Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study
The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular bi...
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| creator | Papaxoinis, George Kotoula, Vassiliki Alexopoulou, Zoi Kalogeras, Konstantine T Zagouri, Flora Timotheadou, Eleni Gogas, Helen Pentheroudakis, George Christodoulou, Christos Koutras, Angelos Bafaloukos, Dimitrios Aravantinos, Gerasimos Papakostas, Pavlos Charalambous, Elpida Papadopoulou, Kyriaki Varthalitis, Ioannis Efstratiou, Ioannis Zaramboukas, Thomas Patsea, Helen Scopa, Chrisoula D Skondra, Maria Kosmidis, Paris Pectasides, Dimitrios Fountzilas, George |
| description | The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.
Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.
PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients. |
| doi_str_mv | 10.1371/journal.pone.0140293 |
| format | Article |
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Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.
PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0140293</identifier><identifier>PMID: 26452060</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Adjuvant chemotherapy ; Adult ; Aged ; AKT protein ; Analysis ; Androgen receptors ; Biomarkers ; Biomarkers, Tumor - metabolism ; Breast cancer ; Breast Neoplasms - diagnosis ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cancer ; Carcinoma ; Chemotherapy ; Chemotherapy, Adjuvant ; Class I Phosphatidylinositol 3-Kinases ; Clinical trials ; Drug therapy ; ErbB-2 protein ; Female ; Gene mutation ; Genetic aspects ; Histology ; Humans ; Immunohistochemistry ; Insulin-like growth factors ; Kinases ; Middle Aged ; Mutation ; Mutation Rate ; Neoplasm Staging ; Patients ; Phosphatidylinositol 3-Kinases - genetics ; Physiological aspects ; Prognosis ; PTEN protein ; Signal Transduction ; Statistical analysis ; Statistical methods ; Subgroups ; Tumors ; Young Adult</subject><ispartof>PloS one, 2015-10, Vol.10 (10), p.e0140293-e0140293</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Papaxoinis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Papaxoinis et al 2015 Papaxoinis et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-583a25d49a17cbe0fbb198205d4d988c3a1aacc7b89a1a270011515d6f5611853</citedby><cites>FETCH-LOGICAL-c692t-583a25d49a17cbe0fbb198205d4d988c3a1aacc7b89a1a270011515d6f5611853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599795/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599795/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26452060$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Agoulnik, Irina U</contributor><creatorcontrib>Papaxoinis, George</creatorcontrib><creatorcontrib>Kotoula, Vassiliki</creatorcontrib><creatorcontrib>Alexopoulou, Zoi</creatorcontrib><creatorcontrib>Kalogeras, Konstantine T</creatorcontrib><creatorcontrib>Zagouri, Flora</creatorcontrib><creatorcontrib>Timotheadou, Eleni</creatorcontrib><creatorcontrib>Gogas, Helen</creatorcontrib><creatorcontrib>Pentheroudakis, George</creatorcontrib><creatorcontrib>Christodoulou, Christos</creatorcontrib><creatorcontrib>Koutras, Angelos</creatorcontrib><creatorcontrib>Bafaloukos, Dimitrios</creatorcontrib><creatorcontrib>Aravantinos, Gerasimos</creatorcontrib><creatorcontrib>Papakostas, Pavlos</creatorcontrib><creatorcontrib>Charalambous, Elpida</creatorcontrib><creatorcontrib>Papadopoulou, Kyriaki</creatorcontrib><creatorcontrib>Varthalitis, Ioannis</creatorcontrib><creatorcontrib>Efstratiou, Ioannis</creatorcontrib><creatorcontrib>Zaramboukas, Thomas</creatorcontrib><creatorcontrib>Patsea, Helen</creatorcontrib><creatorcontrib>Scopa, Chrisoula D</creatorcontrib><creatorcontrib>Skondra, Maria</creatorcontrib><creatorcontrib>Kosmidis, Paris</creatorcontrib><creatorcontrib>Pectasides, Dimitrios</creatorcontrib><creatorcontrib>Fountzilas, George</creatorcontrib><title>Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.
Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.
PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Adjuvant chemotherapy</subject><subject>Adult</subject><subject>Aged</subject><subject>AKT protein</subject><subject>Analysis</subject><subject>Androgen receptors</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - diagnosis</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Chemotherapy</subject><subject>Chemotherapy, Adjuvant</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Clinical trials</subject><subject>Drug therapy</subject><subject>ErbB-2 protein</subject><subject>Female</subject><subject>Gene mutation</subject><subject>Genetic aspects</subject><subject>Histology</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Insulin-like growth factors</subject><subject>Kinases</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Mutation Rate</subject><subject>Neoplasm Staging</subject><subject>Patients</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Physiological aspects</subject><subject>Prognosis</subject><subject>PTEN protein</subject><subject>Signal Transduction</subject><subject>Statistical analysis</subject><subject>Statistical methods</subject><subject>Subgroups</subject><subject>Tumors</subject><subject>Young 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Rate</topic><topic>Neoplasm Staging</topic><topic>Patients</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Physiological aspects</topic><topic>Prognosis</topic><topic>PTEN protein</topic><topic>Signal Transduction</topic><topic>Statistical analysis</topic><topic>Statistical methods</topic><topic>Subgroups</topic><topic>Tumors</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Papaxoinis, George</creatorcontrib><creatorcontrib>Kotoula, Vassiliki</creatorcontrib><creatorcontrib>Alexopoulou, Zoi</creatorcontrib><creatorcontrib>Kalogeras, Konstantine T</creatorcontrib><creatorcontrib>Zagouri, Flora</creatorcontrib><creatorcontrib>Timotheadou, Eleni</creatorcontrib><creatorcontrib>Gogas, Helen</creatorcontrib><creatorcontrib>Pentheroudakis, George</creatorcontrib><creatorcontrib>Christodoulou, Christos</creatorcontrib><creatorcontrib>Koutras, Angelos</creatorcontrib><creatorcontrib>Bafaloukos, 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Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Papaxoinis, George</au><au>Kotoula, Vassiliki</au><au>Alexopoulou, Zoi</au><au>Kalogeras, Konstantine T</au><au>Zagouri, Flora</au><au>Timotheadou, Eleni</au><au>Gogas, Helen</au><au>Pentheroudakis, George</au><au>Christodoulou, Christos</au><au>Koutras, Angelos</au><au>Bafaloukos, Dimitrios</au><au>Aravantinos, Gerasimos</au><au>Papakostas, Pavlos</au><au>Charalambous, Elpida</au><au>Papadopoulou, Kyriaki</au><au>Varthalitis, Ioannis</au><au>Efstratiou, Ioannis</au><au>Zaramboukas, Thomas</au><au>Patsea, Helen</au><au>Scopa, Chrisoula D</au><au>Skondra, Maria</au><au>Kosmidis, Paris</au><au>Pectasides, Dimitrios</au><au>Fountzilas, George</au><au>Agoulnik, Irina U</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-10-09</date><risdate>2015</risdate><volume>10</volume><issue>10</issue><spage>e0140293</spage><epage>e0140293</epage><pages>e0140293-e0140293</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.
Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.
PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26452060</pmid><doi>10.1371/journal.pone.0140293</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-10, Vol.10 (10), p.e0140293-e0140293 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1721147992 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 1-Phosphatidylinositol 3-kinase Adjuvant chemotherapy Adult Aged AKT protein Analysis Androgen receptors Biomarkers Biomarkers, Tumor - metabolism Breast cancer Breast Neoplasms - diagnosis Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer Carcinoma Chemotherapy Chemotherapy, Adjuvant Class I Phosphatidylinositol 3-Kinases Clinical trials Drug therapy ErbB-2 protein Female Gene mutation Genetic aspects Histology Humans Immunohistochemistry Insulin-like growth factors Kinases Middle Aged Mutation Mutation Rate Neoplasm Staging Patients Phosphatidylinositol 3-Kinases - genetics Physiological aspects Prognosis PTEN protein Signal Transduction Statistical analysis Statistical methods Subgroups Tumors Young Adult |
| title | Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study |
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