Sex steroid induced apoptosis as a rational strategy to treat anti-hormone resistant breast and prostate cancer.

[pjoshea13]

New paper below [1].

It reminds me of a paper I read in 2004-5, but was published years earlier. It was a hypothesis in an obscure journal & certainly not at all influential. The idea was that CRPC cells might find life difficult if testosterone [T] were restored. Exposure to T might select for PCa cells that were not CRPC, resensitizing the patient to ADT. The ADT/T cycles might be repeated indefinitely.

From a 2009 Phase I trial:

Fifteen "Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone." - "2.5, 5.0, or 7.5 mg/day"

"Testosterone increased from castrate to median concentrations of 305 ng/dl, 308 ng/dl, and 297 ng/dl for dosages of 2.5 mg/day (n=4), 5.0 mg/day (n=5), and 7.5 mg/day (n=5), respectively."

These numbers are well below the 350 ng/dL level commonly used to define hypogonadism. & without Arimidex (a drug that suppresses the conversion of T to estradiol), some of those men would be estrogen-dominant. Restoration should have aimed for T~600 ng/dL IMO. Anyway, in spite of that:

"three (20%) patients demonstrated a decrease in PSA (largest was 43%)"

No mention whether anyone was resensitized to ADT.

Anyway, I suppose it's partial proof of concept that some might benefit.

{I should mention that "Dr. Bob" Liebowitz [3] has used T replacement at high levels under certain conditions [4]. Although not in CRPC cases?}

In another 2009 Phase I study [5] of men with metastatic CRPC, at Sloan-Kettering:

"Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3." & "received testosterone for 1 wk, 1 mo, or until disease progression."

"One patient achieved a PSA decline of >50% from baseline."

Yes, but 7 of the 12 saw a decline. And 5 didn't, of course.

"Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels on average were supraphysiologic in cohort 3."

I wouldn't use T without taking Avodart to limit conversion to DHT (& Arimidex to limit estradiol).

T levels were all over the place, with all but one over 400 ng/dL, but the aim was for supraphysiologic levels. Don't know why, since there are only so many androgen receptors.

Something interesting in a 2013 German mouse study [6]:

"The pronounced decrease of tumor cell proliferation was accompanied by a marked downregulation of AR expression regarding full-length AR and splice variant AR V7."

(Many men here are aware of AR-V7 drug resistance.)

{"Testosterone boosts on CRPC VCaP cells eliminate tumor cells to a higher extent than androgen withdrawal in androgen tolerant cells."}

...

Back to the new paper from MD Anderson:

"Sex steroid deprivation therapy remains the orthodox strategy for the treatment of both breast and prostate cancer. Despite major initial therapeutic success, the strategies of long term anti-hormone therapies with either tamoxifen or aromatase inhibitors (AI) or antiandrogens or abiraterone for breast and prostate cancer, respectively, eventually lead to a significant proportion of anti-hormone resistant or stimulated tumor growth."

"Paradoxically, anti-hormone resistant cell populations emerge and grow but are vulnerable to the cytotoxicity of estrogen or androgen-induced apoptosis for both breast and prostate cancer, respectively."

"Rotating anti-hormonal and sex steroid targeted cocktails could maintain patients at a microscopic tumor burden to enhance the quality of life, enhance survival ..."

...

Looks like the journal Discovery Medicine has only been around for 2 years. So the paper is as buried as the one I mentioned that I read 12 years ago.

I think that the authors are a little gung ho. We need to be able to identify those who might do well & those who definitely would not.

Also, there is the matter of timing. Is CRPC (after ADT treatment failure) the best stage? I think that T intervention should be used to prevent CRPC and thereby prolong ADT. (just my view)

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/273...

[2] ncbi.nlm.nih.gov/pubmed/192...

[3] compassionateoncology.org/p...

[4] compassionateoncology.org/p...

[5] ncbi.nlm.nih.gov/pmc/articl...

[6] ncbi.nlm.nih.gov/pubmed/238...

[AlanMeyer]

Hello Patrick,

You wrote: "... Also, there is the matter of timing. Is CRPC (after ADT treatment failure) the best stage? I think that T intervention should be used to prevent CRPC and thereby prolong ADT. (just my view)"

Men who are on intermittent hormone therapy typically recover normal, or close to normal, T levels during the "off" phase of treatment. However, if I understand what I've read, they don't have prolonged survival. They do about the same as men on continuous ADT.

Do you think that counts against the view that T brings back hormone sensitivity in a useful way?

Maybe some do better and some do worse so that, on average, they do about the same but, as you say, if we understood the characteristics of each patient's disease, maybe we could pick out some who would indeed benefit.

