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A practical overview of aromatase inhibitors in postmenopausal women with hormone receptor-positive breast cancer


Bulletin du Cancer. Volume 92, Number 4, 10039-44, Avril 2005, Electronic journal of oncology


Summary  

Author(s) : Jawaid Younus, Theodore A Vandenberg , Department of Medical Oncology, London Regional Cancer Centre, 790 Commissioners Road, East London, Ontario N6A 4L6, Canada.

Summary : Tamoxifen has been the standard adjuvant therapy for patients with breast cancer for the last several decades. Several recently completed adjuvant trials using aromatase inhibitors have shown the superiority of these agents over Tamoxifen or placebo, when used in postmenopausal women. The results from these trials present a challenging situation for practicing oncologists with regards to the choice, duration, sequence of therapy, follow up and side effects of aromatase inhibitors. We have discussed various management issues from a practical angle for oncologists to effectively use these agents, with an evidence-based approach.

Keywords : adjuvant therapy, aromatase inhibitor, breast cancer, tamoxifen

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ARTICLE

Auteur(s) :, Jawaid Younus, Theodore A Vandenberg

Department of Medical Oncology, London Regional Cancer Centre, 790 Commissioners Road, East London, Ontario N6A 4L6, Canada

The relationship between estrogen and breast cancer has been extensively investigated and hormonal manipulation against estrogen have been used for the last several decades. Such interventions have included tamoxifen and more recently aromatase inhibitors/inactivators (AIs). Tamoxifen has remained a time tested hormonal therapy for estrogen receptor (ER) or progesterone receptor (PR) positive breast cancer. The efficacy of tamoxifen is clearly reflected through meta-analysis by the Early Breast Cancer Trialists’ Cooperative Group (EBCTCG). This meta-analysis showed that adjuvant tamoxifen reduces the relative risk of breast cancer recurrence by 47% and mortality by 26% [1]. Both pre- and post-menopausal women, with or without the involvement of axillary lymph nodes, benefit from the use of adjuvant tamoxifen. The benefits are additive when tamoxifen is used after completing adjuvant chemotherapy. At present five years of tamoxifen is recommended as adjuvant therapy in patients with breast cancer.Aromatase inhibitors (anastrozole and letrozole) and inactivators (exemestane) are third generation compounds, currently indicated for post-menopausal women with breast cancer in metastatic and in adjuvant settings. These hormonal agents have replaced earlier drugs like aminoglutethemide. In post-menopausal women, estrogen is produced by peripheral conversion of androgens mediated through the enzyme aromatase. Inhibition of this enzyme either reversibly (anastrozole and letrozole) or irreversibly (exemestane) leads to extremely low levels of estrogen, which in turn is responsible for anti-tumor effects. These agents differ in their pharmacokinetic properties and with respect to their overall effect on various systems and tissues [2].In metastatic breast cancer patients, aromatase inhibitors/inactivators (AIs) are superior to tamoxifen as first or second line hormonal therapy [3–8]. A similar effect has emerged for these agents as adjuvant therapy for post-menopausal patients. There have been three clinical trials completed and published after using AIs in this setting. The uniformity of results from these trials especially regarding the disease free survival advantage, in addition to the better toxicity profiles makes it quite compelling to prescribe AIs in this setting. However, several questions remain unanswered including, which AI to use, sequentially or up front, order of sequence, duration, optimal follow up, and side effects. At present, these issues make decision-making challenging for oncologists.To understand these issues further, let us review the results of the trials, which have used AIs in adjuvant setting (tables 1 and 2( Table 1 )( Table 2 )). All of the published trials used a phase III, randomized, double blind, and placebo controlled approach except the ITA study.The Arimidex and Tamoxifen Alone or in Combination (ATAC) trial recruited 9366 women with breast cancer and randomized them to tamoxifen, anastrozole (1 mg once daily by mouth) or a combination of tamoxifen and anastrozole, after completing surgery, chemo and radiation therapy [9]. The combination