Incomplete estrogen suppression with GnRH agonists may reduce clinical efficacy in premenopausal women with early breast cancer.
Mitch Dowsett1, Per E. Lonning2, Nancy E. Davidson3
1. Academic Department of Biochemistry, Royal Marsden Hospital,
London SW3 6JJ United Kingdom
-44-2078082885
mitch.dowsett@icr.ac.uk
2. Section of Oncology, Department of Clinical Science, University of Bergen, and Department of Oncology, Haukeland University Hospital, Bergen, Norway -47-55975000
per.lonning@helse-bergen.no
3. University of Pittsburgh Cancer Institute and UPMC CancerCenter 5150 Centre Avenue, Suite 500
Pittsburgh, PA 15232 412 623 3205
davidsonne@upmc.edu
Background:
Oophorectomy was the first endocrine therapy for breast cancer but has been largely superseded by Gonadotrophin Releasing Hormone agonists (GnRHas) due to their reversible, less invasive suppression of ovarian function.
The concept was developed over 2 decades ago that GnRHa efficacy in treating estrogen receptor (ER)-positive breast cancer in premenopausal women might be improved by combination with an antiestrogen or aromatase inhibitor (AI) to antagonise or inhibit the synthesis of the residual non-gonadal estrogen. 1,2. Now,
the results of three phase III studies comparing ovarian function suppression (OFS) with and without tamoxifen or comparing OFS+tamoxifen with OFS+AI are available;3-5 however, the results are conflicting.
Here we consider the endocrine pharmacology of these combination therapies and provide potential explanations for the variable clinical findings as well as a possible means of improving combination therapy involving OFS.
Clinical studies:
Understanding of the clinical efficacy of OFS ± other endocrine approaches remains incomplete. Two meta-analyses of ovarian ablation as accomplished by oophorectomy, ovarian irradiation or GnRHa found breast cancer recurrence and mortality in women < 50 years to be reduced, with no significant difference between patients having medical versus surgical or radiological ablation. No statistically significant effect of ablation was observed among individuals having concomitant chemotherapy which itself can cause ovarian failure 6,7; hazard
ratios (HR±95% CI) for recurrence were 0.86±0.18 and 0.95±0.14 for <40 and 40-49 year patients, respectively7,. A metanalysis of GnRHa versus no-treatment
but these effects were not statistically significant, likely due to the low number of patients.8
Three large trials of GnRHa-based combination endocrine therapy in
premenopausal patients with hormone receptor positive tumors have recently reported with inconsistent results. 3-5 In summary, ABCSG12 and TEXT
compared a GnRHa plus tamoxifen against the same GnRHa plus a third-generation AI.3,4 SOFT made a similar comparison but with another arm,
comparing tamoxifen monotherapy versus the combination of OFS plus tamoxifen. 5 Notably, OFS included surgical, radiological or medical ovarian
suppression. In TEXT, unlike ABCSG12, patients were allowed to switch from triptorelin to ovarian ablation (radiological or surgical) following 6 months’ therapy.
At final analysis of ABCSG12 after median 94 months of follow-up there was no DFS difference between goserelin plus tamoxifen or goserelin plus anastrozole but an increased risk of death for the latter.3 An earlier secondary analysis found
that overweight patients treated with anastrozole plus goserelin had an approximate 50% greater risk of recurrence (HR 1.49, 95%CI 0.93-2.38) and three-fold greater risk of death (HR 3.03, 95%CI 1.35-6.82) compared with similar patients treated with tamoxifen plus goserelin. 9
In contrast, a joint analysis of TEXT and SOFT of 4690 women receiving OFS plus tamoxifen versus OFS plus exemestane after a median follow-up of 68 months showed a significantly improved DFS with OFS plus exemestane but no
detectable difference in survival.4
The recent report from SOFT with 67 months median follow-up showed no significant difference between tamoxifen and tamoxifen plus GnRHa, the primary comparison. A secondary analysis comparing tamoxifen with GnRHa plus
exemestane showed a significant improvement in freedom from breast cancer with the combination but no difference in survival. 5 Another study, E3193, failed
in premenopausal women in the absence of chemotherapy. 10 However, patients
in this underpowered trial were at low risk and the trial was closed early due to poor accrual.
