PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.

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Frequency of PIK3CA mutations in HER2+ surgically resected breast cancers in a Hispanic cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11066 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11066-e11066

Author(s):

Carlos Munive ◽

Aly Gallo ◽

Silvia P. Neciosup ◽

Franco Doimi ◽

Richard Dyer ◽

...

Keyword(s):

Targeted Therapy ◽

Pik3ca Mutation ◽

Breast Tumors ◽

Breast Cancers ◽

Pik3ca Gene ◽

Pik3ca Mutations ◽

Mutational Status ◽

Pi3k Signaling Pathway ◽

Exon 9 ◽

Exon 20

e11066 Background: PI3K signaling pathway is responsible for balancing cell survival and apoptosis, and plays an important role in the pathogenesis and progression of human breast cancers. Alterations in this pathway could influence the response to targeted therapy. Our aim is to know the frequency of mutations in the PIK3CA gene in HER2+, operable breast tumors in an Andean population. Methods: We include a cohort of 59 patients with HER2+ surgically resected breast cancer that received adjuvant anti-HER2 targeted therapy at the Instituto Nacional de Enfermedades Neoplásicas. Genomic DNA was extracted from Paraffin embedded-formalin fixed tumor samples and mutational status of PIK3CA gene was using PCR-based DNA sequencing Results: At the current date, the median of follow-up in our cohort is 2.4 years and two recurrences have been registered. Four samples were not evaluable for molecular analysis. Mutation in PIK3CA gene was detected in 12 cases (20.3%). In cases where PIK3CA mutation was detected, eight cases (66.7%) had mutations in exon 9 (A1634C/E545A in 6 cases; G1624A/E542K in 1 case and G1633A/E545K in 1 case). Four cases (33.3%) had exon 20 mutated (A3140G/H1047R in all cases). There was not coexistence of mutations in both exons. One case of tumor recurrence had mutation in exon 9. Conclusions: We found similar rates of PIK3CA mutations as described previously to HER2+, breast tumors. A longest follow upwill show the prognostic value of PIK3CA status in our cohort treated with targeted anti-HER2 therapy. [Table: see text]

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PIK3CA mutation in gastric cancer and the role of microsatellite instability status in mutations of exons 9 and 20 of the PIK3CA gene

Advances in Clinical and Experimental Medicine ◽

10.17219/acem/70795 ◽

2018 ◽

Vol 27 (7) ◽

pp. 963-969 ◽

Cited By ~ 4

Author(s):

Karol Polom ◽

Daniele Marrelli ◽

Giandomenico Roviello ◽

Valeria Pascale ◽

Costantino Voglino ◽

...

Keyword(s):

Gastric Cancer ◽

Microsatellite Instability ◽

Pik3ca Mutation ◽

Pik3ca Gene

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The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4020 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4020-4020 ◽

Cited By ~ 1

Author(s):

