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Long-term Consequences of the Aromatase Inhibitors

Joanne Mortimer, MD

Posted: 11/16/2005

Introduction

As first- and second-line treatment for advanced postmenopausal hormone-sensitive breast cancer, aromatase inhibitors (AIs) produce higher response rates and prolonged time to treatment failure compared with tamoxifen or megestrol acetate. Since the initial presentation of the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial in 2001, acceptance for using AIs in the adjuvant setting has steadily increased. This trial[1] demonstrated the superiority of anastrozole compared with tamoxifen as adjuvant therapy for postmenopausal women through an improvement in disease-free survival and lower incidence of contralateral breast cancer in women assigned anastrozole. An improvement in overall survival has not yet been shown.

As usage of AIs increases, control trials have addressed their incorporation as adjuvant therapy in postmenopausal women using 3 different study designs: initial adjuvant therapy compared with tamoxifen,[1,2] crossover after 2-3 years of tamoxifen,[3-5] and extended adjuvant therapy following 5 years of tamoxifen.[6,7] Which approach will prove the most successful is still unclear, but one of the factors that may ultimately help to guide treatment decisions -- particularly if efficacy results remain similar among the strategies -- is the extent of toxicities seen with the use of the AIs vs those resulting from tamoxifen use.

Distinguishing Toxicities

Tamoxifen was first approved in this country in 1976 for the treatment of advanced breast cancer, and until 2001 was consistently used as adjuvant therapy in hormone-sensitive breast cancers. Over the 25 years of tamoxifen domination, we have been able to assess its effects on normal tissues and to appreciate the different toxicity profile of this selective estrogen receptor modulator (SERM) in pre- and postmenopausal women. Tamoxifen has both estrogen agonist and antagonist effects. Consistent with estrogen agonist effects, tamoxifen use is associated with an increased incidence of venothromboemboli, endometrial thickening, uterine polyps, and endometrial cancer. Although bone mineral density (BMD) is increased in postmenopausal women, tamoxifen has an adverse effect on the bones of premenopausal patients. Despite a favorable effect on lipid profiles, it has been difficult to show that tamoxifen use decreases cardiovascular complications. Estrogen antagonist effects are credited for tamoxifen's antitumor efficacy and hot flashes.

The 3 third-generation AIs are structurally and biologically unique. Anastrozole and letrozole are nonsteroidal inhibitors binding reversibly to the aromatase enzyme, while exemestane is a steroidal inactivator that binds irreversibly to the enzyme. Letrozole suppresses estrogen most significantly. Yet in treating advanced disease, the 3 agents have shown equivalent response rates and time to disease progression. Subtle differences in toxicity are more likely to become apparent in the adjuvant setting because most women diagnosed with early-stage breast cancer will die of other causes. An understanding of the benefits and toxicities of adjuvant therapy is critical. Patients have readily accepted the substitution of AIs for tamoxifen because of the preliminary data and a lower incidence of acute toxicities such as hot flashes.

Distinguishing toxicities that are attributed solely to the AIs is difficult in all but the placebo-controlled trials, and toxicity data are available for only 1 of the 2 mature trials. For the other controlled trials, the magnitude of toxicity from the AI may be falsely higher or lower because the comparison arm is tamoxifen, which is an SERM. This is especially pertinent for BMD, where tamoxifen has favorable effects. This paper summarizes the long-term effects of the AIs based on the available data from adjuvant therapy trials. The trial designs, end points, results, and toxicities are summarized in the .

  Summary of Toxicities Unique to the Use of AIs in the Adjuvant Setting

Trial (Number) Design Median follow-up Results favoring AI Osteoporosis AI vs Control Fracture AI vs Control Myalgias AI vs Control Arthralgia AI vs Control Cardiovascular AI vs Control
Initial therapy ATAC[1]
(n=6331)
Anastrozole x 5 yrs vs Tamoxifen x 5 yrs vs Anastrozole + Tamoxifen x 5 yrs 68 mos ↑ DFS; ↓ contralateral breast cancer ? 11.0% vs 7.7%
P ≤ .0001
? 35.6% vs 29.4%
P < .0001
4.1% vs 2.8%
P = .1 altered lipids[8]
BIG[2]
(n=8010)
Letrozole x 5 yrs vs Tamoxifen x 5 yrs vs Let x 2 yrs→ Tam x 3 yrs vs Tam x 2 yrs → Let x 3 yrs 26 mos ↑ DFS 5.7% vs 4.0%
P < .0006
6.4% vs 6.1% 20.3% vs 12.3% ↑ cholesterol 43.5% vs 19.1%; 3.6% vs 2.5%
Switching trials IES[3]
(n=4734)
Tamoxifen x 5 yrs vs Tam x 2-3 yrs → Exemestane x 2-3 yrs 30.6 mos ↑ DFS; ↓ contralateral breast cancer 7.4% vs 5.7%
P < .05
3.1% vs 2.3%
P < .08
X 5.4% vs 3.6%
P < .01
Non-MI CVD 42.6% vs 39.2%
P = .1[9]
ITA[4]
(n=426)
Tamoxifen x 5 yrs vs Tam x 2-3 yrs → Ana x 2-3 yrs 36 mos ↑ DFS X 1.0% vs 1.3% - 8.4% vs 12% Lipid disorders 9.3% vs 4.0%
(P = .04)
7.9% vs 9.3%[10]
ABCSG/ARNO[5]
(n=3224)
Tamoxifen x 5 yrs vs Tam x 2-3 yrs → Ana x 2-3 yrs 28 mos ↑ DFS - 16 (1%) vs 34 (2%)
P = .015
- 16% vs 19%
P = .0546
MIs < 1% vs < 1%
Extended adjuvant MA-17[6]
(n=5157)
Tam x 5 yrs vs Tam x 5 yrs → Let x 5 yrs 30 mos ↑ DFS; ↓ contralateral breast cancer 8.1% vs 6.0%
P = .003
5.3% vs 4.6%
P = .25
15% vs 12%
P = .004
25% vs 21%
P < .001
5.8% vs 5.6%
P = .76
ABCSGa[7]
(n=796)
Tam x 5 yrs vs Tam x 5 yrs → Ana x 5 yrs 60 mos ↑ DFS; ↓ contralateral breast cancer ? ? ? ? ?

