PIK3CA Mutations Research Articles

Guidelines on tests of PIK3CA mutation in breast cancer in China (2025 version)

Guidelines on tests of PIK3CA mutation in breast cancer in China (2025 version)

CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells

BackgroundHER2-positive patients comprise approximately 20% of breast cancer cases, with HER2-targeted therapy significantly improving progression-free and overall survival. However, subsequent reprogramed tumor progression due to PI3K signaling pathway activation by PIK3CA mutations and/or PTEN-loss cause anti-HER2 resistance. Previously, alpha isoform-specific PI3K inhibitors were shown to potentiate HER2-targeted therapy in breast cancer cells carrying PI3K pathway alterations with less potent effects on PTEN-loss than PIK3CA-mutant cells. Therefore, seeking for alternative combination therapy needs urgent attentions in PTEN-loss anti-HER2 resistant breast cancer.MethodsSince remodeling of fatty acid (FA) metabolism might contribute to HER-positive breast cancer and is triggered by the PI3K signal pathway, herein, we examined the effects of the inhibition of endogenous FA conversion, SCD-1 or exogenous FA transport, CD36, in combination with PI3K inhibitors (alpelisib and inavolisib) in anti-HER2 resistant PTEN-loss breast cancer cells.ResultsThe activated HER2/PI3K/AKT/mTOR signaling pathway positively correlated with SCD-1 and CD36 expression in PTEN-loss breast cancer cells. PI3K inhibition downregulated SCD-1, and accordingly, the addition of the SCD-1 inhibitor did not augment the antiproliferative effects of the PI3K inhibitors. CD36 was upregulated by blocking the PI3K signal pathway or limited serum supplementation, indicating that suppressing CD36 may decrease the excess transport of exogenous FA. The addition of the CD36 inhibitor synergistically enhanced the anti-proliferative effects of the PI3K inhibitors.ConclusionSimultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer.

PIK3CA Mutation in FAVA of Adults With Unusual Anatomical Localization.

PIK3CA Mutation in FAVA of Adults With Unusual Anatomical Localization.

Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are hemorrhagic vascular disorders with varied clinical and radiological presentations, occurring sporadically due to MAP3K3 or PIK3CA mutations or through inherited germline mutations of CCM genes. This study aimed to clarify the clinical, genetic, and pathological features of CCMs using a multicenter cohort across three Chinese centers. We analyzed 290 surgical specimens from symptomatic CCM patients, utilizing whole-exome sequencing, droplet digital PCR, and targeted panel sequencing, alongside immunohistology to examine genotypic and phenotypic differences. Among 290 cases, 201 had somatic MAP3K3, PIK3CA, or germline CCM mutations, each associated with distinct clinical parameters: hemorrhage risk (P < 0.001), lesion size (P = 0.019), non-hemorrhagic epilepsy (P < 0.001), Zabramski classifications (P < 0.001), developmental venous anomaly presence (P < 0.001), and MRI-detected edema (P < 0.001). PIK3CA mutations showed a higher hemorrhage risk than MAP3K3 and combined MAP3K3 & PIK3CA mutations (P < 0.001). Within PIK3CA mutations, the p.H1047R variant correlated with higher bleeding risk than p.E545K (P = 0.007). For non-hemorrhagic epilepsy, patients with single MAP3K3 mutations or combined MAP3K3 & PIK3CA mutations were at greater risk than those with PIK3CA mutations alone. Histopathologically, lesions with PIK3CA mutations displayed cyst walls, pS6-positive dilated capillaries, and fresh blood cells, while MAP3K3 and double mutation lesions exhibited classic CCM pathology with SMA-positive and KLF4-positive vessels, collagen, and calcification. PIK3CA lesions had fewer KLF4-positive cells than double mutations lesions (P < 0.001), and EndMT (SMA-positive) cells compared to double mutation lesions (P < 0.05) and MAP3K3 mutations (P < 0.001), with more pS6 compared to MAP3K3 mutations (P < 0.05). This study underscores the diverse clinical, genomic, and histopathological characteristics in CCMs, suggesting potential predictive markers based on mutation subtypes and MRI features.

