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edge

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Managing AI-Induced Musculoskeletal Effects – Part 2

 

 

v Interventions for AI Adverse Events Relief:
(2) Thinking Radically - Estrogen Add-Back

Being already acquainted with the concept of estrogen add-back (see below) from my research in other cancers, I first broached and discussed the concept and its potential some while ago in a series of emails with JoanOfArdmore on the Breastcancer.org forum, who uncannily then anticipated with rare insight and appreciation virtually all of the developments I cover here; thereafter, prompted by the extreme ravages of AI-induced adverse effects she reported, I decided to review not only its applicability in the breast cancer domain, but also beyond, finding extensive use and confirmation across many disciplines.  In a nutshell, the concept of estrogen add-back can be explained as follows: given the state of near-complete estrogen deprivation induced by AI therapy and its associated adverse effects on musculoskeletal symptomology, it is reasonable to speculate whether decreasing, but not abolishing, circulating estradiol levels may still provide breast cancer risk reduction and therapeutic benefit but without such adverse events. In this connection, Anne Kendall, Mitch Dowsett and colleagues at Royal Marsden Hospital conducted a novel pilot study to establish whether otherwise healthy women on aromatase inhibitor therapy (letrozole (Femara)) on VLD estrogen add-back in the form of very low dose of estradiol replacement using a transdermal patch to assure a target  predictable serum level of 10–20 pmol/L would reduce or reverse the increased bone turnover associated with AI use, measured by changes in the CTx bone resorption biomarker, given that this biomarker is elevated by AI therapy, reflecting the adverse effect of AIs of increasing bone marker resorption.  The team did find that elevated bone marker resorption was corrected with low dose estradiol replacement using a quarter of Estraderm MX 25 transdermal patch which induced the target serum estradiol level of median 12pmol in postmenopausal women on AI therapy, and although not decisive, this suggests a potential of this estrogen add-back regiment to reverse the negative impact of AIs on bone metabolism, with final determination awaiting further ongoing study results. 

 

The VLD estrogen add-back regimen can be implemented with any transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly (or the equivalent dose and regimen using another estradiol patch - Alora, Climara, Esclim, FemPatch, Menostar, Vivelle, among many others).

 

In addition, Carol Fabian and her colleagues at the University of Kansas conducted a study to determine the safety of 6 months of letrozole (Femara) AI therapy (2.5 mg / daily for 6 months) administered to postmenopausal women at high risk for development of breast cancer on stable dose of HRT (either estrogen, or estrogen plus progestin), with the goal of reducing breast cancer risk as signaled by reduction in the proliferation biomarker Ki-67, while maintaining adequate systemic levels of estradiol to avoid adverse perimenopausal symptoms. Ki-67 was reduced dramatically by a median relative value of 66%, despite continuing HRT, with no significant change in breast cell cytomorphology, ER weighted index score, serum estradiol, testosterone, the insulin like growth factor 1 (IGF-1) risk biomarker, mammographic breast density, or frequency or severity of perimenopausal symptoms including hot flashes.

 

Furthermore, Andrea Decensi at the European Institute of Oncology and her colleagues explored the effects of LD-TAM + HRT, that is, combination low-dose tamoxifen plus hormone replacement therapy (HRT), finding that the LD-TAM + HRT regimen retained the benefits, while reducing the risks, of either agent. They concluded that doses of tamoxifen of no more than 5 mg/day favorably modulated biomarkers of breast carcinogenesis, as well as cardiovascular risk, in HRT users, but with no increase of either endometrial proliferation or menopausal symptoms, and in comparison to tamoxifen doses of 10 mg, 5 mg, and 1 mg, daily, a dose of 5 mg/daily was the most effective. The LD-TAM + HRT regimen decreased insulin growth factor (IGF-I), lowered antithrombin-III [this decrease is cardiovascular-favorable], C reactive protein (CRP), and mammographic density, with greatest effects using the optimal 5 mg/day; Ki-67 expression, a proliferation marker, was not increased, and was in fact decreased maximally at this dose level.  Thus a favorable reduction in risk was achieved without a significant increase in endometrial proliferation or hot flashes, and furthermore with no clinical evidence of a thromboembolic event.  These positive findings are plausible in part because HRT users exhibit estrogen hormone levels mimicking premenopausal levels, and it is known that the premenopausal hormonal milieu is one in which tamoxifen is demonstrably highly effective yet far less toxic, as there is no excess risk of endometrial cancer or thromboembolic events in premenopausal women on tamoxifen, these risks being solely evidenced in the postmenopausal context.

