PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers

Castañeda, Carlos A.; López-Ilasaca, Marco; Pinto, Joseph A.; Chirinos-Arias, Michelle C.; Doimi, Franco D.; Neciosup, Silvia P.; Rojas, Katerin Ingrid; Vidaurre, Tatiana; Balko, Justin M.; Arteaga, Carlos L.; Gómez, Henry L.

doi:10.1016/j.hemonc.2014.09.007

Cited by 21 publications

(18 citation statements)

References 24 publications

(20 reference statements)

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“…However, targeting HER2 alone was less effective for breast cancer patients with PIK3CA mutations in clinical studies ( 17 , 18 ). In line with these observations, several groups reported that HER2 amplification and mutation of PIK3CA genes could be co-occurring in certain breast cancer population ( 6 , 19 - 22 ). However, the cooperative effect of these two genetic alterations in comparison with either single genetic change on cell oncogenic properties has not been well investigated.…”

Section: Introductionmentioning

confidence: 57%

Cooperative oncogenic effect and cell signaling crosstalk of co-occurring HER2 and mutant PIK3CA in mammary epithelial cells

Meng

Mitchell

et al. 2017

International Journal of Oncology

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Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.

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Section: Introductionmentioning

confidence: 57%

Cooperative oncogenic effect and cell signaling crosstalk of co-occurring HER2 and mutant PIK3CA in mammary epithelial cells

Meng

Mitchell

et al. 2017

International Journal of Oncology

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“…In this study, Silvia et al 53 indicated that TP53 mutations did not predict the NCT response in TNBC patients. Furthermore, analysis of the predictive of PIK3CA mutation on TNBC agents was performed in a biomarker analysis of 81 patients with residual disease after NCT, with finding of PIK3CA mutation not associated with pCR 54.…”

Section: Early Stagementioning

confidence: 99%

Potential Management of Circulating Tumor DNA as a Biomarker in Triple-Negative Breast Cancer

Mao¹,

Chang²,

Pei³

et al. 2018

J. Cancer

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As a specific subtype of breast cancer, Triple-negative breast cancer (TNBC) is associated with worse prognosis and higher tumor aggressiveness than HER2-amplified or hormone receptor positive breast cancers. Circulating tumor DNA (ctDNA), as a non-invasive “liquid biopsy”, is an emerging original blood-based biomarker for early breast cancer diagnosis, monitoring treatment response, and determining prognosis. In TNBC patients, ctDNA has an inherent tendency to characterize tumor heterogeneity and metastasis-specific mutations providing a key alternative to tumor tissue profiling. Several studies have already demonstrated the potential of ctDNA in TNBC patients from early to advanced stages of the disease including diagnosis, therapy decisions and assessment of prognosis. This review provides a critical brief summary of the evidence that gives credence to the utility of ctDNA as a biomarker for its role into clinical management in TNBC.

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“…Mutation p.E542K has been already proved as pathogenic with constitutively activating effect in PI3K/AKT/mTOR signalling pathway in a large number of tumor diseases [28]. In contrast to this well characterized point mutation, the other mutation p.D549N has been described only in a few cases of colorectal carcinoma, breast or endometrial carcinoma so far [29][30][31]. Concerning to its low frequency, the information about its effect in the protein function is still absent.…”

Section: Discussionmentioning

confidence: 99%

Detection of oncogenic mutations in cervical carcinoma using method High Resolution Melting (HRM)

Wayhelova¹,

Mikulášová²,

Smetana³

et al. 2016

neo

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Oncogenic mutations in proto-oncogenes and tumor suppressor genes represent one of key events in cancerogenesis. In this study, we analysed mutation status in PIK3CA, KRAS and EGFR proto-oncogenes and TP53 tumor suppressor gene in a cohort of twenty-four patients diagnosed with squamous cell carcinoma or adenocarcinoma using the screening method "High Resolution Melting" (HRM). Positive findings were confirmed and identified by Sanger sequencing. Totally, we detected DNA sequence changes in targeted regions in seven patients (7/24, 29.2%). In PIK3CA gene, we found six sequence changes in four patients (4/24, 16.7%) and four of them were confirmed as oncogenic mutations. In KRAS gene, we detected sequence changes in four patients (4/24, 16.7%). Conversely, we identified pathogenic or potentially pathogenic sequence changes neither in EGFR nor TP53 genes. Our results suggest that sequence changes are specific neither for a certain histological subtype, clinical stage nor lymph node involvement and they appear independently on the presence of HPV (human papillomavirus) infection since early clinical stages. We observed the correlation between the presence of DNA sequence changes and hTERC gene amplification, but we did not find a significant relationship between the identified DNA sequence changes and detected copy-number alterations using the technique of array-CGH (array-based comparative genomic hybridization). Regardless our results confirmed an important role of oncogenic mutations in PIK3CA and KRAS genes in the neoplastic transformation process in the cervical carcinoma pathogenesis. Their identification in the early clinical stages should encourage further studies to better understand these mutations and exploit them for more detailed diagnostics.

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PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers

Abstract: We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors.

Cited by 21 publications

References 24 publications

Cooperative oncogenic effect and cell signaling crosstalk of co-occurring HER2 and mutant PIK3CA in mammary epithelial cells

Cooperative oncogenic effect and cell signaling crosstalk of co-occurring HER2 and mutant PIK3CA in mammary epithelial cells

Potential Management of Circulating Tumor DNA as a Biomarker in Triple-Negative Breast Cancer

Detection of oncogenic mutations in cervical carcinoma using method High Resolution Melting (HRM)

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