Dysfunctional mechanotransduction regulates the progression of PIK3CA-driven vascular malformations

Somatic activating mutations in PIK3CA are common drivers of vascular and lymphatic malformations. Despite common biophysical signatures of tissues susceptible to lesion formation, including compliant extracellular matrix and low rates of perfusion, lesions vary in clinical presentation from localized cystic dilatation to diffuse and infiltrative vascular dysplasia. The mechanisms driving the differences in disease severity and variability in clinical presentation and the role of the biophysical microenvironment in potentiating progression are poorly understood. Here, we investigate the role of hemodynamic forces and the biophysical microenvironment in the pathophysiology of vascular malformations (VMs), and we identify hemodynamic shear stress and defective endothelial cell mechanotransduction as key regulators of lesion progression. We found that constitutive PI3K activation impaired flow-mediated endothelial cell alignment and barrier function. We show that defective shear stress sensing in PIK3CAE542K endothelial cells is associated with reduced myosin light chain phosphorylation, junctional instability, and defective recruitment of vinculin to cell–cell junctions. Using three dimensional (3D) microfluidic models of the vasculature, we demonstrate that PIK3CAE542K microvessels apply reduced traction forces and are unaffected by flow interruption. We further found that draining transmural flow resulted in increased sprouting and invasion responses in PIK3CAE542K microvessels. Mechanistically, constitutive PI3K activation decreased cellular and nuclear elasticity resulting in defective cellular tensional homeostasis in endothelial cells which may underlie vascular dilation, tissue hyperplasia, and hypersprouting in PIK3CA-driven venous and lymphatic malformations. Together, these results suggest that defective nuclear mechanics, impaired cellular mechanotransduction, and maladaptive hemodynamic responses contribute to the development and progression of PIK3CA-driven vascular malformations.

Treatment and reasons for choosing treatment in breast cancer patients who underwent next-generation sequencing test.

Next-generation sequencing (NGS) is commonly used in clinical practice to decide treatment based on genomic information. This study was performed to optimize the proportion of actionable gene profiling and treatment based on genetic alterations in breast cancer at one of cancer centers in Japan. Patients with breast cancer who reported NGS results at one of cancer centers in Japan from August 2019 to December 2023 were retrospectively investigated by reviewing their electronic medical records. Patients were examined using the OncoGuideTM NCC Oncopanel System, FoundationOne® CDx, or FoundationOne® Liquid CDx. The evidence levels for drug recommendation were added for each gene alteration according to the guidelines from three Japanese oncology-related societies. ''Actionable alterations'' were those at evidence levels A-D, including high microsatellite instability and high tumor mutation burden status. "Patients with recommended drug" (approved, investigational, and off-label drugs) were defined as those who were selected by the Molecular Tumor Board. Of the 106 patients, 54 were tested using the NCC Oncopanel System and 50 using FoundationOne CDx. The most frequent alterations were TP53 mutations (52.8%) and PIK3CA mutations (31.1%). Of the 56 patients (52.8%) with recommended drugs, 11 (10.4%) received genome-matched therapy and only three (2.8%) participated in clinical trials. The most common reason for not receiving genome-matched therapy was patient refusal for personal reasons, although clinical trials were available (18 patients). The top reasons for patients not receiving the recommended genome-matched therapy were factors related to the patient, including a number of prior treatments higher than what was allowed by the eligibility criteria of the clinical trials, and poor physical condition. Most patients received four or more regimens of cytotoxic chemotherapy before NGS. NGS is only available at the late phase of treatment in Japan, which would constitute a problem for the treatment of breast cancer.

Genotype-phenotype spectrum and correlations in Chinese patients with keratinocytic epidermal naevus: A retrospective study of 22 cases

Background Keratinocytic epidermal naevus is characterised by hyperkeratotic lesions arranged along Blaschko’s lines. So far, multiple genes have been implicated, but there is no detailed data or genotype-phenotype correlation studies of keratinocytic epidermal naevi in Chinese patients. Objective To evaluate the clinical, histopathological and genetic features, genotype-phenotype correlations of keratinocytic epidermal naevus in the Chinese population. Methods A retrospective study of patients with keratinocytic epidermal naevi referred to the Department of Dermatology, West China Hospital, in the last four years. Medical history, clinical data, histopathological characteristics, and evidence of genetic mutations were collected from 22 unrelated Chinese patients with this problem. Results The distribution of the keratinocytic epidermal naevi exhibited right-side dominance. Non-epidermolytic epidermis naevus was much more common. Eight reported missense mutations were found in this study, which were detected in five genes, including HRAS, KRT10, FGFR3, GJB2, and PIK3CA. HRAS was the most commonly affected gene (9/22, 40.91%) in this study, with the c.37G&gt;C (6/22, 27.27%) substitution representing a possible hotspot mutation. Mutation allele loads were higher in the affected lesions than blood samples. Epidermolytic epidermal naevus was found in three patients exclusively carrying KRT10 mutations. Inflammatory epidermal naevi were caused by mutations of KRT10 and PIK3CA. Most of the mosaic mutations detected in keratinocytic epidermal naevi patients were the same as germline mutations identified in systemic diseases caused by these genes. Limitations The retrospective nature of the study. Conclusion Our findings reveal the genotype-phenotype spectrum and their correlation amongst Chinese patients with keratinocytic epidermal naevi. In addition, our data underscores the importance of genetic testing in lesional skin to help characterise and categorise keratinocytic epidermal naevi, decide on a therapeutic strategy, and offer genetic counselling and prenatal diagnosis.

