Histologically, NEPC is archetypally characterized as the presence of small round blue neuroendocrine cells with a lack of AR expression. Phenotypically, NEPC frequently metastasizes to visceral organs, has disease burden out of proportion to serum PSA levels, and may express elevated serum neuroendocrine markers such as chromogranin A, synaptophysin, and neuron specific enolase. Clinically speaking, these findings are neither specific nor sensitive, so more definitive molecular characterization is needed to recognize this subgroup of patients who may be good candidates for platinum compounds.
DNA Damage Repair Pathway
Genomic instability has long been known to be a hallmark of cancer, leading to genomic heterogeneity that gives variable clinical courses and response to treatment. With recent advances in genomic profiling, changes to the cancer genome—both germline and somatic—have been better characterized.
Germline mutations that disrupt DNA damage repair, especially the process of homologous recombination, such as BRCA1, BRCA2, ATM, CHEK2, PALB2,
have prognostic consequence. Various study results show them to be associated with increased risk of prostate cancer diagnosis at a younger age, higher histologic grade on diagnosis, more aggressive clinical course, and increased risk of cancer-specific mortality.38-41
It has also been suggested that homologous recombination is associated with relative insensitivity and worse outcomes with ADT.
The presence of germline mutations in DNA damage repair genes had previously been thought to be relatively low, with The Cancer Genome Atlas reporting a prevalence of 4.6% in men with localized prostate cancer.42
However, recent study results demonstrate a significantly higher proportion of men with mCRPC harboring these germline mutations, 11.8%, irrespective of family history of cancer.43
When considering both germline and somatic genomic alterations, the prevalence may be as high as 20% in mCRPC.44-46
Outside of specific mutations in the defined DNA damage repair pathway genes, a “BRCA
ness” genomic signature may exist for an even wider population of patients with mCRPC.
These genomic findings have therapeutic implications in that there has been evidence to suggest increased sensitivity to platinum therapy in ovarian47,48
and breast cancers49,50
with germline BRCA1/2
mutations. Platinum compounds exert their antineoplastic activity by forming covalent DNA adducts, causing double-stranded DNA breaks. Loss-of-function mutations or alterations to BRCA1, BRCA2, ATM, CHEK2, PALB2,
among other genes, all of which serve important roles in the repair process for double-stranded DNA breaks— including homologous repair, nonhomologous end joining, or altered DNA damage checkpoints—put the disease at a handicap in overcoming the effects of platinum agents.45,51
Early evidence suggests that prostate cancers that harbor deficiencies in the DNA damage repair pathway are also associated with a higher likelihood of response to platinum agents and poly (ADP-ribose) polymerase (PARP) inhibitors.52-54
In a retrospective analysis at Dana-Farber Cancer Institute of 141 men with CRPC who received at least 2 cycles of carboplatin/docetaxel chemotherapy, 75% (6/8) of men carrying deleterious BRCA2
variants experienced a >50% decline in PSA within 12 weeks of treatment initiation compared with 17% (23/133) in those who lacked the BRCA2
Twenty-five percent of BRCA2
carriers had a >90% PSA decline versus 4.5% of noncarriers.52
Median OS from time of platinum therapy initiation was 18.9 months for carriers versus 9.5 months for noncarriers (P
= .03). Prospective studies are needed to fully realize the benefits of platinum compounds in molecularly selected patients (NCT02311764, NCT02598895).