 

As in other studies, we find that tamoxifen administration even at low-dose is associated with reduction in both breast proliferation and in mammographic density, particularly in a high estrogen environment, and with the positive benefit of a lack of a significant increase in endometrial proliferation. (And note in connection with the viability of LD-TAM [low-dose tamoxifen], that the same researchers had previously shown that all tested levels of reduced dose tamoxifen were equivalent to the standard dose in reducing proliferation in women with newly diagnosed breast cancer).

 

The ongoing HOT trial, a phase III study of placebo versus 5 mg of tamoxifen for women on HRT, is exploring this further, but the safety of combined tamoxifen and HRT has already been demonstrated in several large European trials, including that of UK researcher Trevor Powles and colleagues, that of Jack Cuzick at the Wolfson Institute of Preventive Medicine and colleagues reporting on the IBIS I trial, and Umberto Veronesi and colleagues at the European Institute of Oncology reporting on the Italian Tamoxifen Prevention Study, among others. Furthermore, based on its prolonged half-life, the potential strategies for improving tamoxifen's risk–benefit ratio via dose reduction, or weekly instead of daily administration  - a weekly dose of 10 mg was used and found to favorably modulate breast carcinogenesis biomarkers and cardiovascular risk in HRT users, again with no increase of endometrial proliferation or menopausal symptoms - is especially appealing given the potential to reduce the risks of endometrial cancer and VTE (venous thromboembolic) events, and of course the cost–benefit ratio is unambiguously extremely favorable in premenopausal women.

 

Estrogen Risk In Perspective

Although it would appear that women using combination HRT (estrogen plus a progestin) can expect a substantial 6% to 10% increase in relative risk of breast cancer per year of current use, the largest American and UK HRT trials suggest that women using standard dose oral or transdermal estrogen without a progestin might anticipate either no increase or a very small relative increase of up to 2% per year of current use, as also noted by Carol Fabian in her recent JCO editorial, and younger postmenopausal women who use estrogen alone for a moderate period may not face any appreciably greater risk; indeed the WHI investigators found a 20% reduction in incidence of invasive breast cancer for women between age 50 and 79 who have undergone a hysterectomy on estrogen alone for an average of 7 years (average risk women in their 50s with intact uterus on the other hand might see their absolute 5-year risk increase from 1% to 1.5% with HRT given the need to add progesterone or a progestin). Given these facts and this broader perspective, then for a woman taking estrogen alone, even the worst case scenario might seem a small price to pay for relief of incapacitating and possibly wholly intolerable symptoms, as Carol Fabian recently concluded and as an increasing number of clinical investigators and researchers are substantially in agreement with.

 

Final Thoughts on  Estrogen Add-Back

Clearly any reasoned evaluation of tamoxifen versus the aromatase inhibitors (AIs) suggests the tradeoffs to be far more complex than most clinicians seem aware of in rendering relatively simplistic judgments of a "winner".  This author counsels that the  assessment of cognitive status, female sexual functioning and gynecological health, and musculoskeletal status need to be systematically and regularly assessed  for all women on any form of endocrine / hormonal therapy, and the measured impact on quality of life and functioning  must be integrated into any clinical judgments that decide and modulate the type, duration and deployment of agents with very different impact profiles, even consideration of no endocrine therapy if risk and QoL parameters support this option.  It needs to additionally be remembered that the only large RCTs comparing users and non-users of hormone replacement therapy during menopause, although finding a small increased breast cancer risk with use of combined estrogen/progestin therapy, failed to find any risk increase from estrogen-only therapy after 5 years of use.

 

Clinical Pearls

From the above discussion and review, these lessons can be drawn:

 

For Existing Users of Tamoxifen
Although tamoxifen users typically experience less severe adverse musculoskeletal and menopausal symptoms than users on AI therapy, nonetheless those who are adversely symptomatic may wish to explore the possibility of symptom amelioration through either:

1.      low-dose tamoxifen at 5mg / daily (or weekly administration at 10 mg), bearing in mind that the evidence presented and discussed above is highly suggestive and reassuring but without further prospective RCTs, is not absolutely dispositive.
OR

2.      standard dose tamoxifen with estrogen add-back, via transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly, again with the same proviso as above.

