Schwaederle
Gregory A
GA
Daniels
David E
DE
Piccioni
Santosh
S
Kesari
Paul T
PT
Fanta
Richard B
RB
Schwab
Kelly A
KA
Shimabukuro
Barbara A
BA
Parker
Razelle
R
Kurzrock
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D005260:Female; D016147:Genes, Tumor Suppressor; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D063868:Patient Outcome Assessment; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D012044:Regression Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
APC; CDKN2A; PTEN; TP53; cancer; next-generation sequencing; patient's outcome; tumor suppressor