The doc and I are scratching our heads over the failure a high dose (4g/day) of arimidex to reduce estradiol below 150. I took my last T injection November 1 when my PSA jumped to 9 and then to 12.5 December 1. Subsequently in mid December the PSA retreated back to 10.0
However the estradiol has not budged, even though my mid-December T is down to 18. And to make matters more confusing, I am rather thin. So where the heck is this E2 coming from? And what else might I try to get this under control?
While I am grateful, for the PSA improvement, the E2 cannot be good in the long run. I hate holding the record for E2 in my doc's practice, lol.
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. 2013 Oct 1;133(7):1589-602. doi: 10.1002/ijc.28182. Epub 2013 May 2.
Molecular characterization of anastrozole resistance in breast cancer: pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK-2206 with an aromatase inhibitor
Paul Vilquin 1 , Marie Villedieu, Evelyne Grisard, Sabrina Ben Larbi, Sandra E Ghayad, Pierre-Etienne Heudel, Thomas Bachelot, Laura Corbo, Isabelle Treilleux, Julie A Vendrell, Pascale A Cohen
Affiliations collapse
Affiliation
1 ISPB, Faculté de Pharmacie, Université Lyon 1, Lyon, France.
PMID: 23553037 DOI: 10.1002/ijc.28182
Free article
Abstract
Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ERα)-positive breast cancers. The Res-Ana cells, a new model of acquired resistance to anastrozole, were established by long-term exposure of aromatase-overexpressing MCF-7 cells to this drug. These resistant cells developed ER-independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ERα antagonists. They also displayed a constitutive activation of the PI3K/Akt/mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho-Akt/Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce de novo resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK-2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole-acquired resistance based on the selection of cancer-initiating-like cells possessing self-renewing properties, intrinsic resistance to anastrozole and sensitivity to MK-2206. Altogether, our work demonstrated that the Akt/mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt/mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone-dependent breast cancer patients.
Although AI endocrine therapy provides obvious clinical benefit, its efficacy is in particular limited by acquired therapeutic resistance. The most relevant cells in which to study the response to AIs are cells transfected with the human aromatase gene, as breast cancer cell lines usually display very low or no expression of endogenous aromatase22 and studies investigating AI response on those cells should be considered with caution.36 Most preclinical studies investigating AI resistance have been conducted on LTED models, but it has been previously shown that LTED cells are not totally equivalent with models of endocrine therapy-acquired resistance.2-4 Models of acquired resistance by long-term exposure to AI may more closely reflect the clinical situation and be more pertinent to investigate AI resistance. As acquired anastrozole resistance has been poorly investigated,3, 8 we established a new cellular model of acquired resistance to this compound. Importantly, Res-Ana cells are total populations of AI-resistant cells and may, thus, mimic the heterogenous phenotype and behavior of resistant cells possibly present in the tumor of patients who relapse under AI endocrine therapy. Despite the presence of ERα, the endocrine resistance developed by the Res-Ana cells resulted from ER-independent mechanisms. Indeed, the Res-Ana cell resistance is not ascribed to any change in aromatase activity, in ERα expression or in ERα canonical transcription function. Moreover, and conversely to Chen's findings,3 the resistance developed by the Res-Ana cells does not involve any adaptative mechanism linked to any phosphorylation of ERα that would lead to activated ligand-independent transcriptional activity. In long-term letrozole- or exemestane-resistant models, both ER-independent5 and ER-dependent3, 7, 9 mechanisms have been described. Differences observed between different models of AI resistance may reflect the different subtypes of clinically AI-resistant tumors.37
Endocrine resistance is thought to involve a switch from steroid signaling to a steroid-independent tumor growth29 and to growth factor signaling pathways.10 Conversely to that observed in several letrozole- or exemestane-resistant models,4, 5, 7, 9, 18 no MAPK pathway activation was detected in the Res-Ana cells. However, we demonstrated for the first time that the anastrozole-resistant cells lose their estrogen-dependent phenotype in favor of a global constitutive activation of the PI3K/Akt/mTOR pathway associated with the overexpression of the EGFR, ErbB2 and ErbB3 upstream receptors. Deregulation of the ErbB system could therefore represent one of the mechanisms involved in the constitutive activation of the PI3K/Akt/mTOR pathway, but one cannot exclude other mechanisms. The pivotal role played by the Akt pathway in anastrozole resistance was further emphasized by showing that ectopic expression of myrAkt1 is sufficient to induce de novo resistance to anastrozole. Finally, our data were