ADT and COVID-19 — A therapeutic discussion
Everyone knows that these are tough times, and those of us in health care are constantly trying to figure out how to deal with COVID-19.
That said, we need to stay focused on the progress in our clinical fields beyond the pandemic. This homily focuses on an amalgam of the two, and some very interesting reports that have come across my desk.
ADT and prevention of COVID-19
A study that captured my instant attention, entitled “Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2,” is currently “in press” in Annals of Oncology. I have always liked that journal, particularly when I was one of its editorial board members for many years. They pick interesting manuscripts from around the world, and it is a great forum for high-profile clinical and translational science.
By way of background, I need to draw on my experience in genitourinary oncology — one of the genes involved in the genesis of prostate cancer is TMPRSS2, a serine protease located on the cell surface, which is involved in several biological functions including cellular invasion by viruses. TMPRSS2 has been shown to be involved in the spread of influenza A, COVID-19 and MERS-CoV viruses.
COVID-19 binds to the angiotensin-converting enzyme (ACE) system, which seems to be involved in cellular entry. This also is associated with proteolysis of S protein, allowing fusion of the viral and cell membranes. Hoffmann and colleagues have suggested that inhibition of this interface may prevent COVID-19 infection.
It is worth mentioning that transcription of TMPRSS2 is under control of the androgen receptor, and it is a protein that is highly expressed in all types of adenocarcinoma of the prostate.
This thinking has led to the fascinating report from Montopoli and colleagues discussing their studies in Padua and Venice, two of the Italian epicenters of COVID-19 infection. Based on the above thinking, these thoughtful investigators proposed the hypothesis that ADT may protect against COVID-19 infection by disrupting the function of TMPRSS2. They therefore studied 9,280 patients with confirmed COVID-19 infection, including 4,532 men, from 68 hospitals in Venice. Their report included several data points of interest:
- 0.2% of men without cancer and 0.3% of men with cancer had COVID-19 infection.
- When considering COVID-positive patients, men with prostate cancer not receiving ADT had a significantly higher risk for infection than those treated with ADT (OR = 4.05; 95% CI, 1.55-10.59).
- Patients with any type of cancer had a nearly fivefold increased risk for COVID-19 infection than men with prostate cancer who had been treated with ADT (OR = 4.86; 95% CI, 1.88-12.56).
- Although women were more frequently infected by COVID-19 (56% vs. 44%), men were more frequently hospitalized with severe infection (60% vs. 40%) and suffered a higher death rate (62% vs. 38%). ICU admissions also were dominated by men (78% vs. 22%).
An important caveat is that the number of COVID-positive patients receiving ADT was relatively small (n = 4).
However, that is exactly the point.
In the Venice region, 5,273 men were receiving ADT at the time of the study, and an additional 37,161 men were known to have prostate cancer but were not treated with ADT. Only four of the 5,273 men were shown to have COVID-19, compared with 114 of the 37,161 men who were not treated with ADT.
Again, emphasizing the small numbers, it is interesting to note that two of the four men treated with ADT required hospitalization, compared with 76 of 114 other men with prostate cancer and 214 of 312 patients with other tumors.
Protective effect of TMPRSS2
While on this interesting theme, I would be negligent were I not to mention an equally provocative and creative study from my old pal, Phil Kantoff, and his colleagues, published online in Cancer Discovery — and it might hurt his feelings!
They also focused on TMPRSS2, as their labs have studied this protein as a regulator of prostate cancer, noting that it is more heavily expressed in prostate cancer tissue than in noncancerous prostate tissue.
I did not mention it above, but TMPRSS2 is involved in gene fusion with ERG and other members of the ETS family, which occurs in up to 50% of primary prostate cancers among European men. This fusion seems to bring ERG under androgenic control. This leads us to the biological quagmire in which TMPRSS2, ACE2 and ERG may all interact in the lung, which may explain the prominence of pulmonary symptoms in COVID-19 infection — and each may be influenced by androgenic function.
In addition to the possibility that castration may reduce the risk for COVID-19 infection, Kantoff and his colleagues question whether specific gene targeting of TMPRSS2 may provide protection (that is, without the need for clinical castration) either from COVID-19 infection or perhaps the severity of pulmonary involvement (a major cause of COVID-19-related death). Previous in vitro studies, using a range of protease inhibitors, support this contention. This is a domain that should be watched closely.
In the interregnum, prior to this producing a defined clinical result and/or the introduction of either effective COVID-19 therapies or vaccines, any well-connected reader who wishes to help any national or locoregional leaders who have been captivated by the swirl (absent clear data) surrounding the chloroquine derivatives might offer them this more data-driven option that suggests that ADT may really protect against COVID-19 infection.
Whether they choose unproven, potentially ineffective therapy over a potentially effective but toxic therapy will be a matter of independent choice, preference and logic — and logic has not characterized many of the decisions in recent weeks.
Hoffmann M, et al. Cell. 2020;doi:10.1016/j.cell.2020.02.052.
Montopoli M, et al. Ann Oncol. 2020;doi:10.1016/j.annonc.2020.04.479.
Stopsack KH, et al. Cancer Discov. 2020;doi:10.1158/2159-8290.CD-20-0451.
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Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at email@example.com.