PORTOS: a gene signature that predicts salvage radiation success

Salvage radiation is curative in roughly half of all cases. There are many factors that contribute to an unfavorable prognosis, including waiting too long, high PSA and rapid PSA doubling time, adverse post-surgery pathology (stage, Gleason score, positive margins), and high Decipher or CAPRA-S score. But, other than a detected distant metastasis, none can predict failure of salvage therapy. For the first time, there seems to be a genetic signature that predicts when adjuvant or salvage radiation  (A/SRT) will succeed.

The study is all the more impressive because of the many top prostate cancer researchers attached to it, representing a collaborative effort from many top institutions: Harvard, University of Michigan, Johns Hopkins, Northwestern University, University of California San Francisco, Mayo Clinic and others.

The process

Zhao et al. started with data on 545 patients who had a prostatectomy at the Mayo Clinic between 1987 and 2001. They attempted to find patients who were matched on pre-RP PSA, Gleason score, stage, and positive margins, but differed on whether they received A/SRT or not. They also had to have complete information on diagnosis and whether they eventually had metastatic progression. This yielded 98 matched pairs. They then did complex genetic screening of archived tissue samples from those prostatectomy patients, focusing on 1800 genes that have been implicated in response to DNA damage after radiation. They found 24 genes that were correlated with occurrence of metastases after salvage radiation. After correcting for other factors, they determined what they call a “Post Operative Radiation Therapy Outcomes Score (PORTOS).” A PORTOS of zero (called a “low” PORTOS) means it predicts no benefit from salvage radiotherapy. A PORTOS greater than zero (called a “high” PORTOS) predicts a benefit from salvage radiation.

Validation

The next phase was to predict how well the 24-gene signature would predict salvage radiation success in a larger data set. They analyzed 840 patient records from patients treated at the Mayo Clinic from 2000-2006, Johns Hopkins (1992-2010), Thomas Jefferson University (1999-2009) and Durham VA Medical Center (1991-2010). They were able to find 165 matched pairs – half treated with A/SRT, half with no radiation. Tissue samples were screened and scored, and 10-year incidence of detected metastases was obtained. 1 in 4 men were categorized as “high PORTOS,” 3 in 4 were “low PORTOS.”

In the “high PORTOS” group: 

• Only 4% suffered metastatic progression if they had A/SRT
• 35% suffered metastatic progression if they did not have A/SRT
• They had an 85% reduction in 10-year incidence of metastases after A/SRT, which was statistically significant.

In the “low PORTOS” group:

• 32% suffered metastatic progression if they had A/SRT
• 32% suffered metastatic progression if they did not have A/SRT

None of the other prognostic tools (Decipher, CAPRA-S, or Prolaris) that are sometimes used to predict metastases after prostatectomy could predict the response to A/SRT.

Caveats

This should be interpreted with caution for several reasons:

It was retrospective, and therefore subject to selection bias. That is, the physicians may have decided on the basis of patient characteristics or other disease characteristics not captured here to give A/SRT to some patients, but not to others. Only a prospective, randomized trial can tell us if the association with PORTOS is the cause of the differential response.

Among the disease characteristics the researchers were unable to capture for this study were the time between prostatectomy and A/SRT, PSA at time of A/SRT/maximum PSA reached, nadir PSA achieved after prostatectomy, PSA doubling time, extent of positive margins, Gleason score at the positive margin, and comorbidities. Patients were not treated uniformly with respect to radiation dose received and duration of adjuvant androgen deprivation therapy (ADT). Only 12% received any adjuvant ADT, and only 12% received adjuvant (rather than salvage) radiation.

Metastases were detected by bone scan and CT. Lymph node dissection, if performed, was limited. It was detected in 4% of the “low PORTOS” group, but in none of the “high PORTOS” group. It is unclear how today’s newer PET scans would affect outcomes.

Radioresistance

Prostate cancer has long been known to be radioresistant relative to other cancers. To understand radioresistance, we must first understand how ionizing radiation (X-rays or protons) kills cancer cells. The radiation causes a chemical reaction with water and oxygen to generate molecules known as “reactive oxygen species” or ROS. One such ROS molecule, the hydroxyl radical, inserts itself into the cell’s DNA to break both strands of the double helix, called “double strand breaks.” The cell dies when it can’t replicate because of those double strand breaks.