supported by studying clinical samples of breast tumors collected from patients who relapsed under anastrozole adjuvant therapy representative of an in vivo acquisition of anastrozole resistance. Remarkably, although the number of clinical samples is small, the phospho-Akt/Akt ratio was found to be significantly increased in the recurrent tumors compared to primary tumors and, for any given patient, an over twofold increase was significantly associated with distant localization of the recurrent tumor, an event known to be linked with tumor aggressiveness and/or poor outcome.38 Earlier studies first associated the loss of PR expression in breast tumors with loss of ERα function (as PR is an estrogen-regulated gene); however, later studies went on to discover that ERα-independent mechanisms such as growth factor signaling pathways can directly downregulate PR levels via the PI3K/Akt/mTOR pathway.39 We observed a general loss of PR-positive status between the primary breast tumor and the matched recurrent tumor, possibly reflecting the hyperactivation of the PI3K/Akt/mTOR pathway in the recurrent tumors. To our knowledge, our work is the first to investigate the molecular events that are deregulated between the primary and the matched recurrent tumors in patients who relapse under adjuvant anastrozole treatment.
PI3K/Akt/mTOR pathway activation has been observed in one recent study of long-term letrozole-resistant cells5 however unlike our Res-Ana cells it was coupled with activation of the MAPK pathway. While our manuscript was under revision, ectopic expression of Akt in MCF-7aro cells was demonstrated to confer de novo resistance to letrozole, associated with unaltered aromatase or ERα expression or activity, and no deviation in ERα transcriptional activity compared to the parental cell line.40 Altogether, these and our data may have important clinical repercussions, as not only do they strongly implicate Akt activation in acquired resistance to AIs but also in the de novo resistance to AIs.
Strategies using drugs capable of blocking cell survival pathways are among the most promising approaches for the treatment of breast cancers. Our work is, to our knowledge, the first to investigate the effect of the new allosteric inhibitor of all Akt isoforms, MK-2206 or the effect of an mTOR inhibitor (rapamycin) on the pharmacological response to anastrozole in a model of acquisition of AI endocrine resistance. Our study has revealed that MK-2206 or rapamycin associated with anastrozole can enhance the endocrine therapeutic response in endocrine-sensitive cells and overcome resistance to endocrine therapy in resistant cells and thereby recover the endocrine therapeutic response. Our work strongly supports the notion that these compounds or their analogs, when combined with endocrine therapy, could represent an attractive strategy to increase the efficacy of AIs and to prevent or overcome AI resistance. As the activation of distinct upstream tyrosine kinase receptors (e.g., IGF/IGFR, ErbB and FGF/FGFR systems) could all independently induce the activation of the PI3K/Akt/mTOR pathway, signal transduction inhibitors targeting this downstream signaling pathway may thus represent a valuable strategy. Consistently, previous observations showed that mTOR inhibition increases the activity of letrozole in MCF-7aro cells41 and the mTOR inhibitor everolimus increases the efficacy of neoadjuvant letrozole therapy of ER+ breast cancers.42 The relevance of combining everolimus and endocrine therapy in patients displaying resistance to nonsteroidal AIs is supported by data from two recent randomized clinical trials indicating the benefit of such a combination on clinical outcome.43, 44 Finally, the MK-2206 has recently been shown to act synergistically with several therapeutic agents used in breast cancer.45-47
Selection under therapy of cancer-initiating-like cells is one of the mechanisms that could explain escape from cancer therapy.20, 21, 33, 34 Previous studies found that residual breast cancer cells after letrozole therapy display tumor-initiating features20 and that antiestrogen-resistant cellular clones of MCF-7 cells are derived from a common progenitor.48 Recently, compared to MCF-7aro cells, letrozole-resistant cells were shown to exhibit a higher percentage of TICs.49 In our work, we found that residual cell populations surviving after anastrozole therapy were enriched in subpopulations of cells with self-renewal characteristics and MK-2206 sensitivity, suggesting the presence of an activated Akt pathway in these subpopulations. Supporting observations came from a recent study finding that cancer stem cells isolated from primary ER+ breast cancers possess high expression levels of genes that drive the PI3K pathway, suggesting that this survival pathway is hyperactive in such cell populations.50 We propose that in our cell model, these cell subpopulations, present in the MCF-7aro cells and enriched in the Res-Ana cells, may account for the pharmacological response observed when anastrozole and MK-2206 are combined. Altogether, these data suggest that these cell subpopulations may be susceptible to therapeutic agents targeting this signaling pathway in vivo, thus leading to a better response when combined with endocrine therapy.