Oncomine panel testing in the clinical management of colorectal cancer: An Irish experience.

212 Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. It has been hypothesized that the molecular signatures of EOCRC could differ from those of late onset CRC (LOCRC). Next Generation Sequencing (NGS) using the Oncomine Precision Assay is a useful tool to guide treatment decisions based on the presence or absence of oncogene drivers. While not all of these mutations currently influence the clinical management of CRC patients, ongoing research on the function of these genes and the development of new drugs could offer insights into patient prognosis, treatment choices and prediction of therapy resistance. Methods: Of &gt;1500 CRC identified between 2010 and 2024, we investigated the clinical and genetic characteristics of 38 EOCRC and 41 LOCRC cases. All cases were microsatellite stable and staged I-III. NGS was performed with the Ion Torrent Genexus integrated platform using the Oncomine 45-gene Precision Assay panel. DNA hotspot mutations and copy number variations (CNVs) were assessed, followed by the classification of clinically relevant mutations using the genetic variant OncoKB database. Results: There were 38 EOCRC and 41 LOCRC cases. The age range was 27 to 49 and 50 to 91, with median ages of 44 and 72, in the EOCRC and LOCRC groups, respectively. Based on the stratification of NGS mutation levels as per the OncoKB classification, all patients in both groups (100%) had level 1 actionable mutations. NRAS wild type (WT) status was present in 100% of patients in both groups. However, differences were observed in KRAS status: 84% (32/38) of EOCRC were KRAS WT, while only 65% (27/41) of LOCRC were KRAS WT. While 3 % (n=1) of the EOCRC cohort had an ERBB2 amplification, none were detected in the LOCRC group. BRAF V600E mutations were present in 11% (4/38) of EOCRC and 12% (5/41) of LOCRC. Level 4 mutations were detected in 18% (n=7) of EOCRC, all of which were PIK3CA mutations, while these were seen in 24% (n=10) of the LOCRC group, including 9 PIK3CA mutations and 1 FGFR1 mutation. Regarding concurrent mutations, 2 patients in the EOCRC group had two mutations each: one with concurrent KRAS and PIK3CA mutations, and another with concurrent JAK2 and KRAS mutations. The LOCRC group had a higher incidence of concurrent mutations, with 8 patients affected: 6 had concurrent KRAS and PIK3CA mutations, and 2 had concurrent BRAF and PIK3CA mutations. Conclusions: Our study demonstrates that EOCRC have higher KRAS WT status and fewer concurrent mutations compared to LOCRC, who exhibit more frequent KRAS non-G12C oncogenic mutations. It also underscores the importance of routine NGS mutation panel analysis in CRC management. Additionally, identifying specific mutations in patients that relapse can guide targeted therapies, potentially improving outcomes and offering personalized treatment options.

Impact of RAS and BRAF heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .

Molecular profiling of a gastroesophageal adenocarcinoma (GEA) multicohort using next-generation sequencing (NGS).