The available data do not therefore provide a uniform background for therapy selection. Although the data from SOFT suggest better outcomes for young women with GnRHa combined with either an AI or tamoxifen compared with tamoxifen monotherapy, the discordance between the ABCSG12 and TEXT/SOFT joint analysis in the comparative results between AI and tamoxifen are
disconcerting and confound confident selection between these agents.
The trials differed in several aspects that may have contributed to differences in outcome including means of OFS, identities of the GnRHa and AI used, different sample size and different duration (discussed fully in reference 11) and these
differences confound direct comparisons. However, careful examinations of the endocrine effects of these therapies provides insight that may help toward a better understanding and enhance the selection of the most beneficial therapy for individual patients.
Endocrine studies:
Chronic non-pulsatile application of GnRHa leads over a period of days to down-regulation of GnRH-receptors in the pituitary, reduced secretion of LH and FSH and marked reduction of gonadal steroidogenesis. This leads to a state
frequently described in women as medical oophorectomy. This name suggests that the steroidal effects of GnRHas are equal to those of ovarian ablation. However, some not widely appreciated details differ. Given the recent report on higher FSH levels relating to poorer outcome in ABCSG12, we make particular note of the impact of the treatment regimens on FSH.12
1), with breast cancer patients on leuprorelin, and in males with prostate cancer on a GnRHa. 13,14 The recovery in FSH levels has been ascribed to feedback
through inhibin. Little attention has been paid to the FSH increase because it was felt to be inconsequential but, as shown below, this is far from the case.
While the decrease in ovarian stimulation leads to a profound fall in plasma estradiol levels due to reduced ovarian estrogen synthesis, complete suppression is not permanent. For example, in one of our studies,15 plasma estradiol levels fell
to a mean 18pmol/l after 1 month of goserelin but subsequently increased in 15/18 patients to values in the upper postmenopausal range (36pmol/l after 6 months) in parallel with increased FSH levels (Figure 1). Similar incomplete ovarian suppression was observed in women with fibroids treated with goserelin.16
Detailed endocrine studies of goserelin±tamoxifen by Walker and colleagues also indicate that FSH recovery may stimulate estradiol secretion.17 They observed
that the recovery in FSH levels after 1 month on goserelin was prevented by adding concurrent tamoxifen. This is likely due to tamoxifen’s agonistic effect on the hypothalamic-pituitary axis in the setting of low prevailing estrogen levels.18
Notably in the Walker study 17 plasma estradiol levels were significantly lower in
the group receiving tamoxifen and goserelin, supporting the difference in estradiol levels being due to FSH stimulation of the ovary.
Adding the second-generation AI, 4-hydroxyandrostenedione, to goserelin, 19
suppressed plasma estradiol levels below those on goserelin alone, due to the expected inhibition of the peripheral estrogen synthesis. However, while a larger study 2 similarly reported that vorozole, an AI similar to anastrozole and
letrozole, in combination with goserelin suppressed estradiol levels below those with goserelin alone, mean levels on the combination were highly variable (range 8.6 to 56.8 pmol/l ) and substantially above those seen with vorozole in postmenopausal women in the same study (4.4 to 5.9 pmol/l).
GnRHa described above, it is pertinent that AIs are established agents for ovulation induction in premenopausal women.20 This exploits their partial
blockade of ovarian synthesis, resultant increase in gonadotrophin levels, and consequent enhanced ovarian estrogen synthesis. The ability of AIs to induce ovulation led to publication of a cautionary note to alert oncologists to the possibility of ovarian function recovery and risk of pregnancy in women who were amenorrheic after cytotoxic chemotherapy and been placed on an AI. 21
These early data therefore indicated that (i) GnRHa usage leads to profound but incomplete suppression of ovarian estrogen synthesis due to recovery of FSH levels and (ii) addition of an AI does not uniformly suppress the residual ovarian synthesis but rather in some cases may lead to increased synthesis.
