Genomic Analysis of Three Metastatic Prostate Cancer Patients with Exceptional Responses to Carboplatin Indicating Different Types of DNA Repair Deficiency

Abstract

Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin.

Keywords: DNA repair genes; Homologous recombination defects; Platinum; Prostate cancer.

Fig. 1

Family tree of patient 1. H&N cancer = head and neck cancer.

Fig. 2

Liver biopsy of patient 1 showing poorly differentiated adenocarcinoma with minor degree of neuroendocrine differentiation. There is strong ERG and androgen receptor expression, focal positivity for prostate-specific antigen, and some neuroendocrine features: focal expression of CD56, synaptophysin, chromogranin, and neuron-specific enolase (not shown). AR = androgen receptor; PSA = prostate-specific antigen.

Fig. 3

A male patient aged 54 yr with metastatic castration- resistant prostate cancer showing incremental radiological response after two cycles (middle column) and six cycles (right column) of carboplatin. (A) Coronal computed tomography (CT)-enhanced images showing incremental radiological response with almost complete resolution of the soft tissue disease associated with lytic right iliac bone metastasis (black circle). (B) Coronal CT-enhanced images showing dramatic reduction in the total liver metastatic burden and resolution of the hepatomegaly. Note the intralesional calcification associated with response. (C) Axial-enhanced CT brain images showing good radiological response to carboplatin challenge of the solitary left cerebellar metastasis after two cycles of treatment (middle column) with further improvement after CyberKnife and further carboplatin; note intralesional calcification.

Fig. 4

Prostate-specific antigen responses on treatments in patient 1.

Fig. 5

Circos plot of the genetic alterations in patient 1 based on the data generated from tumour-normal paired exome sequencing. Inner track indicates the type of the mutations and the genes that have the mutation. The middle and outer track indicate the B-allele frequency and logR ratio, respectively, which is derived from copy number alteration analysis.

Fig. 6

Distribution of three types of homologous recombination defect (HRD) score in a cohort of metastatic castration-resistant prostate cancer (n = 228). Red colour bar labels patient 1 HRD score. CRPC = castration-resistant prostate cancer; HRD = homologous recombination defect.

Fig. 7

Family tree of patient 2.

Fig. 8

Coronal diffusion-weighted imaging (DWI; b900 s/mm²), coronal fused T2W-DWI and axial apparent diffusion coefficient images (ADC) through the seventh rib showing a good response after six cycles of carboplatin (AUC5) and docetaxel with reduction in tumour diffusion value and increase in mean tumour ADC (>35%) of most of the metastatic bone disease but heterogeneous ADC values in the seventh rib in keeping with residual focal areas of low ADC (white arrows), suggestive of residual high tumour cellularity/active disease. ADC = apparent diffusion coefficient; DWI = diffusion-weighted imaging.

Fig. 9

Histology of patient 3 showing prostate adenocarcinoma with significant neuroendocrine differentiation. Immunohistochemistry shows that the tumour cells are very focally positive for prostate-specific antigen and negative for PSPA. Of note, tumour cells were negative for CD56 and chromogranin and positive (90%) for synaptophysin. The tumour cells lack nucleoli, have fine granular “salt-and-pepper” chromatin, and form occasional loose rosettes.

Fig. 10

Family tree of patient 3.

Fig. 11

Colour-coded coronal maximum intensity projection diffusion-weighted imaging showing (b900 s/mm²) incremental improvement with reduction in the tumour diffusion volume accompanied by increase in apparent diffusion coefficient values. Of note are focal areas such as in the left-sided ribs or in the bony pelvis (white arrows) showing lack of improvement throughout the studies in keeping with tumour response heterogeneity.