D. Lambrechts ◽

W. De Roock ◽

H. Prenen ◽

J. De Schutter ◽

B. Jacobs ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Pik3ca Mutation ◽

Braf V600e ◽

Kras Mutations ◽

Exact Test ◽

Pik3ca Mutations ◽

Exon 20

4020 Background: KRAS mutations (MUT) negatively affect outcome after cetuximab (CTX) in metastatic colorectal cancer (mCRC). As only 40% of KRAS wild-type (WT) respond it is possible that other MUT, constitutively activating the Ras/Erk or PI3K/Akt pathways, are present in the non-responding KRAS WT. We analyzed the KRAS, BRAF, NRAS & PIK3CA MUT status in 276 chemorefractory CRC treated with CTX +- irinotecan and correlated the MUT status with outcome. Methods: KRAS codon 12,13, 61&146, BRAF V600E, NRAS codon 12&13, PIK3CA E542K, E545K, A, G, V (exon 9), H1047Y, R, L (exon 20), N345K, R88Q and Q546K MUT were evaluated on FFPE primary CRC using the Sequenom MALDI TOF MassArray system. A two- sided Fisher's exact test was used to evaluate the association between PIK3CA, KRAS, BRAF & NRAS MUT and objective response (OR). Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: 116/276 (42%) CRC had a KRAS MUT, 96% of which occurred in codon 12 or 13. KRAS WT was associated with OR (p<.0001), longer median PFS (p<.0001) and OS (p<.0001). 15/153 (9.8%) KRAS WT had a BRAF MUT. BRAF WT was associated with OR (p=.01), longer PFS (p<.0001) and OS (p=.007). 5/98 (5%) KRAS WT had an NRAS MUT and none of these showed OR. KRAS, BRAF and NRAS MUT were mutually exclusive. The combined KRAS/BRAF/NRAS WT state was associated with OR (p<.0001), longer PFS (p<.0001) and OS (p<.0001). 23/200 (12%) CRC carried a PIK3CA mutation: 5/39 (13%) of responders and 18/160 (11%) of non-responders (p=.781). Median PFS and OS were not associated with PIK3CA MUT state (p=.760 & p=.698) overall, nor in the KRAS/BRAF/NRAS WT subgroup (p=.946 & p=.509). 5/13 (38.5%) PIK3CA MUT KRAS/BRAF/NRAS WT CRC showed an OR. 13/107 (12%) of KRAS/BRAF/NRAS WT and 10/93 (11%) of KRAS/BRAF/NRAS MUT tumors harbored a PIK3CA MUT (p=.826). Conclusions: KRAS, BRAF & NRAS MUT are mutually exclusive and occur in at least 47% of CRC. Like KRAS WT, BRAF WT state of the primary is significantly associated with outcome in mCRC treated with CTX. The combined KRAS/BRAF/NRAS WT state is significantly associated with outcome. PIK3CA MUT occur independently of the KRAS/BRAF/NRAS MUT status. We cannot provide any evidence for a strong role of PIK3CA MUT as a marker in determining outcome to CTX. [Table: see text]

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Frequent Mutation of the PIK3CA Gene in Saudi Arabian Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.4308.4308 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4308-4308

Author(s):

Jehad A. Abubaker ◽

Prashant P. Bavi ◽

Sayer Al-Harbi ◽

Valerie L. Atizado ◽

Fouad Al-Dayel ◽

...

Keyword(s):

Somatic Mutations ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Ki 67 ◽

Pik3ca Gene ◽

Pik3ca Mutations ◽

Over Expression ◽

Large B Cell Lymphoma ◽

High Level

Abstract Phosphotidylinositol 3′-kinases are lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, motility, and are implicated to play an important oncogenic role in many cancer types. The PIK3CA gene encodes the p110α catalytic subunit of PI3K-like gene. Recently, high frequencies of PIK3CA somatic mutations have been detected in various kinds of human cancers notably colorectal, gastric, and breast cancers. It has also been shown that somatic mutations in the PIK3CA gene have been associated with a higher expression of p-AKT in certain cancers. However, the role of PIK3CA mutations in hematological malignancies has not been elucidated in detail. Therefore, we tested whether PIK3CA is subject to mutations in diffuse large B-cell lymphoma (DLBCL). Exons 9 and 20, encoding the highly conserved helical and kinase domains of PIK3CA, which account for 85% of somatic mutation in PIK3CA gene, were subjected to direct sequencing analysis in 219 cases of DLBCL. Somatic missense mutations were observed in 17 of 212 (8%) DLBCL cases. Out of which, 10 mutations (60%) occurred at codon 1047 in the kinase domain, which is one of the previously reported hot spot within the PIK3CA gene. Additionally, a silent polymorphism (T1025T) was found in one of the DLBCL sample. Moreover, activation of AKT was observed in 14 out of 17 (82%) of the DLBCL harboring PIK3CA mutations. Further, 9 out of 17 cases showed high level of pAKT. Additionally, 12 out of 17 DLBCL patients with PIK3CA mutations showed over-expression of the proliferative marker Ki-67. Expression of high level of pAKT was significantly correlated with over-expression of Ki-67 (p=0.0097). Overall survival in DLBCL cases harboring PIK3CA mutation showed poor survival as compared to the DLBCL cases lacking mutations though it was not statistically significant. These data indicate that mutations of PIK3CA play an oncogenic role in DLBCL tumors and argue for a role of PIK3CA targeting in treatment of DLBCL patients.

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Prevalence of KRAS, BRAF, NRAS, PIK3CA, and PTEN alterations in colorectal cancer: Analysis of a large international cohort of 5,900 patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.399 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 399-399 ◽

Cited By ~ 4

Author(s):

Gargi Dan Basu ◽

Joanne Xiu ◽

David Arguello ◽

Rebecca A. Feldman ◽

Sherri Z. Millis ◽

...