494 Background: The mutational landscape of GEA is rapidly evolving with the identification of promising molecular targets. However, histological subtypes are insufficient to capture the molecular heterogeneity in these patients (pts). We aim to assess the histopathological and molecular features in a GEA cohort using NGS techniques, and to evaluate the mutational frequency and its prognostic correlation. Methods: We conducted a retrospective study on GEA from 2019 to 2024. Immunohistochemistry (IHC) was used to evaluate HER2 expression, microsatellite instability (MSI), Epstein-Barr virus (EBV) and PD-L1 status. In-house and commercial NGS platforms were used to detect molecular alterations from tumor samples. Cox regression model was used to analyze overall survival (OS) based on the clinicopathological and molecular subgroups. Results: Using NGS techniques, we identified the following alterations with potential clinical relevance in the 115-pts included: pathogenic mutations in PIK3CA (5.2%), BRCA1/2 (3.5%) and POLD1 (0.9%), along with copy number alterations (CNA) in ERBB2 (10.4%), EGFR (8.7%), MET (5.2%) and FGFR2 (4.3%) genes, among others. Additionally, a high tumor mutational burden (≥ 13 Mut/Mb) was observed in 6 pts (5.2%). Clinical characteristics are detailed in the table. We detected a higher rate of alterations in CDH1 (10.42% vs 4.48%; p=0.22) and PIK3CA (8.33% vs 2.99%; p=0.20) genes in early (&lt;50y) vs late-onset (≥50y) GEA. Additionally, we identified a significantly higher mutation frequency in diffuse vs intestinal tumors; ARID1A (17.6% vs 2.2%; p=0.01) and CDH1 (11.8% vs 0%; p=0.02) genes. Also, pts with peritoneal involvement showed a greater prevalence of mutations in CDH1 (12% vs 0%; p=0.04) and RHOA (10% vs 0%; p=0.06) compared to those with liver disease. We observed a significantly worse OS in pts with diffuse vs intestinal tumors (15.7m vs 19.1m; p=0.04) and a trend toward shorter survival in pts with CDKN2A mutations (11.97m vs 17.83m; p=0.42). Although not significantly, CNA in ERBB2 were associated with a better prognosis (22.2m vs 16.2m; p=0.09). Conclusions: Our results support the utility of NGS platforms in detecting novel molecular targets with prognostic and clinical impact, beyond ERBB2 . Additionally, we observed poorer prognosis in diffuse subtype tumors, which exhibited a higher frequency of mutations in ARID1A and CDH1 genes. Clinicopathological characteristics of the 115-pts with GEA. N=115 (%) AgeMedian years [range] 54 [18-83] Sex Male 69 (60.0) Tumor site Gastric 72 (62.6) Gastroesophageal junction 37 (32.2) Esophagus 6 (5.2) Histological subtype Diffuse or pooly cohesive 51 (44.3) Intestinal or tubular 46 (40.0) Others 18 (15.7) Stage at diagnosis Advanced 74 (66.9) Localized 41 (33.1) Metastatic site Peritoneum 53 (46.1) Liver 34 (29.6) Molecular profile (IHC) HER2 (+) 20 (17.4) MSI 5 (4.3) EBV (+) 2 (1.8) PDL1 (CPS) ≥1 35 (30.4)

Multiple Mutations-A Genetic Marker for Extracapsular Spread in Human Papillomavirus/p16-Positive Oropharyngeal Carcinoma.

In the 8th edition of the TNM classification, extracapsular spread (ECS) became a factor in classifying the UICC stage of oropharyngeal carcinomas (OPSCC). We aimed to find genetic markers for ECS and to identify differences between HPV/p16-positive and HPV/p16-negative cases. We performed targeted next-generation sequencing on 99 samples of operable OPSCC and a retrospective analysis of clinical data. We included 55 HPV/p16-positive and 44 HPV/p16-negative patients. We found a significant difference between both groups, particularly in TP53 mutation (p < 0.001). Among other things, a small primary tumor (p < 0.001), no ECS (p = 0.026) were identified as predictors for survival. Multiple mutations were associated with an increased incidence of ECS, especially in HPV+/p16+ cases (p = 0.017). A mutation in PIK3CA occurred more frequently in nonsmokers, especially in HPV-/p16- patients (p = 0.027). A PTEN mutation-which only occurred in HPV+/p16+ tissues-reduced disease-free survival (DFS, p = 0.026). The presence of multiple mutations in HPV+/p16+ OPSCC was associated with a higher risk of ECS. 3.

Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAF V600E metastatic colorectal cancer following progression on prior BRAF+EGFR targeted therapies.