Alan

[pjoshea13 in reply to AlanMeyer]

Hi Alan,

Dr. Stephen Freedland has said that the off-phase of IADT (intermittent ADT) is largely a continuation of ADT. The reason for this is that it takes many months for testosterone to recover. Also, many men are close to the T cutoff for hypogonadism (350 ng/dL) when they enter ADT **.

A problem I see with the 'Lupron holiday' is that for a number of months, estradiol is the dominant hormone.

If we are looking to shock the cancer cells that have become used to low levels of androgen, the obvious approach is for the men to inject T weekly, or use a T patch at the start of the holiday. I would use a target T of ~1,000 ng/dL

A 2000 study [1]:

"Serial serum testosterone was prospectively measured at 3-month intervals in 68 men after withdrawal of androgen deprivation therapy. The number of months to return to normal serum testosterone 270 ng./dl. or greater, was calculated for each patient."

Right away, I have a problem with 270 ng/dL being described as 'normal'. Older definitions of hypogonadism used 300 ng/dL, but 350 ng/dL now seems preferred.

"Median time to normalization of testosterone was 7 months (range 1 to 58)."

"At 3, 6 and 12 months 28%, 48% and 74% of men had normal serum testosterone, respectively."

This is quite dismal - that more than a quarter of the men had not attained 270 ng/dL after 12 months. And that more than half of the men hadn't reached 270 ng/dL within 6 months.

"Androgen deprivation has an effect on serum testosterone that extends beyond the cessation of treatment."

A 2012 study [2]:

There is a tendency for T not to completely recover in the off-phase, & recovery to take longer:

"Testosterone recovery to baseline values was achieved in 79.3% during the first and in 64.9% during the second IAD cycle, respectively. Median time to testosterone normalisation was 100 days in the first and 115 days in the second cycle, respectively."

A 2013 study [3]:

"Without ADT testosterone remained at castrate level for 4 months."

"After the first and second IAD cycle 92% and 46%, respectively, had a normalized testosterone."

A 2014 French study [4]:

"Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively."

i.e. Time to testosterone >50 and >220 ng/dL was 112 and 168 days, respectively.

This is not good & I can't imagine that there was much effect on QoL.

** regarding serious PCa & low testosterone:

A 2011 Danish study [6]:

"Low pretreatment serum testosterone levels correlate with a higher risk of {biochemical failure }, and testosterone may possess biological information about prostate cancer progression potential, which makes it an independent predictor of biochemical failure after {radical retropubic prostatectomy}."

The T level that predicts failure is <11 nmol/L - which is <317 ng/dL.

If such men opt for IADT, they will never recover sufficient T to shock the cancer.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/110...

[2] ncbi.nlm.nih.gov/pubmed/227...

[3] ncbi.nlm.nih.gov/pubmed/215...

[4] ncbi.nlm.nih.gov/pubmed/249...

[chascri in reply to pjoshea13]

I was on intermittent ADT 9 months on, 9 months off, at MD Anderson from 2006 to 2012. My personal experience was it took about three months into the off cycle for quality-of-life to return to a pretty good level so I got about a six-month vacation from the side effects of ADT. As of progression of metastasis in the Thoracic spine, it was recommended I start continuous ADT at the end of 2011. I am still on it. I miss those six months vacations.

[chascri in reply to chascri]

PS: For anyone interested, my full course of treatment over the last 17 years since I was diagnosed in 1999 is in my profile.

[AlanMeyer in reply to pjoshea13]

Thanks for the informative reply.

One thought that comes to my mind is that anyone wanting to test these theories on himself should find a real PCa scientist to work with him, not just the first oncologist who practices nearby. It sounds like it would be essential for a doctor to know what your T levels are at many points in time during the treatment, how the PSA varies with T at those times, and how it may lag T replacement. There are probably other tests that should also be done on a regular basis in order to hope to understand what the real effects of T are, for what kind of patient, at what stage of treatment, at what dosages and on what schedule of treatment.

I would hope that, in the future, all cancer patients would be referred to real specialists in their particular kind of cancer and not just to general oncologists who treat everything from prostate, to blood, to lung disease. General oncologists are way better than no oncologists at all, but everything I've read convinces me that the human body is too complicated and diseases too various to allow the kind of one size fits all medicine that is too often all that patients can get.

Alan

[gusgold in reply to AlanMeyer]

Alan..how long were those men on IADT...Patrick is doing 3 months on then 3 months off with T....All the studies I read the men were on IADT for 12 months or more which gives PCa time to develop resistance

[AlanMeyer in reply to gusgold]

Good question gusgold.

