PIK3CA E110K

Recently, alpelisib, a PI3Kα inhibitor, combined with hormonotherapy has improved progression-free survival in mutated advanced luminal BC... In our cohort, a wide spectrum of PIK3CA mutations was found in patients with metastatic breast cancer, suggesting the clinical relevance of molecular screening. Double PIK3CA mutations were identified in 15.8% of mutant tumors and maybe related to higher sensitivity to PI3K inhibitors. E545D mutation was always associated with a second mutation suggesting a different biological behavior.

In conclusion, we provided detailed immunohistochemical and molecular data in a series of ECC, demonstrating a high incidence (33%) of MMR deficiencies detected by immunohistochemistry as well as a synchronous mutation affecting PIK3CA and KRAS genes. A more extensive interrogation of the genomic features of a much larger series of clear cell carcinomas will be required to define the genomic landscape of this subtype and to determine whether there are molecular alterations that are unique to, or significantly enriched in, clear cell tumors compared to other subtypes.

There is still a limited number of cases with comprehensive molecular analyses reported in the literature. Therefore, we herewith contribute to a better understanding of the morphological and molecular characteristics as well as the clinical behavior of this rare entity.

Pik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

The ShortHER trial randomized 1254 patients with HER2-positive early breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Within the HER2-enriched molecular subtype, PIK3CA mutated patients showed better DFS as compared to PIK3CA wild-type patients. These results highlight the need to integrate multiple biomarkers in order to dissect the heterogeneity of HER2-positive breast cancer.Legal entity responsible for the study: University of Padua. Funding: Italian Medicines Agency (AIFA, grant FARMS5KR); Italian Association for Cancer Research (AIRC, grant MFAG-15938).

"Background: FGFR2/3 rearrangements are promising therapeutic targets, especially in advanced urothelial cancer (aUC) with FDA-approved erdafitinib...FGFR2/3 fusion partners detected by a highly specific assembly-based de novo fusion caller were heterogeneous and individually rare, highlighting the importance of a de novo approach. We observed an FGFR3 fusion prevalence in cfDNA from aUC patients that is comparable to previous reports for tissue testing, demonstrating an ability to capture targetable genomic rearrangements with plasma-based NGS in this patient population. Research Funding: Guardant Health"

The selectivity of LX-086 in PI3Kα over PI3Kβ/δ/γ is similar with that of alpelisib, which had been approved by FDA in 2019. We have identified a novel potent and safe PI3Kα inhibitor LX-086. Preclinical studies show antitumor efficacy of LX-086 in PIK3CA mutant and amplified solid cancer models. LX-086 represents a promising clinical candidate for the treatment of solid cancers with PIK3CA mutation or amplification.

This study, for the first time, revealed that approximately 13% PIK3CA positive Chinese solid tumor pts harboring multiple PIK3CA mutations. Several novel dual-PIK3CA-mutations were detected and multiple-PIK3CA-mutant pts more likely had high TMB, which may guide potential immunotherapy or PI3K-targeted therapy for multiple PIK3CA Chinese solid tumor patients. Research Funding: None

Endocrine agents mainly include aromatase inhibitors, which target ER-driven transcription, and fulvestrant, which functions as ER antagonist...Tracking ctDNA mutations to predict endocrine resistance in a real-world setting represents a critical step towards precision medicine in oncology. Research Funding: ASTRAZENECA

Background: The PI3K-inhibitor, alpelisib, was approved for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancers with PIK3CA mutations based on findings from the SOLAR-1 trial...An association was seen between PIK3CA mutation and prior treatment with CDK4/6 inhibitors (palbociclib, ribociclib) or mTOR inhibitor (everolimus), with 58% of PIK3CA-mutant cases having received these treatment previously compared to only 20% of PIK3CA-wild type (wt) cases... We report similar PIK3CA mutation frequencies (~30%) with amplicon-based NGS on cfDNA compared to tumor tissue testing in breast cancer. Importantly, other driver mutations were also observed at similar frequencies as external tissue studies, implying high sensitivity as the primary reason for performance. This supports the clinical utility of an amplicon-based NGS-based approach to liquid biopsy for the sensitive detection of actionable mutations in breast cancer.