Unfortunately, the comparison of endocrine effects of triptorelin+letrozole versus triptorelin+tamoxifen in the HOBOE trial is compromised by reduced ovarian function of most patients at baseline, 22 but a substudy from the SOFT
trial 23, termed SOFT-EST, was completely consistent with these observations.
The substudy evaluated the endocrine effects during the first 12 months of the GnRHa (triptorelin) with either tamoxifen or exemestane. The group used highly sensitive GC/MS-MS to measure estrogen levels, avoiding the problem of
exemestane or its metabolites cross-reacting with commonly used immunoassays. 24 As expected, mean estradiol levels were lower with
exemestane than tamoxifen; however, with exemestane 27/79 patients had what the authors considered to be suboptimal estradiol suppression
(estradiol>10pmol/l) based on earlier guidelines21 on at least one of three points
during treatment. FSH levels were suppressed by 78% after 3 months, but by only 62% and 66% after 6 and 12 months, respectively. Low baseline LH and FSH (both p<0.01) and no chemotherapy (p=0.06) correlated with
estradiol>10pmol/l on exemestane indicating a greater likelihood of incomplete estrogen suppression for patients with full ovarian function. The significant correlation of higher estradiol levels with high BMI (p=0.05) was notable given the poorer relative efficacy of the OFS+anastrozole arm in ABCSG12 in
Clinical implications:
The above data strongly support increases in FSH levels in patients on a GnRHa alone or with an AI being associated with, and probably causative of, increases in plasma estradiol levels above those seen with complete surgical ovarian ablation. In each case the suppression of estradiol levels is less than that desired. Given the evidence in postmenopausal women for a relationship between the degree of estradiol suppression and AI efficacy, 25 it is reasonable to consider partial
suppression in premenopausal women also being likely to be clinically
suboptimal. The observation noted above that ABCSG12 patients expressing on-treatment FSH levels above the trial population mean had significantly worse distant metastasis-free survival 12 is therefore particularly pertinent.
Unfortunately results were not reported for the separate study arms but they nonetheless lend mechanistic support for the relationship between FSH levels and clinical efficacy of the GnRHa plus AI.
With regard to the combined TEXT/SOFT analyses, it would be of great value to have sub-analyses related to outcome in patients having surgical or radiological OFS compared with those treated solely with triptorelin for OFS.
It is not clear whether the increases in FSH and estradiol with a GnRHa plus AI treatment are persistent in individuals or occur across the patient population. Whatever the case, both a mechanism-based view and the evidence from ABCSG12 suggest that avoidance of these increases might be advantageous therapeutically. The use of fulvestrant with a GnRHa could be considered but, like aromatase inhibitors, fulvestrant leads to increases in estradiol levels in premenopausal women 26,27 and would likely do the same to FSH in women on
GnRHas.
GnRH antagonists might provide an alternative and more consistently effective approach. These antagonists lead to immediate down-regulation of gonadal activity rather than to the initial surge found with GnRHas. 14,16 Detailed study of
completely suppressed in contrast to increases with leuprolide. 14 We have not
been able to identify data on gonadotrophin levels during chronic usage of GnRH antagonists in breast cancer patients but the IBCSG 41-13 TRial on the Endocrine activity of Neoadjuvant Degarelix (TREND) will allow comparison to be made of the endocrine and clinical effects of degarelix plus letrozole compared with triptorelin plus letrozole over 6-months.
Conclusion:
Incomplete suppression of ovarian estrogen synthesis may be achieved with GnRHa due to recovery of FSH levels and this appears to reduce the impact of added aromatase inhibition in at least some women. The possibility that this leads to suboptimal efficacy merits detailed study. Particular attention should be paid toward this problem in overweight patients. 9 Monitoring endocrine
changes in individual patients to manage their OFS with or without AI or tamoxifen cannot be recommended because the basis of our understanding is incomplete and sufficiently sensitive estradiol assays are not widely available. In circumstances where there is gross evidence of incomplete oestrogen
suppression the clinician and patient may wish to consider oophorectomy.
Acknowledgements:
References:
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Legend to Figure:
The line charts show the individual changes in patients treated with goserelin alone for FSH between baseline, 1 month and 6 months and for estradiol (E2) between 1 month and baseline (extended from 15)