I read studies about this some years ago and don't remember the details of the study designs. I did a Google search just now and reviewed some of the studies. It looks like each one was different. Of the four I looked at, not a single one found a survival advantage to intermittent ADT. However some thought that intermittent therapy was "non-inferior" or only a little inferior in survival to continuous therapy.

It's not clear to me what strategy would be best for scheduling intermittent therapy. Should there be a large number of short on-off cycles or a small number of long ones? Should iADT only be used if and when PSA gets below a certain value? Should ADT resume when the PSA reaches some specific higher value? What role, if any, should drugs other than LHRH agonists (Lupron, Zoladex, Eligard) play in the on or off cycles, for example dutasteride? Can the new drugs (Firmagon, Zytiga, Xtandi) work with iADT?

I know that there are theories about one or another approach but I doubt if anyone has hard data from trials that establish the best strategy. I doubt even more if anyone has real biological data, for example data from sampling actual tumor cells at different stages in the cycle and studying them for new mutations, testosterone sensitivity, and tumor growth. Maybe there are mouse studies that have looked at this, but I haven't done the extensive searching and reading that would be required to ferret them out.

My non-expert speculation is that no clinical trial is going to find the best answer. There are too many variables - Gleason, PSA, time on, time off, "on" drugs, "off" drugs, patient age, local disease, metastatic disease. Most of those variables have many possible values. I think what we really need is more basic science research to understand what happens to tumor cells during the on and off periods, and how different tumors in different people might respond differently.

I believe we're still decades away from a full understanding of prostate or other cancers, but we're slowly getting there. People of our generation are already benefiting from the great advances in cancer research in the last 50 years. Our grandchildren will benefit even more.

In the meantime, I think the best a patient can do is to find an oncologist with an open mind who will perform frequent PSA and/or other tests to see what is working or not working with that patient, and change the treatment accordingly as needed. I like that better than sticking to some hard and fast fixed plan.

Alan

[gusgold in reply to AlanMeyer]

Alan...thanks for the reply. Patrick's protocol is to try and delay the onset of CRPC. Since long cycles of ADT almost always result in CRPC and Patrick is 5 years into his protocol we have to give a lot of weight to his results. I just read a study that answers one question. The thinking was to delay IADT until the PSA reached 5-10 because most men develop CRPC after just 3 cycles. The study found a PSA of .5 should be the trigger point because the more PCa cells produced the greater the chance of cells that have the genetic code to develop castrate resistance.

[aupauledwards]

Patrick The technique is now described as Bipolar Androgen Therapy (BAT) - Google search of "bipolar androgen therapy prostate cancer". Dr Michael Schweizer, previously at John Hopkins now at Fred Hutchinson Cancer Research Center, Seattle, is one of the leading researchers in this area.

[pjoshea13 in reply to aupauledwards]

Paul,

I'm familiar with the BAT term introduced by Denmeade (Johns Hopkins) in his 2000 paper [1].

"we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel-based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy. This “bipolar androgen therapy” will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions."

I did not read about the BATMAN study until yesterday (Schweizer/Denmeade). It's a bit different from the above. I will post separately.

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[BigRich]

Patrick,

It is 3:oo AM, I might have missed it; however, you started this effort before you became CRPC. Is that correct?

[pjoshea13 in reply to BigRich]

Rich,

I am not yet CRPC.

I do 3 months of castrate T followed by 3 months of T shots.

My PSA doubling time while on testosterone is very short. & I have had a solitary bony met. So I wonder how long it will be before CRPC. But so far, I see no resistance when I switch to castrate.

-Patrick

[BigRich in reply to pjoshea13]

Patrick,

"I do 3 months of castrate T." What drugs do you use to become castrate? When on testosterone therapy your doubling time is short; what is short?

Rich

[pjoshea13 in reply to BigRich]

Rich,

I use a product that was sold under different names - mine is Quercetin Plus. I have the last batch with the unlisted active ingredient. I should switch to low-dose DES.

PSADT is 2-3 months in the last month of T injections.

-Patrick

[BigRich in reply to pjoshea13]

Patrick,

We have chosen different paths; I get my first ever Lupron shot today. I will drop my Casodex to 50 mg. from 150mg. daily. I hope, for both of us it is a long journey into the night.

Rich

[BigRich]

Thank you for the reply. Now, I am trying to decide whether to take Provenge, for my tumor burden is small. Provenge, like all the treatments has so many side effects. I am taking 150 mg of Casodex daily, and the only side effect beside fatigue is that it increased my uric acid blood level which resulted in inflamation in my big toe joint. I resolved that by diet and increasing my water intake.