 

For Existing Aromatase Inhibitor (AI) Users
Two viable options exist:

 

1.      exploring a switch to tamoxifen which although also exhibiting a non-trivial degree of musculoskeletal and menopausal symptoms, tends to induce these symptoms at a significantly lower level of severity (with individual variation however being considerable).
OR

2.      exploring the option of estrogen add-back, again via transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly, again with the same proviso as above.

 

Although we are awaiting further data from clinical trials to weigh in decisively and finally on the efficacy and safety of the above innovative strategies, nonetheless:
 

1.      These options are not irrational in the face of the ravages that endocrine / hormone therapy in the form of tamoxifen, and especially AI agents, can afflict and impact on the quality of the lives, reasonable enjoyment, and functioning of vast numbers of women, even if there is some small incurrence of additional risk (and to date the provisional evidence is against this).


2.      These options may even be compelling regardless of risk (if any) in just those cases in which the adverse impact of the endocrine therapy is such as to force partial or total noncompliance of otherwise significantly valuable disease treatment and/or risk reduction that endocrine therapy can bring, as the risk of noncompliance is almost assuredly likely to be much higher by at least an order of magnitude over whatever small risk the relieving strategy might be associated with, again if any.


3.      These strategies
low-dose tamoxifen (
LD-TAM
)
- very-low-dose estrogen add-back (
VLD estrogen add-back
)
not only have to potential for ameliorating the adverse musculoskeletal and menopausal effects of endocrine therapy (tamoxifen or AI therapy), but in the case of tamoxifen may indeed in addition reduce the risks of endometrial cancer and VTE (venous thromboembolic) events.

 

No doubt to many oncologist the concepts of LD-TAM and VLD estrogen add-back may seem too much on the frontier edge of oncotherapeutics, but with mounting evidence of the high incidence and severity of the often near-crippling adverse musculoskeletal and menopausal side effects of endocrine / hormone therapies with aromatase inhibitors and to a lesser extent even tamoxifen,  and the highly undesirable associated level of partial or complete noncompliance, the frontier edge may very well be where we should be, and bold thinking may not really be radical but rather inevitable as a compassionate response to an invidious, and much overlooked and clinically underestimated problem.

 


Constantine Kaniklidis
Medical Researcher 
edge@evidencewatch.com
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This latest edition of  AI info is wonderful Constantine- THANK YOU!!!

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Bren

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Constantine,

Thank you for the information.  I had read an older study about lowering the dosage of Tamox to 5 mg.  This study was not in concert with the info you provided regarding adding back low doses of estrogen.  My SE's were gastro and not musculoskeletal in nature. 

I see my latest PCP in a couple of weeks and will discuss going back to Donnatol, as it worked for me years ago, and starting on Tamox at 5 mg.  She prescribed Phenergan, which completely interferred with anti-depressants and Topamax.  Also, it didn't do squat for my gastro symptoms. 

As I've posted before, I'm 52, had a total hysterectomy, Stage I (6 mm tumor), grade II, IDC, 100% er/pr+, with 6 mm margins and no nodes.  Had lumpectomy and finished rads 4 months ago.

Thanks again,
Bren
edge

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Brenda:

 

Glad the information was of help to you. 

 

However, one CAUTION about co-ingesting Donnatal during tamoxifen therapy: the phenobarbital component of Donnatal is a powerful and well-established CYP3A4 inducer, which means roughly that it can stimulate the production of this hepatic (liver) enzyme.  This by itself is unproblematic, but tamoxifen is critically metabolized primarily by the CYP2D6 and CYP3A4 enzymes, part of the P4540 Cytochrome System, a family of metabolic hepatic enzymes involved in the pharmacokinetics of most drugs, including oncotherapeutic ones. 

 

The effect of a CYP3A4 inducer like phenobarbital is to  increase the rate of metabolism of a CYP3A4-metabolized drug like tamoxifen (called a substrate in this complex and somewhat arcane world of pharmacokinetics and pharmacodynamics), causing the substrate drug – in this case tamoxifen - to clear out of the system faster, a definitely highly undesirable effect that can potentially affect individual response to the medication adversely, allowing the possibility oft tamoxifen's efficacy being significantly compromised, or even rendered largely ineffective, due to its not having been in the system long enough to exert its therapeutic effect. This is a recognized adverse interaction, and all tamoxifen formulations must, and do, carry an FDA mandated warning of this potential clinically significant compromise to efficacy. Patients on tamoxifen monotherapy typically exhibit mean steady state serum levels of 122 ng/ml, but with phenobarbital coadministration, mean tamoxifen levels drop by almost one-fifth, to 26 ng/ml, likely to severely compromise clinical therapeutic benefit, possibly even to subtherapeutic near-placebo levels. 

