PIK3R1 mutation

AEBP1 amplification was associated with shorter OS in GBM. Our study suggests that clinical sequencing can recapitulate previous findings, which may provide a powerful approach to discover diagnostic, therapeutic and prognostic markers for precision medicine in adult-type diffuse gliomas.

Differential diagnosis with combined immunodeficiency and diseases of immune dysregulation make molecular genetic analysis crucial for diagnosing mTOR pathway defects. It is easy to differentiate APDS and homozygous PIK3R1 defects with specific laboratory features. Additionally, mTOR pathway functional analysis is a definitive diagnostic and pathogenicity assessment tool for novel APDS mutations.

P2, N=100, Recruiting, Nationwide Children's Hospital | Not yet recruiting --> Recruiting

P1, N=12, Recruiting, Nader Sanai | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

Plasmacytoid UC is an aggressive histologic subtype that demonstrates frequent somatic gene mutations and CNVs, which may underlie its oncogenesis and progression. Gene mutations of the mTOR pathway are associated with poor outcome in a subset of patients with plasmacytoid UC.

P2, N=100, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Jan 2034 --> May 2034 | Initiation date: Jan 2024 --> May 2024 | Trial primary completion date: Jan 2028 --> May 2028

RGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis.

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.

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2026 --> Aug 2024 | Trial primary completion date: Oct 2026 --> Aug 2024

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=78 --> 7

Salvage therapy comprised re-irradiation (n=52, 43%), temozolomide (TMZ) (n=39, 32%), lomustine (n=47, 39%), and/or bevacizumab (n=22, 18%). Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.

Notably, only one patient received sequential ctDNA testing, and in that case, there was a gain of TP53 p.N239S following sacituzumab govitecan administration compared to the baseline ctDNA test, followed by a gain of PIK3CA p.P449_L455del after trastuzumab deruxtecan administration. As we observe changes in subtypes following treatment progression, researchers are actively seeking biomarkers to better characterize real-time changes in tumor biology that can predict response and resistance to treatments. Further studies are needed to identify additional genes present in ctDNA that can provide mechanistic insights into why certain patients respond favorably to ADCs while others do not. We are currently enrolling patients for a prospective study that aims to assess baseline ctDNA levels and monitor changes in variant allele frequency following treatment with ADCs and immunotherapy.

Seventy-five patients were identified. Unlike stage I, grade 1 EECs, which are mostly of copy number (CN)-low molecular subtype, most of our stage I, grade 3 EECs were of POLE (25/75, 33%) or microsatellite instability (MSI)-high (24/75, 32%) molecular subtypes; 20% (15/75) were CN-high and 15% (11/75) CN-low. Patients with MSI-high EECs, compared to other subtypes, were more likely to have deep myometrial invasion (p=0.02) and to have received chemotherapy (p=0.01).

P3, N=15, Recruiting, Pharming Technologies B.V. | Not yet recruiting --> Recruiting

P2, N=100, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Aug 2033 --> Jan 2034 | Initiation date: Aug 2023 --> Jan 2024 | Trial primary completion date: Aug 2027 --> Jan 2028

The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

In particular, normal-like and luminal A subtypes in TNAC have much better DFS and OS than other intrinsic subtypes. Our findings are expected to impact medical practice for patients diagnosed with TNAC.

We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or co-driver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.

When compared to those with the SD phenotype, the mono-IBD patients had significant early-onset and poor responses to empiric antibiotics, IVIG, and steroids. Anti-inflammatory biologics and suitable HSCT still have the potential to control or even cure the mono-IBD phenotype.

PIK3R1 deficiency leads to increased PI3K/AKT signaling which regulates cell cycle and the spliceosome machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.

The tumor with c.-92_-91ins had NF1/PIK3CA mutations; the case with c.-123_-76dup had PTEN/MYCN mutations and chromosome 7 gain/10 loss/CDK4, MDM2 amplification; and the tumor with c.-118_-117ins had a CBL mutation. Conclusions Our findings expand the spectrum of TERTp non-canonical variants in brain tumors and further suggest that they typically occur in tumors with features of GBM-IDHWT as a clinically/diagnostically relevant alternative TERTp activating mechanism.

Divergent genetic profiles between A-DCIS and invasive carcinoma were identified in 1 case. In summary, our findings support TNAC as a morphologically, immunohistochemically, and genetically homogeneous subgroup of triple-negative breast carcinomas and suggest overall favorable clinical behavior.

On multivariable analysis, stage, lymphovascular invasion, and tumor mutational burden were prognostic for disease-free survival, whereas advanced stage and TP53-mutant subgroup - but not a TP53 mutation in isolation - were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatments, such as immunotherapy and anti-HER2 agents.

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

P2, N=100, Not yet recruiting, Nationwide Children's Hospital

In ER+/HER2- mBC, first line chemotherapy efficacy was similar for PIK3CA-mutated and PIK3CA-WT tumors, whereas in triple negative mBC, chemotherapy appeared to be more effective in PIK3CA-WT tumors. In this large, real-life pan-cancer patient cohort, our results indicate that PIK3CA/PIK3R1 mutations are widely spread, and plead in favour of evaluating the efficacy of PI3K inhibitors outside of ER+/HER2- mBC and outside of hotspot mutations.

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

We previously reported that breast cancer cells lacking protein expression of PIK3R1 had elevated levels of activated MEK, sensitizing them to the MEK inhibitor trametinib. Mutations in PIK3R1 sensitize TNBCs to MEK inhibitors like binimetinib. In the absence of functional PIK3R1, aberrant PI3K signaling occurs, which explains the sensitivity of breast cancers that are PIK3CA wild-type and PIK3R1 mutant to alpelisib. The combination of both MEK and PIK3CA inhibition appears to be an effective combination therapy in TNBCs harboring mutations in PIK3R1.AMA is employed by the U.S. FDA, but contributed to this publication in his own capacity.

In conjunction with previous data of metaplastic (spindle cell) carcinoma with and without fibromatosis-like morphology, FLMC is most likely distinguished by TERT promoter mutation. Thus, our data support the notion of a distinct subgroup within low-grade metaplastic breast cancer with spindle cell morphology and associated TERT mutations.

Patients with poor prognoses exhibited high activation of EGFR, PIK3R1, and ERBB2. Comprehensive kinase activity profiles may provide predictive biomarker candidates for screening patients with advanced NSCLC harboring sensitizing EGFR mutations.

P=N/A, N=48, Completed, Consorzio Oncotech

FAAC is rare but associated with poor clinical outcome. Tissue acquisition is crucial for early diagnosis and therapy and should be performed in long-standing, non-healing, IBD-associated fistulas in particular. The immunophenotype of FAAC seems more similar to the rectal-type mucosa than the anal glands.

This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Not all mutations related to TMB-H can enhance antitumour immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs.

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

High TMB is present in 23% of CN-L EC, associated with ARID1A and TP53 mutations and recurrence in low grade, early stage disease. These results identify ARID1A and p53 immunohistochemistry as potential prognostic markers or triage tools for TMB testing via NGS in early stage endometrioid carcinoma.