Radiobiologists cite 5 reasons for radioresistance:

1. Hypoxia

Prostate cancer thrives in an oxygen-poor environment, and often does not have a good blood supply that brings oxygenation. It therefore requires more radiation to provide adequate ROS, especially into thick tumors.

2. Cell-Cycle Phase

As a cancer cell attempts to build new DNA and replicate, it goes through several phases. In one of those phases, the “S phase,” the cell is building new DNA. It is particularly radioresistant in this phase. Radiotherapy is typically carried out over a period of time in multiple fractions, rather than in a single shot, to allow the cancer cells to cycle into more radiosensitive phases. However, in a recent lab study, McDermott et al. showed that fractionated radiation increases the population of radioresistant S-phase prostate cancer cells.

3. Repair of DNA damage

Non-cancerous cells that can’t repair the DNA damage, commit suicide (called apoptosis). Many non-cancerous cells are able to repair the DNA damage and survive. Fractionation gives them time to self-repair. Cancerous cells usually lack that DNA-repair mechanism and most cannot undergo apoptosis. If they are not killed immediately, they die when they try to replicate. However, some cancerous cells may escape destruction by turning the genetic cell repair mechanism back on.

4. Repopulation

Some cancers grow so quickly that fractionated radiation gives them time to grow back between treatments. This is not the case for prostate cancer.

5. Inherent radioresistance

Some kinds of cells are inherently impervious to radiation damage; muscle, nerves, and stem cells are radioresistant, as are melanoma and sarcoma. Prostate cancer stem cells, thought to play a role in prostate cancer proliferation, are inherently radioresistant. A recent lab study showed that radiation may paradoxically activate stem-cell like features of prostate cancer cells, turning them into radioresistant stem cells.

How should PORTOS be used?

GenomeDx is already supplying PORTOS to post-prostatectomy patients who order Decipher. Should it be used to guide A/SRT decision-making? Given the caveats (above), there are many uncertainties in how predictive it actually will be when it is used prospectively in larger patient populations. But the information is certainly interesting.

I wonder whether PORTOS reflects a genetic change that occurs in local prostatic cancer cells as they undergo a change (called “epithelial-to-mesenchymal transition” (EMT)) into metastatic-capable cells. Or is it a genetic characteristic, there from the start? A recent study showed that 12% of men with metastases have faulty DNA-repair genes. (This included 16 DNA-repair genes, compared to the 24 in the PORTOS study). Such faults occurred in 5% of men with localized prostate cancer, and 3% in men with no prostate cancer. DNA-repair mutations seem to accumulate as the cancer progresses. It may well be that PORTOS is an early detector of systemic micrometastases. Perhaps it will be found to be redundant to detection of small metastases using new PET indicators. I would love to see a PORTOS analysis on metastatic tissue as well (lymph node, bone and visceral) and maybe on circulating tumor cells to see whether radioresistance is an acquired trait of PC progression. If it is an early indicator of metastatic progression, it may already be too late for primary radical therapy.

While a “high” PORTOS suggests that A/SRT will be curative, only a quarter of the men had a high PORTOS. Does that really mean that three-quarters of recurrent men should give up on curative therapy? If PORTOS is not an indicator of EMT, I hope that those recurrent cancers still can be cured. But it may mean that certain adjuvant measures may be required, including higher radiation doses, systemic therapies that are known to enhance radiation effectiveness, and investigational adjuvant therapies.

•      A/SRT doses are typically in the range of 66-70 Gy. Some A/SRT studies used doses as high as 72-76 Gy. With modern IGRT/IMRT technology, such doses may be delivered with acceptable toxicity. Also, if larger lesions can be identified with the new PET scans and multiparametric MRIs, it may be possible to deliver a simultaneous integrated boost dose to those lesions.

