The commonly cited goal of ‘personalized medicine’ in regards to treatment selection based on
genomic testing is early in the ‘work in progress’ stage. Breathtaking advances in next generation
sequencing are very promising, but currently there are only limited options for therapeutic
guidance. This was acknowledged by Dr. Oliver Sartor in the recent NEJM review, Metastatic
Prostate Cancer, Feb 2018: “The use of advanced genomic analysis is now feasible to a greater
extent than ever before. Whether its use improves treatment decisions is not yet clear.”

The intent of this Commentary is to highlight where in the course of cancer progression genomic
information might have a beneficial impact on clinical management. The focus will be on ‘predictive
biomarkers’, i.e., those which indicate the likelihood that a certain treatment will provide benefit …
or no benefit.

Currently the predominant clinically informative mutations are BRCA1/2, ATM, CHEK2, PALB2 and
a few others whose function is to repair damaged DNA. A second group is the androgen receptor
splice-variants, predominantly AR-V7, overexpression of which predicts for little or no responses to
agents targeting the androgen receptor (AR), e.g., Zytiga and Xtandi and others. A third class is
the family of ‘mismatch repair genes’ (MMR) and CDK12. These mutations increase
responsiveness to immunotherapy.

All of these mutations are found at low levels at the onset of the disease, but their expression
increases significantly during the course of progressive cancer as an adaptive response to the
pressure of treatment, i.e., androgen deprivation therapy and chemotherapy.

*Testing for germline (inherited) and somatic (acquired) mutations:

Germline mutations can be diagnosed from blood, saliva, scrapings of buccal mucosa or skin
biopsies. Currently, somatic mutations are diagnosed by sequencing circulating tumor cells. Tests
using blood plasma assaying for cell-free DNA are available and being refined. Multiple tests are
available to identify mutations in MMR genes.

*Genomic testing in men with low- or favorable intermediate-risk prostate cancer:

Currently there is little utility in germline genomic analysis for men in this category. The low
percentages of predictive markers, such as mutations in BRCA 2 (~6%) and in the family of
mismatch repair genes (MMR) (~1.5%), do not merit the search. It is unlikely that at this early
stage, knowledge about predictive mutations would change standard therapy.

Of note, mutated BRCA2 is both predictive and prognostic – prognostic for greater disease
aggressiveness; predictive as to response to PARP inhibitors and platinum-based chemotherapy.

*Germline genomic testing in men with high-risk and locally advanced and
metastatic disease:

Men in this group (i.e. Gleason 8-10, PSA>20 ng/mL, locally advanced tumor stage or nodal
spread, >50% positive cores) may well benefit from foreknowledge of their mutational landscape
since they are at risk for shorter durations of response to standard androgen suppression, earlier
development of CRPC and metastasis. Knowledge of a man’s genomic status will then be on
record to guide future therapy choices.

The National Cooperative Cancer Network recommends germline testing of men with these
characteristics and those with metastatic disease.

*Genomic testing for germline mutations in DNA damage repair genes:

~BRCA2 and other members of the DNA damage repair gene family predict for more
aggressive disease. Recently reported results (J Clin Oncol. Feb 2019, Castro et al.) from the
PROREPAIR-B protocol found that in men with metastatic CRPC germline mutations in
BRCA 1/2 and ATM conferred a significant negative impact on treatment outcome compared
to non-carriers.

~When a man has developed metastatic castration-resistant prostate cancer (mCRPC) and
already had been found on germline testing to have mutated BRCA1/2 (or mutations in ATM,
CHEK2,RAD51D and PALB2) he then is a candidate for the many protocols open for
treatment with PARP inhibitors. In the metastatic state the likelihood of being positive for DNA
damage repair mutations increases to ~12 % (16% if ATM and BRCA1 are included).

In a small study of 50 men, heavily pretreated and unselected for mutations, Mateo et al.,
NEJM 2015 Oct, reported a >50% decline in PSA in 33%; in 16 men showing mutations in the
DNA repair genes the response was 88%.

In another study 6 of 8 men carrying a BRCA2 mutation showed a >50% decline in PSA
within 12 weeks when treated with carboplatin/Taxotere).

~ When a man has developed mCRPC it becomes informative to submit blood for assessment
of somatic mutations, i.e., those mutations that have evolved in adaptation to suppressed
testosterone. Assays for somatic mutations increased the total number of mutations in DNA
repairs genes to ~25%, thereby expanding the eligibility for protocol-based PARP inhibition.