AI = aromatase inhibitor; DFS = disease-free survival; MI = myocardial infarction; CVD = cardiovascular disease

Bone Loss

An increase in osteoporosis has been reported in the AI trials that systematically addressed bone health. BMD was decreased when women who had received 2-5 years of tamoxifen were switched to exemestane.[3] Extended adjuvant therapy with letrozole also increased the incidence of osteoporosis.[6] However, a statistical increase in bone fractures has been reported only with the nonsteroidal inhibitors anastrozole and letrozole.[1-6] The chemical structure of exemestane is similar to androstenedione, and the primary metabolite 17 hydro-exemestane has been shown to increase BMD in ovariectomized rats.[11] The effect of exemestane on bone was addressed in a controlled trial in women with low-risk breast cancer or ductal carcinoma in situ.[12] After 2 years of therapy, women assigned exemestane experienced a significant decline in BMD in the hip, but not spine, compared with the control group. Although the bone substudy of the Intergroup Exemestane Study (IES) reported a significant bone loss in both hip and spine, an increased incidence of fractures was not identified.[13]

With the exception of the bone substudy in the MA-17 trial, adequate calcium and vitamin D intake has not been mandated in the AI trials. Furthermore, we do not have information about calcium or vitamin D intake in study participants or if bisphosphonates were utilized in these trials. Such information will be important in future trials that are designed to assess the long-term effects of AIs. Because it has been shown that only 10% of breast cancer survivors take the recommended daily amount of calcium (1 g/day) and vitamin D (400 mg/day), it is incumbent upon the physician to educate women and to reinforce the need for adequate dietary intake or supplementation.[14] Clinicians should remember to follow BMD in women who are treated with the AIs and should manage osteoporosis according to defined guidelines.

Myalgias and Arthralgias

In the early trials of AIs in the treatment of advanced breast cancer, there was a suggestion that arthralgias and myalgias were more commonly reported with the AIs than tamoxifen or megestrol acetate. The true incidence was probably confounded by the fact that neither bone nor muscle toxicities were anticipated toxicities. Furthermore, any increase in bone pain could have been ascribed to metastatic disease or to hormone flare reactions. In the adjuvant setting, myalgias and arthralgias have been consistently reported with all 3 of the AIs. But before we can fully understand this toxicity, it will be necessary to define a term that reflects the problem. Is this a myalgia, arthralgia, or arthritis?

It has been suggested that lower levels of estrogen observed after menopause or induced by the AIs produce an increase in inflammatory conditions and a decreased tolerance for pain.[15] Controlled trials of hormone replacement therapy in postmenopausal women suggest that bone discomfort is less common in women receiving hormone replacement, supporting estrogen deficiency as a possible mechanism.[16,17] With the data available from the use of adjuvant AIs, it appears that all 3 of the AIs cause musculoskeletal problems -- but there is no consensus about possible mechanisms or ways to relieve the discomfort. Anecdotally, patients have been treated with anti-inflammatory agents, vitamin D, discontinuation of the AI, or switched to a different AI.[18] Clinical trials addressing the pathophysiology and treatment of this side effect are important as we strive to optimize not only our patients' longevity but their quality of life as well.

Heart Disease

Despite a favorable impact on lipid profile, tamoxifen use has not been shown to have an impact on cardiovascular disease. Therefore it seems unlikely that a favorable effect from tamoxifen will have confounded the incidence of cardiovascular disease in the adjuvant AI trials. All three AIs have been shown to adversely affect lipid profiles.[1,8,10] In the BIG trial, letrozole use was associated with a significant increase in grade 3-5 ischemic heart disease (1.1% vs 0.6% p=0.013) and CHF (0.5% v 0.1%; p=0.006) compared with tamoxifen. Although a higher number of cardiac events were observed in the women crossing over to exemestane in the IES trial, the number was predefined as p=0.02 and therefore not significantly higher than that observed in the tamoxifen arm.[19] However, these preliminary data are of concern, in that cardiac disease may emerge as a long-term adverse effect. Further follow-up will be important in determining whether these findings are consistent.

