PIK3CA mutation + PTEN mutation

P1, N=26, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

PI3K pathway alteration can affect response to NAT in TNBC, and targeted agents may improve outcomes, particularly in patients with M and LAR TNBC.

About half of the breast SCCs exhibited high sTILs and positive PD-L1 expression, which indicated the potential opportunity for immunotherapy. Genomic profile revealed clinically meaningful alterations that might guide targeted treatment decisions in SCC patients.

This analysis demonstrated efficacy for lenvatinib plus pembrolizumab regardless of biomarker status. Results from this study do not support clinical utility of the evaluated biomarkers. Further investigation of biomarkers for this regimen is warranted.

The biological characteristics of CRC in Chinese patients have some unique clinical features, which can be explained by the genetic mutation profile, correlations among gene mutations and clinical characteristics. These distinctions set the Chinese patient population apart from their Western counterparts.

The presence of TP53 mutations is strongly associated with both cigarette smoking and elevated Tv/Ti ratios. The tier status of TP53, EGFR, and PTEN variants does not show a specific domain distribution, but interesting associations are observed between the tier status and domain distribution in PIK3CA variants. Therefore, further comprehensive investigations are needed to explore this entity, as well as the underlying factors contributing to the increased Tv/Ti rates in the TP53 gene. Such research will provide deeper insights into the genetic alterations associated with smoking and tumor heterogeneity, ultimately aiding in the development of targeted therapies.

TP53 mutation was found to be recurring in the 14/19 (73.6%) patients and, therefore, can be considered as a potential biomarker. Finally, these mutations were studied in the context of their potential association with different hormonal and social factors.

Molecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.

P1/2; Trial completion date: Nov 2023 --> Nov 2024 | Trial primary completion date: Nov 2023 --> Nov 2024

P1, N=54, Recruiting, M.D. Anderson Cancer Center | N=84 --> 54

All patients received radiotherapy and temozolomide as first-line therapy...TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts)... Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest deeper explorations in targeting ROS1 and FGFR. Further correlation among patients' outcome, molecular characteristics and TT timing are still under investigation.

Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

Conclusions The combination of copanlisib and nivolumab is well tolerated with antitumor activity in pts with PIK3CA hotspot and PTEN mutations including PD-1/L1i-exposed pts. Translational analyses are ongoing.

All pts received radiotherapy and temozolomide as first-line...TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), vebreltinib (2 pts), capmatinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts)...We had a dramatic response to a MET inhibitor. Deeper explorations are needed in targeting FGFR e ROS1.

Based on NGS and PD-L1 IHC, gene mutation, TMB and PD-L1 expression are analyzed. Cox single factor and PFS are used to verify that these molecular markers are independent of TMB and PD-L1 for targeted therapy of lung cancer.

P1/2; Recruiting --> Suspended

P1, N=12, Recruiting, Nader Sanai | Not yet recruiting --> Recruiting

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Feb 2023 --> Dec 2023 | Trial primary completion date: Feb 2023 --> Dec 2023

P1, N=12, Not yet recruiting, Nader Sanai

We identified pts with EGFR mutations or ALK rearrangements who developed PIK3CA/PTEN alterations in tissue biopsy and/or circulating tumor DNA upon progression to first-line osimertinib/alectinib. Activating PI3KCA mutations and molecular events leading to PTEN loss are frequent events at resistance to first-line EGFR/ALK TKIs, and can be detected concomitantly. Functional assays confirmed that these alterations act as resistance mechanisms. These observations are of interest as PI3KCA/mTOR inhibitors may have a role in overcoming resistance.

By-pass alterations included KRAS p.G12C/A mutations (N=2, ALK+), PIK3CA p.E545K/Q (N=3, ALK+), PTEN splice-site mutation (N=1, RET+), MYC amplifications (N=3, ALK+ / RET+) and MET amplification (N=1, ROS1+).Conclusion LB was able to detect resistance mechanisms in one third of NSCLC patients with ALK, RET or ROS1 fusions. However, LB frequently failed to detect circulating-tumor DNA especially in patients with limited disease progression or with ongoing treatment at time of sample collection.