 

My concern is therefore for your health and optimal care, and I would strongly advise avoiding Donnatal + tamoxifen coadministration.  I can suggest using as an alternative the Donnagel preparation, which removes the offending phenobarbital, adds kaolin and pectin, but leaves the other three ingredients of Donnatal (Hyoscyamine Sulfate, Atropine Sulfate, Scopolamine Hydrobromide), which are known to be the components that matter for GI  relief (phenobarbital itself is simply a sedative and exerts no GI activity on its own); the sedative component can be electively added separately if needed (avoiding the barbiturate class that would reintroduce the problem). So the virtue of Donnagel, supplemented or not, is the inclusion of the effective ingredients of Donnatal without the potential for compromising your critical endocrine therapy on tamoxifen.     

 

Constantine Kaniklidis

Medical Researcher 

edge@evidencewatch.com 

Bren

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Wow Constantine!!!

Thanks for the info and such a quick response.  You rock!  I'll discuss this with my PCP in early December.

Again, thanks so much.  I'll print your response out and take it with me.

Bren
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Dear Constantine,

This is my first time posting but I've been a member since last year. I was dx'ed in Jan 2003 with stage 2, grade 3, Er/Pr/Her+, 2 of 25  lymph nodes positive, IDC. I was 45 at the time, had mastectomy, CEF chemo, no radiation. I was on tamoxifen for 3 and a half years and then started aromasin. I was in the TEACH trial for tykerb last year since I didn't qualify for receiving herceptin when it became available in Canada for earlier stages.

I've been on endocrine therapy for 5 years 4 months, and my onc renewed my prescription for another year. I don't know how much longer I can put up with all the side effects, although I am grateful to have remained NED for this length of time. My question is would it be really stupid of me to stop taking aromasin? Would I be increasing my chances of recurrence considerably, or does the benefit of the therapy continue after stopping?

I would really appreciate any information and advice from you.

Jan



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Hi Jan!
I am sure Constantine will be along soon. But from the latest studies coming out, they are finding long term use of AIs has benefits in reducing risk of recurrence. If you don't like Aromasin or the side effects are too much, have you considered switching to Femara? I take that and make sure I take plenty of Vitamin D and my D levels are in the good range- you can have this checked at your next onc visit by a blood test-
Vitamin D helps reduce the side effects of AIs- Femara in my case. I have been ok on it.

I am glad you jumped in and posted!
g


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edge

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Jan:

 

This may not be the news you want to hear, but I will be candid and open with you, as the decision is ultimately yours in consultation with your oncologist, and is made best when you are armed with the best evidence we have.  So . . .

 

Thinking about Extended Risk

You're triple positive in terms of tumor biology, so that includes endocrine-responsive, but also includes the elevated risk of HER2-positivity (HER2+), and weighing in also node-positivity and high-grade tumor  plus relative youth (less than or 50 years of age - you're around 50 or so at present), extended therapy would be prudent even if you are peri- or postmenopausal.  If we factored only endocrine-positivity (ER+/PR+), then based of the best evidence to date including the latest Oxford EBCTCG data, that status incurs an accumulating risk of approximately 4% per year (2% if node-negative), so your risk of recurrence / relapse in reasonable forward life horizons at ten years is 40%, while at twenty years hence is 80%.  But note that your risk is in fact higher via the HER2-positivity. 

 

But What Extended Therapy?

That raises to me the question of what kind of extended therapy?  There isn't just endocrine therapy that can be extended, but also anti-HER2 therapy.  HER2-positivity typically incurs a higher risk than endocrine-positivity, so you may want to explore the option of extended trastuzumab (Herceptin) or lapatinib (Tykerb) if this is feasible for you in terms of availability and coverage, or in the alternative, in a clinical trial.  Given the likelihood of crosstalk between the estrogen receptor (ER) signaling pathways and the HER2 pathway, to achieve a goal of curative therapy, blocking more than just the pathway targeted by trastuzumab (Herceptin) may be required, entailing that a combination of anti-HER2 and hormonal therapies may be  warranted to be optimal. On the extended endocrine therapy front, we have SERMs such as tamoxifen, the aromatase inhibitors and  the antiestrogen fulvestrant (Faslodex), and anti-hormonal options such as surgical ovarian ablation (aka, oophorectomy) and medical ovarian suppression via LHRH/GnRH analogs like goserelin (Zoladex) and leuprolide (Lupron). 

