Himisha Beltran, MD, associate professor of medicine and physician in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at Dana-Farber Cancer Institute and Harvard Medical School, discusses the significance of genomic sequencing in prostate cancer.

Not all men with prostate cancer will respond to PARP inhibitors; thus, the role of genomic sequencing has become increasingly important, says Beltran.

As such, the field of prostate cancer continues to enhance its knowledge of genomic sequencing in metastatic disease​, Beltran says.

Further refining genomic sequencing may provide insight into the role of DNA repair aberrations, the natural history of rare variants, the impact of co-occurring alterations, ​and the develop​ment of resistan​ce, Beltran adds.

Ultimately, harnessing genomic and non-genomic information will continue to play a critical role in treatment selectionfor men with prostate cancer, Beltran concludes.

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Himisha Beltran, MD, discusses the significance of genomic sequencing in prostate cancer.

 Dr. Beltran on the Significance of Genomic Sequencing in Prostate Cancer

Himisha Beltran, MD, associate professor of medicine and physician in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at Dana-Farber Cancer Institute and Harvard Medical School, discusses the need to identify non–androgen receptor (AR) targets in prostate cancer.

Ongoing research efforts are attempting to identify druggable targets for patients with non–AR-driven prostate cancers, such as neuroendocrine prostate cancer, Beltran says.

Neuroendocrine prostate cancer is a histologic variant of prostate cancer that tends to occur in late-stage disease when prostate adenocarcinoma transforms to small-cell neuroendocrine prostate cancer, explains Beltran.

Moreover, neuroendocrine prostate cancer is biologically distinguishable and harbors many potentially targetable alterations, Beltran says.

As such, the field should move toward developing clinical trials specific to non–AR-driven prostate cancer, concludes Beltran.

Himisha Beltran, MD, discusses the need to identify non–androgen receptor targets in prostate cancer.  



Dr. Beltran on the Need to Identify Non–AR Targets in Prostate Cancer

Himisha Beltran, MD, associate professor of medicine and physician in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, discusses the limitations of tissue biopsies versus liquid biopsies in castration-resistant neuroendocrine prostate cancer (CRPC-NE).

Tissue biopsies have innate risks because they are invasive procedures, says Beltran. Performing multiple sequential tissue biopsies to identify cancer subtypes that may emerge in late stages of prostate cancer, such as CRPC-NE, can be challenging.

Additionally, tracking the dynamic changes that occur during CRPC-NE progression is difficult with tissue biopsy because it can only provide information for a single timepoint, explains Beltran. Studying this evolving process of acquired resistance using liquid biopsies could eventually be translated into noninvasive tools to identify patients who are at risk of developing CRPC-NE for earlier and targeted treatment approaches.

If researchers can show that the molecular features that are identified with liquid biopsies are robust biomarkers, they could augment current clinical features that are identified with tissue biopsies. These biomarkers could shed light on the mechanisms underlying resistance to therapy, says Beltran.

The utilization of liquid biopsy could continue to push the treatment paradigm in CRPC-NE toward precision medicine, concludes Beltran.

Himisha Beltran, MD, discusses the limitations of tissue biopsies versus liquid biopsies in castration-resistant neuroendocrine prostate cancer.


Dr. Beltran on the Limitations of Tissue Biopsies Versus Liquid Biopsies in CRPC-NE

Himisha Beltran, MD, associate professor of medicine and physician in the Lank Center for Genitourinary Oncology and the Division of Molecular and Cellular Oncology at the Dana-Farber Cancer Institute and Harvard Medical School, discusses the use of cell-free DNA (cfDNA) to detect castration-resistant neuroendocrine prostate cancer.

Investigators started to examine dynamic changes in the cfDNA that occur during the course of treatment resistance. In some cases, they saw that prostate cancer patients had multiple clones in the circulation that changed with time; others were dominated by a resistant clone that persists, says Beltran. These areas beg for further exploration, adds Beltran: understanding clonal evolution through serial cfDNA sampling can help understand how and when patients develop resistance during the course of their treatment, paving the way for strategies geared towards early intervention.

