Circulating tumor DNA (ctDNA) for predicting tumor prognosis and guiding individualized treatment is a hot topic in malignant tumor research. ctDNA exists in the peripheral blood of tumor patients in a cell-free state and can dynamically evaluate the tumor condition, overcoming tumor heterogeneity biases. The 2023 American Association for Cancer Research (AACR) Annual Meeting was held from April 14 to 19, 2023, in Orlando, USA. In this AACR conference, three ctDNA-related studies evaluated its application value in urological tumors.
Utility of Circulating Tumor DNA and Transcriptome Analysis in Predicting the Prognosis of Patients with Muscle Invasive Bladder Cancer
Standard treatment for localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC), followed by radical cystectomy (RC). However, only 40%-50% of patients respond to NAC, and about 50% of patients relapse. Hence, assessing treatment outcomes and early detection of recurrence is a major clinical challenge.
Researchers updated a previously reported cohort of 68 patients receiving NAC before RC (with a median follow-up of 58 months) and assessed a retrospective cohort of 120 patients who did not receive NAC (with a median follow-up of 71 months). They used Signatera™ to analyze ctDNA before and after NAC and RC. RNA sequencing was done on 176 tumors.
Updated follow-up data showed that patients with positive ctDNA had a significantly worse relapse-free survival (RFS) compared to those with negative ctDNA. 84% of patients were ctDNA negative after NAC, of which 81% achieved pathological complete remission (pCR), while those positive for ctDNA did not achieve pCR. For the non-NAC cohort, the presence of ctDNA at both time points also had prognostic significance.
Transcriptome analysis revealed carcinogenic pathways enriched in tumors of ctDNA positive patients. This might indicate that tumors shedding ctDNA possess a more aggressive cancer phenotype. Among patients positive for ctDNA after NAC, there was enrichment of EMT and TGF-β signaling, while in those who cleared ctDNA after NAC, anti-tumor immune pathways were enriched.
Conclusion:
The presence of ctDNA is related to poorer prognosis in patients, regardless of whether they received NAC. Transcriptome analysis of primary tumors showed that anti-tumor immune response might be associated with an excellent prognosis, while EMT might promote more aggressive disease.
Genomic Alterations in Circulating Tumor DNA (ctDNA) and Clinical Outcomes with [177Lu]Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer (mCRPC)
[177Lu]Lu-PSMA-617 (LuPSMA) radioligand therapy can improve overall survival in mCRPC and recently received FDA approval. However, due to mCRPC heterogeneity, responses to LuPSMA treatment may vary, and resistance is inevitable. Hence, there’s a need for biomarkers related to LuPSMA clinical outcomes.
Using plasma ctDNA, a comprehensive genomic analysis was performed on a prospective cohort of mCRPC patients treated with LuPSMA. Clinical outcomes analyzed included prostate-specific antigen (PSA) responses and PSA progression-free survival (PSA-PFS).
Out of 100 patients, 83 had detectable ctDNA. Patients with AR or PTEN abnormalities had significantly shortened PSA-PFS, as did those with PI3K pathway abnormalities. Additionally, patients with a high ctDNA burden had significantly worse PSA-PFS.
Conclusion :
AR and PI3K pathway abnormalities, as well as the pre-treatment detectable ctDNA fraction, while unrelated to PSA-RR, have predictive significance for the duration of response to LuPSMA.
Real-world Biomarker Testing Patterns in Patients with Metastatic Castration-Resistant Prostate Cancer
Homologous recombination repair gene mutations (HRRm) lead to gene mutations and genomic instability. It is estimated that up to 28% of advanced prostate cancer patients have HRRm, including mCRPC. Testing for HRRm can provide information for mCRPC treatment options. This study aimed to assess the HRRm testing rate and observe patient factors related to testing in treated mCRPC patients.
From the Integra Connect PrecisionQ database, mCRPC patients treated between January 5, 2020, and March 31, 2022, were selected. Patient age, race, tumor stage, Gleason score, treatment line number (LOT), ECOG score, metastasis site, and recent PSA values were collected at the time of mCRPC diagnosis.
The study cohort included 798 patients (HRRm tested, n=389, 48.7%). Older age, higher LOT, worse ECOG score, and metastasis to bone and viscera were all associated with increased HRRm testing rates. It was observed that younger age, low PSA value, and lower Gleason score led to lower HRRm testing rates.
Conclusion :
Less than half of mCRPC patients were tested for HRRm, although there was an upward trend in testing rates during the study period. Several patient characteristics were observed to influence the likelihood of HRRm testing.