 

The Issue of Carryover Benefit versus Persistent Risk

You are right that there is some carryover benefit from endocrine therapy that sustains after it is terminated, so for example a 50% carryover effect, or risk reduction, associated with anastrozole (Arimidex), significantly larger than the verified 33% carryover effect previously reported by EBCTCG for tamoxifen, and  according to the results of the NSABP B-33 trial, extended adjuvant therapy with exemestane (Aromasin) resulted in a significant improvement in relapse-free survival (RFS) (and a borderline improvement in DFS, likely due to the short followup), with no reason to not expect comparable benefits from the other AIs - compared with tamoxifen.   Given that endocrine breast carcinoma disease is itself chronic, with a persistent residual risk out indefinitely per annum, we fortunately  in some sense have the "antidote"' in the form of extended endocrine therapy (EET) which provides continuing long-term benefit of risk reduction beyond therapy cessation in terms of disease-free survival (DFS), time-to-recurrence TTR), time-to-distant recurrence (TTDR), and the contralateral breast-cancer (CBC) incidence. 

 

In sum, data from ATAC / MA.17, NSABP B-33, and ABCSG trial 6a all provide robust proof of concept that extending the duration of endocrine therapy can be appreciably beneficial in terms of risk reduction and improved outcome.  As the gifted clinical investigator John Forbes at Newcastle Hospital (NSW, Australia) remarked in a recent interview on this issue, extended endocrine therapy holds the promise that "we could prevent half the relapses in these women" [women electing to undergo endocrine therapy after cessation of standard primary therapy].  My sense is from the current and emerging data that we can save as many lives with extended endocrine therapy as we do with the extraordinary leader-of-the-pack of anti-HER2 trastuzumab (Herceptin).

 

Mitigating AI-Induced Adverse Events
Finally as you know from my multi-part series (4 parts + summary of options) on Managing AI-Induced Musculoskeletal Effects,  there are many agents that can mitigate AI-induced adverse events: besides those noted (Votaren Gel, Traumeel, SAM-e, etc.), there HD-D3 (high-dose Vitamin D3) as Gina shrewdly suggested and I have documented separately, as well as a switching strategy: (1) to another AI, (2) to the antiestrogen fulvestrant (Faslodex) (as coffeepot has suggested) or (3) to the unique SERM toremifene (Fareston), and both Faslodex and Fareston may be more tolerable for many patients, although another AI may be also.  Finally, there are also emerging options that can mute and mitigate the adverse sequelae of endocrine therapy, such as intermittent (quarterly) administration which is being explored, among many other options.

 

Decisions

So bottom line is that there is some odds analysis you can count on, as I do: that the carryover effect of 50% post-termination from AI therapy could possibly reduce your persistent risk for the next 3 or 4 years from a 4% chronic per annum risk, down to 2% for the first year (and so at best, 6% at year 3, 8% at year four), but remember (1) that this is not assured in all cases, (2) that in any event, the risk returns to 4% or above thereafter (4+ years), and (3) that this fails to account for the additional intrinsic risk of HER2-positivity, and so balancing all these factors,  extended therapy (endocrine and/or anti-HER2) would still be favored.  But one way to get and exact odds computation would be via Oncotype DX genomic assay (if this can be covered by insurance), as this returns a recurrence score (RS) for associated risk based specifically on your own biological, genetic and molecular profile, and I would judge that only if this return a low RS would chancing no extended therapy be entertainable; intermediate and high RS would motivated extended therapy.  

 


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

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Dear Constantine,

Thanks so much for your response. I guess it was just real wishful thinking on my part. I already took part in the TEACH (Tykerb Evaluation After Chemotherapy) trial, but I think I was on placebo. The only way I can get herceptin is if I get a recurrence. I'll try some of the suggestions for managing side effects, and probably look into switching drugs .My onc said that Aromasin is easier on the bones than Arimidex or Femara so that's why he put me on it. I think fulvestrant and toremifene are only available here to treat metastatic breast cancer. The Oncotype Dx test sounds great but we don't have any insurance that would cover it, and it's probably very expensive. I do like the idea of intermittent use of endocrine therapy.

Oh well, I'll just carry on and try to be more thankful that I have these medications available to me. Thanks again.

Jan

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