182 Background: A BRAF V600E mutation, present in approximately 8-10% of all colorectal cancers (CRC), is a poor prognostic biomarker for patients with metastatic CRC. The BRAF V600E inhibitor encorafenib (E) and the anti-EGFR antibody cetuximab (C) are approved for refractory, BRAF V600E mCRC based upon on overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.2 months . A single-arm trial adding the anti-PD1 antibody nivolumab (N) to E+C in the same (BRAF-inhibitor naïve) population showed promising efficacy, with an ORR of 50% and median PFS of 7.4 months. We evaluated the efficacy of E+C+N in patients with microsatellite stable (MSS), BRAF V600E mCRC who had progressed on prior E+C. Methods: Patients with MSS, BRAF V600E mCRC with documented prior progression on E+C were eligible for treatment with E (300 mg PO daily), C (500 mg/m 2 q14 days), and N (480 mg IV q28days) were included in the study. Primary endpoint was best overall response by RECIST 1.1. Secondary endpoints were PFS, overall survival (OS), and toxicity (by CTCAE v5). Circulating tumor DNA assessment of molecular alterations in the MAPK pathway in association with response were performed by NGS. Descriptive statistics were used to summarize outcomes. Results: Among the 12 participants, none achieved a radiographic response, and 5 experienced stable disease. Disease control rate was 41.7% (95% CI, 13.8-69.6). Median PFS was 3.7 months (95% CI, 1.7-5.7), and median OS was 8.3 months (NE-NE). Four patients (16.7%) had concomitant MAPK-activating alterations at baseline, and APC , TP53 , and PIK3CA mutations were present in 25.0%, 66.7%, and 33.3% of patients, respectively. The presence of MAPK-activating mutation was not associated with disease progression (odds ratio 1.3; 95% CI 0.11-16; p=0.82). The most common grade 1-2 treatment-related adverse events (AEs) were anemia (N=5), arthralgia (N=5), rash (N=4), headache (N=4), and fatigue (N=3); 1 of the 12 patients experienced a grade 3 small bowel obstruction. Conclusions: In this pilot study, addition of N to E+C did not appear to overcome resistance to prior BRAF + EGFR targeted therapies in patients with MSS, BRAF V600E mCRC. While the addition of immunotherapy has demonstrated promising signal in early-phase clinical trials for this population, the benefit appears unlikely when offered sequentially after progression on BRAF combination therapies. Clinical trial information: NCT04017650 .

Low-dose aspirin to reduce recurrence rate in colorectal cancer patients with PI3K pathway alterations: 3-year results from a randomized placebo-controlled trial.

LBA125 Background: Colorectal cancer (CRC) affects 1.9 million individuals globally each year. Among patients with stage II-III CRC, 20-40% develop metastatic disease. Aspirin lowers the incidence of adenomas and CRC in high-risk patients. In addition, observational studies suggest that post-diagnosis aspirin treatment improves disease-free survival (DFS) in unselected populations. Furthermore, retrospective findings indicate that somatic PIK3CA mutations predict treatment response, but requires validation in randomized trials. Methods: The ALASCCA trial was a randomized, double-blind, multicenter, placebo-controlled trial with two parallel arms, across 33 hospitals in Sweden, Denmark, Finland, and Norway. Patients with stage I-III rectal cancer or stage II-III colon cancer exhibiting somatic alterations in the PI3K signaling pathway were included. Patients were randomized to receive either 160 mg of aspirin daily or placebo, initiated within three months post-surgery and continued for three years. To detect a hazard ratio (HR) of 0.36 for the primary outcome of time to recurrence (TTR) assessed at 3 years, with 80% power and a two-sided alpha of 0.05, 150 patients with PIK3CA mutations in exon 9 and/or 20 (“Group A”) were required per arm. An additional 300 patients with other somatic PI3K pathway driver alterations (PIK3CA outside exon 9/20, PIK3R1, or PTEN; "Group B") were required for secondary analyses. A stratified Cox proportional hazards model was fitted for the primary efficacy analysis. Results: A total of 3508 patients were screened for somatic alterations in the PI3K pathway. Of the 2980 patients with conclusive genomic analyses, 1103 patients (37%) had an alteration in the PI3K pathway: 515 patients (17.3%) in Group A and 588 patients (19.7%) in Group B. In total, 626 patients were randomized. After three years of follow-up, the HRs for TTR comparing aspirin to placebo were 0.49 (95% CI; 0.24-0.98; p=0.044) in Group A and 0.42 (95% CI; 0.21-0.83; p=0.013) in Group B. For DFS, the HRs were 0.61 (95% CI; 0.34-1.08; p=0.091) in Group A, and 0.51 (95% CI; 0.29-0.88; p=0.017) in Group B. Three patients experienced aspirin-related severe adverse events (one GI-bleeding, one hematoma, one allergic reaction). Conclusions: Primary endpoint was met. Adjuvant treatment with 160 mg aspirin daily for three years reduced recurrence rate in CRC patients with somatic alterations in the PI3K signaling pathway. These findings could lead to immediate changes in clinical praxis for about a third of CRC patients. Clinical trial information: NCT02647099 .