Keyword(s):

Colorectal Cancer ◽

Pik3ca Mutation ◽

Pi3k Pathway ◽

Wild Type ◽

Pten Protein ◽

Pik3ca Mutations ◽

Pten Loss ◽

Biomarker Testing ◽

Molecular Aberrations

399 Background: Colorectal cancer (CRC) is the third most common cancer worldwide, with metastatic disease accounting for 40 to 50% of newly diagnosed patients. EGFR monoclonal antibodies (Mab), cetuximab and panitumumab, are effective treatment for KRAS wild type CRC. Although mutations in KRAS predict resistance to EGFR Mab therapy, only 80% of CRC patients with KRAS wild-type (WT) status respond to treatment. This study is a retrospective evaluation of genomic alterations in the EGFR pathway such as alterations in KRAS, BRAF, NRAS, PIK3CA and PTEN that may predict lack of response to EGFR Mab therapy in CRC patients. Methods: A large database of 5,900 consecutive CRC patients was analyzed from 2011 onwards for demographics (sex, age, geography, site of tumor) and biomarkers that might correlate with response to EGFR Mab therapy. Comprehensive testing included gene sequencing for KRAS, BRAF, NRAS, PTEN, and PIK3CA (next-generation sequencing, Sanger, pyrosequencing) and immunohistochemistry for PTEN protein expression. Results: Analysis revealed the incidence of KRAS mutation of 42% which is consistent with published literature. Analysis of the KRAS WT cohort revealed a mutation rate of 13.8 % for BRAF, 6.8% for NRAS, and 40% for patients with either PTEN loss of expression/mutation or a PIK3CA mutation. Earlier studies support that mutations in NRAS, BRAF and activation of the PI3K pathway by PTEN/PIK3CA analysis result in lower response rates to EGFR Mab therapy in CRC. Furthermore, multiplex biomarker testing revealed the rare occurrence of concurrent mutations: 1/5,900 subject harboring a BRAF and NRAS mutations, 7/5,900 others with BRAF and PIK3CA mutations, and 8/5,900 subjects with NRAS and PIK3CA mutations. Conclusions: This is a comprehensive analysis of a large international cohort evaluating the prevalence of predictive molecular aberrations suspected of lack of response to EGFR Mab therapy in patients with WT KRAS. Prospective controlled studies are in progress to validate the role of BRAF, NRAS, PIK3CA, and PTEN in clinical management of CRC. It is imperative to further explore the molecular pathology of CRC beyond KRAS in patient selection for EGFR Mab therapy.

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KRAS and PIK3CA Mutation Frequencies in Patient-derived Xenograft Models of Pancreatic and Colorectal Cancer Are Reflective of Patient Tumors and Stable Across Passages

The American Surgeon ◽

10.1177/000313481408000920 ◽

2014 ◽

Vol 80 (9) ◽

pp. 873-877 ◽

Cited By ~ 16

Author(s):

Christopher J. Tignanelli ◽

Silvia G. Herrera Loeza ◽

Jen Jen Yeh

Keyword(s):

