Influence of biospecimen variables on proteomic biomarkers in breast cancer

Funda Meric-Bernstam, Argun Akcakanat, Huiqin Chen, Aysegul Sahin, Emily Tarco, Selin Carkaci, Beatriz E. Adrada, Gopal Singh, Kim Anh Do, Zerzhinski M. Garces, Elizabeth Mittendorf, Gildy Babiera, Isabelle Bedrosian, Rosa Hwang, Savitri Krishnamurthy, William F. Symmans, Ana Maria Gonzalez-Angulo, Gordon Mills

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers. Methods: Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer. Specimens were assessed with reverse-phase protein arrays (RPPA) and immunohistochemistry (IHC). Results: There was a moderate or strong correlation between the expression of 149 (97%) of the 154 different RPPA markers in the center and periphery. Correlation was higher for smaller tumors, in patients whodid not undergo neoadjuvant therapy, and with shorter cold ischemia time. Of 154 markers, 132 (86%) were not statistically different between the center and periphery, and 97 (63%) were not different between the CNB and the surgical specimen (average of the central and peripheral specimen). pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimen. However, pAkt S473, pS6 S235/236, and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC. Conclusions: Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity. However, protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation, or with cold ischemia of surgical specimens.

Original languageEnglish (US)
Pages (from-to)3870-3883
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2014
Externally publishedYes

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Large-Core Needle Biopsy
Proteomics
Biomarkers
Protein Array Analysis
Breast Neoplasms
Phosphatidylinositol 3-Kinases
Cold Ischemia
Immunohistochemistry
Neoplasms
Neoadjuvant Therapy
Phosphoproteins
Phosphorylation
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Meric-Bernstam, F., Akcakanat, A., Chen, H., Sahin, A., Tarco, E., Carkaci, S., ... Mills, G. (2014). Influence of biospecimen variables on proteomic biomarkers in breast cancer. Clinical Cancer Research, 20(14), 3870-3883. https://doi.org/10.1158/1078-0432.CCR-13-1507

Influence of biospecimen variables on proteomic biomarkers in breast cancer. / Meric-Bernstam, Funda; Akcakanat, Argun; Chen, Huiqin; Sahin, Aysegul; Tarco, Emily; Carkaci, Selin; Adrada, Beatriz E.; Singh, Gopal; Do, Kim Anh; Garces, Zerzhinski M.; Mittendorf, Elizabeth; Babiera, Gildy; Bedrosian, Isabelle; Hwang, Rosa; Krishnamurthy, Savitri; Symmans, William F.; Gonzalez-Angulo, Ana Maria; Mills, Gordon.

In: Clinical Cancer Research, Vol. 20, No. 14, 15.07.2014, p. 3870-3883.

Research output: Contribution to journalArticle

Meric-Bernstam, F, Akcakanat, A, Chen, H, Sahin, A, Tarco, E, Carkaci, S, Adrada, BE, Singh, G, Do, KA, Garces, ZM, Mittendorf, E, Babiera, G, Bedrosian, I, Hwang, R, Krishnamurthy, S, Symmans, WF, Gonzalez-Angulo, AM & Mills, G 2014, 'Influence of biospecimen variables on proteomic biomarkers in breast cancer', Clinical Cancer Research, vol. 20, no. 14, pp. 3870-3883. https://doi.org/10.1158/1078-0432.CCR-13-1507
Meric-Bernstam F, Akcakanat A, Chen H, Sahin A, Tarco E, Carkaci S et al. Influence of biospecimen variables on proteomic biomarkers in breast cancer. Clinical Cancer Research. 2014 Jul 15;20(14):3870-3883. https://doi.org/10.1158/1078-0432.CCR-13-1507
Meric-Bernstam, Funda ; Akcakanat, Argun ; Chen, Huiqin ; Sahin, Aysegul ; Tarco, Emily ; Carkaci, Selin ; Adrada, Beatriz E. ; Singh, Gopal ; Do, Kim Anh ; Garces, Zerzhinski M. ; Mittendorf, Elizabeth ; Babiera, Gildy ; Bedrosian, Isabelle ; Hwang, Rosa ; Krishnamurthy, Savitri ; Symmans, William F. ; Gonzalez-Angulo, Ana Maria ; Mills, Gordon. / Influence of biospecimen variables on proteomic biomarkers in breast cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 14. pp. 3870-3883.
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abstract = "Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers. Methods: Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer. Specimens were assessed with reverse-phase protein arrays (RPPA) and immunohistochemistry (IHC). Results: There was a moderate or strong correlation between the expression of 149 (97{\%}) of the 154 different RPPA markers in the center and periphery. Correlation was higher for smaller tumors, in patients whodid not undergo neoadjuvant therapy, and with shorter cold ischemia time. Of 154 markers, 132 (86{\%}) were not statistically different between the center and periphery, and 97 (63{\%}) were not different between the CNB and the surgical specimen (average of the central and peripheral specimen). pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimen. However, pAkt S473, pS6 S235/236, and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC. Conclusions: Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity. However, protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation, or with cold ischemia of surgical specimens.",
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T1 - Influence of biospecimen variables on proteomic biomarkers in breast cancer