* Testing for overexpression of the splice-variant AR-V7:

AR-V7 is a modified form of the basic androgen receptor. It is continuously active in promoting
tumor growth, and is not suppressed by agents targeting the AR such as Zytiga and
Xtandi. Although AR-V7 is minimally expressed at the onset of prostate cancer, in the metastatic
setting AR-V7 expression increases so that it is found in ~30 – 40% of men. A positive assay for
acquired (i.e., ‘somatic’) overexpression of the AR-V7 splice variant predicts the unlikelihood of a
response to drugs such as these.

-~A study by Antonarakis et.al. (J Clin Oncol. 2017 Jul) examined the clinical significance of ARV7
found in the circulating tumor cells (CTC) of 202 men with mCRPC progressing on ADT
and were about to start therapy in either Zytiga or Xtandi. Three cohorts were established:
those who were CTC negative (and therefore not testable for cellular AR-V7); those CTC+
and AR-V7 negative and those both CTC+ and AR-V7 positive. Before therapy with either
drug 36 men (17.8%) were already CTC+ and AR-V7+ and those men were more likely to
have Gleason score > 8, a higher PSA and metastases at diagnosis. In men who had
previously received Zytiga or Xtandi 27% were CTC+ and AR-V7+.

~Response to treatment was defined as a >50% decline in PSA. Only 14% of CTC+/AR-V7+
group met that criteria for response. After first-line therapy the PSA median progression-free
survival in this group was 2.9 months; after second-line hormone therapy and 4.1 months,
compared to >21.6 months and 6.2 months, respectively, for the CTC- group. The
Antonarakis study did not have chemotherapy treatment arm, however the superiority of
taxane therapy over (say) Zytiga and Xtandi in men CTC+/ARV7+ was indicated in the study
by Scher et al., (JAMA Oncology Nov 2016).

~Knowledge of the CTC/AR-V7 status in men newly diagnosed with metastatic disease has
therapy implications. Currently treatment in this group of men is customarily an LHRH inhibitor
(Lupron or Firmagon) combined with Zytiga, Xtandi, or chemotherapy. A positive test of
AR-V7 might favor chemotherapy. In men who have progressed to mCRPC after initial
hormone suppression, knowledge of the AR-V7 status could influence the choice of the next
therapy and also the choice of the subsequent second-line therapy after progression.

~ Unfortunately testing for AR-V7 is limited by the cost: QIAGEN’s AdnaTest
ProstateCancerPanel AR-V7 lists at $2784. Epic Sciences OncotypeDx Nuclear Detect
employs a different technology and is commercially available through Genomic Health
(included into the NCCN Guidelines for MCRPC and Medicare is covering it List price,
$3950). It is still available at Johns Hopkins. The recent PROPHESY study found both
assays to be equivalent. ‘Liquid Biopsy’ tests for AR-V7 are already available.

*Mismatch repair gene mutations – A predictive biomarker for response to
immunotherapy:

Although minimally expressed in the primary tumor, as with other mutations, mutations in these
genes (MSH2, MSH6, MLH1, PSM2) increase in metastatic disease, e.g. to 5 to 10%. “Clinically,
due to the high number of neoantigens generated by this hypermutation phenotype, patients with
mismatch repair defects are prime candidates for checkpoint blockade…,” Isaac et al., Asian J of
Urol Nov 2018.

In 2018 the FDA approved the PD-1 blocker pembrolizumab, KETRUDA, for treatment of
metastatic prostate cancer exhibiting these mutations. Men expressing PD-1 In the Keynote study
had a 17% response to KETRUDA.

BOTTOM LINE:

Genomic research for clinical relevant mutations is producing an immense quantity of data.
Currently for efficiency, the practicing clinician and interested patients can focus on identifying
mutations in three important genomic areas: the mutations in the DNA repair family of
genes, overexpression of the AR-V7 splice variant, and mutations in MMR genes. These data can
have important bearing on treatment choices.Your content goes here. Edit or remove this text inline or in the module Content settings. You can also style every aspect of this content in the module Design settings and even apply custom CSS to this text in the module Advanced settings.

Edward Weber M.D., Author

Dawn Scott, Editor

Mike Scully, Librarian