Alterations In PIK3CA Gene Research Articles

Next-Generation Sequencing of Breast Cancer in the Neoadjuvant Setting.

Many patients with locally advanced breast cancer are proposed to neoadjuvant chemotherapy (NAT) before surgery. Only some of them achieve a pathological complete response (pCR). The determination of gene somatic alterations using next-generation sequencing (NGS) in the non-pCR tumors is important, in order to identify potential opportunities of treatment for the patients, if targeted therapies are available. Breast cancer tissue samples of 31 patients, collected before NAT, were analyzed by NGS using the Oncomine™ Comprehensive Assay Plus (OCA-Plus) panel. Twelve patients achieved pCR after NAT. ERBB2 gene alterations were the most frequent in this cohort of pCR patients, followed by BRCA 1 and 2, MYC, TP53, PIK3CA, and MET alterations. Tumors that did not achieve a pCR were mainly triple negative. In this subgroup some BRCA 1 and 2 and PIK3CA gene alterations were identified, as well as TP53 mutations. The NGS panel employed in this study also allowed for the determination of tumor mutation burden (TMB). This study showcases the significance of employing comprehensive genomic testing in breast cancer cases, primarily due to the scarcity of specific target assays. The detection of somatic mutations, coupled with the availability of targeted therapies, holds promise as a potential therapeutic avenue to enhance tumor response rates during NAT, or as a complementary treatment following surgery. Moreover, evaluating the TMB in non-pCR samples could serve as a valuable criterion for selecting patients suitable for immunotherapy. Further exploration through clinical trials is imperative to investigate these prospects.

Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives.

The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA-mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2– advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2– advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.

Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

BackgroundThere is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome.MethodsBetween 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome.FindingsAt a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters.InterpretationOur data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset.FundEuropean Union's Seventh Program grant agreement No 304810.

Clinical and Genetic Landscape of Treatment Naive Cervical Cancer: Alterations in <i>PIK3CA</i> and in Epigenetic Modulators Associated with Sub-Optimal Outcome

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013-2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median FU of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65*4% [CI95%: 60*2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulatorgene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harbouring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Funding: European Union's Seventh Program grant agreement No 304810. Declaration of Interest: All authors declared: No conflict of interest. Ethical Approval: Ethical review was conducted according to national requirements and in accordance with the Declaration of Helsinki. All tumour and serum samples and clinical data were registered in a common database using a unique barcode system assuring data privacy.

PIK3CA Mutations Frequently Coexist with EGFR/KRAS Mutations in Non-Small Cell Lung Cancer and Suggest Poor Prognosis in EGFR/KRAS Wildtype Subgroup

Purpose PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer. Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC).Materials and methodsOncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC. PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110α), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation.Results PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma. Among 34 PIK3CA mutant cases, 17 tumors harbored concurrent EGFR mutations and 4 had KRAS mutations. PIK3CA mutation was significantly associated with high expression of PI3K p110α (p<0.0001), p-Akt (p = 0.024) and mTOR (p = 0.001), but not correlated with PIK3CA amplification (p = 0.463). Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004). A significantly worse survival was also found in patients with PIK3CA mutations than those without PIK3CA mutations in the EGFR/KRAS wildtype subgroup (p = 0.043)Conclusions PIK3CA mutations frequently coexist with EGFR/KRAS mutations. The poor prognosis of patients with single PIK3CA mutation in NSCLC and the prognostic value of PIK3CA mutation in EGFR/KRAS wildtype subgroup suggest the distinct mutation status of PIK3CA gene should be determined for individual therapeutic strategies in NSCLC.

PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors

Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment.

PIK3CA Gene Mutations and Amplifications in Chinese Patients With Ovarian Clear Cell Carcinoma

The role of genetic alterations in PIK3CA gene has not been fully explored in ovarian clear cell carcinoma (OCCC). The present study was undertaken to assess mutations and amplifications of exons 9 and 20 of PIK3CA in 51 Chinese OCCC patients. Activating missense mutations of PIK3CA were found in nine (17.6%) cases. One novel mutation T544P was identified in exon 9 which can increase AKT phosphorylation in cell culture. Amplifications of PIK3CA were observed in six cases (11.8%). PIK3CA mutations and amplifications are mutually exclusive. Our study demonstrates relatively low frequency of PIK3CA mutations and amplifications in OCCC.

Abstract B273: Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079).

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 &amp; 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had &amp;gt; 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: &amp;#8211;]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B273.

PIK3CA gene alterations in bladder cancer: Analysis of correlative series of transurethral resection (TUR)—Correlation with grade histology and tumor size.

4584 Background: PI3K pathway involvement in bladder cancer is well documented and activating mutations of the gene have been identified, particularly in tumors of low grade and stage. We have analyzed hot spot mutations and copy number in PIK3CA gene as well as mRNA expression levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent normal tissue was collected. All pts signed an informed consent and basic demoghrapics data were collected. Histology confirmation of UCC was required. PIK3CA alterations were analyzed by quantative-PCR. Results: Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences were observed. 13% normal tissue and 51,8% tumor samples harbored alterations in PIK3CA gene, including alterations affecting the helical domain (mutations 65%, amplifications 60%, both 21%). According to T stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p&lt;0.05). When analyzing factors related to tumor recurrence, it was found that PIK3CA gene mutations in E542 or E545 had a lower recurrence risk (p-value ²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) showed that tumors bearing altered PIK3CA gene are more similar to non-tumoral samples comparing with tumors bearing wtPIK3CA gene. Moreover, overexpressed genes in mutant samples are mainly involved in G-protein and Wnt signaling, whereas underexpressed genes are involved in cell morphogenesis and cell polarity. Conclusions: We observed that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, and more frequently found in larger tumor stages. These data support that PIK3CA status may constitute a good prognostic tool, as well as a therapeutic target in stratified groups for bladder cancer.

PIK3CA as a molecular target in mantle cell lymphoma

8612 Background: We sought to determine the contribution of PIK3CA gene alterations to the pathogenesis of mantle cell lymphoma (MCL). PIK3CA is known to be involved in the PI 3-kinase/AKT signaling pathway, which is activated in MCL. Methods: We analysed 35 primary MCL cases (14 frozen and 21 paraffin-embedded specimens) and 2 MCL cell lines (Granta, REC1). To search for PIK3CA mutations, we isolated genomic DNA from primary MCL cases and MCL cell lines and performed direct sequencing of the exons 9 and 20 of PIK3CA. We used real-time quantitative PCR to investigate genomic amplification of the PIK3CA gene. We also analyzed PTEN and phoshorylated Akt protein levels in primary cases and cell lines using western blotting and immunohistochemistry (IHC). Flow cytometry analysis was used to assess apoptosis after treatment of MCL cell lines and the Raji Burkitt lymphoma cell line with LY294002, a specific inhibitor of PI3KCA. Results: We found that 14 of 23 (58%) primary MCL cases with amplifiable β- globin and two of two cell lines harboured a gain (>3) of PIK3CA gene copy number. PIK3CA gene mutations were not identified. In addition, amplification of PIK3CA correlated with the status of Akt phosphorylation in 7 of 12 (58%) primary MCL cases and the two MCL cell lines. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by western blotting whereas five of 33 (15%) cases tested by IHC had loss of PTEN protein expression. Only one of the 5 MCL cases with loss of PTEN expression harboured gain of PIK3CA gene copy number. Therefore, PI3KCA gene amplification and PTEN loss were nearly mutually exclusive. Conclusions: We conclude that PIK3CA is an oncogene in MCL and PIK3CA amplification may be linked to pathogenesis and survival in MCL. No significant financial relationships to disclose.