October 3, 2022

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Does Prostate Cancer belong to Family Inherited Tumors?

Does Prostate Cancer belong to Family Inherited Tumors?



Does Prostate Cancer belong to Family Inherited Tumors?

Prostate cancer is a highly hereditary cancer, and it is estimated that about 40% to 50% of prostate cancers are related to genetic factors.

Epidemiological and pedigree studies have confirmed that prostate cancer has obvious familial aggregation.

In these familial prostate cancers, genetic factors play a particularly important role.

Germline mutations in multiple DNA damage repair genes have been demonstrated to be associated with genetic susceptibility to prostate cancer.

DNA damage repair genes represented by BRCA1 and BRCA2 are the most well-recognized prostate cancer susceptibility genes so far, other DNA damage repair genes such as ATM, PALB2, CHEK2 and mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) It is also thought to be associated with an increased risk of prostate cancer. Other genes that may be associated with hereditary prostate cancer include genes such as HOXB13.

Germline mutations in the above susceptibility genes not only lead to an increased risk of prostate cancer, but also make prostate cancer have unique clinicopathological phenotypes, such as early age of onset, familial aggregation, strong invasiveness, and poor prognosis.

At the same time, the germline mutations of the above susceptibility genes are also drug targets, so the clinical management strategy of familial prostate cancer is quite different from that of sporadic prostate cancer.

Does Prostate Cancer belong to Family Inherited Tumors?


Prostate cancer with germline mutations in DNA damage repair genes

Although the frequency of germline mutations in DNA damage repair genes was low in limited-stage prostate cancer (4.6%), in metastatic prostate cancer, up to 11.8% (82/692) of patients had germline mutations in DNA damage repair genes, These included BRCA2 (mutation rate 5.3%), ATM (mutation rate 1.6%), CHEK2 (mutation rate 1.9%), BRCA1 (mutation rate 0.9%), RAD51D (mutation rate 0.4%) and PALB2 (mutation rate 0.4%).

Pathogenic germline mutations in these genes are strongly associated with an increased risk of prostate cancer in men.

A study of 1,864 prostate cancer patients found that men with a germline BRCA2 mutation had an 8.6-fold increased risk of prostate cancer at age 65 compared with non-carriers, with an absolute risk of about 15%.

Another study conducted annual prostate-specific antigen (PSA) screening for men with germline BRCA1 or BRCA2 mutations, and performed needle biopsy for those with abnormal PSA, and found that BRCA1 or BRCA2 mutation carriers had Higher incidence of prostate cancer, and the incidence of intermediate-risk and high-risk prostate cancer is higher than that of non-carriers.

In addition to BRCA1/2 genes, germline mutations in other DNA damage repair genes may also increase the risk of prostate cancer to varying degrees.

Germline mutations in DNA damage repair genes are not only associated with the risk of prostate cancer, but also with rapid tumor progression and poor prognosis.

A Canadian cohort study found that germline mutations in DNA damage repair genes including BRCA2, ATM, CDK12, PALB2, and FANCA were detected in 319 patients with metastatic castration-resistant prostate cancer.

The time to progression to castration-resistant prostate cancer (CRPC) after androgen-deprivation therapy (ADT) was shorter than that of non-mutated patients (11.8 months vs. 19.0 months), while mutation patients had a shorter time to progression to castration-resistant prostate cancer (CRPC).

PSA progression was significantly faster in patients with metastatic castration-resistant prostate cancer (mCRPC) after first-line endocrine therapy than in non-mutated patients (3.3 months vs. 6.2 months, P=0.01).

Data from a  study showed that new-onset metastatic hormone-sensitive prostate cancer patients with germline DNA damage repair gene mutations progressed to the castration-resistant stage more quickly than those without mutations (8.3 months vs. 13.2 months, HR =2.37, P<0.001).

The multicenter prospective cohort PROREPAIRB study found that mCRPC patients with germline mutations in DNA damage repair genes have a higher risk of prostate cancer-specific mortality, especially patients with BRCA2 germline mutations, and tumor-specific survival time is longer than patients without mutations The shortening was nearly half, and the risk of death increased significantly (17.4 months vs. 33.2 months, HR=2.10, P=0.026 6).


Other gene germline mutation prostate cancer

Studies have found that healthy men with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) have a 2- to 5-fold increased risk of prostate cancer compared with non-carriers.

