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

doi:10.1007/s10549-017-4533-9

Clinical Trial

. 2018 Feb;167(3):731-740.

doi: 10.1007/s10549-017-4533-9. Epub 2017 Nov 7.

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 Rimawi¹, Carmine De Angelis², Alejandro Contreras², Fresia Pareja³, Felipe C Geyer³, Kathleen A Burke³, Sabrina Herrera², Tao Wang², Ingrid A Mayer⁴, Andres Forero⁵, Rita Nanda⁶, Matthew P Goetz⁷, Jenny C Chang⁸, Ian E Krop⁹, Antonio C Wolff¹⁰, Anne C Pavlick², Suzanne A W Fuqua², Carolina Gutierrez², Susan G Hilsenbeck², Marilyn M Li¹¹, Britta Weigelt³, Jorge S Reis-Filho³, C Kent Osborne², Rachel Schiff²

Affiliations

¹ Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA. rimawi@bcm.edu.
² Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.
³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Vanderbilt University, Nashville, TN, USA.
⁵ University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ University of Chicago, Chicago, IL, USA.
⁷ Mayo Clinic, Rochester, MN, USA.
⁸ Houston Methodist Hospital, Houston, TX, USA.
⁹ Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
¹¹ University of Pennsylvania, Philadelphia, PA, USA.

PMID: 29110152
PMCID: PMC5821069
DOI: 10.1007/s10549-017-4533-9

Clinical Trial

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 et al. Breast Cancer Res Treat. 2018 Feb.

. 2018 Feb;167(3):731-740.

doi: 10.1007/s10549-017-4533-9. Epub 2017 Nov 7.

Authors

Affiliations

¹ Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA. rimawi@bcm.edu.
² Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.
³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Vanderbilt University, Nashville, TN, USA.
⁵ University of Alabama at Birmingham, Birmingham, AL, USA.
⁶ University of Chicago, Chicago, IL, USA.
⁷ Mayo Clinic, Rochester, MN, USA.
⁸ Houston Methodist Hospital, Houston, TX, USA.
⁹ Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
¹¹ University of Pennsylvania, Philadelphia, PA, USA.

PMID: 29110152
PMCID: PMC5821069
DOI: 10.1007/s10549-017-4533-9

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.

Keywords: HER2-positive breast cancer; Lapatinib; PIK3CA mutations; PTEN levels; Trastuzumab; pCR.

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Conflict of interest statement

Conflicts of Interest:

Mothaffar F. Rimawi: Research grant from GlaxoSmithKline (to Institution), Consulting with Genentech.

Carmine De Angelis: Nothing to disclose

Alejandro Contreras: Nothing to disclose

Fresia Pareja: Nothing to disclose

Felipe C. Geyer: Nothing to disclose

Kathleen A. Burke: Nothing to disclose

Sabrina Herrera: Nothing to disclose

Tao Wang: Nothing to disclose

Ingrid A Mayer: Nothing to disclose

Andres Forero: Research grants from GlaxoSmithKline and Genentech (to Institution)

Rita Nanda: Nothing to disclose

Matthew P. Goetz: Nothing to disclose

Jenny C. Chang: Nothing to disclose

Ian E. Krop: Consulting: Genentech/Roche. Research grant from Genentech/Roche (to Institution)

Antonio C. Wolff: Research grant from Genentech (to Institution)

Anne C. Pavlick: Nothing to disclose

Suzanne A. W. Fuqua: Nothing to disclose

Carolina Gutierrez: Nothing to disclose

Susan G. Hilsenbeck: Nothing to disclose

Marilyn M. Li: Nothing to disclose

Britta Weigelt: Nothing to disclose

Jorge S. Reis-Filho: Nothing to disclose

C. Kent Osborne: Nothing to disclose

Rachel Schiff: Nothing to disclose

Figures

**Figure 1. Study schema of the neoadjuvant phase II TBCRC 006 clinical trial**
Patients with stage II/III HER2-positive breast cancers were eligible. Patients received lapatinib and trastuzumab with letrozole when estrogen receptor-positive, without chemotherapy, and biopsies were obtained at baseline and weeks 2, 8 and 12 of treatment (at surgery). HER2, human epidermal growth factor 2. Pretreatment baseline biopsies (dashed line) were evaluated for the current study.

**Figure 2**
Evaluable material for baseline biomarker analysis and associated pathologic complete response (pCR) rates

**Figure 3. Immunohistochemical staining and associated H scores for PTEN in baseline specimens**
Representative micrographs of breast cancer biopsies showing negative (left), low (middle), and high (right) PTEN expression levels. PTEN status was dichotomized by H-score median. Please note the stromal cells, which were used as internal positive controls. Scale bars, 100μm.

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References

1. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12. - PubMed
1. Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst. 1998;90(18):1346–60. - PubMed
1. Zardavas D, Fouad TM, Piccart M. Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015. Breast. 2015;24(Suppl 2):S143–8. doi: 10.1016/j.breast.2015.07.034. - DOI - PubMed
1. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16. - PubMed
1. Rimawi MF, Schiff R, Osborne CK. _targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111–28. doi: 10.1146/annurev-med-042513-015127. - DOI - PubMed

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[1] Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12. - PubMed

[2] Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–12. - PubMed

[3] Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst. 1998;90(18):1346–60. - PubMed

[4] Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst. 1998;90(18):1346–60. - PubMed

[5] Zardavas D, Fouad TM, Piccart M. Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015. Breast. 2015;24(Suppl 2):S143–8. doi: 10.1016/j.breast.2015.07.034. - DOI - PubMed

[6] Zardavas D, Fouad TM, Piccart M. Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015. Breast. 2015;24(Suppl 2):S143–8. doi: 10.1016/j.breast.2015.07.034. - DOI - PubMed

[7] Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16. - PubMed

[8] Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16. - PubMed

[9] Rimawi MF, Schiff R, Osborne CK. _targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111–28. doi: 10.1146/annurev-med-042513-015127. - DOI - PubMed

[10] Rimawi MF, Schiff R, Osborne CK. _targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111–28. doi: 10.1146/annurev-med-042513-015127. - DOI - PubMed

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

Affiliations

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

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