Investigators also looked at DNA methylation of cfDNA. Notably, neuroendocrine prostate cancer has common genomic alterations as prostate adenocarcinoma; however, the DNA methylation profile is very different and many of the genes that are differentially methylated and dysregulated are genes involved in differentiation and plasticity, explains Beltran. As such, the cfDNA methylation profiles were also compared with tumor biopsies and they were found to be fairly robust. The methylation profiles are going to be an important layer in trying to better identify this resistant subgroup, predicts Beltran.

The exploratory study initially examined highly selected patients doing extensive, in-depth analyses. Using this information, investigators developed a more targeted panel of genes, which is much more clinically applicable—especially in situations where there are not a lot of cfDNA due to lower tumor burden, explains Beltran. The next steps of this research are to apply the targeted panel to clinical trial cohorts to see how often neuroendocrine prostate cancer alterations arise after androgen receptor—directed therapies. Are they early or are they selected for? How do these cfDNA alterations correlate with expression of emerging therapeutic targets that are being developed for this subgroup? After validation, all of this will hopefully lead to the identification of a biomarker that could help identify patients developing neuroendocrine prostate cancer and help in treatment selection for clinical trials, concludes Beltran.

Himisha Beltran, MD, discusses profiling of circulating tumor DNA to detect castration-resistant neuroendocrine prostate cancer.

Dr. Beltran on Using cfDNA to Detect Castration-Resistant Neuroendocrine Prostate Cancer

Himisha Beltran, MD, associate professor of medicine, Lank Center for Genitourinary Oncology, Division of Molecular and Cellular Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses the utility of liquid biopsies versus tissues biopsies in castration-resistant neuroendocrine prostate cancer (CRPC-NE).

An abstract presented at the 2020 Genitourinary Cancers Symposium demonstrated a high concordance between circulating tumor DNA (ctDNA) in plasma-based testing and tissue-based testing with regard to identifying common alterations in prostate cancer, says Beltran.

To look beyond common mutations, whole-exome sequencing across the genome was compared between sample types, says Beltran. Results showed that a higher genomic similarity between plasma and tissue samples was noted in the CRPC-NE subgroup compared with traditional CRPC, explains Beltran.

This suggests that there is less disease heterogeneity in men with CRPC-NE. Moreover, this complements other data that suggest as patients progress to more advanced disease, there is likely clonal selection of a resistant clone, concludes Beltran.

Himisha Beltran, MD, discusses the utility of liquid biopsies versus tissues biopsies in castration-resistant neuroendocrine prostate cancer.

Dr. Beltran on the Utility of Liquid Biopsies Versus Tissue Biopsies in CRPC-NE

Himisha Beltran, MD, associate professor of medicine, Lank Center for Genitourinary Oncology, Division of Molecular and Cellular Oncology, Harvard Medical School, director of Translational Research, and physician, Dana-Farber Cancer Institute, discusses the potential use of circulating tumor DNA to detect castration-resistant neuroendocrine prostate cancer.

Patients with advanced prostate cancer can develop resistance through multiple mechanisms, including those that are independent of the androgen receptor, says Beltran. In some cases, these resistance mechanisms can lead to a histologic transformation from a prostate adenocarcinoma to a small cell neuroendocrine carcinoma. Typically, a tissue biopsy is performed to confirm diagnosis and to guide treatment decisions, says Beltran.

Historically, tissue biopsies have shown that neuroendocrine transformations retain prostate-specific alterations and acquire new alterations in DNA and DNA methylation which may have therapeutic implications. However, tissue biopsies are invasive. As such, investigators wanted to determine whether ctDNA could be useful in detecting molecular features of neuroendocrine tumors, concludes Beltran.

Himisha Beltran, MD

Articles

Dr. Beltran on the Significance of Genomic Sequencing in Prostate Cancer

Dr. Beltran on the Need to Identify Non–AR Targets in Prostate Cancer

Dr. Beltran on the Limitations of Tissue Biopsies Versus Liquid Biopsies in CRPC-NE

Dr. Beltran on Using cfDNA to Detect Castration-Resistant Neuroendocrine Prostate Cancer

Dr. Beltran on the Utility of Liquid Biopsies Versus Tissue Biopsies in CRPC-NE

Dr. Beltran on Use of ctDNA to Evaluate Treatment Resistance in Prostate Cancer