Genetic backgrounds, such as the HPV 16 genotype and PIK3CA mutations, were common regardless of ethnicity. p16 status may be a prognostic biomarker for CCRT in Japanese patients with ASCC.

P1, N=27, Completed, St. Joseph's Hospital and Medical Center, Phoenix | Active, not recruiting --> Completed | Trial completion date: Jul 2022 --> Feb 2022 | Trial primary completion date: Jun 2022 --> Feb 2022

P1/2; Trial completion date: Nov 2022 --> Nov 2023 | Trial primary completion date: Nov 2022 --> Nov 2023

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2022 --> Feb 2023 | Trial primary completion date: Sep 2022 --> Feb 2023

1. Some mutations affecting the function of tumor cells and the activation of special signaling pathways may be related to the primary resistance of EGFR-TKIs. 2.

Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. Toxicity profile proved to be manageable with hyperglycemia (20-24%), diarrhea (14-17%) and maculopapular rash (11-16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer.

P1, N=27, Active, not recruiting, St. Joseph's Hospital and Medical Center, Phoenix | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2021 --> Jun 2022

Importantly, our in vitro experiments from multiple cell line models indicated that PIK3CA-mediated resistance to osimertinib could be partially reversed by co-treatment with AKT (capivasertib, AstraZeneca) and PI3K alpha (alpelisib, Novartis) inhibitors; PTEN-mediated resistance could be rescued by co-treatment with capivasertib and PI3K beta (AZD8186, AstraZeneca) inhibitors. Our in vivo analysis show that PIK3CA GOF CRISPR engineered cells displayed diminished response to osimertinib when implanted in mice; importantly, combination with AKT (capivasertib) or PI3K alpha (alpelisib) inhibitors enhanced response on treatment and delayed outgrowth after withdrawal treatment. In addition, we observed that combination treatment with capivasertib induced tumour stasis in a PIK3CA-E454K and two PTENloss PDX models.Altogether our in vitro and in vivo data provide evidence of PIK3CA mutants and PTEN loss-driven mechanisms of resistance to osimertinib and offer possible therapeutic combination strategies for those patients that develop resistance or experience a sub-optimal response to osimertinib through PIK3CA/PTEN mutations

After controlling for stage at diagnosis and subtype, we observed significant differences in BC mutational spectrums, gene expression, and relevant pathway activities between patients with genetically determined AA and EA, particularly within the TNBC and HR+/HER2- subtypes. These findings may guide future development of treatment strategies by providing data for biomarker-informed research and precision cancer care.

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

In summary, progressive microsatellite instability develops in recurrent tumors of MSI-H endometrial endometrioid carcinomas. Damaging ARID1A mutations were strongly associated with MSI-H endometrial carcinomas and activating CTNNB1 mutations may play an important role in the development of tumor recurrence.

P1/2, N=204, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

However, widespread genomic alterations were detected involving a variety of cancer-associated genes further characterizing CNA in BPDCN. Analysis of additional BPDCN cases is progress.

In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.

Patients (pts) with advanced HER2-positive breast cancer whose disease had progressed on at least 1 line of Trastuzumab/T-DM1 based treatment in the metastatic setting were eligible if they met following criteria: ECOG PS ≤ 2 and adequate organ function. The combination of Copanlisib and Trastuzumab is a safe and tolerable regimen and is associated with clinical efficacy in a heavily pre-treated metastatic HER2-positive breast cancer population. Translational studies may have identified novel resistance biomarkers in this pt cohort.

PIK3CA-mutated PTEN-lost tumors (n = 33) showed higher prevalence of CD274-positivity (82%) than PIK3CA-wild-type PTEN-lost tumors (n = 204; 70% CD274-positivity) and PTEN-expressed tumors (n = 147; 50% CD274-positivity) (P = .003). Our findings support the role of PI3K signaling in the CD274/PDCD1 pathway.

P2, N=124, Recruiting, Alliance for Clinical Trials in Oncology | Suspended --> Recruiting | N=69 --> 124

Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.