Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients

Morales, Leilani; Timmerman, D.; Neven, Patrick; Konstantinovic, Maja; Carbonez, An; Huffel, Sabine Van; Ameye, Lieveke; Weltens, Caroline; Christiaens, Marie Rose; Vergote, Ignace; Paridaens, Robert

doi:10.1093/annonc/mdi021

Cited by 51 publications

(29 citation statements)

References 19 publications

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“…Given the short-term evaluation in our study and the absence of a wash-out period between prior AI therapy and succeeding fulvestrant therapy, the decrease in DET and UV on top of prior AI therapy cannot be attributed to fulvestrant alone with absolute certainty. However, it is clear that after 3 months of therapy with fulvestrant, there were no signs on TVUS of a stimulatory effect on the endometrium in contrast to what has been detected on TVUS after 3 months of tamoxifen therapy [8].…”

Section: Discussionmentioning

confidence: 81%

“…Although most of these changes are benign, the wide range of abnormalities induced by tamoxifen has led to a number of gynecological interventions in symptomatic women to exclude malignant disease. The third generation aromatase inhibitors (AIs) which are increasingly used as an alternative or as an additional treatment to tamoxifen [5][6][7] do not have an estrogenic effect on the uterus and may even reverse tamoxifen-associated endometrial pathologies as shown in several studies [8][9][10][11][12][13][14][15]. The potential use of AIs specifically for the management of endometrial pathologies is promising [16].…”

Section: Introductionmentioning

confidence: 99%

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Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

Morales

Neven

Timmerman

et al. 2008

Breast Cancer Res Treat

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This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This singlecenter study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 ± 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

Morales

Neven

Timmerman

et al. 2008

Breast Cancer Res Treat

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“…Overall, nearly 10% of tamoxifentreated patients develop endometrial pathology within 5 years 19 . Within 3 months of initiation of tamoxifen therapy, significant increases in endometrial thickness and in uterine volume are reported, including endometrial cysts and polyps and growth of preexisting fibroids 20 .…”

Section: S21mentioning

confidence: 99%

“…By inhibiting estrogen synthesis, the third-generation AIs reduce endometrial thickness and uterine volume in patients previously treated with tamoxifen ( Figure 2) 20 . However, patients receiving anastrozole alone reported more vaginal dryness, painful intercourse (dyspareunia), and loss of sexual interest, but significantly fewer cold sweats and less vaginal discharge 28,29 than did patients on tamoxifen alone.…”

Section: S22mentioning

confidence: 99%

Management of Sexual Dysfunction in Postmenopausal Breast Cancer Patients Taking Adjuvant Aromatase Inhibitor Therapy

2007

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Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifeninduced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements-all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement-most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)-may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be attended with potential risk. Therefore, non-hormonal alternatives should in all cases be initially tried with the expectation that symptomatic relief can often be achieved.First-line therapy for urogenital symptoms, notably vaginal dryness and dyspareunia, should be the non-hormonal group of preparations such as moisturizers and precoital vaginal lubricants. In patients with estrogen-dependent breast cancer (notably those receiving anti-estrogenic adjuvant therapies) and severely symptomatic vaginal atrophy that fails to respond to non-hormonal options, menopausal hormone replacement or prescription vaginal estrogen therapy may considered. Systemic estrogen may be associated with risk and thus is best avoided. Judicious use of hormones may be appropriate in the wellinformed patient who gives informed consent, but given the potential risk, these agents should be prescribed only after mutual agreement of the patient and her oncologist. KEY WORDSAromatase inhibitor therapy, breast cancer, gynecologic side effects, hormone therapy, sexual dysfunction, si...

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“…Absence of such an effect in a poor metabolizer may be another proof that the drug is not metabolized with the potential for this marker to serve as an early surrogate for poor treatment outcome. It is well known that tamoxifen intake induces uterine abnormalities like endometrial polyps, endometrial thickening and subepithelial cysts in a large proportion of postmenopausal tamoxifen users early in treatment [3,28]. Also, tamoxifen leads to a decrease in serum levels of FSH and increase in serum levels of SHBG in postmenopausal women [4].…”

mentioning

confidence: 99%

Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users

Dieudonné

Lambrechts

Claes

et al. 2009

Breast Cancer Res Treat

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Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.

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Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients

Cited by 51 publications

References 19 publications

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

Management of Sexual Dysfunction in Postmenopausal Breast Cancer Patients Taking Adjuvant Aromatase Inhibitor Therapy

Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users

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