PIK3CA mutation

A 62-year-old man with metastatic PSA underwent splenectomy followed by first-line paclitaxel, achieving stable disease for 7 months...Sequential treatment with liposomal doxorubicin, eribulin, toripalimab, and lenvatinib failed to control the disease failed to control the disease...To our knowledge, this is the first reported use of inavolisib in angiosarcoma. The rapid biochemical and radiological response observed in this PIK3CA-mutated PSA supports early genomic profiling to identify actionable alterations and warrants prospective evaluation of combined phosphoinositide 3-kinase and vascular endothelial growth factor pathway inhibition in refractory angiosarcoma.

A transcriptional signature associated with SARM sensitivity was identified, primarily driven by proliferation-related processes, consistent with a significant decrease in S-phase cell cycle proteins upon treatment in EP0062-sensitive models. In some EP0062-resistant tumors, the combination with palbociclib enhanced the antitumor effect of EP0062, suggesting a potential strategy for metastatic patients with acquired ET resistance.

Our findings suggest HIV-1 dysregulates cervical cell signaling via paracrine mechanisms to phenocopy PIK3CA-activating mutations through IRS1-PI3K-AKT pathway activation. Our findings highlight IRS1 and the PI3K pathway as a potential therapeutic target for cervical cancer in women living with HIV-1.

Notably, low-dose Capivasertib, an AKT inhibitor targeting tumors with PIK3CA/AKT1/PTEN mutation(s), induced senescence selectively in FUCA2-high LUAD irrespective of PIK3CA/AKT1/PTEN/TP53 mutational status, and its combination with the nutraceutical senolytic procyanidin C1 achieved potent and low-toxicity suppression of LUAD across multiple preclinical models. Together, our results uncover the FUCA2-ErbB3 fucosylation-AKT pathway as a central regulator of senescence and propose a FUCA2-guided drug repurposing strategy for LUAD.

Moving forward, the "HER2-positive" designation must be refined through integrated, biomarker-driven frameworks. Incorporating these molecular nuances into prospective clinical trials is essential for optimizing therapeutic de-escalation and overcoming the persistent challenges of resistance in HER2-targeted care.

Due to limited germline and epigenetic data, MSI-H tumors could not be classified as Lynch-associated or sporadic. Overall, MSI-H and MSS CRCs in the Chinese population demonstrate distinct molecular landscapes in terms of TMB, HRD, EBV status, and driver gene alterations, underscoring the molecular heterogeneity of MSI-H CRC and the need for future studies integrating germline and epigenetic data to refine subtype classification.

Future studies should focus on evaluating the efficacy of PI3K inhibitors, alone or in combination with immunotherapy and other targeted treatments, in selected patients. This evaluation should be based on molecular alterations that may predict therapeutic benefit.

This large clinicogenomic study in an Asian population highlights unique mutational landscapes and survival associations, which may inform personalized treatment strategies.

CEP is active in R/M ACC, and prior TKI exposure did not appear to reduce efficacy. Higher response rates in ACC-I tumors and the apparent PIK3CA-related survival deficit are exploratory observations that need prospective testing before they can guide treatment.

In EOCRC, clinical and treatment-related factors remained independently associated with overall survival after adjustment for disease stage, whereas the evaluated genetic variables did not retain statistical significance. These findings highlight the importance of clinical management strategies, while the prognostic value of genetic alterations requires further investigation.

P1/2, N=435, Active, not recruiting, Stemline Therapeutics, Inc. | Recruiting --> Active, not recruiting

In BCs with alterations in the AKT/PIK3CA pathway, capivasertib, alpelisib, and inavolisib have recently improved progression-free survival (PFS). Inavolisib (GC0077) differs from the other drugs targeting this pathway by its high potency and tolerability when combined with endocrine therapy, mostly with fulvestrant, and a CDK4/6 inhibitor. Its recent use in the first-line combined treatment for advanced HR+/HER2-negative BC has shown a PFS benefit compared to placebo in the INAVO120 trial, suggesting its role as a valid treatment option in PIK3CA-mutated patients. Further studies are warranted to confirm these results in terms of prolonging efficacy and maintaining durable responses - with a manageable safety profile - in clinical practice.