Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer

Mothaffar F. Rimawi, Carmine de Angelis, Alejandro Contreras, Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Sabrina Herrera, Tao Wang, Ingrid A. Mayer, Andres Forero, Rita Nanda, Matthew Philip Goetz, Jenny C. Chang, Ian E. Krop, Antonio C. Wolff, Anne C. Pavlick, Suzanne A.W. Fuqua, Carolina Gutierrez, Susan G. Hilsenbeck, Marilyn M. LiBritta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.Patients and methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Nov 7 2017

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Breast Neoplasms
Drug Therapy
Mutation
Phosphatidylinositol 3-Kinases
Estrogen Receptors
Neoplasms
Immunohistochemistry
Clinical Trials
Trastuzumab
lapatinib
Therapeutics
Biomarkers

Keywords

  • HER2-positive breast cancer
  • Lapatinib
  • pCR
  • PIK3CA mutations
  • PTEN levels
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. / Rimawi, Mothaffar F.; de Angelis, Carmine; Contreras, Alejandro; Pareja, Fresia; Geyer, Felipe C.; Burke, Kathleen A.; Herrera, Sabrina; Wang, Tao; Mayer, Ingrid A.; Forero, Andres; Nanda, Rita; Goetz, Matthew Philip; Chang, Jenny C.; Krop, Ian E.; Wolff, Antonio C.; Pavlick, Anne C.; Fuqua, Suzanne A.W.; Gutierrez, Carolina; Hilsenbeck, Susan G.; Li, Marilyn M.; Weigelt, Britta; Reis-Filho, Jorge S.; Kent Osborne, C.; Schiff, Rachel.

In: Breast Cancer Research and Treatment, 07.11.2017, p. 1-10.

Research output: Contribution to journalArticle

Rimawi, MF, de Angelis, C, Contreras, A, Pareja, F, Geyer, FC, Burke, KA, Herrera, S, Wang, T, Mayer, IA, Forero, A, Nanda, R, Goetz, MP, Chang, JC, Krop, IE, Wolff, AC, Pavlick, AC, Fuqua, SAW, Gutierrez, C, Hilsenbeck, SG, Li, MM, Weigelt, B, Reis-Filho, JS, Kent Osborne, C & Schiff, R 2017, 'Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer', Breast Cancer Research and Treatment, pp. 1-10. https://doi.org/10.1007/s10549-017-4533-9
Rimawi, Mothaffar F. ; de Angelis, Carmine ; Contreras, Alejandro ; Pareja, Fresia ; Geyer, Felipe C. ; Burke, Kathleen A. ; Herrera, Sabrina ; Wang, Tao ; Mayer, Ingrid A. ; Forero, Andres ; Nanda, Rita ; Goetz, Matthew Philip ; Chang, Jenny C. ; Krop, Ian E. ; Wolff, Antonio C. ; Pavlick, Anne C. ; Fuqua, Suzanne A.W. ; Gutierrez, Carolina ; Hilsenbeck, Susan G. ; Li, Marilyn M. ; Weigelt, Britta ; Reis-Filho, Jorge S. ; Kent Osborne, C. ; Schiff, Rachel. / Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. In: Breast Cancer Research and Treatment. 2017 ; pp. 1-10.
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abstract = "Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.Patients and methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32{\%} in high PTEN vs. 9{\%} in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30{\%}) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4{\%}) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39{\%}) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.",
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author = "Rimawi, {Mothaffar F.} and {de Angelis}, Carmine and Alejandro Contreras and Fresia Pareja and Geyer, {Felipe C.} and Burke, {Kathleen A.} and Sabrina Herrera and Tao Wang and Mayer, {Ingrid A.} and Andres Forero and Rita Nanda and Goetz, {Matthew Philip} and Chang, {Jenny C.} and Krop, {Ian E.} and Wolff, {Antonio C.} and Pavlick, {Anne C.} and Fuqua, {Suzanne A.W.} and Carolina Gutierrez and Hilsenbeck, {Susan G.} and Li, {Marilyn M.} and Britta Weigelt and Reis-Filho, {Jorge S.} and {Kent Osborne}, C. and Rachel Schiff",
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TY - JOUR

T1 - Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer

AU - Rimawi, Mothaffar F.

AU - de Angelis, Carmine

AU - Contreras, Alejandro

AU - Pareja, Fresia

AU - Geyer, Felipe C.

AU - Burke, Kathleen A.

AU - Herrera, Sabrina

AU - Wang, Tao

AU - Mayer, Ingrid A.

AU - Forero, Andres

AU - Nanda, Rita

AU - Goetz, Matthew Philip

AU - Chang, Jenny C.

AU - Krop, Ian E.

AU - Wolff, Antonio C.

AU - Pavlick, Anne C.

AU - Fuqua, Suzanne A.W.

AU - Gutierrez, Carolina

AU - Hilsenbeck, Susan G.

AU - Li, Marilyn M.

AU - Weigelt, Britta

AU - Reis-Filho, Jorge S.

AU - Kent Osborne, C.

AU - Schiff, Rachel

PY - 2017/11/7

Y1 - 2017/11/7

N2 - Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.Patients and methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.

AB - Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.Patients and methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR). Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006). Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.

KW - HER2-positive breast cancer

KW - Lapatinib

KW - pCR

KW - PIK3CA mutations

KW - PTEN levels

KW - Trastuzumab

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