•      ADT has been shown to reduce hypoxic cancer survival and inhibit DNA repair. It is possible that prolonged neoadjuvant use, perhaps with second-line hormonal agents (Zytiga or Xtandi) may improve radiation cell kill. Docetaxel, which has shown limited usefulness in non-metastatic patients, may prove useful in low-PORTOS situations. Perhaps immunotherapy can play a role as well.

•     There are many investigational agents that may enhance radiosensitization. PARP1 inhibitors (e.g., olaparib) and heat shock protein inhibitors may prove useful in restoring radiation sensitivity (see this link). PI3K/mTor inhibitors and HDAC inhibitors (e.g., vorinostat) may increase cell kill in hypoxic conditions (see this link) and to cancer stem cells (see this link). Cell oxygenation may be enhanced by a measure as simple as 15 minutes of aerobic exercise before each treatment (see this link). There are common supplements like resveratrol and soy isoflavones, and drugs like statins, aspirin, and metformin that have shown promise as radiosensitizers in lab studies.

It is possible that PORTOS may also prove useful in predicting radiation response among newly diagnosed unfavorable risk patients. GenomeDx  currently requires whole-mount prostate specimens. I don’t know if PORTOS can be done on biopsy cores, or if it provides any prognostic information beyond what the conventional risk factors (PSA, Gleason score, stage and tumor volume) provide. It would have to be similarly validated before we would be able to incorporate it in primary therapy decision-making.

This test is very expensive. For now it only is available along with Decipher, which costs about $4,000. Medicare may cover it, but private insurance may or may not. Always get pre-authorization first.

Metastases after early vs. delayed salvage radiation

Until we have the results of randomized clinical trials on the relative efficacy of early salvage radiation, we have to look for other clues to inform the timing of that decision. Adjuvant radiation carries a high risk of overtreatment, whereas delayed salvage may preclude the window of opportunity during which salvage radiation might have been curative.

Den et al. posted the outcomes of their investigative analysis at the ASCO Genitourinary Conference (Abstract 12). Data on 422 patients treated at 4 institutions were retrospectively analyzed. All had adverse pathology (either stage T3 or positive margins) after RP. Patients were arbitrarily divided according to their PSA after surgery at the time they received radiation:

• ·      <0.2 ng/ml – “adjuvant RT” (111 patients)
• ·      >0.2 but <0.5 ng/ml – “early salvage RT” (70 patients)
• ·      >0.5 ng/ml – “delayed salvage RT” (83 patients)
• ·      No radiation received (157 patients)

CAPRA-S scores and Decipher genomic classifier scores were found to independently predict risk of metastatic progression. Adjusting for those scores:

• ·      Delayed salvage RT increased risk of metastases by 4.3 times over adjuvant RT
• ·      No radiation increased risk of metastases by 5.4 times over adjuvant RT
• ·      Early salvage and adjuvant RT had about the same risk of metastases
• ·      Men with low CAPRA-S and Decipher scores had low risk of metastases
• ·      Men with high CAPRA-S and Decipher scores benefit from adjuvant RT, but had high rates of metastases nonetheless.

This study once again underscores the importance of early salvage radiation for curative therapy after failed surgery when there is adverse pathology. They didn’t investigate the use of ultrasensitive PSA to determine what the lowest level that avoids overtreatment might be. Adverse pathology and PSA are important to consider, but other clinical/genomic factors can contribute to the decision-making process as well. Low Decipher scores can help rule out those cancers that are unlikely to metastasize in the next 5-10 years. However, it is less useful at indicating those cancers that will metastasize.  And there are no good tests for determining if the cancer is already systemic and micrometastatic, in which case salvage radiation would be futile. This remains a challenging situation for discussion between the patient and radiation oncologist.

Genomic classifier can help identify patients who may not need adjuvant radiation.

A decision that tortures patients with adverse findings (positive margins, and/or stage T3/4) after prostatectomy is whether to jump into adjuvant radiation right away, or wait until PSA rises to 0.2 ng/ml before having salvage radiation. We want early treatment while the cancer is still local, but we don’t want to over-treat cancers that may never require treatment in one’s lifetime. Currently, only about 10% of post-prostatectomy patients with adverse pathology are getting adjuvant radiation. In a recent article, I noted that PSA, Gleason score, and stage may not adequately capture the risk of progression. Radiation oncologists commonly rely on tools like the CAPRA-S score or the Stephenson nomogram to predict the outcome of salvage radiation.