AU - Meric-Bernstam, Funda

AU - Akcakanat, Argun

AU - Chen, Huiqin

AU - Sahin, Aysegul

AU - Tarco, Emily

AU - Carkaci, Selin

AU - Adrada, Beatriz E.

AU - Singh, Gopal

AU - Do, Kim Anh

AU - Garces, Zerzhinski M.

AU - Mittendorf, Elizabeth

AU - Babiera, Gildy

AU - Bedrosian, Isabelle

AU - Hwang, Rosa

AU - Krishnamurthy, Savitri

AU - Symmans, William F.

AU - Gonzalez-Angulo, Ana Maria

AU - Mills, Gordon

PY - 2014/7/15

Y1 - 2014/7/15

N2 - Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers. Methods: Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer. Specimens were assessed with reverse-phase protein arrays (RPPA) and immunohistochemistry (IHC). Results: There was a moderate or strong correlation between the expression of 149 (97%) of the 154 different RPPA markers in the center and periphery. Correlation was higher for smaller tumors, in patients whodid not undergo neoadjuvant therapy, and with shorter cold ischemia time. Of 154 markers, 132 (86%) were not statistically different between the center and periphery, and 97 (63%) were not different between the CNB and the surgical specimen (average of the central and peripheral specimen). pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimen. However, pAkt S473, pS6 S235/236, and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC. Conclusions: Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity. However, protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation, or with cold ischemia of surgical specimens.

AB - Background: PI3K/Akt/mTOR signaling is being actively pursued as a therapeutic target for breast cancer. We sought to determine if tumor heterogeneity and biospecimen variables affect the evaluation of PI3K/Akt/mTOR pathway markers. Methods: Intraoperative image-guided core-needle biopsies (CNB), and central and peripheral surgical tumor specimens were prospectively collected in 53 patients with invasive breast cancer. Specimens were assessed with reverse-phase protein arrays (RPPA) and immunohistochemistry (IHC). Results: There was a moderate or strong correlation between the expression of 149 (97%) of the 154 different RPPA markers in the center and periphery. Correlation was higher for smaller tumors, in patients whodid not undergo neoadjuvant therapy, and with shorter cold ischemia time. Of 154 markers, 132 (86%) were not statistically different between the center and periphery, and 97 (63%) were not different between the CNB and the surgical specimen (average of the central and peripheral specimen). pAkt S473 and PTEN had a significant correlation between central and peripheral specimens, and between CNB and surgical specimen. However, pAkt S473, pS6 S235/236, and pS6 240/244 levels were significantly higher in CNB than the central specimens both by RPPA and by IHC. Conclusions: Most individual proteomic biomarkers studied do not have significant intratumoral heterogeneity. However, protein and phosphoprotein levels are affected by biospecimen type and other preanalytic variables. PI3K pathway activation is greater in CNB compared with postexcision surgical samples suggesting a potential loss of phosphorylation during surgical manipulation, or with cold ischemia of surgical specimens.

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