Proteomic Analysis in Cancer Patients

4068 Background: No predictive biomarker for chemotherapy has been validated for clinical use. A relationship between resistance to taxanes and expression of class III β-tubulin (TUBB3) protein has been suggested by small clinical studies, but not confirmed in randomized trials. Immunohistochemical definitions of “TUBB3 positive” vary widely between studies and depend on subjective measures of strong vs weak staining. We retrospectively evaluated the relationship between survival and TUBB3 protein quantitated by mass spectrometry in the tumor samples of 247 patients from the Intergroup Trial of Adenocarcinoma of the Stomach (ITACA-S). Patients had been randomized to a docetaxel-containing adjuvant regimen or to monotherapy with fluorouracil and leucovorin (5-FU/LV). Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified with a mass spectrometry-based assay. A TUBB3 protein cutoff of 750 amol/ug was predetermined based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among gastric cancer (GC) patients treated with docetaxel-containing chemotherapy (n = 125), those with TUBB3 levels below the cutoff (750 amol/µg of total protein) had a longer median overall survival (mOS) than patients with TUBB3 levels above the cutoff (1563 vs 886 days, p = 0.04). TUBB3 level made no difference in survival among patients who received 5-FU/LV. Of note, among patients with high TUBB3 levels ( > 750 amol), those treated with 5-FU/LV survived 3 years longer than patients in the docetaxel arm (mOS = 1991 vs 886 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 identified a subset of GC patients who benefitted from the addition of docetaxel to adjuvant chemotherapy. GC patients with TUBB3-expressing tumors had worse outcomes on a docetaxel-containing regimen than on 5-FU/LV. An ongoing study of triple-negative breast cancer patients treated with docetaxel suggests that proteomic TUBB3 may be predictive in other cancer indications. Personalized chemotherapy based on quantitated TUBB3 is promising and warrants broader evaluation.

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Quantitative proteomic analysis of TUBB3 to identify gastric cancer patients who may benefit from docetaxel: A reevaluation of the ITACA-S trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.59 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 59-59 ◽

Cited By ~ 2

Author(s):

Fabiola Cecchi ◽

Daniel V.T. Catenacci ◽

Yuan Tian ◽

Rosalba Miceli ◽

Filippo Pietrantonio ◽

...

Keyword(s):

Mass Spectrometry ◽

Gastric Cancer ◽

Cancer Patients ◽

Proteomic Analysis ◽

Limit Of Detection ◽

Selected Reaction Monitoring ◽

Rank Test ◽

Class Iii ◽

Quantitative Proteomic Analysis ◽

Gastric Cancer Patients

59 Background: Chemotherapy (CTX) becomes targeted therapy when biomarkers can predict a patient’s response. A relationship between resistance to taxanes and overexpression of class III b-tubulin (TUBB3) has been suggested by small clinical studies, but not confirmed in randomized trials. The Intergroup Trial of Adjuvant CTX in Adenocarcinoma of the Stomach (ITACA-S) evaluated the survival advantage of postoperative sequential CTX with FOLFIRI followed by docetaxel plus cisplatin in comparison to monotherapy with 5-FU/LV in patients with radically resected gastric cancer (N = 1106). The results showed no difference in survival between the two CTX arms. In a random subset of patients (N = 247) from the ITACA-S trial, we applied mass spectrometry-based proteomics to assess the role of TUBB3 as a predictive biomarker for response to taxane-containing therapy. Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified using a mass spectrometry-based selected reaction monitoring assay. A predetermined TUBB3 cutoff of 700 amol/µg was based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among patients treated with taxane-containing CTX (n = 125), those with TUBB3 levels below the cutoff had nearly twice the median overall survival (OS) as patients with TUBB3 levels above the cutoff (1566 vs. 801 days, p = 0.0282). TUBB3 levels made no statistical difference in survival among patients who did not receive taxane. Of note, among patients with high TUBB3 levels ( > 700 amol), those treated without taxane-containing CTX survived far longer than patients in the taxane arm (OS = 1991 vs 801 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 expression identified a subset of gastric cancer patients who benefitted from the addition of docetaxel to adjuvant CTX. Patients with high TUBB3 expression levels had worse outcomes on a taxane-containing regimen than on CTX without taxane. Personalized CTX based on the TUBB3 biomarker is promising and warrants further validation. Clinical trial information: NCT01989858.

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