Gene Expression Signature Predicts Hormonal Resistance in Prostate Cancer

R. Jeffrey Karnes, MD

Using the Decipher Prostate Cancer Classifier assay to predict which patients might respond to hormonal therapy has resulted in the discovery and validation of an adjuvant androgen-deprivation therapy resistance signature (ARS), according to researchers at the Mayo Clinic. The ARS may predict men who are at high risk of failing hormone therapy.

The genomic classifier (GC), which uses a whole genome RNA-sequence gene expression signature to determine metastasis-free survival (MFS) and response to adjuvant radiation therapy, has been validated multiple times and focuses on the primary tumor. Neuroendocrine prostate cancer (NEPC) is less sensitive or even resistant to androgen-deprivation therapy (ADT). This type of tumor can arise de novo (eg, small cell prostate cancer), but more commonly arises after exposure to ADT. The gene expression of NEPC may be useful for predicting patients with innate resistance to ADT.

R. Jeffrey Karnes, MD, a consultant at the Department of Urology at the Mayo Clinic, as well as a urologic oncologist, said the 2-arm study looked at the gene expression profiles of 1212 prostate cancer (PCa) patients who underwent radical prostatectomy (RP) collected from 3 studies of high risk PCa in collaborative research between Mayo Clinic and Johns Hopkins Medicine.

“We wanted to assess whether analysis in the primary tumor after surgery of genes involved in neuroendocrine differentiation might predict who responds to adjuvant hormone therapy,” said lead author Karnes, who presented the findings from his poster during the 2016 AUA Annual Meeting. “There are certain patients who have a greater likelihood of not responding to hormonal therapy. This signature could identify those patients even before they receive therapy, and would limit morbidity after ADT is administered.”

The researchers conducted a literature review of ADT resistance and neuroendocrine genes and identified 1632 candidates. This set was further filtered, using logistic regression and forward feature selection in a 1:1 matched ADT and no-ADT patients training subset to identify a 48-gene ARS. In the training subset, treated and untreated patients were matched on pathologic Gleason score, extra-prostatic extension, seminal vesicle invasion, and adjuvant radiation therapy. ARS was then applied to 2 validation cohorts comprised of 667 patients, including 102 men that received adjuvant ADT.

In the validation cohort, the ARS was predictive of metastasis in cohorts receiving adjuvant ADT with a 10-year MFS of 73% (95% CI 0.63-0.82) as compared with 65% in patients not treated with ADT (95% CI 0.51-0.78). The researchers also found that among patients treated with ADT, those with low ARS scores had a 10 year MFS of 86%, versus 68% in those with high ARS scores (P = .026). In multivariable analysis adjusting for confounding variables with metastasis as an endpoint, ARS was validated with a significant interaction with ADT treatment (P = .009), which demonstrates ARS’s adjuvant ADT predictive capability.

“If patients had a high gene signature with those sets of genes, they did poorly if they were given ADT, as opposed to those patients with a lower score and did not respond to ADT,” said Karnes.

Researchers reported that there was no overlap in this potential signature and the Decipher Prostate Cancer Classifier assay. Because the signature is not yet commercially available for clinical use, Karnes and colleagues developed “a potential schema that suggests that a high Decipher score would reflex into an androgen resistant signature. If a low score is obtained after taking a biopsy sample and applying the Decipher GC to it, the option is to go with radiation therapy or RP as a potential curative treatment,” continued Karnes. “If you get a patient with a high GC score and a high ARS, this patient may be a candidate for some form of systemic treatment, rather than just hormonal therapy for treatment.”

Karnes added that a similar schema could be applied to patients after prostatectomy. In this setting, patients with a high GC score could have their ARS score verified. A low ARS score would suggest observation or ADT, but if ARS is high, the patient could be a candidate for enrollment in a clinical trial of a non-ADT therapeutic approach.

The bottom line is that this signature identifies patients who may not respond well to ADT, said Karnes. Importantly, this will prevent needless morbidity and will inform clinicians to try a different systemic therapy, he added.

“This is another example of using genomic technology and data to move away from the ‘one size fits all’ treatment algorithm to a more personalized approach to advanced prostate cancer.”

Karnes RJ, Ashab HA, Trock BJ, et al. Development and validation of genomic signature that predicts ADT treatment failure. Presented at: 2016 American Urological Association Annual Meeting; May 6-10, 2016; San Diego, CA. Abstract MP07-20.