A byproduct of an oligometastatic phenotype is that aggressive local therapies to these metastatic lesions might result in durable disease control and, in some cases, even cure. Our group’s recently reported Belgian STOMP and Baltimore ORIOLE trials have demonstrated such a hypothesis appears to be true and revealed metastasis-directed therapy (MDT), as opposed to observation in men with metachronous oligometastatic castration-sensitive prostate cancer (oligo mCSPC), prolongs ADT-free survival and progression-free survival (PFS). Several other trials have similarly demonstrated improvements in overall survival (OS) with MDT.
While evidence suggests a benefit to MDT in oligo mCSPC, there remain gaps in our knowledge of the oligometastatic state. First, our definition of oligometastasis is binary and based on arbitrary lesion number cut-offs, and second, much of our treatment decision-making process regarding MDT relies solely on clinical characteristics, with little known regarding the biology of oligo mCSPC. For these reasons, our group attempted to better characterize the molecular landscape of oligo mCSPC within the wider context of mCSPC in order to define a more biological definition of the oligometastatic state and to understand the implications of this more refined description on prognosis and treatment outcomes.
Patients were classified into four metastatic categories: the biochemically recurrent (BCR) (micrometastatic) category had rising prostate-specific antigen (PSA) following definitive therapy without evidence of overt macro-metastatic disease through current follow-up; the metachronous oligometastatic (met oligo) category had £ five sites of metastasis at first recurrence; the metachronous polymetastatic (met poly) category had > five sites of metastatic recurrence, and the de novo category had metastatic disease at first presentation. We found driver mutations in genes of interest were significantly different across metastatic categories and represented a spectrum of frequency for several genes and pathways (Figure 1), including TP53 (p=0.01), Wnt (p = 0.08), and the cell cycle (p = 0.004).
Figure 1. Cancer-relevant gene mutations correlate directly across the spectrum of metastatic castration-sensitive prostate cancer. Oncoprint of metastatic categories shows mutation frequency increases with increasing metastatic tendency and burden in genes and pathways such as TP53 (p=0.01), Wnt (p = 0.04), and the cell cycle (p = 0.004).
TP53 mutational status also provided prognostic information for individuals with metachronous recurrence. Those with pathogenic TP53 mutations experienced shorter radiographic progression-free survival (rPFS) [median: 26.7 months vs. 48.6 months, log-rank p = 0.002] as well as shorter time to CRPC [median: 95.6 months vs. 155.8 months, log-rank p = 0.02]. Interestingly, TP53 mutation status could define a population of met poly patients with a prognosis similar to met oligo category patients, and thus these individuals might also benefit from MDT.
These findings demonstrate somatic mutational profiles reveal a spectrum of metastatic biology that may help refine the definition of oligometastasis beyond a simple binary state of lesion enumeration and provides insight into potential biomarkers for individuals with oligo mCSPC biology. Further validation studies are warranted including the development of integral biomarker clinical trials.
Written by: Matthew Deek, MD, Resident in Radiation Oncology, and Phuoc Tran, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, Maryland
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The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer - Matthew Deek & Phuoc Tran