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Noninvasive Assay Predicts Drug Response, Early Dissemination in Prostate Cancer

Key findings

  • Researchers at Massachusetts General Hospital have developed a highly sensitive, high-throughput RNA-based strategy to digitally quantify prostate circulating tumor cells (CTCs) in blood
  • In a prospective study of 27 men with metastatic prostate cancer, the digital CTC score predicted poor response to the drug abiraterone
  • In a prospective study of 34 men who underwent radical prostatectomy for localized cancer, the CTC score predicted the presence of cancer dissemination that had not been detected by standard preoperative imaging
  • This noninvasive assay may prove suitable for guiding treatment selection in both advanced and localized prostate cancer

Now that multiple potent drugs for metastatic prostate cancer are available, biomarkers are needed that can predict response. Better prognostication is also needed for patients with early-stage localized prostate cancer, which can become disseminated outside the prostate. Risk stratification for those patients currently depends primarily on biopsies, which are subject to undersampling and often underestimate the pathologic stage, on top of their burden to the patient.

Douglas M. Dahl, MD, chief of Urologic Oncology, Francis J. McGovern, MD, member of the tumor thrombus team in the Department of Urology at Massachusetts General Hospital and the Mass General Cancer Center, and colleagues have developed a noninvasive strategy to digitally quantify prostate circulating tumor cells (CTCs) in blood. In Cancer Discoverythey describe their new assay and explain why it may prove suitable for guiding treatment selection in both metastatic and localized prostate cancer.

The assay relies on the researchers' previous discovery that by using a high tech method for capturing circulating tumor cells (CTCs), they can preserve RNA integrity. The cells thus provide an excellent signal for quantification of cancer-specific genes with digital polymerase chain reaction (PCR). Furthermore, the digital scoring can be readily automated for high-throughput analyses.

The research team first assembled a panel of eight prostate-specific genes whose expression is virtually absent in normal blood cells. They derived a digital CTC score, dubbed CTCM, by weighting each gene based on the relative signal-to-noise ratio in patients with metastatic prostate cancer relative to healthy blood donors.

Separately, the researchers developed PCR assays for the TMPRSS2–ERG fusion gene, which is present in about half of prostate cancer patients, and the ARV7 mRNA splice variant, which is a marker of resistance to the drugs abiraterone and enzalutamide.

To test the predictive power of the assays, the researchers prospectively evaluated blood samples from 27 men with metastatic castration-resistant prostate cancer who were starting first-line abiraterone. The digital CTC assay was similar to traditional immunofluorescence-based scoring when samples had high numbers of CTCs, and it was far more sensitive than the older method in identifying cases that were below microscopic detection.

After median follow-up of 13 months among living patients, an elevated CTCM score or a high level of ARV7 in CTCs was significantly associated with worse overall survival and worse radiographic progression-free survival. The TMPRSS2–ERG translocation did not predict clinical outcome.

The team also prospectively tested the CTC assay in 34 men with localized prostate cancer. Such patients are much less likely than those with metastatic prostate cancer to have detectable CTCs, so the researchers used whole-transcriptome amplification to increase the signal.

None of the patients had evidence of cancer dissemination on standard imaging, so they were scheduled for radical prostatectomy. At the time of surgery, however, six patients were found to have pathologic seminal vesicle invasion or lymph node involvement. An elevated preoperative CTCL score (derived similarly to the CTCM score) was strongly associated with detection of dissemination (P < .001).

The researchers comment that if the high predictive value of the CTCL score is confirmed in larger studies, it could be used to identify patients with localized prostate cancer who would benefit from alternative treatment approaches, such as preoperative systemic therapy or radiotherapy combined with novel systemic therapy.

They add that ultimately, rather than obtain only a single preoperative CTCL score, it may be possible to use serial CTCL monitoring to assist in active surveillance of men with indolent prostate cancer.

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