TEST:

UW-Oncoplex™

P1, N=18, Recruiting, University of Washington | Trial primary completion date: Sep 2024 --> Dec 2025

After left lower lobectomy, she subsequently developed bilateral pulmonary metastases and began treatment with her first EGFR tyrosine kinase inhibitor in 2003 with gefitinib...In the interim, she was treated with osimertinib from 2016 to 2021 until she developed progression in bilateral lung nodules...Recently her treatment was switched to afatinib, and she quickly obtained clinical improvement...Second, amivantamab is a reasonable treatment option for patients with an EGFR-KDD. Lastly, EGFR-targeted resistance mechanisms can evolve over time and space, and biopsies at the time of resistance can help inform treatment recommendations.

Clinically relevant genomic alterations are detectable using CSF-derived cfDNA across a range of pediatric brain tumors. Next-generation sequencing platforms are capable of producing a high yield of DNA alterations with 100% concordance rate with tissue analysis.

Inflammatory infiltrate is a promising prospectively tested predictive biomarker in pre-treated mCRPC. Although NIVO 1 mg/kg + IPI 3 mg/kg had more toxicities than NIVO 3 mg/kg + IPI 1 mg/kg, the efficacy results were consistently better. This dose schedule and biomarker should now be tested in a phase 3 clinical trial.

Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.

CSF liquid biopsy has potential as a minimally invasive method of disease detection for measuring treatment response and longitudinal disease surveillance. lpWGS on CSF-derived cfDNA can identify tumor-derived sCNVs even when CSF cytology is negative for malignant cells. lpWGS can reveal sCNVs that are clinically actionable without need for a tissue biopsy.

P2; N=30 --> 2 | Trial completion date: May 2025 --> Oct 2023 | Recruiting --> Terminated | Trial primary completion date: May 2025 --> Oct 2023; Withdrawal of funding

Subsequent evaluation of the patient's recurrence using a DNA-based targeted NGS panel at the University of Washington (UW OncoPlex) detected a ZFTA::NCOA2 fusion, prompting methylation reanalysis (NIH) using the recently released v12b6 DKFZ classifier, which matched to "Supratentorial Ependymoma, ZFTA fusion-positive". Conclusions While this case is unusual in the lack of traditional ependymal morphology, the morphologic findings are consistent with the underlying ZFTA::NCOA2 fusion.

These cases highlight the challenges in identifying MLH1-deficient prostate cancers using standard MSI testing and commercial sequencing panels, and support the utility of immunohistochemical assays and LMR- or sequencing-based MSI testing for detection of MMRd prostate cancers.

Patients received 12 weeks of apalutamide, abiraterone acetate plus prednisone, degarelix, and indomethacin followed by radical prostatectomy (RP). The findings show the potential for 3D microdissection of morphologically distinct subclones in samples from neoadjuvant-treated patient, to enable sequencing of specific cellular populations. The sparsity of carcinoma necessitated a spatially targeted approach for extracting material for sequencing. The increased yield from avoiding FFPE processing and carcinoma enrichment from targeted 3D microdissection of carcinoma ROIs enabled the detection of spatially distinct molecular subclones.

Background: LuPSMA, a radioligand targeting the cell surface protein PSMA, is approved for men with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) following an androgen receptor (AR)-signaling inhibitor (ARSI) and docetaxel. Mutations in DDR genes were associated with a higher PSA50 response rate following LuPSMA compared to patients without a DDR mutation. There was no difference in baseline PSMA expression based on DDR mutational status, suggesting that higher response rates in the DDR cohort may have been mediated primarily by increased sensitivity to ionizing radiation. Evaluation for associations between DDR mutational status and survival endpoints is needed and will require a larger sample size and longer follow up.

We identified a diverse landscape of somatic mutations - the prevalence of BRCA1, BRCA2, and PIK3CA mutations are considerably higher than in other documented populations. A better understanding of the mutational profile can provide biological insights, inform prognosis, and serve as a predictive biomarker. As mutations in BRCA1/2 and PIK3CA can potentially be treated with targeted therapies (e.g.

P2 | N=31 | Completed | Sponsor: National Cancer Institute (NCI) | Suspended ➔ Completed | Trial completion date: Sep 2023 ➔ Oct 2022 | Trial primary completion date: Sep 2023 ➔ Oct 2022

Post-hoc analysis in a phase I/II trial indicated a benefit of carboplatin+cabazitaxel in men with AVPCm+ metastatic castrate resistant prostate cancer (mCRPC). We show the operational characteristics of the AVPCm detection using CLIA certified assays. IHC detected a greater proportion of patients with AVPCm+ tumors than stDNA, likely due, partly, to the challenges of copy number loss detection. ctDNA detected the greatest proportion of AVPCm+ tumors but was not evaluable in two thirds of patients.

In this pilot study, FDG TLG showed a significant correlation with ctDNA. There is an encouraging association with ctDNA fraction and number of FDG lesions and with ctDNA fraction and extent of FES avid disease (TLER) in the 9 patients that had FES. Research Support: RG1005258 Table 1.

P2; Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023

P2, N=30, Recruiting, University of Washington | Not yet recruiting --> Recruiting

P1; Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> Apr 2022

This study confirmed that cfDNA from supernatant is a viable alternative to FFPE cell blocks for molecular biomarker testing using both amplicon-based and capture-based assays with potential for decreasing additional tissue sampling and faster turnaround time.

These data provide evidence that primary prostate tissue accurately reflect the mutational status of actionable DDR genes in men with metastatic PC, supporting the hypothesis that DDR alterations are early truncal events . After excluding likely CHIP events, ctDNA profiling accurately captured these truncal DDR mutations, while also detecting reversion alterations that may suggest potential resistance mechanisms.

NIVO + IPI demonstrated significant activity in biomarker selected, pre-treated pts with mCRPC. The safety profile is consistent with this dosing schedule. Accrual to expansion cohort 2 started in September 2020.

"Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens."

"These data are consistent with emerging data showing that DNA repair alterations are enriched among castration-resistant prostate cancer and aggressive subsets of primary tumours. Given that these patients are potential candidates for poly(ADP-ribose) polymerase inhibitor and/or immune checkpoint blockade, and have a poor prognosis with standard therapy, we recommend that tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant-cell features."