Alpelisib-Induced Hyperglycemia in PIK3CA+ Breast Cancer Patients.

Alpelisib is a phosphatidylinositol 3-kinase inhibitor approved by the US Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α) mutation. In recent years a number of adverse effects have been observed to be associated with this therapy, the most notable of which is hyperglycemia. A literature search was conducted to include case studies, case series, systematic reviews, and meta-analyses within the last 10 years that evaluated patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. Hyperglycemia was a notable adverse effect that was found in the majority of patients without preexisting diabetes mellitus. Patients with hyperglycemia were in the high-risk groups of advanced age, prediabetes mellitus or history of insulin resistance, increased body mass index, increased blood monocyte count, and increased hemoglobin A1c (glycated hemoglobin). Hyperglycemia was manageable with antihyperglycemic agents and dose modification/discontinuation of alpelisib with no severe progression. Other notable adverse effects were rash, stomatitis, diarrhea, pneumonitis, reduced appetite, elevated liver enzymes, nausea, fatigue, and rare reports of diabetic ketoacidosis. This literature review aims to highlight the incidence and risk factors of alpelisib-induced hyperglycemia in greater depth.

Landscape of metastatic colorectal cancer (CRC) using comprehensive circulating tumor DNA (ctDNA) next-generation sequencing (NGS) in India: Expanding beyond RAS and RAF.

49 Background: Traditional testing in mCRC primarily focuses on RAS and RAF mutations. However, a broader range of emerging biomarkers, collectively termed the "Pressing panel" (PP), identifies patients with RAS/RAF wild-type (wt) tumors who may particularly benefit from anti-EGFR therapy. Comprehensive liquid biopsies provide a non-invasive method for identifying traditional and emerging biomarkers. Limited genomic data, including the prevalence of PP alterations (alts), is available for mCRC patients in India tested by ctDNA NGS. Methods: We reviewed the results of Guardant360 (Guardant Health, Inc.) ordered for patients with mCRC as part of routine clinical practice in India through July 2024. NGS analyzed plasma samples at a CLIA-certified, CAP-accredited central laboratory. Guardant360 analyzes ctDNA for mutations (mts), insertions and deletions, amplifications (amps), and fusions in up to 83 genes, including PP genes, i.e., KRAS, NRAS, BRAF, ERBB2, PIK3CA, PTEN, AKT1, ALK, ROS1, NTRK, RET, and MSI status. The Indian cohort's prevalence of PP mts was compared to that from other countries in Asia and Middle East (AME). Timing of testing relative to line of therapy was unknown. Results: Among 145 samples from India, ctDNA was detected in 92% (n=134). Median age was 59 years, with women comprising 40%. The median turnaround time from blood collection to result was 7 days. The mean mts count per sample was 5, and the median variant allele frequency was 1.5%. Frequent mts were in APC (53%), KRAS (56%), and SMAD4 (13%), while amps of EGFR (16%) and FGFR1 (9%) were common. Clinically relevant fusions were observed in 3% of patients. KRAS, NRAS, and/or BRAF V600E alterations were found in 63% of both India and AME samples. PP alts were identified in 24% and 27% of Indian and AME patients, respectively. Most frequent PP alts included PIK3CA (15%), PTEN (3%), and MET amp (2%). The prevalence of most of the PP alts was similar between the Indian and AME cohorts (Table), with minor differences observed in PIK3CA (15% vs 18%) and MSI-High (3% vs 1%). In patients with RAS/RAF wild-type lacking EGFR-amp, 9.5% (India) and 18% (AME) harbored at least one PP alt. Conclusions: This study highlights the role of liquid CGP for characterizing the mutational landscape and identifying PP mts for patients from India with advanced CRC. Pressing panel alterations. PP Alteration INDIA % (n=134) AME % (n=720) ERBB2 Amp 1% 2% MET Amp 2% 3% ALK Fusion 0% 0% ROS1 Fusion 0% 0% NTRK1 Fusion 1% 0% RET Fusion 0% 1% ERBB2 Mut 1% 2% PIK3CA Mut 15% 18% PTEN Mut 3% 3% AKT1 Mut 0% 1% MSI-High 3% 1%

Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2.