Another study found that prostate cancer patients with germline mutations in mismatch repair genes had an earlier age of onset and a more aggressive phenotype than non-mutated patients.

However, the frequency of germline mutations in mismatch repair genes is low in prostate cancer.

Previous studies on the Caucasian population have found HOXB13 gene mutations (mainly G84E) in familial prostate cancer patients. 

Currently, there are no drugs that target HOXB13 mutations, which are only valuable for tumor risk assessment in immediate family members.


Risk assessment and genetic testing

1. Target population and detection content

Risk assessment for hereditary prostate cancer requires a combination of family history, clinical, and pathological features of prostate cancer patients. Where family history should be considered:

1) Whether a brother, father or other family member was diagnosed with or died of prostate cancer before the age of 60;

2) Whether there are 3 or more cases in the same family, including bile duct cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, kidney cancer, melanoma, small bowel cancer and urinary tract cancer Patients with skin cancer, especially the age of diagnosis ≤ 50 years;

3) Whether the patient has a history of male breast cancer or pancreatic cancer;

4) Whether the family is known to carry related germline pathogenic gene mutations.

Obtaining family history and genetic counseling are necessary steps before testing for very low- to intermediate-risk prostate cancer patients without risk assessment at the initial diagnosis:

  • DNA damage repair genes (especially BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2) are recommended for patients with the above risk levels with a clear relevant family history and known family members to carry germline pathogenic gene mutations ) germline variant detection;
  • For patients with the above-mentioned risk levels with unknown family history, it is necessary to comprehensively judge whether relevant testing is necessary after genetic counseling combined with clinical characteristics.

Germline mutation testing of DNA repair genes (especially BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2) is recommended for patients with high-risk, very high-risk, locally advanced, and metastatic prostate cancer.

In addition, intraductal carcinoma of the prostate (IDC-P) and ductal adenocarcinoma of the prostate (DAP) are subtypes of prostate cancer with unique pathological features.

The incidence of DAP is low, accounting for only 1% of all prostate cancer patients; while IDC-P has different proportions in prostate cancer patients with different sample types, risks and clinical stages: low-risk, intermediate-risk, high-risk and metastatic In recurrent prostate cancer, the proportions of IDC-P were 2.1%, 23.1%, 36.7% and 56.0%, respectively.

Compared with adenocarcinoma patients, IDC-P and DAP patients have higher germline mutation rates of mismatch repair genes and DNA damage repair genes (especially BRCA2 gene), and IDC-P and DAP patients have poorer prognosis.

Therefore, germline genetic testing is recommended for prostate cancer patients with this pathological feature, regardless of whether there is a clear family history of the tumor.

Expert group opinion: It is recommended that the genetically high risk group of prostate cancer who meets any of the following conditions consider germline mutation testing of DNA damage repair genes, including BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2 and other genes:

1) Known family members carry pathogenic mutations in the above genes.

2) There is a clear family history of tumors, and there are multiple cases in the same family including bile duct cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, kidney cancer, melanoma, small bowel cancer and Patients with urothelial cancer, especially if they were diagnosed ≤50 years old; and had a brother, father, or other family member diagnosed with or died of prostate cancer before the age of 60.

3) Suspicious or unknown family history, recommended after full genetic counseling and evaluation.

4) The pathogenic mutations of the above genes were found in the tumor tissue test, and the germline verification was not carried out.

5) Intraductal carcinoma and ductal adenocarcinoma.

6) High risk and above, locally advanced and metastatic prostate cancer.

In addition, prostate cancer patients with a clear family history of tumors are recommended to consider HOXB13 germline mutation testing.

2. Processing of genetic testing samples and interpretation of results

The quality of the test samples is a key factor in determining the success of genetic testing. Usually germline DNA damage repair gene testing can use blood (preferred), saliva, oral swab and other samples.

Blood sample requirements: Collect 2-3 mL of whole blood, store it in an EDTA anticoagulant tube, transport it to the testing laboratory at room temperature (15°C to 35°C), and extract DNA after leukocyte separation.

Since it is a multi-gene detection and no hotspot mutation, it involves single nucleotide variation (single nucleotide variation), small fragment indel (small fragment indel), copy number variation (copy number variation) and large fragment rearrangement The detection process includes sample acquisition and processing, nucleic acid extraction, library construction, NGS sequencing, data analysis, variant interpretation and clinical testing.

