Purpose Immunotherapy with chemotherapy significantly improves progression-free survival in advanced endometrial cancer (EC), especially in microsatellite instability-high (MSI-H) cases. Despite this, for recurrent EC in the postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target. Patients and Methods In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on PIK3CA mutational status. Results In our analysis, the four most frequently mutated genes were TP53 , PIK3CA , ARID1A , and PTEN. PIK3CA mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different PIK3CA mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent PIK3CA mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all The Cancer Genome Atlas categories. Conclusion In this post hoc analysis from the MITO END-3 trial, we confirmed the high frequency of PIK3CA mutations in EC, establishing this tumor as an ideal candidate for testing of PI3K inhibitors in clinical trials.
Purpose TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations. Results of two cohorts of patients with advanced thyroid (TC) or biliary tract cancer (BTC) with BRAF V600E mutations treated with cobimetinib plus vemurafenib (C + V) are reported. Methods Eligible patients had measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. Simon's two-stage design was based on a null DC rate of 15% versus 35% (power = 0.85; α = .10). Both cohorts expanded to stage II but closed before reaching the target sample size by pharmaceutical company request; inferences are based on thresholds set forth in the protocol to maintain the α level. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. Results Patients with TC (N = 22; n = 16 evaluable) or BTC (N = 18; n = 15 evaluable) with BRAF V600E mutations were enrolled. In the TC cohort, the DC and OR rates were 94% (one-sided 90% CI, 78 to 100) and 63% (95% CI, 35 to 85), respectively. In the BTC cohort, the DC and OR rates were 67% (one-sided 90% CI, 47 to 100) and 53% (95% CI, 27 to 79), respectively. The null hypothesis of 15% DC rate was rejected for both cohorts ( P < .0001). Twenty-one patients (53%) had ≥1 treatment-related grade 3 to 4 adverse event (AE) or serious AE. Conclusion The combination of C + V met the prespecified criteria to declare a signal of activity in patients with TC and BTC with BRAF V600E mutations.
Purpose BRCA1/2 mutation testing identifies patients with metastatic castration-resistant prostate cancer (mCRPC) eligible for poly(ADP-ribose) polymerase inhibitors; however, clinical outcomes remain heterogeneous within these genotypes. We evaluated whether plasma-derived genomic instability status (GIS) was associated with outcomes beyond BRCA1/2 and PALB2 mutation status in the phase II TRITON2 study. Methods This retrospective biomarker analysis included TRITON2 patients with available baseline plasma profiled using Guardant360 Liquid. GIS is a probabilistic measure of homologous recombination deficiency (HRD) inferred from genome-wide copy number variants and somatic mutational signatures. Analyses were restricted to patients with baseline tumor fraction (TF) ≥ 25%. Radiographic progression-free survival (rPFS) was analyzed using Kaplan-Meier methods and Cox models adjusted for age and baseline TF. Secondary end points included objective response rate (ORR), serum prostate-specific antigen (PSA50) declines, and overall survival (OS). Results Among 104 patients with TF ≥ 25%, 43 (41%) had GIS detected. Compared with GIS detected, absence of GIS was associated with shorter rPFS (hazard ratio [HR], 2.81 [95% CI, 1.61 to 4.93]; P <.001). Joint stratification demonstrated patients with both GIS detected and BRCA/PALB2 mutation experienced the longest rPFS, whereas absence of GIS was associated with shorter rPFS regardless of BRCA/PALB2 mutation status. In BRCA2 -mutated patients, rPFS trended being longer in those with GIS detected (compared with those without GIS detected; HR, 2.02 [95% CI, 0.95 to 4.29]; P = .069), with numerically higher ORR (25.7% v 14.3%) and PSA50 response rate (65.7% v 42.9%). No statistically significant differences in OS were observed. Conclusion Plasma-derived GIS was associated with improved rPFS and higher response rates in rucaparib-treated patients and further stratified outcomes within mutation-defined populations. These findings support genomic instability assessment as a complementary biomarker to mutation testing and warrant prospective validation.
PURPOSE There are few established prognostic biomarkers in metastatic hormone-sensitive prostate cancer (mHSPC). Disease volume and timing of metastases are prognostic and predictive factors but may be inadequate due to heterogeneity. Circulating tumor DNA (ctDNA) provides both circulating volume (tumor fraction [TF]) and genomic data. There are limited data on ctDNA in mHSPC. METHODS This was a multicenter, prospective study of ctDNA testing in mHSPC. Presented here are the results before androgen-deprivation therapy initiation. The primary objective was to evaluate the association between TF and overall survival (OS) and time to mCRPC (TTCRPC). Secondary analyses included evaluating outcomes in subgroups of interest and key genomic subtypes. RESULTS Between 2018 and 2024, 85 patients were enrolled, of whom 72 (25% Black) had evaluable baseline ctDNA samples and are included herein. Baseline TF was positive in 46 patients (64%). Compared with patients with negative ctDNA TF, most patients with positive ctDNA TF had de novo (87% v 39%, P < .001) and high-volume disease (80% v 46%, P = .01). At a median follow-up of 20.8 months, median OS was not reached (NR) with those with negative ctDNA TF and 33 months with positive ctDNA TF (hazard ratio [HR], 3.33 [95% CI, 1.1 to 9.9]; P = .03). However, a negative TF at baseline was associated with an undetectable 7-month prostate-specific antigen, a validated OS surrogate. Median TTCRPC was NR versus 13 months (HR, 3.43 [95% CI, 1.5 to 7.9]; P = .004). ctDNA TF was also potentially prognostic in high-volume disease and those who received doublet therapy. CONCLUSION In this diverse cohort, a positive ctDNA TF at baseline was associated with worse outcomes in mHSPC and may potentially complement current further risk stratification tools.
