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.