For steps such as report issuance, the specific testing process can refer to the “Expert Consensus on Next-Generation Gene Sequencing Testing in Clinical Molecular Pathology Laboratory” and “Guidelines for BRCA1/2 Gene Testing Based on Next-Generation Sequencing Technology (2019 Edition)”.

Germline mutations can be graded and interpreted for pathogenicity according to the sequence variant interpretation standards and guidelines published by the American College of Medical Genetics and Genomics (ACMG) and the American Academy of Molecular Pathology (AMP) in 2015.

Patients with germline mutations require genetic counseling by a professional.

Expert group opinion: It is recommended to use next-generation sequencing methods to simultaneously detect germline mutations in multiple prostate cancer susceptibility genes.


The treatment strategy

The treatment methods of prostate cancer mainly include surgery (radical prostatectomy), radiotherapy, endocrine therapy, chemotherapy, targeted therapy and immunotherapy.

Hereditary prostate cancer is not much different from sporadic prostate cancer in terms of surgery, radiotherapy and endocrine therapy, while hereditary prostate cancer has a highly unstable genome due to germline mutations in DNA damage repair genes.

It is sensitive to inhibitors and immunotherapy, so this consensus will focus on specific treatment strategies for hereditary prostate cancer.

Does Prostate Cancer belong to Family Inherited Tumors?

1. Platinum-based chemotherapy

Although the phase II clinical study of platinum-based chemotherapy in the whole mCRPC population has failed, the efficacy in the BRCA2 mutation population is still being explored.

A small study showed that in carboplatin-based chemotherapy, 6 of 8 patients (75%) with BRCA2 mutations experienced a PSA drop of >50% within 12 weeks, compared with only 50% of non-carrier patients. 17% (23/133) had a >50% decrease in PSA within 12 weeks (P<0.01).

However, due to the small sample size and the inclusion of only patients with BRCA2 mutations, further clinical studies are still needed to clarify the efficacy and safety of platinum-based chemotherapy in patients with DNA damage repair gene mutations.

Expert Group Opinion: The efficacy of platinum drugs for hereditary prostate cancer is not yet sufficient, and further research is needed.

2. PARP inhibitor targeted therapy

Poly(ADP-ribose) polymerase inhibitor (PARP) is a novel antitumor drug targeting DNA damage repair defects.

In recent years, more and more studies have confirmed the therapeutic efficacy of PARP inhibitors in hereditary prostate cancer.

The results of the TOPARP-A study in 2015 were the first to report the antitumor activity of PARP inhibitors in metastatic prostate cancer with DNA damage repair defects.

Subsequently, a number of phase II clinical studies such as TRITON2, GALAHAD and TOPARP-B have successively found that mCRPC patients carrying germline and/or somatic mutations of DNA damage repair genes are sensitive to PARP inhibitors, and most of them are homologous recombination repair genes. mutation.

The PROfound study is a large phase III randomized, controlled, open clinical trial. The study showed that olaparib significantly prolonged median radiographic progression-free survival in patients with BRCA1/2 or ATM mutations compared with physician-selected novel endocrine therapy (7.4 months vs. 3.6 months, HR=0.34, 95% CI: 0.25-0.47, P<0.000 1); at the same time, olaparib can also significantly prolong the median radiographic progression-free survival of patients with homologous recombination repair (HRR) gene mutations (5.8 months vs. 3.5 months, HR = 0.49, 95% CI: 0.38 to 0.63, P < 0.000 1).

In terms of overall survival, the study finally showed that olaparib could reduce the risk of all-cause mortality by 31% in patients with BRCA1/2 or ATM mutations (HR=0.69, 95%CI: 0.50-0.97, P=0.0175), and reduced the risk of all-cause mortality in patients with HRR mutations21 % risk of all-cause mortality (HR = 0.79; 95% CI: 0.61-1.03); after adjusting for the effect of crossover between experimental and control patients, the risk of all-cause mortality was reduced by 58% and 45%, respectively.

Therefore, in patients with DNA repair gene mutations, PARP inhibitors can effectively prolong the long-term survival of patients.

Based on the above evidence, in 2020 the U.S. Food and Drug Administration (FDA) officially approved two PARP inhibitors for the treatment of prostate cancer.