Karnes et al. in a study at the Mayo Clinic in 2013 retrospectively looked at the genomes of prostatectomy patients with adverse findings to see if they could predict whether they would progress to metastasis. Metastatic progression is used as a surrogate endpoint for prostate cancer mortality because of the very long natural history of progression. Even progression to metastases takes a very long time – 8 years median among those who progress. The researchers only followed the patient case files for up to five years, so we expect to see proportionately fewer metastatic cases. They found that a genomic classifier (GC), Decipher ™, could reliably predict those patients with adverse pathology after RP that would go on to develop metastases.

They performed GC analysis on tissue samples from a random sample of 256 patients who were at high risk of recurrence owing to any of several factors: PSA>20 ng/ml, GS≥8, pT3 or positive margins. They augmented the sample to include 73 patients who were known to eventually progress to metastases. They tracked whether patients progressed to metastasis within 5 years. Median time to metastases was 3.1 years. The researchers found that:

·      GC had a predictive accuracy of .79, which was significantly better than any of the clinicopathological risk factors or the Stephenson nomogram.

·      Independent of all other risk factors, every 10% increase in GC raised the risk of metastases by 58%.

·      60% had a GC score <0.4. They had a 5-yr cumulative incidence of metastases of only 2.4%.

·      20% had a GC score > 0.6. They had a 5-yr cumulative incidence of metastases of 22.5%.

·      While there was some correlation between Gleason score and GC score, 36% of those with GS≥8, had low GC scores and 77% of that subset remained metastasis-free.

Researchers at Thomas Jefferson University and the Mayo Clinic (Den et al.) performed a similar study, but they only looked at the cases of patients who had adjuvant or salvage radiation after RP. Because the patients had both RP and RT, we expect that the cytoreduction would slow down the rate of metastases, if not prevent them, if they weren’t already micrometastatic. The 188 patients in their study had positive margins or stage pT3, and were all treated with radiation after RP between 1990 and 2009. Their cases were analyzed for up to 5 years following RP.

They used the genomic classifier (GC) on prostatectomy tissue samples to classify them as low, average, and high GC scores. GC scores range from 0 to 1. Based on the Karnes et al. study, they classified low scores as 0-0.4, average scores as 0.4-0.6, and high scores as 0.6-1.  The researchers found:

·      Of all the risk factors comprising GC, CAPRA-S score, age, preoperative PSA, Gleason score, stage, surgical margins, time between RP and RT, and whether adjuvant or salvage RT was given, only three were helpful in predicting metastatic progression: GC, preoperative PSA, adjuvant RT, and CAPRA-S score. Of those, GC was the strongest predictor. Independent of all other risk factors, every 0.1 increase in GC raised the risk of metastases by 66%.

·      5-year rates of metastasis were:

o   0% in those with low GC score

o   9% in those with average GC score

o   29% in those with high GC score

·      In patients with GC score less than 0.4, there was no difference in incidence of metastases whether they received adjuvant or salvage radiation.

·      In patients with GC scores at or greater than 0.4, the 5-year cumulative incidence of metastases was:

o   6% if they received adjuvant radiation

o   23% if they received salvage radiation

·      The “survival concordance index,” a measure of how accurate a tool is for predicting survival (or in this case, metastases), was much greater for GC (0.83) than for the CAPRA-S score (0.66) or the Stephenson nomogram (0.67).

This study suggests that adjuvant radiation may be beneficial if the patient has a high GC score, while those with a low GC score can comfortably wait for salvage radiation.

In this study, all the tissue samples were from patients who went on to receive adjuvant or salvage radiation. What happens to patients who decide not to have radiation after RP?

