ASCO GU 2018: Hypoxia related mRNA biomarker to predict biochemical failure and metastasis for prostate cancer.

San Francisco, CA ( Dr. Choudhury and colleagues presented work on the development of a gene signature for hypoxia in prostate cancer (PC). Hypoxia is an important biological feature that appears to associate with the biological aggressiveness of PC tumors. For example, it is known that tumor hypoxia associates with radio-resistance, and some data also shows that it portends poor outcomes after prostatectomy, indicating that tumor hypoxia is an indicator of aggressive disease.

Importantly, hypoxia is a targetable clinical characteristic. In other solid tumors, combining hypoxia-targeting treatments with radiation has been shown to improve local control and patient survival. Less is known about these effects in PC, however, even though hypoxia appears to be an important driver of tumor aggression. The investigators therefore sought to create a validated gene signature to better identify hypoxic tumors so as to make hypoxia a usable variable for future studies.

After performing in vitro studies, the investigators identified a 28-gene signature that was overexpressed in tumors under 1% hypoxia conditions. Using this signature as a binary classifier (high vs. low hypoxia), patients who had high hypoxia tumors did worse than those who had low hypoxia tumors (validated using prostatectomy specimens).

They also validated this signature in radiotherapy cohorts. For both definitive XRT and adjuvant XRT, high hypoxia signatures demonstrated worse survival. Interestingly, the signature could also be used as a continuous variable, which appears to demonstrate increasing tumor aggressiveness as hypoxia signature increases.

The hypoxia gene signature significantly associated with biochemical recurrence when analyzed within a multivariable model with covariates such as Gleason grade group, decipher signature, and important clinical characteristics. It also significantly associated with metastasis-free survival in another multivariable model, as did the decipher signature and SV invasion.

In sum, this newly-generated hypoxia gene signature demonstrates strong prognostic validity in both surgical and radiation cohorts. It can be used both as a binary classifier and as a continuous variable, depending on the needs of future prognostic models. Hypoxia is an actionable clinical feature, so the ability to study it more deeply is an exciting development. It still needs to be used in future trials to understand its predictive properties and its utility in prognostic modeling. It also needs to be used to study if hypoxia-targeting therapies have utility in the treatment of prostate cancer.

Presented by: Ananya Choudhury, MA, PhD; University of Manchester

Written by: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA, Twitter: @ssjoshimd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA

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