Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study

Papaxoinis, George; Kotoula, Vassiliki; Alexopoulou, Zoi; Kalogeras, Konstantine T.; Zagouri, Flora; Timotheadou, Eleni; Gogas, Helen; Pentheroudakis, George; Koutras, Angelos; Bafaloukos, Dimitrios; Aravantinos, G.; Papakostas, Pavlos; Charalambous, Elpida; Papadopoulou, Kyriaki; Varthalitis, Ioannis; Efstratiou, Ioannis; Zaramboukas, Thomas; Patsea, Helen; Scopa, Chrisoula D.; Skondra, Maria; Kosmidis, P.; Pectasides, Dimitrios; Fountzilas, George

doi:10.1371/journal.pone.0140293

Cited by 29 publications

(26 citation statements)

References 38 publications

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“…Clinical studies demonstrated 73%–83% concordance for PIK3CA status in ctDNA and archival tumor tissue, measured using PCR . Good concordance (approximately 90%) has been demonstrated among next‐generation sequencing, Sanger sequencing, and quantitative PCR for assessing wild‐type PIK3CA or mutations in exon 9 or 20 of PIK3CA . However, it should be noted that PCR‐based/hybridization methods or gene panels that focus on hotspot mutations may miss up to 20% of PIK3CA mutations .…”

Section: Methodsmentioning

confidence: 99%

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

2019

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Resistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post‐ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3‐kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α‐isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan‐PI3K‐targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor‐resistant, HR+, human epidermal growth receptor 2 negative (HER2−) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA‐mutated disease versus PIK3CA‐wild‐type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform‐selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform‐selective inhibitors alpelisib and taselisib in patients with PIK3CA‐mutated HR+, HER2− ABC. Ongoing biomarker‐guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost‐effective manner. Implications for Practice The development of phosphoinositide 3‐kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early‐phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα‐isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.

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Section: Methodsmentioning

confidence: 99%

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

2019

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“…With this criterion, another 349 samples (15.5%) were considered as technically failed; finally, primary tumors from 1766 patients were eligible for statistical analysis (Figure 6). TP53 and PIK3CA NGS variants were orthogonally validated with dd-sequencing, as previously shown for this panel [67, 71]. …”

Section: Methodsmentioning

confidence: 99%

TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting

Fountzilas

Giannoulatou

Alexopoulou³

et al. 2016

Oncotarget

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BackgroundWe investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.ResultsTP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009).Materials and MethodsTP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off).ConclusionsTP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.

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“…That observation was not reproduced in the clinic where PIK3CAm did not have any prognostic significance in a large group of predominantly lymph nodepositive breast cancer patients treated with adjuvant chemotherapy [19]. Similar results were obtained in the neoadjuvant setting.…”

Section: Pik3ca In Hormone Receptor-positive Breast Cancermentioning

confidence: 68%

“…Therefore, the clinical implication of PIK3CAm could, in part, depend on the specific hot spot mutation. The different hot spot mutations in PIK3CA have subtype predilection, with helical domain mutations more frequently observed in the molecular luminal A subtype and in lobular carcinoma, and kinase domain mutation (exon 20) more frequent in luminal B carcinoma as compared to other molecular subtypes or ductal carcinoma, respectively [11,17,19].…”

Section: Pik3ca Mutations In Breast Cancermentioning

confidence: 99%

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

Al-Sukhun¹,

Lataifeh

Al-Sukhun³

2016

Curr Breast Cancer Rep

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PIK3CA is one of the most commonly mutated oncogenes in breast cancer, albeit at variable distribution among the different biological subtypes. Overall, it appears that PIK3CA mutations are most likely found in tumors with less aggressive characteristics, especially estrogen receptor (ER)-positive, luminal A tumors. Studies assessing its prognostic or predictive role have reported conflicting data, in part due to different methodologies used for detection and small sample sizes. The majority of reports used retrospective data from clinical trials thus could not exclude the effect of treatment heterogeneity when evaluating prognostic factors, and analysis was not subtype specific. Since breast cancer subtypes differ in terms of biology, treatment, and outcomes, it is critical that the effects of PIK3CA mutations on pathophysiology and therapy responsiveness are analyzed independently in each subtype. This short review discusses these issues and the significance of PIK3CA mutations in relation to the expression of HER2 and hormone receptors.

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Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study

Cited by 29 publications

References 38 publications

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

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