One such study by Ross et al. of Johns Hopkins of the genomic classifier was presented at the 2015 Genitourinary Cancers Symposium. The sample of patients they studied had the following characteristics:

·      260 patients

·      Intermediate or high risk treated with surgery between 1992 and 2010

·      Undetectable PSA after surgery

·      No therapy prior to detected metastases

·      77% were stage pT3a, 28% were stage pT3b, 28% had positive margins, 20% were N(1), 36% were GS≥8

·      By 15 years, 38% had biochemical recurrence, 21% had metastases, and 9% died of prostate cancer.

·      Median GC score was .47 among those who had metastases, and .28 among those who didn’t.

·      The risk of metastases increased by 48% for every 10% increase in GC Score.

·      GC Score predicted metastases independent of other clinical risk factors.

Most men (79%) did not go on to have metastases, even after 15 years and even with no salvage radiation, again raising the issue of potential over-treatment if they had received adjuvant or salvage radiation. Clearly, we need a tool to help us better predict risk of metastatic progression.

Another small study by Klein et al. at the Cleveland Clinic looked at patients who did develop metastases within 5 years of surgery, and who had no adjuvant or salvage radiation. They found 15 such patients, called “rapid metastases,” who had been treated between 1987 and 2008. These were compared to 154 control patients who did not develop rapid metastases. The controls were nevertheless at very high risk for developing metastases; they were screened for the following characteristics:

·      Preoperative PSA>20 or stage pT3 or positive margin or GS≥8, and

·      N(0), and

·      Undetectable post-RP PSA, and

·      No neoadjuvant or adjuvant therapy, and

·      Minimum 5 years of follow up

The researchers found that GC could distinguish those who developed rapid metastases from those who did not, with an odds ratio of 1.48. They also found that GC was a better predictor than the CAPRA-S score or the Stephenson nomogram.

These studies corroborate a similar finding by Feng et al. in an earlier study. They found that among patients with biochemical progression (PSA≥0.2 ng/ml), GC was a better predictor of metastatic progression than other clinical or pathologic risk factors. 40% of those with high GC scores developed metastases within 3 years of biochemical recurrence, compared to only 8% among those with low GC scores.

Genome Dx wrote that the positive predictive value (PPV) of a GC score greater than 0.4 was 69 percent in the Karnes validation study. This means that more than two-thirds of the time, it correctly (albeit retrospectively) predicted those men who went on to suffer metastases. Conversely, it means that about a third of men with high scores might be over-treated, at least with 5 years of follow-up, if they relied on a high GC score to make their salvage treatment decision. Complicating the interpretation is the fact that the natural history of progression is quite long, and may be further delayed by the debulking of the tumor burden from the initial prostatectomy. So longer follow-up, say, 10 or 15 years, might reveal that it predicted progression better.

The negative predictive value (NPV) of 98.5% for a GC score < 0.4 is particularly impressive. However, we still have the problem of the long natural history of progression. While a GC score under 0.4 almost certainly rules out risk of metastatic progression in the next 5 years, we don't know how safe we are in a 10- or 15-year time frame.

Even with these uncertainties, it is a better decision tool than our other available alternatives.

All of the above studies were retrospective, but I am doubtful that a prospective study will be undertaken because of the very long time needed to obtain sufficient metastatic cases.

Cumulatively, these studies build a good case that Decipher™ can do a reasonably good job of discerning which patients with adverse postoperative pathology but undetectable PSA could reasonably forego adjuvant and salvage radiation. It seems to be less accurate at predicting which patients would require radiation to prevent metastases, although it is a better predictor than other tools we have at our disposal. I was hoping Genome Dx would supply the sensitivity, specificity, and positive and negative predictive value at various cut-offs, but they did not respond to my request.

At $4,000+ this is an expensive test. However, considering that a course of adjuvant or salvage radiation can cost over $30,000, and the potentially worse side effects associated with adjuvant radiation, this test seems to have a reasonable cost/benefit ratio. It is covered by Medicare, many private insurance providers, and there is a financial assistance program available.

This is a difficult decision even with a GC score in hand, and one that should only be made in a shared decision-making process between patient and doctor.

note: Thanks to Dr. Robert B. Den for allowing me to see the full text.