Quality of Life

Over 1000 women participated in a quality-of-life substudy in the ATAC trial.[9] Functional Assessment of Cancer Therapy -- Breast (FACT-B) and Endocrine Subscale (ES) questionnaires were completed at baseline and weeks 3, 6, 12, 18, and 24 on study. Compared with women assigned tamoxifen, those receiving anastrozole experienced fewer cold sweats and has less vaginal discharge. However, they also noted a decrease in libido, more vaginal dryness, and dyspareunia. The Short Form 36-item Health Survey (SF-36) and Menopause Specific Quality of Life (MENQoL) were completed at baseline, 6 months, and annually by over 3600 participants in the MA-17 study. Compared with those receiving a placebo, quality of life was not significantly altered in the women assigned extended adjuvant letrozole. However, in subset analyses, women receiving letrozole experienced more bodily pain, menopausal symptoms, and compromise in sexual function.[20]

Conclusion

After the AIs were established to be superior to tamoxifen in advanced, postmenopausal, hormone-sensitive breast cancer, the breast cancer research community conducted a number of carefully designed trials that incorporated AIs in the adjuvant setting. Although disease-free survival and the incidence of contralateral breast cancer consistently favor the AI over tamoxifen or as extended adjuvant therapy, overall survival has yet to be impacted. Therefore, toxicities are and will be an important mitigating factor in determining which therapy to undergo. The "short-term toxicities," such as vasomotor symptoms, venothromboemboli, and gynecologic complications, favor the use of AIs. However, long-term bone loss, altered lipid profiles, and possible compromise in sexual functioning appear to be adversely affected by the AIs. The unexpected and clinically significant development of musculoskeletal pain will need to be understood and appropriate treatment defined.

The standard of care for the treatment of malignant diseases is changing rapidly as new drugs are developed and new indications for drugs are identified. The lessons we learned about the long-term effects of tamoxifen have helped us to be proactive in identifying possible long-term sequelae of the AIs. Further information will be forthcoming from the ongoing trials that were designed to answer many of these questions.

References

  1. Howell A, Cuzick J, Baum M, et al. The ATAC Trialists' Group results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60-62. Abstract
  2. Thurlimann BJ, Kashawiah A, Mouriani H, Mauria L. BIG 1-98: randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol. 2005;23:6s. Abstract 511.
  3. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-1092. Abstract
  4. Boccardo F, Rubagotti A, Putoni M, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol. 2005;23:5138-5147. Abstract
  5. Jakesz R, Jonat W, Gnant M, et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of the ABCSG trial 8 and ARNO95 trial. Lancet. 2005;366:455-462. Abstract
  6. Goss P, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97:1262-1271. Abstract
  7. Jakesz R, Samonigg H, Greil R, et al. Extended adjuvant treatment with anastrozole results from the Austrian Breast and Colorectal Cancer Study Group Trial 6a (ABCSG 6a). Proc Am Soc Clin Oncol. 2005;23:10s. Abstract 527.
  8. Wasan KM, Goss PE, Pritchard KI, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen. Ann Oncol. 2005;16:707-715. Abstract
  9. Fallowfield L, Cella D, Cuzick J, Francis S, Lacker G, Howell A. Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant breast cancer trial. J Clin Oncol. 2004;22:4261-4271. Abstract
  10. Boccardo FM, Rubagottti A, Puntoni M, et al. Switching to anastrozole vs continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole trial. Proc Am Soc Clin Oncol. 2005;23:10s. Abstract 526.
  11. Goss PE, Qi S, Cheung AM, et al. Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res. 2004;10:5717-5723. Abstract
  12. Lonning PE, Geisler J, Krag LE, et al. Effects of exemestane administration for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol. 2005;23:5126-5137. Abstract
  13. Coleman RE, Banks LM, Hall E, et al. Intergroup Exemestane Study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat. 2004;88(suppl 1):S35 (abstract).
  14. Zinaman RS, Van Poznak CH, Goldberg LM, Hudis CA. Supplemental calcium and vitamin D intake in women with early stage breast cancer. Breast Cancer Res Treat. 2004;88(suppl 1). Abstract 4006.
  15. Felson DT, Cummings SR. Aromatase inhibitors in the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum. 2005;52:2594-2498. Abstract
  16. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones; results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92:982-988. Abstract
  17. Nevitt MC, Felson DT, Williams EN, Grady D, for the Heart and Estrogen/Progestin Replacement Study Research Group. The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2001;44:811-818. Abstract
  18. Taylor ME, Rastelli A, Civitelli R, Ellis M. Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology. Breast Cancer Res Treat. 2004;88(suppl 1). Abstract 3072.
  19. Coombes RC, Hall E, Snowdon CF, Bliss JM. The Intergroup Exemestane Study: a randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen-updated survival analysis. Breast Cancer Res Treat. 2004;88(suppl 1):S7. Abstract 3.
  20. Whelan TJ, Goss TE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol. 2005:23:6931-6940. Abstract
 

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