The approval of trastuzumab deruxtecan has prompted the subgrouping of human epidermal growth factor receptor 2-negative (HER2-) breast cancers (BCs) to HER2 0 and HER2 low on the basis of immunohistochemistry, although the biological significance of these subgroups remains uncertain. This study is aimed to better understand the molecular and genetic differences among HER2- tumors stratified by quantitative levels of HER2. We analyzed the transcriptomic and genomic data from the Molecular Taxonomy of BC International Consortium (discovery cohort) and The Cancer Genome Atlas (independent validation cohort). HER2- BCs, including hormone receptor positive and triple negative, were divided into three subgroups based on ERBB2 messenger RNA (mRNA) levels: minimal, moderate and enhanced. We observed significant differences in mutational and transcriptional profiles across the subgroups. Tumors with enhanced ERBB2 mRNA expression had a higher prevalence of PIK3CA mutations and increased estrogen receptor signaling, while tumors with minimal ERBB2 mRNA expression displayed higher expression of proliferation and immune-related genes. We identified a distinct subgroup of BCs characterized by a large deletion of chromosome 17q12 (17q12del) with heterozygous loss of ERBB2, very low ERBB2 mRNA and HER2 protein expression. This subgroup was also enriched for heterozygous losses of TP53 and other tumor suppressor genes. Analysis of two large real-world cohorts of patients with HER2- metastatic BC (Dana-Farber Cancer Institute cohort n= 1063 and Memorial Sloan Kettering MetTropism cohort n= 1018) showed that patients with 17q12del and heterozygous loss of ERBB2 had poorer overall survival (OS). We identified a biologically and clinically distinct subgroup of BCs characterized by a 17q12del with a heterozygous loss of ERBB2 and low ERBB2 mRNA and HER2 protein expression. In two large real-world cohorts of patients with HER2- metastatic BC, this subgroup was associated with poor OS, highlighting its clinical significance.

Clinicopathological and Molecular Insights into Primary Retroperitoneal Squamous Cell Carcinoma: HPV Association and Discovery of Recurrent PIK3CA E545K Mutation.

Primary retroperitoneal squamous cell carcinoma (PRSCC) is extremely rare, and its diagnosis and management are challenging. Previous reports have highlighted the potential role of human papillomavirus (HPV) in the pathogenesis of PRSCC. This study aimed to determine the clinicopathological and molecular characteristics of PRSCC. We searched PubMed for previously published PRSCC cases. Immunostaining, human papillomavirus (HPV) testing, and targeted DNA and RNA sequencing were performed. A total of 25 cases of PRSCC were analyzed. The mean age was 54.3 years, with the majority being women. They presented with pain in the lower abdomen, pelvis, and lower extremities; deep vein thrombosis; urinary symptoms; hydronephrosis; and ureteral obstruction. Treatment modalities included chemotherapy, radiation therapy, and concurrent chemoradiotherapy, with varying outcomes. HPV DNA was detected in most cases, with tumors exhibiting diffuse p16 positivity. Additionally, two patients carried a hotspot E545K mutation in phosphatidylinositol-4,5-bis-phosphate 3-kinase catalytic subunit alpha (PIK3CA). This study provides insights into the clinico-pathological features of PRSCC and identified a novel recurrent PIK3CA mutation in HPV-associated PRSCCs. Our findings suggest the potential utility of next-generation sequencing for identifying therapeutic targets. Further studies are warranted to clarify whether PIK3CA E545K mutation has diagnostic and therapeutic potential in patients with PRSCC.

Differential Efficacy of Alpelisib by PIK3CA Mutation Site in Head and Neck Squamous Cell Carcinoma: An Analysis from the KCSG HN 15-16 TRIUMPH Trial.

The TRIUMPH trial was a biomarker-driven umbrella trial for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). This analysis focuses on the PIK3CAɑ inhibitor alpelisib (arm 1) in patients with phosphoinositide 3-kinase (PI3K) pathway alterations. Patients with PI3K pathway altered tumors were enrolled in the alpelisib arm of the TRIUMPH study. We conducted a detailed analysis of the correlation between PI3K pathway mutations and treatment outcomes including disease control rate (DCR), overall survival (OS), and progression-free survival (PFS). From Oct 2017 and Aug 2020, 203 were enrolled, with 42 treated with alpelisib. Response evaluation was possible for 33 patients. Genomic profiles revealed PIK3CA amplifications in 26.2%, and point mutations in E542K (26.2%), E545K (23.8%), and H1047R (9.5%). Neither PIK3CA amplification nor co-occurring TP53 mutations had a notable influence on alpelisib response or survival outcomes. Although the overall response rates were similar between helical domain mutations (E542, E545) and kinase domain mutations (H1047), patients with H1047 mutations exhibited significantly poorer PFS compared to those with non-H1047 PIK3CA alterations (1.6 vs. 7.3 months, p=0.017). OS in patients with H1047 kinase domain mutations showed a trend toward being shorter compared to others, though this difference did not reach statistical significance. Alpelisib showed differential efficacy based on PI3K pathway alterations in patients with R/M HNSCC and was well-tolerated. These findings suggest the usefulness of NGS testing-based decision-making when using the targeted agents in R/M HNSCC. We need to confirm results in larger cohorts.

