Genomic Alteration Burden in Advanced Prostate Cancer and Therapeutic Implications

Ryan, Matthew; Bose, Rohit

doi:10.3389/fonc.2019.01287

Cited by 29 publications

(19 citation statements)

References 93 publications

(150 reference statements)

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“…Mb), which may be somewhat uncertain, given the low tumor content in our case (the complete set of variants are listed in Supplementary Table S3 ), yet a high TMB for primary PCa. It has been estimated that the TMB of unselected and usually treatment-naïve locoregional prostate adenocarcinoma cohorts typically falls between 0.94 and 1.74 nonsynonymous mutations per megabase [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…According to the preliminary results of an ongoing trial, PCa patients with tumors having a PD-L1 level of at least 1%, HR deficiency mutations, DNA damage repair mutations, or a TMB greater than the median of 74.5 mutations showed enhanced responses to a combined nivolumab/ipilimumab treatment [ 65 ]. Our subject has signs of HR deficiency (the most dominant mutational signature), an ATM mutation of unknown clinical significance, a BRCA2 fusion transcript that likely reduces full BRCA2 functionality, and a significantly higher TMB than the median for PCa [ 26 ]. BRCA2-altered PCa tumors have been shown to harbor enhanced intra-tumoral immune infiltrates compared to wild-type tumors [ 60 ], suggesting treatment options targeting immune cell modulation [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

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The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Nakken

Lilleby

Switlyk

et al. 2021

JPM

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Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Nakken

Lilleby

Switlyk

et al. 2021

JPM

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“…While blockade of these checkpoints has led to improved responses and changed the treatment paradigm in malignancies such as melanoma, non-small cell lung cancer (NSCLC), efficacy in prostate cancer remains modest [ 22 , 76 , 77 ]. There have been ongoing efforts to identify predictors of response to immunotherapy, such as PD-L1 expression, tumor mutational burden (TMB), and other mutations such as CDK12 [ 78 , 79 , 80 , 81 ]. One study of tumor tissue from patients with mCRPC revealed that 19% demonstrated high PD-1/PD-L1 immunoexpression [ 82 ].…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

Bansal

Reimers

Knoche

et al. 2021

Cancers

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Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.

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“…have been uncovered in a significant percentage of metastatic castration-resistance prostate cancer (mCRPC) patients. Defects in these DNA repair genes can increase TMB and neoantigen load potentially predicting response to immunotherapy [ 56 , 57 ]. In a study involving a cohort of 4129 prostate cancer patients 1.8% (74/4129) of patients had POLE/POLD1 mutations.…”

Section: Predictors Of Response To Immune Checkpoint Blockadementioning

confidence: 99%

Immune Checkpoint Inhibitors in Prostate Cancer

Venkatachalam

McFarland

Agarwal

et al. 2021

Cancers

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Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.

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Genomic Alteration Burden in Advanced Prostate Cancer and Therapeutic Implications

Cited by 29 publications

References 93 publications

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer

Immune Checkpoint Inhibitors in Prostate Cancer

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