All patients with prostate cancer, except for those with low-risk or very low-risk localized disease, should be tested for germline mutations, and somatic testing should be done in all patients with metastatic disease as there are therapeutic implications.
All patients with prostate cancer, except for those with low-risk or very low-risk localized disease, should be tested for germline mutations, and somatic testing should be done in all patients with metastatic disease as there are therapeutic implications, according to Emmanuel S. Antonarakis, MD.1
“Homologous repair mutations and mismatch mutations have therapeutic implications in the context of PARP inhibitors and PD-1 inhibitors, respectively,” said Antonarakis, who is the Clark Endowed Professor of Medicine in the Division of Hematology/Oncology and Transplantation at the University of Minnesota, Masonic Cancer Center. “[Additionally,] the identification of a germline mutation, but not a somatic mutation, has family counseling and genetic implications for first-degree relatives.”
Many commercial and in-house platforms are available to assay the germline and somatic DNA of patients with prostate cancer. The landscape has become complicated, according to Antonarakis, who added that this is a both “good and a bad thing.”
Options that target either a genetic alteration or a particular protein in prostate cancer have become available: olaparib (Lynparza) and rucaparib (Rubraca) for homologous recombination repair (HRR)–deficient or BRCA1/2-mutated disease, pembrolizumab (Keytruda) for mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) cancers, and Lu 177 vipivotide tetraxetan (Pluvicto) for those with prostate-specific membrane antigen (PSMA)–positive, metastatic castration-resistant prostate cancer (mCRPC).
A germline mutation is a genetic change in a parental germ cell that becomes incorporated into the DNA of every cell in the body of the offspring, Antonarakis said, adding that a variant contained in the germline can be passed from parent to their offspring; therefore, this kind of mutation is hereditary.
A somatic mutation is an alteration in DNA that occurs following conception, he added. These kinds of mutations can present in any cell of the body except the germ cells, and they are acquired; as such, they cannot be passed on to children.
Twenty-three percent of men with mCRPC harbor somatic DNA repair alterations, and the frequency of these alterations increases in metastatic disease vs localized disease. Moreover, 12% of men with metastatic disease have a germline DNA repair defect.
According to the National Comprehensive Cancer Network’s 2022 guidelines, germline genetic testing is recommended for patients with prostate cancer who have high-risk, very high-risk, regional, or metastatic disease, those with Ashkenazi Jewish ancestry, those with a family history of high-risk germline mutations like BRCA1/2, and a family history of cancer.
“At the somatic level, tumor genomic testing should be recommended for all patients with metastatic prostate cancer, but it should be strongly considered in those also with nodal metastatic disease,” Antonarakis said.
Importance of Family History and Cascade Testing
Family history has become increasingly important. According to Antonarakis, it is important to ask about if there is a family history of prostate cancer, but also of breast cancer, ovarian cancer, and pancreatic cancer. At least 4 BRCA-associated cancer types can increase the risk of a patient with prostate cancer having a germline mutation.
“If a patient is diagnosed with a germline mutation, this brings up the point of cascade testing, meaning that this patient has a 50% chance that his family members have the same mutation,” Antonarakis said. “This can lead to cascade genetic testing in other family members to look for the presence or absence of the same germline mutation. As such, there are family implications, if we find a germline mutation in a patient with prostate cancer.”
Two review articles recommend that a fresh metastatic tumor biopsy is the optimal choice of sample to use to identify HRR alterations using next-generation sequencing.2,3 “There are some differences [between the publications in terms of] what is the second and third best options,” Antonarakis said.
In one review article, the second and third choices were circulating tumor DNA (ctDNA) and archival biopsy/primary tumor tissue, respectively; in the other article, the archival biopsy/primary tumor tissue was thought to be the second-best option and ctDNA was the third best option.
“One important thing about ctDNA is the ability to get a positive or evaluable test depends on the prostate-specific antigen [PSA] level,” Antonarakis said. “ctDNA content increases with PSA level…In my practice, if a patient has metastatic disease with a PSA of less than 5 ng/mL, I think the yield of a ctDNA test will be low. For those with a PSA above 5 ng/mL, and especially those with a PSA above 20 ng/mL, the ctDNA yield is likely to be much higher, and therefore, giving rise to an evaluable test.”
A research group from Memorial Sloan Kettering Cancer Center set out to answer the question of what proportion of mutations found on tumor testing could be of germline origin. “There are certain gene mutations that, when found in the tumor, are virtually never germline mutations,” Antonarakis said. He added that when mutations like TP53, PTEN, and RB1 are found in the tumor, they are virtually always somatic-only mutations.
“However, when you look at other genes like BRCA2, CHEK2, or even APC, a significant proportion of those mutations can reflect a germline mutation,” Antonarakis explained. “If someone begins with tumor-only testing and finds one of these mutations, you should strongly consider germline testing afterward to disambiguate a germline from a somatic mutation.”
Guidelines presented by the same authors also offer insight into when to proceed to germline testing after tumor-only testing. If a HRR gene mutation is found in the tumor, germline testing should be done afterward. If a TP53, PTEN, or RB1 mutation is found, “you may be able to get away with omitting germline testing,” Antonarakis said.
He added that the caveat is if the patient meets NCCN guidelines, metastatic disease, node-positive disease, or high-risk localized disease, “they should undergo germline genetic testing anyway.”
How should a patient with MSI-H and BRCA1/2 in the same cancer be treated? If the patient had mCRPC, a PARP inhibitor could be an option due to the BRCA1 mutation, as could pembrolizumab because of the mismatch-repair deficiency, according to Antonarakis. The patient did not respond to olaparib but did have a robust response of approximately 12 months when subsequently given pembrolizumab.
“The lesson here, which is the first caveat, is that a BRCA1/2 mutation in the context of MSI is usually a passenger mutation, not a driver mutation, and these patients in most cases, should probably be treated preferentially with a PD-1 inhibitor rather than a PARP inhibitor,” Antonarakis said.
The second caveat that Antonarakis mentioned in his presentation was the issue of CHIP alterations; these are mutations that come from the leukocytes from the white blood cells, which especially on a ctDNA assay, could appear to come from the tumor and could erroneously be classified as a tumor-derived mutation when it is a leukocyte mutation.
“These mutations increase with age and are present in about 10% of the prostate cancer population,” Antonarakissaid. “Interestingly enough, these mutations can occur in the same genes for which PARP inhibitors are approved, such as ATM, CHEK2, and in rare cases, even BRCA2. These mutations are difficult to resolve but can be identified by sequencing matched ctDNA and leukocyte DNA.”
Antonarakis shared a patient case who was found to have an ATM mutation but upon testing was noted to have a variant in the gene that may be derived from a non-tumor source like clonal hematopoiesis. “That ATM mutation was, in fact, shown to be a CHIP mutation—not a tumor-derived mutation. As such, this patient would not be expected to respond to a PARP inhibitor such as olaparib,” Antonarakis concluded.