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. 2019 May;12(5):739-748.
doi: 10.1016/j.tranon.2019.02.010. Epub 2019 Mar 14.

Prognostic Impact of Src, CDKN1B, and JAK2 Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab

Panagiota Economopoulou  1 , Vassiliki Kotoula  2 , Georgia-Angeliki Koliou  3 , Kyriaki Papadopoulou  4 , Christos Christodoulou  5 , George Pentheroudakis  6 , Georgios Lazaridis  7 , Petroula Arapantoni-Dadioti  8 , Angelos Koutras  9 , Dimitris Bafaloukos  10 , Pavlos Papakostas  11 , Helen Patsea  12 , Kitty Pavlakis  13 , Dimitrios Pectasides  14 , Athanasios Kotsakis  15 , Evangelia Razis  16 , Gerasimos Aravantinos  17 , Epaminondas Samantas  18 , Konstantine T Kalogeras  19 , Theofanis Economopoulos  20 , Amanta Psyrri  21 , George Fountzilas  22
Affiliations

Prognostic Impact of Src, CDKN1B, and JAK2 Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab

Panagiota Economopoulou et al. Transl Oncol. 2019 May.

Abstract

Background: Src, CDKN1B, and JAK2 play a crucial role in the coordination of cell signaling pathways. In the present study, we aim to investigate the prognostic significance of these biomarkers in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab (T).

Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 197 patients with HER2-positive MBC treated with T were retrospectively collected. All tissue samples were centrally assessed for ER, PgR, Ki67, HER2, and PTEN protein expression; EGFR gene amplification; PI3KCA mutational status; and tumor-infiltrating lympocytes density. Src, CDKN1B, and JAK2 mRNA expression was evaluated using quantitative reverse transcription-polymerase chain reaction.

Results: Only 133 of the 197 patients (67.5%) were found to be HER2-positive by central assessment. CDKN1B mRNA expression was strongly correlated with Src (rho = 0.71) and JAK2 (rho = 0.54). In HER2-positive patients, low CDKN1B conferred higher risk for progression [hazard ratio (HR) = 1.58, 95% confidence interval (CI) 1.08-2.32, P = .018]. In HER2-negative patients, low Src was associated with longer survival (HR = 0.56, 95% CI 0.32-0.99, P = .045). Upon multivariate analyses, only low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in de novo and relapsed (R)-MBC patients, respectively (HR = 2.36, 95% CI 1.01-5.48, P = .046 and HR = 1.76, 95% CI 1.01-3.06, P = .047, respectively).

Conclusions: Low CDKN1B and JAK2 mRNA expressions were unfavorable prognosticators in a cohort of T-treated MBC patients. Our results suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T resistance, which seems to be associated with distinct pathways in de novo and R-MBC.

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Figures

Figure 1
Figure 1
Violin plots of CDKN1B, JAK2, and Src distribution by (A) HER2 status and (B) disease presentation status.
Figure 2
Figure 2
Kaplan-Meier plots according to (A) CDKN1B mRNA expression (using the median value as a cutoff) with respect to PFS in HER2-positive patients, (B) Src mRNA expression (using the median value as cutoff) with respect to PFS and OS in HER2-negative patients, (C) CDKN1B mRNA expression (using the upper quartile as cutoff) with respect to PFS in de novo MBC patients, and (D) CDKN1B and JAK2 mRNA expression with respect to PFS and Src mRNA expression with respect to OS in R-MBC patients.
See this image and copyright information in PMC

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