Olaparib is approved for the treatment of mCRPC patients who have progressed after receiving new endocrine drugs and carry any homologous recombination repair gene mutation (mutated genes include BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL , PALB2, RAD51B, RAD 51C, RAD51D, and RAD54L); Lucaparib is approved for the treatment of mCRPC patients with BRCA1 or BRCA2 mutations who have progressed after prior chemotherapy with novel endocrine drugs and paclitaxel.

Expert group opinion: It is recommended that mCRPC patients should undergo homologous recombination repair gene germline mutation testing, and patients with positive mutations are preferentially treated with PARP inhibitors.

3. Immunotherapy

A single-arm phase II clinical trial (NCT01876511) involving 86 patients with advanced solid tumors showed that advanced solid tumors with mismatch repair deficiency were resistant to programmed death 1 (programmed death-1, PD-1) antibody Pabo Livizumab is highly sensitive, with 21% of patients achieving complete response (CR) and 53% achieving objective radiographic response (ORR), and the response rate is independent of tumor type.

Therefore, pembrolizumab was approved by the US FDA in 2017 for unresectable or metastatic mismatch repair defect (deficiency of mismatch repair, dMMR) or microsatellite instability-high (MSI-H) type solid tumor treatment.

In prostate cancer, the study showed that 4 patients with prostate cancer with germline mutations in the MMR gene were treated with pembrolizumab, 2 patients had a PSA drop of >50%, and the median progression-free survival was 9 months, 3 patients The patient presented with an objective soft tissue response on imaging.

Expert group opinion: It is recommended that mCRPC patients undergo dMMR or MSI-H testing. If MSI-H or dMMR type is diagnosed, pembrolizumab treatment can be considered, and further genetic counseling and MMR gene germline mutation testing can be considered.

4. Family management

If a pathogenic germline mutation in a DNA damage repair gene (eg, a BRCA1/2 pathogenic germline mutation) is identified in a proband following genetic testing of a patient with prostate cancer, the discussion should focus on BRCA1/2 with the patient The role of mutations in the clinical management of prostate cancer, as well as the patient’s risk of other BRCA1/2 mutation-related cancers and the corresponding early diagnosis and screening methods, including male breast cancer, pancreatic cancer, etc. Expert consensus on diagnosis and treatment (2021 edition)-familial hereditary breast cancer, familial hereditary pancreatic cancer].

At the same time, the relatives of the proband should be advised to perform genetic testing at the same locus to confirm whether they have inherited the mutation.

Among them, healthy female relatives who carry the mutation should focus on breast and ovarian cancer risk assessment, early diagnosis and risk reduction management  – familial hereditary breast cancer, familial hereditary ovarian cancer]. Prostate cancer screening strategies should be actively discussed in healthy relatives of males who carry the mutation.

Currently, the National Comprehensive Cancer Network (NCCN) guidelines recommend that BRCA2 mutation carriers start prostate cancer screening after age 40, and BRCA1 mutation carriers should also consider starting prostate cancer screening after age 40, including PSA screening examination and digital anorectal examination.

Studies have shown that multiparametric magnetic resonance (mpMRI) has high diagnostic efficacy for prostate cancer in BRCA1 or BRCA2 mutation carriers, and it is recommended that BRCA1 or BRCA2 mutation carriers aged >55 years should undergo mpMRI as soon as PSA elevation is found. to further clarify the diagnosis.

If the proband has no pathogenic germline mutations in DNA damage repair genes detected by genetic testing and there are no known mutations in the family, it is recommended to recommend appropriate prostate cancer screening methods for healthy men in the family based on their family history .

In patients with first-degree male relatives (especially sons and brothers), PSA screening and digital anorectal examination may be recommended starting after age 40.

If the genetic report after the test indicates that there is a variant of uncertain significance (VUS) in the tested gene, the current consensus in the field of genetic testing is that the diagnosis and treatment recommendations of patients will not be changed immediately after the discovery of VUS, but patients are advised to conduct long-term follow-up and collect more data.

Based on multiple evidence, the final decision should be made whether these VUS need to be reclassified and new treatment options should be developed.

Many VUSs are reclassified as pathogenic/probably pathogenic (disease-related)/benign, usually after a period of time. When VUS is reclassified, the genetic laboratory will notify the designated physician, who should interview the patient again to discuss treatment options.

Does Prostate Cancer belong to Family Inherited Tumors?

(source:internet, reference only)


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