1. Goodwin, Peter M.

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MILAN, Italy-Genomic testing combined with clinical assessment could be the best way to identify patients with prostate cancer who can benefit from early radiotherapy after prostatectomy, according to a study in The Lancet Oncology reported at the European Multidisciplinary Meeting on Urological Cancers (doi:

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"A certain sub-population of patients would benefit from having early postoperative radiotherapy, and the genomic test will hopefully help identify that subset," said one of the investigators Jeffrey Karnes, MD, a urologic oncologist at the Mayo Clinic in Rochester, Minn.


Under senior author Felix Feng, MD, from the University of California in San Francisco, the study reported on the use of genomic classifiers to help therapy decision-making in patients being treated with prostatectomy.


Because around half of all patients do not have recurrences after radical prostatectomy, Karnes said the study was needed to help identify those with aggressive prostate cancers who do-and who could therefore benefit from early postoperative radiotherapy.


"We identified four risk factors-stage T3b or 4, lymph-node invasion, Gleason score 8, 9, or 10, and high genomic risk. Patients benefited from adjuvant radiotherapy if they had at least two of those risk factors," Karnes explained.


Genomic Classifiers

The study assessed the use of a combination of clinical factors and genomic classifiers in the Post-Operative Radiation Therapy Outcomes Score (PORTOS). Patients with high PORTOS had marked reductions of metastasis over 10 years from adding radiotherapy to their prostatectomy.


Among the 39 patients with high PORTOS (out of an overall cohort of 197) only 5 percent of the 20 men who had radiotherapy had metastases by 10 years postoperatively compared with 63 percent of the 19 patients who did not have radiotherapy.


However, the benefit of radiotherapy was not seen in the 157 patients who had low PORTOS among whom the metastasis rate by 10 years was nearly doubled in those who had radiotherapy-57 percent, as compared with 31 percent among patients having no adjuvant therapy.


The study concluded that treatment with postoperative radiotherapy should now be considered in patients with high PORTOS, but that the use of PORTOS as a predictive tool still needs to be investigated further in additional independent cohorts.


Karim Touijer, MD, MPh, from the Sidney Kimmel Center for Prostate and Urologic Cancers, at the Memorial Sloan Kettering Cancer Center in New York, said that including genomic classifiers gave "good discrimination in selecting patients" and he described Karnes' data as "a great signal" to be subjected to careful statistical analysis-mainly decision curve analysis-which he considered would be "of great value" to help optimize the use of adjuvant radiation therapy by integrating clinical and genomic features.


Implications for Current Practice

Quoting the new data, Karnes made a strong case for the combined use of genomic classifiers from tumor specimens together with clinical features for predicting prostate cancer response to radiotherapy.


In the genomic research, he said the original aim had been "to better prognosticate patients who had high-risk prostate cancer" by quantifying the risk of metastasis at 5 years and 10 years. But the technique had proved to have predictive value, too.


Karnes explained that the standard clinical criteria had not been sufficient to decide on post-surgical radiotherapy. "At the end of the day, we [were] still left with this dilemma: Do we actually give radiation early-maybe [with] the consequence that the patient may not recover fully-versus waiting for PSA progression?"


But he noted that using genomic classifiers made it possible to identify which men should receive radiation earlier rather than later.


"In my practice [for patients with clinical risk factors], I reflexively get a genomic test. If it's high, I immediately refer that patient for radiotherapy," he said.


Additional Evidence

More evidence came from another study Karnes was involved with led by Ashley Evan Ross, MD, PhD, Assistant Professor of Urology, Oncology, and Pathology at the James Buchanan Brady Urological Institute at Johns Hopkins Hospital in Baltimore, which allocated four groups of patients on the basis of PSA levels to be treated with adjuvant radiotherapy, early salvage radiotherapy, salvage radiotherapy, or no radiotherapy (Prostate Cancer Prostatic Dis 2016;19(3):277-282).


"We did show that the higher the genomic score the more separation in the curves. When the genomic score was low, the metastasis rate at 10 years didn't differ that much. The higher the genomic score the more separation. Patients benefit from early or adjuvant radiotherapy the higher the genomic complexity," said Karnes.


The study concluded, however, that any decision about the timing and the need for additional local therapy after surgery was "nuanced and requires providers and patients to balance risks of morbidity with the improved oncological outcomes."


Avoiding Radiotherapy

While patients at high risk were candidates for clinical trials, adjuvant treatment could safely be avoided by men found to have low-risk when assessed by combined clinical and genomic scoring.


"It does improve what we call the 'area under the curve.' By using our usual clinical-pathologic parameters, adding genomic information does allow us to prognosticate or rightfully assign therapy better," Karnes said, noting that the higher the PORTOS the more likely the benefit of incorporating "multi-modal therapy" including post-operative radiation.


Although there were no data yet on overall survival, Karnes said there was a balance to be weighed against the risk of adverse side effects of adjuvant radiotherapy in any individual patient.


However, he is optimistic about the future of genomically-guided therapy decision-making in prostate cancer. "We're seeing genomics utilized in the entire prostate cancer spectrum from very localized disease to metastatic castration-resistant disease," he concluded. "The higher the genomic complexity the more likely the patient is to benefit from early salvage or adjuvant radiotherapy."


Peter M. Goodwin is a contributing writer.