SCIENTIFIC BACKGROUND

AKT1, AR, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCL, FOXA1, IDH1, MYC, NCOR1, PALB2, PIK3CA, PTEN, RAD51B, RAD51C, RAD51D, RB1, SMAD4, SPOP, TP53; Fusion Genes: ESRP1-RAF1, RAF1-ESRP1, SLC45A3-BRAF, SND1-BRAF, TMPRSS2-ERG, UBE2L3-KRAS

Prostate carcinoma (PCa) is the most common non-cutaneous cancer in men worldwide, with about 1.6 million cases and 366,000 deaths annually. Approximately 80% to 90% of all PCa arise in the peripheral zone of the prostate, about 10% in the transition zone, and few in the other three areas of the prostate (central, anterior, around the urethra). Three stages of development have been identified: (a) intraepithelial neoplasia, which can be considered precancerous and is characterized by hyperplasia of luminal cells and progressive loss of basal cells; (b) adenocarcinoma androgen-dependent (divided into two stages: latent and clinical), characterized by complete loss of basal cells and luminal phenotype: At this stage, the tumor is androgen-dependent and its growth can be controlled by androgen deprivation; and (c) adenocarcinoma androgen-independent (or castration-resistant).

 

GENOMIC ALTERATIONS AND POSSIBLE THERAPIES

With early diagnosis and treatment, patients have a good prognosis. Treatment of PCa depends on the grade, stage, and age and ranges from active surveillance to a mixture of surgery, chemotherapy, radiation, and/or androgen deprivation therapy (ADT). ADT is often used in combination with surgery or radiation, and often in combination with chemotherapy for metastatic disease. ADT may include two approaches: surgical castration (orchiectomy) or chemical castration with drugs that target the AR pathway.

 

Although most patients initially respond well to this therapy, nearly all cases recur and progress to primary castration-resistant prostate cancer (CRPC) or metastatic CRPC (mCRPC). For example, if this resistance is based on an alteration in AR, in NCOR1/2, or in FOXA1, therapy with AR inhibitors (e.g., enzalutamide) or CYP17A1 inhibitors (e.g., abiraterone) may prolong overall survival.

 

Approximately 25% of mCRPC patients demonstrate homologous DNA repair (HRR) deficiency and may benefit from therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi).

The greatest benefit of PARPi therapy appears to be shown by mCRPC patients with a change in BRCA1 or BRCA2, whereas patients with variants in ATM and CDK12 show limited response. However, patients with CDK12 inactivation may benefit from therapy with immune checkpoint inhibitors alone or in combination with PARPi due to an increased neoantigen load. Variants in the other HRR genes have a relatively low prevalence in mCRPC. Potential combination therapy of PARPi and second-generation antiandrogens could increase response, if appropriate.

Two PARPi for the treatment of PCa have been approved by the FDA: Olaparib for mCRPC patients who have previously received a second-generation hormonal agent and have a variant in an HRR gene (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L); Rucaparib for mCRPC patients who have previously received a second-generation hormonal agent or taxane chemotherapy and have a variant in BRCA or BRCA2.

 

A family history of PCa increases the risk for PCa. In addition, PCa has been associated with hereditary breast and ovarian cancer (HBOC) syndrome (due to germline variants in homologous DNA repair genes) and Lynch syndrome (due to germline variants in DNA mismatch repair genes). Indeed, approximately 11% of patients with PCa and at least one additional primary tumor in the family carry germline variants that are associated with an increased risk of cancer. Therefore, we recommend a thorough review of personal and family history for all patients with PCa and patient education.

 

TEST RECOMMENDATIONS

Guidelines recommend tumor testing for variants in HRR genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, FANCA, RAD51D, CDK12) and determination of microsatellite instability (MSI) or mismatch repair status (MLH1, MSH2, MSH2, PMS2) in all men with regional or metastatic high-risk prostate cancer. In cases of high MSI (MSI-H), therapy with immune checkpoint inhibitors may be considered, as pembrolizumab has been approved by the FDA for the treatment of non-resectable or metastatic solid tumors with dMMR or MSI-H. Targeted germline testing can be linked to identify patients with family members who may be at increased risk for cancer.

 

A TMPRSS2-ERG translocation is found in approximately 15% of prostate intraepithelial neoplasia (PIN) and in approximately 50% of PCa patients. Other translocations of the ETS family have been described, TMPRSS2-ERG-positive tumors exhibit some special features related to androgen metabolism. They have increased androgen-regulated gene expression and altered intratumoral androgen metabolism, as demonstrated by decreased testosterone concentrations and increased dihydrotestosterone (DHT)/testosterone ratios. Therefore, patients with TMPRSS2-ERG-positive PCa may benefit from novel inhibitors targeting alternative DHT biosynthesis. In the future, PARPi may also play a role in PCa patients with TMPRSS2-ERG translocation because PARP1 can interact with ERG. The resulting ERG overexpression could be inhibited by PARPi and the growth of ERG-positive tumor cells slowed.

 

Approximately 15% of PCa show variants in SPOP with favorable prognosis and improved progression-free survival, especially in patients with high PSA levels before treatment. There is also evidence that SPOP-mutated PCa fail to degrade PD-L1 due to a lack of binding to PD-L1, which may support the use of immunotherapy with immune checkpoint inhibitors in these tumors.

 

GENE PANEL

27 genes: AKT1, AR, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCL, FOXA1, IDH1, MYC, NCOR1, PALB2, PIK3CA, PTEN, RAD51B, RAD51C, RAD51D, RB1, SMAD4, SPOP, TP53

 

FUSION GENE PANEL

ESRP1-RAF1, RAF1-ESRP1, SLC45A3-BRAF, SND1-BRAF, TMPRSS2-ERG, UBE2L3-KRAS

 

TARGETED PANEL

ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, PALB2, PTEN, RAD51, MSI

GENES

AKT1, AR, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCL, FOXA1, IDH1, MYC, NCOR1, PALB2, PIK3CA, PTEN, RAD51B, RAD51C, RAD51D, RB1, SMAD4, SPOP, TP53; Fusion Genes: ESRP1-RAF1, RAF1-ESRP1, SLC45A3-BRAF, SND1-BRAF, TMPRSS2-ERG, UBE2L3-KRAS
How to order

LATEST ARTICLES

Overview In January 2024, the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) published new recommendation...

Read more

Endometriosis is a chronic gynecological condition that affects 1 in 10 women of reproductive age worldwide [1]. It can manifest with the first menst...

Read more

Rare Disease Day is a global awareness day held annually to raise awareness of all rare diseases. It was first celebrated in 2008, on the rarest day ...

Read more

Cancer is a group of genetic diseases that can develop almost anywhere in the body. Many people in the world are affected by cancer every year. Follo...

Read more

Aiming to evaluate the role of chromosomal aneuploidy in pregnancy loss, a 2023 study 35 years in the making evaluated the genomic landscape of first...

Read more

Cancer is a complex genetic disease that affects millions of people in the world. It is one of the leading causes of death worldwide, with about ten ...

Read more

Researchers created a detailed map of the placenta during labor. By studying how maternal and fetal cells communicate, they discovered signals in the...

Read more

A recent paper published in Nature Medicine (1) aimed to identify genes and genomic biomarkers which can better predict outcomes and personalized the...

Read more

In honor of the international day of women and girls in science, we interviewed one of our very own, Dr. Evelina Papaioannou. Dr. Evelina Pa...

Read more

Aneuploidies, such as translocations, whole or segmental chromosomal duplications, and deletions, are examples of chromosomal abnormalities that are ...

Read more