We elucidated that ctDNA mutations on PIK3CA and other genes dramatically increased in Stage IV patients compared to Stage III patients which provides a new insight on the Stage III and Stage IV MBC determination. New set of genes especially PIK3CA are identified to correlate with metastasis and affect the outcome which may also be reliably used to monitor the response to therapy. Research Funding: Lynn Sage Breast Cancer Research OncoSET Program, Robert H Lurie Cancer Center

Molecular profiling of MBC in a phase I unit led to matched tx in 25% of cases. Matched pts showed encouraging mPFS with a suggestion of benefit in those matched after sequencing on a broader gene panel (FM1). Research Funding: NCIS Centre Grant - NMRC/CG/M005/2017_NCIS

Several drugs have been tested, but only recently, SOLAR1 phase III trial demonstrated the benefit of addition of alpelisib to fulvestrant, with acceptable tolerability. SimSen-seq based detection of PIK3CA mutations from plasma selected for alpelisib treatment has shown promising results and warrants further validation in a larger cohort of candidate patients. FDA recommendation is to initially carry out the mutation testing in ctDNA and if the test is negative for PIK3CA mutations in plasma, patients should undergo testing for PIK3CA mutations in tumour tissue. Tissue analysis is currently ongoing.Legal entity responsible for the study: The authors.

Background: Alpelisib (a PI3Kα-specific inhibitor) has demonstrated clinical benefit in combination with fulvestrant and is approved for PIK3CA-mutated, ER +,HER- metastatic breast cancer (MBC) patients who relapsed after aromatase inhibitor (Andre F et al, NEJM, 2019). The ddPCR assay is a very sensitive, rapid, and cost-effective technique for the selection of alpelisib treatment in routine clinical practice. We plan to compare these results to those obtained from matched tumour biopsies.Legal entity responsible for the study: The authors. Funding: La Vannetaise.

Background: Alpelisib (a PI3Kα-specific inhibitor) has demonstrated clinical benefit in combination with fulvestrant and is approved for PIK3CA-mutated, ER +,HER- metastatic breast cancer (MBC) patients who relapsed after aromatase inhibitor (Andre F et al, NEJM, 2019). The ddPCR assay is a very sensitive, rapid, and cost-effective technique for the selection of alpelisib treatment in routine clinical practice. We plan to compare these results to those obtained from matched tumour biopsies.Legal entity responsible for the study: The authors. Funding: La Vannetaise.

The ShortHER trial randomized 1254 patients with HER2-positive early breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Within the HER2-enriched molecular subtype, PIK3CA mutated patients showed better DFS as compared to PIK3CA wild-type patients. These results highlight the need to integrate multiple biomarkers in order to dissect the heterogeneity of HER2-positive breast cancer.Legal entity responsible for the study: University of Padua. Funding: Italian Medicines Agency (AIFA, grant FARMS5KR); Italian Association for Cancer Research (AIRC, grant MFAG-15938).

Several drugs have been tested, but only recently, SOLAR1 phase III trial demonstrated the benefit of addition of alpelisib to fulvestrant, with acceptable tolerability. SimSen-seq based detection of PIK3CA mutations from plasma selected for alpelisib treatment has shown promising results and warrants further validation in a larger cohort of candidate patients. FDA recommendation is to initially carry out the mutation testing in ctDNA and if the test is negative for PIK3CA mutations in plasma, patients should undergo testing for PIK3CA mutations in tumour tissue. Tissue analysis is currently ongoing.Legal entity responsible for the study: The authors.

The neoantigen-associated mutations PIK3CA (p.H1047R) and TP53 (p.R175H) are common across several cancer types, indicating their potential usage. Overall, our study illustrates a comprehensive genomic landscape of GC and provides the recurrent neoantigens to facilitate further immunotherapy.

These results support the theory that DNA is released from the primary tumor via apoptotic fragmentation. In conclusion, ctDNA is detectable in metastasis-free LNs and significantly more frequent in SLNs from patients with breast tumors harboring a high apoptotic index, consistent with drainage of ctDNA from apoptotic primary tumor cells into SLNs.

No abstract available

Given the prevalence of mutations in p53 and the PI3K pathways in HNSCC in conjunction with loss of p16 genetically or epigenetically, this universal increased sensitivity to cisplatin and BYL719 combination therapy in cancer cells with PIK3CA mutation represents an opportunity to a subset of HNSCC patients. Implications: Our results suggest that combination therapy of cisplatin and PI3K inhibitor may be worthy of consideration in HNSCC patients with PIK3CA mutation.