Genomic Analysis Reveals Racial and Age-Related Differences in the Somatic Landscape of Breast Cancer and the Association with Socioeconomic Factors.

Cancer genomics consortia have identified somatic drivers of breast cancer subtypes. However, these studies have predominantly included older, non-Black women, and the related socioeconomic status (SES) data is limited. Increased representation and depth of social data are crucial for understanding how health inequity is intertwined with somatic landscapes. Here, we conducted targeted sequencing on primary tumors from the Carolina Breast Cancer Study (N = 357; 52% Black, 47% <50) and compared the results to The Cancer Genome Atlas (N = 948; 18% Black, 27% <50). Race (Black vs. non-Black), age, and SES were evaluated in association with mutations, copy number alterations, and aneuploidy using generalized linear models. Pathway dysfunction was also assessed by aggregating mutation and copy number alterations. Adjusting for age, Black participants (N =350) were significantly more likely to have TP53 and FAT1 mutations and less likely to have PIK3CA, CDH1, DDR2, and GATA3 mutations than non-Black participants. Younger participants had more GATA3 alterations and fewer KMT2C, PTEN, MAP3K1 and CDH1 alterations. Black participants had significant enrichment for MYC (8q) and PIK3CA (3q26) amplifications and higher total aneuploidy, but age was not associated with copy number variation. SES was associated with different patterns of alteration in Black versus non-Black women. Overall, Black participants showed modest differences in TP53, PIK3CA, and other alterations that further varied by SES. Race is a social construct, and varying distributions of etiologic factors across social strata may predispose Black, young, and low SES women to cancer subtypes characterized by these alterations.

Biomarkers of resistance to anti-EGFR therapy in patients with left-sided colorectal cancer: a retrospective NGS analysis

Background: Routine analysis of KRAS, NRAS, BRAF V600 mutations, as well as MSI and HER2 guides treatment selection in colorectal cancer (CRC). Recent findings from the PRESSING and PARADIGM trials have demonstrated that the negative hyperselection of patients based on the results of comprehensive genomic profiling results in better treatment outcomes following anti-EGFR therapy. Study objective: The study aimed to retrospectively analyze the occurrence of alterations associated with potential resistance in samples from CRC patients treated with anti-EGFR therapy.Materials and methods: Patients with confirmed left-sided CRC treated with anti-EGFR therapy due to the lack of RAS / BRAFV600 mutations as per routine PCR were included in the study. FFPE samples were analyzed via NGS (Solo-test Atlas Pro, 38 genes, MSI). Samples determined as RAS / BRAFV600positive by NGS were validated with PCR.Results: A total of 111 samples were analyzed via NGS. A total of 172 alterations in 17 genes were found; alterations in any of the genes covered by the panel were found in 96 (86.5 %) samples. The variant allele frequency ranged 1.3–93.0 %. NGS identified 29 (26.1 %) samples with KRAS (n = 24), NRAS (n = 3) or BRAF p. V600E (n = 4) mutations. Confirmatory PCR testing of 16 RAS / BRAF p. V600E-positive samples resulted in 100 % agreement with NGS. Among RAS / BRAFV600negative samples, 10 (9 %) samples harbored other alterations (ERBB2 amplification, n = 3; PIK3CA, n = 2; MSI, n = 1; BRAF class II mutation, n = 1; ERBB3, n = 1). A total of 11 samples harbored more than 1 alterations associated with potential resistance. BRAF class II / III mutations were found in 4 samples, PIK3CA mutations — in 17 (15.3 %) samples (of those, 5 samples harbored mutations in exon 21).Conclusions: The results of this retrospective analysis demonstrate that a high frequency of false-positive routine PCR results may lead to incorrect indication of anti-EGFR therapy in ~ 26 % cases. Analysis of alterations beyond RAS / BRAFV600 might identify an additional 9 % of patients whose tumors are potentially resistant to anti-EGFR therapy.