Colorectal Cancer ◽

Pik3ca Mutation ◽

Disease Patient ◽

Gene Mutations ◽

Ductal Adenocarcinoma ◽

Kras Mutations ◽

Genetic Changes ◽

Pik3ca Mutations ◽

Patient Derived Xenograft ◽

Pdx Models

One obstacle in the translation of advances in cancer research into the clinic is a deficiency of adequate preclinical models that recapitulate human disease. Patient-derived xenograft (PDX) models are established by engrafting patient tumor tissue into mice and are advantageous because they capture tumor heterogeneity. One concern with these models is that selective pressure could lead to mutational drift and thus be an inaccurate reflection of patient tumors. Therefore, we evaluated if mutational frequency in PDX models is reflective of patient populations and if crucial mutations are stable across passages. We examined KRAS and PIK3CA gene mutations from pancreatic ductal adenocarcinoma (PDAC) (n = 30) and colorectal cancer (CRC) (n = 37) PDXs for as many as eight passages. DNA was isolated from tumors and target sequences were amplified by polymerase chain reaction. KRAS codons 12/13 and PIK3CA codons 542/545/1047 were examined using pyrosequencing. Twenty-three of 30 (77%) PDAC PDXs had KRAS mutations and one of 30 (3%) had PIK3CA mutations. Fifteen of 37 (41%) CRC PDXs had KRAS mutations and three of 37 (8%) had PIK3CA mutations. Mutations were 100 per cent preserved across passages. We found that the frequency of KRAS (77%) and PIK3CA (3%) mutations in PDAC PDX was similar to frequencies in patient tumors (71 to 100% KRAS, 0 to 11% PIK3CA). Similarly, KRAS (41%) and PIK3CA (8%) mutations in CRC PDX closely paralleled patient tumors (35 to 51% KRAS, 12 to 21% PIK3CA). The accurate mirroring and stability of genetic changes in PDX models compared with patient tumors suggest that these models are good preclinical surrogates for patient tumors.

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Clinical-Pathologic Analysis of Breast Cancer With PIK3CA Mutations in Chinese Women

Technology in Cancer Research & Treatment ◽

10.1177/1533033820950832 ◽

2020 ◽

Vol 19 ◽

pp. 153303382095083

Author(s):

Jing Lian ◽

En-Wei Xu ◽

Yan-Feng Xi ◽

Hui-Wen Wang ◽

Peng Bu ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Gene Mutation ◽

Chinese Women ◽

Pik3ca Mutation ◽

Lymph Node Status ◽

Breast Cancer Patients ◽

Pik3ca Gene ◽

Pik3ca Mutations ◽

The Relationship

Purpose: Mutations of PIK3CA have recently been shown to play an important role in the pathogenesis and progression of breast neoplasms. The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA mutation in Chinese breast cancer patients and explored their role in tumor phenotypes. Methods: Mutational analysis of PIK3CA was done in 113 primary breast cancers of Chinese women used Amplification refractory mutation system (ARMS). The relationship of PIK3CA mutations with several clinicopathologic characteristics was analyzed. Results: PIK3CA gene mutation was identified in 43(38.05%) cases and has a more significant difference between exon 9 and 20. HER2 gene amplification was 32.6% in 43 cases of PIK3CA mutation, but 37.1% in 70 cases of non-mutation (χ2 = 0.245, P > 0.05). There was no significant correlation of the age distribution, lymph node status, histological tumor grading, ER and/or PR and P53 between 2 groups (P > 0.05). Conclusion: A high frequency of somatic PIK3CA mutation was detected in Chinese breast cancer patients, especially in exon 20. The relationship between PIK3CA gene mutation and clinical pathological features of breast cancer needs to be further studied in a large series of patients. PIK3CA mutations seem to have the potential to be used in target treatment and as an indicator of prognosis.

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Hepatoid adenocarcinoma of the stomach with PIK3Ca mutation during pregnancy: A case report with molecular profile

Oxford Medical Case Reports ◽

10.1093/omcr/omab078 ◽

2021 ◽

Vol 2021 (9) ◽

Author(s):

Anastasija Ranceva ◽

Rokas Stulpinas ◽

Rimvydas Norvilas ◽

Ugnius Mickys

Keyword(s):

Treatment Options ◽

Pik3ca Mutation ◽

Gene Mutations ◽

Stage Iv ◽

Young Female ◽

Biological Behavior ◽

Molecular Profile ◽

Hepatoid Adenocarcinoma ◽

Pik3ca Gene ◽

Molecular Features

ABSTRACT Hepatoid adenocarcinoma is an extremely aggressive special subtype of gastric tumors. It can be lethal as no standard treatment options for this type of gastric cancer exist. Here, we describe a very rare case of a young female on her 21st week of pregnancy who was diagnosed with stage IV hepatoid adenocarcinoma of the stomach with elevated α fetoprotein (AFP) level. Gene mutation analysis performed by next-generation sequencing identified somatic mutations in the PIK3CA gene. Despite the treatment, patient died 2 months after the initial disease presentation. To our best knowledge, this case represents the first report of pregnancy-associated hepatoid gastric adenocarcinoma with the PIK3CA gene mutations, which can provide further clues for the understanding of molecular features of this type of tumor that can reflect biological behavior and may lead to further effective treatment options.

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