To conclude, our novel findings clearly demonstrate that: (i) activation of the Akt/mTOR pathway is a molecular event that is sufficient to confer de novo or acquired resistance to anastrozole; (ii) combining the pan-Akt MK-2206 inhibitor or mTOR inhibitor rapamycin with anastrozole enhances the endocrine therapeutic response to AI in endocrine-sensitive cells and restores sensitivity to endocrine therapy in resistant cells, and such combinations are globally more effective than each drug alone; (iii) a strategy combining endocrine therapy and specific inhibitors of the Akt/mTOR pathway may be effective in preventing resistance and relapse in ER+ patients by eliminating cancer-initiating-like cells insensitive to endocrine therapy but displaying a constitutively activated Akt/mTOR pathway. In conclusion, our findings support the concept that combining AI therapy with an allosteric Akt inhibitor or with an mTOR inhibitor could represent one of the most promising current therapeutic approaches for the management of postmenopausal patients with ER+ breast cancers.
The higher E2:T levels are associated with age and ADT by a GnRH agonist. I think it's also related to the rate of change of T during TRT. When I stopped ADT, my ADT shot up to 700 from < 12, and along with it, E2 increased to 80 (4x the ULN: 20).
Testosterone, the major circulating androgen in men, serves both as a hormone and as a prohormone. Testosterone is converted in the body to two active metabolites, 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT), which mediate some actions of testosterone in target tissues. Most of the circulating E2 is derived from peripheral aromatization of testosterone in adipose tissue, and DHT is derived by 5α-reduction of testosterone (1, 2). It is generally believed that ratios of E2 to testosterone (E2:T) and DHT to testosterone (DHT:T) do not change during therapy when testosterone is administered parenterally by im injections of testosterone esters. Indeed, DHT and E2 concentrations are low in androgen-deficient men and increase in proportion to the increase in serum testosterone concentrations when these men are treated with testosterone esters (3–7). However, it is not known whether, in the presence of testosterone therapy, E2:T and DHT:T ratios in response are influenced by age and body composition. Serum E2 concentrations are higher in obese men than lean men (8–12), but the effects of body composition, age, and testosterone dose on E2:T ratio during testosterone therapy have not been fully investigated (13).
Using blood samples and data from our previously published testosterone dose-response studies in young and older men (14, 15), we determined the effects of age, body composition, and testosterone dose on E2:T and DHT:T ratios. We found that the E2:T ratio, but not the DHT:T ratio, was higher in older men than young men during administration of graded doses of testosterone enanthate (TE) in men whose endogenous testosterone production had been suppressed by administration of a long-acting GnRH agonist. Because older men had higher body mass index (BMI) than young men, we investigated whether age effects on E2:T ratio during testosterone administration could be explained by differences in BMI in young and older men. We also examined free E2 and DHT concentrations during testosterone administration to determine whether conversion of testosterone to E2 and DHT in men conforms to the Michaelis-Menten kinetics and whether these conversions are affected by age.
May be interesting and possibly beneficial to try a low dose of Sirolimus (Rapamycin) 2mg intermittently as mTOR inhibitor and see if it restores response. I am starting a weekly 3 mg dose of Sirolimus regimen for other reasons not directly related to treating APC but affecting longevity and aging.
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Low PSA and high T=?
Low T
Decision to do High T
