The case presented was that of a 66-year-old male who presented with Gleason score 9 disease with neuroendocrine differentiation in his prostate. Six months after radical prostatectomy he presented with symptomatic lumbar recurrence and oligometastatic disease. The patient received cisplatin/docetaxel with a vigorous response of all of his lesions until 1 year later when he had a parenchymal brain metastasis. This was completely resected, and he is now disease-free for 2 years. Sequencing of the germline DNA revealed that the patient was heterozygous for an inactivating FANCA allele and sequencing of the tumor revealed that he had loss of the WT allele. Given that the tumor also had a hypermutable genotype, the authors hypothesized that the FANCA mutation was responsible for both the hypermutable genotype and the platinum sensitivity due to its role in DNA repair. To prove that FANCA caused platinum sensitivity, the mutation was modeled in a prostate cancer cell line using the CRISPR/Cas9 genome editing system. FANCA-modified cells were moderately sensitized to cisplatin compared to unmodified cells. FANCA modified cell lines were also unable to generate FANCD2 foci after cisplatin treatment. Interestingly, about 15% of prostate cancers in a publically-available sequencing database have deletion or point mutation of FANCA in addition to a large fraction of ovarian cancer which are also frequently chemoresponsive. This suggests that although historically prostate cancer is not considered platinum-sensitive, a subset of these tumors might be amenable to therapy with this drug.
Presented by Himisha Beltran, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
Weill Cornell Medical College, New York, NY USA
Reported by Phillip Abbosh, MD, PhD, medical writer for UroToday.com
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