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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

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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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Acknowledgements

This work was supported in part by NCI grants P50CA58183 and P50CA186784 (SPORE), P30CA125123, P30CA008748, and R01CA72038, Department of Defense grants W81XWH-17-1-0579 and W81XWH-17-1-0580, as well as grants from the Komen Foundation for the Cure, the Avon Foundation, the Breast Cancer Research Foundation, the Cancer Prevention & Research Institute of Texas CPRIT RP 140102, the Conquer Cancer Foundation—Gianni Bonadonna Breast Cancer Research Fellowship and the Translational Breast Cancer Research Consortium. None of the funding agencies had any role in the design, analysis, or reporting of analyses. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Authors and 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

    Mothaffar F. Rimawi, Carmine De Angelis, Alejandro Contreras, Sabrina Herrera, Tao Wang, Anne C. Pavlick, Suzanne A. W. Fuqua, Carolina Gutierrez, Susan G. Hilsenbeck, C. Kent Osborne & Rachel Schiff

  2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Britta Weigelt & Jorge S. Reis-Filho

  3. Vanderbilt University, Nashville, TN, USA

    Ingrid A. Mayer

  4. University of Alabama at Birmingham, Birmingham, AL, USA

    Andres Forero

  5. University of Chicago, Chicago, IL, USA

    Rita Nanda

  6. Mayo Clinic, Rochester, MN, USA

    Matthew P. Goetz

  7. Houston Methodist Hospital, Houston, TX, USA

    Jenny C. Chang

  8. Dana-Farber Cancer Institute, Boston, MA, USA

    Ian E. Krop

  9. Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Antonio C. Wolff

  10. University of Pennsylvania, Philadelphia, PA, USA

    Marilyn M. Li

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  1. Mothaffar F. Rimawi
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  2. Carmine De Angelis
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Contributions

MR, CA, AC, BW, JSR-F, CKO, RS: Study design, data collection, data analysis, data interpretation, and writing. FP, FCG, KAB, SH, TW, SGH, MML: Study design, data analysis, data interpretation, and writing. IAM, AF, RN, MPG, JCG, ACP, SAWF, CG: Study design, data collection, data interpretation, and writing. IEK, ACW: Study design, data interpretation, and writing.

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Correspondence to Mothaffar F. Rimawi.

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Conflict of interest

Mothaffar F. Rimawi: Research grant from GlaxoSmithKline (to Institution), Consulting with Genentech. Andres Forero: Research grants from GlaxoSmithKline and Genentech (to Institution). Ian E. Krop: Consulting: Genentech/Roche. Research grant from Genentech/Roche (to Institution). Antonio C. Wolff: Research grant from Genentech (to Institution). Carmine De Angelis, Alejandro Contreras, Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Sabrina Herrera, Tao Wang, Ingrid A Mayer, Rita Nanda, Matthew P. Goetz, Jenny C. Chang, Anne C. Pavlick, Suzanne A. W. Fuqua, Carolina Gutierrez, Susan G. Hilsenbeck, Marilyn M. Li, Britta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff have conclude nothing to disclose.

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Rimawi, M.F., De Angelis, C., Contreras, A. et al. 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 Res Treat 167, 731–740 (2018). https://doi.org/10.1007/s10549-017-4533-9

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