The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

Ibrahim, Ezzeldin M.; Kazkaz, Ghieth A.; Al‐Μansour, Mubarak; Al‐Foheidi, Meteb

doi:10.1007/s10549-015-3480-6

Cited by 36 publications

(33 citation statements)

References 37 publications

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“…There are conflicting reports in the literature about the prognostic value of PIK3CA mutations in solid tumors. While a number of studies have suggested that the presence of a PIK3CA mutation confers a poor prognosis in several cancers including breast, lung and colorectal [30][31][32], other studies have reported no significant difference between patients harbouring PIK3CA mutations and those with wildtype PIK3CA in their tumors [33][34][35], which is consistent with our findings. However, there are currently several ongoing trials targeting PIK3CA mutated tumors with PI3K inhibitors, with some promising results.…”

Section: Discussionsupporting

confidence: 92%

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

et al. 2020

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Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

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Section: Discussionsupporting

confidence: 92%

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

et al. 2020

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“…Several studies in both the metastatic78–80 and neoadjuvant81–83 settings appear to be in the same line of the findings from preclinical experiments. However, the available data in the adjuvant setting did not show any predictive role for PIK3CA or PTEN 84–87…”

Section: Conclusion and Future Perspectivessupporting

confidence: 65%

Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

Kourié¹,

Rassy²,

Clatot³

et al. 2017

OTT

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Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

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“…play an important role in mechanisms leading to this resistance (Ahmad et al, 2014). Thus, the aim of the present study was to screen CTC for mutations in the PIK3CA gene as one of previously identified resistance mechanisms (Ibrahim et al, 2015;Wilks, 2015). In blood samples from 15 out of 179 CTC-positive patients (8.4%) at least one CTC with strong HER2 expression was detected, but no patient with exclusively HER2-strongly positive CTC could be identified.…”

Section: Patient-idmentioning

confidence: 94%

“…It is important to note that overcoming resistance against HER2-targeted therapy that is frequently observed during the course of treatment has become a major challenge in tumor research (Ibrahim et al, 2015;Rexer and Arteaga, 2012;Wilks, 2015). To date, there is no routine biomarker available to predict resistance to HER2-targeted therapies and to help therapy decision making when resistance occurs.…”

Section: Introductionmentioning

confidence: 99%

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

et al. 2016

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Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2-negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch(®) system. Fifteen of 179 CTC-positive patients (8.4%) contained ≥1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), ≥5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies.

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The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis

Cited by 36 publications

References 37 publications

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples

Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2‐negative metastatic breast cancer

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