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 scores. But, other than a detected distant metastasis, none can predict failure of salvage therapy.

For the first time, there now 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 testing of archived tissue samples from those prostatectomy patients, focusing on 1,800 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” or 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 assess 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 to 2006), Johns Hopkins (from 1992 to 2010), Thomas Jefferson University (from 1999 to 2009), and Durham VA Medical Center (from  1991 to 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 the 10-year incidence of detected metastases was obtained. One in four men were categorized as having a “high PORTOS;” three in four were “low PORTOS.”

In the “high PORTOS” group:

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

In the “low PORTOS” group:

  • 32 percent suffered metastatic progression if they had A/SRT
  • 32 percent 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:

The study 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 percent received any adjuvant ADT, and only 12 percent received adjuvant (rather than salvage) radiation.

Metastases were detected by bone scan and CT. Lymph node dissection, if performed, was limited. Positive lymph nodes were detected in 4 percent 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 five 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.
  1. 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 laboratory study, McDermott et al. showed that fractionated radiation increases the population of radioresistant S-phase prostate cancer cells.
  1. 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.
  1. 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.
  1. 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 laboratory 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 percent of men with metastases have faulty DNA-repair repair genes. (This included 16 DNA-repair genes, compared to the 24 in the PORTOS study.) Such faults occurred in 5 percent of men with localized prostate cancer, and 3 percent of 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 (CTCs) to see whether radioresistance is an acquired trait of prostate cancer 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 to 70 Gy. Some A/SRT studies used doses as high as 72 to 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 also common supplements like resveratrol and soy isoflavones, and drugs like statins, aspirin, and metformin that have shown promise as radiosensitizers in laboratory 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.

Another question raised by PORTOS is whether it predicts radiation toxicity. We want opposite DNA-repair characteristics from cancerous cells and non-cancerous cells. It has long been known that there are some rare gene mutations, notably in the ATM gene, that diminish the ability of healthy cells to self-repair after exposure to ionizing radiation. In such men, any radiation exposure can have disastrous consequences. Perhaps PORTOS can help identify those few men who should not have radiation therapy.

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.

Note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

3 Responses

  1. Bravo, Allen. Very interesting and informative treatment of the complexities of this issue — thank you.

  2. In this analysis recurrence was lumped for radiotherapy given as adjuvant and radiation given as salvage. That opens two problems: Recurrence is generally supposed to occur for a third of the patients given initial radiotherapy whereas half the patients have recurrence after salvage radiotherapy. Biochemical recurrence after salvage radiotherapy is highly dependent on pretreatment PSA levels. So recent study showed that biochemical recurrence happened for about a third of the patients with salvage radiotherapy after RP for a third of the patients treated with PSA 2 ng/ml. Only half the patients with biochemical recurrence later developed distant metastases within 14 years of follow-up, but maybe some patients with biochemical recurrence needed more than 14 years to develop distant metastases.

    I have not seen the details of the study but these findings should have been analysed for making the impact from the gene profile an added value.

    Finn Edler von Eyben
    Odense, Denmark

  3. Finn,

    Of the patients who received either adjuvant or salvage radiation afterwards, 12% received adjuvant radiation and 88% received salvage radiation after PSA had risen. In one study (EORTC 22911) 61% of those who received adjuvant RT did not progress within 10 years of follow-up, but only 38% were progression-free if they waited. There is no question that early radiation treatment can make a difference. Unfortunately, the researchers did not have full data on PSA after prostatectomy.

    You are right that the nadir PSA reached, the PSA kinetics, and the PSA at the time of salvage treatment will affect the prognosis. You are also right that metastases can take a long time to become detectable after surgery + A/SRT + ADT. In the US, it is extremely difficult to obtain complete patient records for even 10 years. Patients die and are lost to follow-up, and without a dedicated clinical trial that is set up from the start to keep track of patients and collect data, only the highest volume centers (like Johns Hopkins and Mayo Clinic) will have an adequate number of records that span even that long. They also have to have prostatectomy specimens archived for over 10 years. Perhaps there will be a national cancer registry some day that is set up for this.

    The authors will follow up soon with another validation study based on data and samples collected for the RTOG 96-01 trial. That study included complete ultrasensitive PSA data post-prostatectomy, as well as complete data on duration of bicalutamide use.

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