PIK3CA Mutation Status Shows Inconsistent Impact on Trastuzumab Response

Trastuzumab response in HER2-positive breast cancer shows complex relationship with PIK3CA mutation status

medwireNews: The impact of phosphatidylinositol 3-kinase catalytic subunit (PIK3CA) mutation status on the response of human Epidermal growth factor receptor 2 (HER2)-positive breast cancer to targeted therapy may depend on the stage of disease, suggests research.

Findings from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial showed that almost a quarter of 355 HER2-positive breast cancers assessed tested positive for PIK3CA activating Mutations, report José Baselga, from Memorial Sloan-Kettering Cancer Center in New York, USA, and colleagues.

Patients with a PIK3CA mutation were significantly less likely to achieve a pathological complete response (pCR) than those without when treated with lapatinib plus trastuzumab (28.6 vs 53.1%), with a trend for reduced pCR rates also found for those treated with single-therapy lapatinib or trastuzumab.

By contrast, a second study by Soonmyung Paik, from National Surgical Adjuvant Breast and Bowel Project (NSABP) in Pittsburgh, Pennsylvania, USA, and team found no correlation between PIK3CA or PAM50 mutants and response to adjuvant trastuzumab.

Using tumour samples taken during the NSABP B-31 trial, the researchers found no significant relationship between PIK3CA status and the likelihood of disease-free survival benefit for patients with HER2-positive or -negative breast cancer, even after adjusting for factors such as age, hormone receptor status and tumour size.

Acknowledging the disparity between their findings and those of trastuzumab trials in the neoadjuvant and metastatic settings, Soonmyung Paik et al comment: “These data support our hypothesis that there is a fundamental difference between macro diseases (advanced and neoadjuvant) and the minimal residual disease setting for trastuzumab response.”

David Cescon and Philippe Bedard, from the University of Toronto in Ontario, Canada, discuss the significance of the findings of the two trials and earlier research in an accompanying comment in the Journal of Clinical Oncology.

In combination with earlier trial findings, the NeoALTTO and NSABP B-31 results indicate that “PIK3CA mutation testing is not a clinically useful test to guide treatment selection at the present time, because it fails to identify a subpopulation of patients who do not benefit from trastuzumab or dual HER2-targeted treatments”, they note.

The commentators also question whether the lower rates of pCR in patients with PIK3CA mutated tumours will translate to patient outcomes for combined adjuvant anti-HER2 treatment, and they encourage further research to determine whether combined regimens of a PIK3 inhibitor plus anti-HER2 treatment is efficacious.

“With rigorous study, we will learn whether knowledge of PIK3CA mutations can improve the precision with which we apply HER2-targeted therapies; for the present, we will continue to rely on the first (and still only) actionable genomic alteration in breast cancer: Amplification of HER2”, they conclude.

References

Majewski IJ, Nuciforo P, Mittempergher L, et al. PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. J Clin Oncol 2015; Published online before print 5 January. doi: 10.1200/JCO.2014.55.2158

Pogue-Geile KL, Song N, Jeong J-H, et al. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol 2015; Published online before print 5 January. doi: 10.1200/JCO.2014.56.2439

Cescon DW, Bedard PL. PIK3CA genotype and treatment decisions in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2015; Published online before print 5 January. doi: 10.1200/JCO.2014.59.3160

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