arm had the same results as tamoxifen alone arm. This interesting finding was initially seen in a nude mice model [10]. Pharmacokinetic analysis of ATAC arms showed that tamoxifen and its metabolites levels were unaffected by Arimidex. Although Arimidex level was 27% less in combination arm, the total oestradiol was unchanged and therefore pharmacokinetics are unable to explain this difference of efficacy in the two arms [11]. One possible mechanism could be related to the significant estrogen deprivation induced by anastrazole, which may not let any further changes take place, once tamoxifen is bound to estrogen receptor. In this situation no further effect will be seen beyond the expected effect of tamoxifen [9]. The primary objectives were disease free survival (DFS) and safety. DFS was defined as the time to earliest local recurrence, distant metastasis, new primary breast cancer or any cause mortality. At 47 months follow-up, more patients were recurrence free in anastrozole arm (86.9%) compared to tamoxifen arm (84.5%), the absolute difference of 2.4% [12]. The hazard ratio was 0.86 (CI = 0.76-0.99, p-value: 0.03). Musculoskeletal events and fractures were seen more frequently in anastrozole alone arm versus tamoxifen (table 2). However, hot flashes, vaginal bleeding and discharge, incidence of endometrial cancer, venous thromboembolic and cerebrovascular events were significantly higher in tamoxifen arm (p value < 0.05). This is the largest trial that compared tamoxifen in a head to head design with anastrozole and has shown a continued benefit over a reasonably sufficient median follow-up. There is no overall survival benefit yet seen.The National Cancer Institute of Canada – Clinical Trials Group jointly with North American Intergroup and the Breast International Group conducted the MA-17 trial with over five thousand postmenopausal women [13]. These patients received adjuvant tamoxifen for four to six and a half years. Within three months of discontinuing tamoxifen, they were randomized to receive letrozole 2.5mg orally once daily or placebo. The primary objective was disease-free survival defined in this trial as loco-regional or metastatic disease or new primary breast cancer in the contra-lateral breast. Secondary cancer, death without a recurrence or a diagnosis of contralateral breast cancer was not considered in the analysis of the results. The data and safety monitoring committee at a median follow-up of 2.4 years unblinded the two arms at 207 events when the pre-defined O’Brien-Fleming boundary reached the value of 0.0008. The estimated four year DFS was 93% in the letrozole group versus 87% in the placebo, an absolute benefit of 6%. The hazard ratio was 0.57 (95% CI = 0.43 to 0.75; p value = 0.00008). The over all survival (OS) was same in both arms. An update in 2004 revealed the improvement in the OS and DFS to be more prominent in node positive women [14]. The letrozole arm had more patients with hot flashes, arthralgia and myalgia. The difference in clinical fracture rates and osteoporosis (self-reported) was not statistically significant. Based on this trial, letrozole may provide extended adjuvant benefits to postmenopausal women after five years of tamoxifen therapy. Interestingly, two thirds of women from placebo group, after unblinding, elected to go on letrozole therapy. With this cross over, any meaningful evaluation of the DFS, OS or side effects will not be further possible. However, this cross over also shows the preference of these patients to continue with the apparent benefits of letrozole, despite the short follow up and lack of information regarding the long-term side effects.The Intergroup Exemestane Study (IES) recruited 4742 patients [15]. These patients had received two to three years of adjuvant tamoxifen. They were then randomized to either continue on tamoxifen or to switch to exemestane (25 mg once daily) to complete five years of therapy. The primary objective was DFS defined as local or metastatic disease, contralateral breast cancer or death. After 30.6 months of follow-up, the hazard ratio in the exemestane arm compared with tamoxifen was 0.68 (95% CI = 0.56 to 0.82 and p-value < 0.001). The absolute benefit was 4.7%. Over all survival was not significantly different in the two arms. Survival free of distant disease was better in exemestane treated patients with hazard ratio 0.66 (95% confidence interval: 0.52 to 0.83; p value = 0.0004). A higher incidence of arthralgia and diarrhea was seen in exemestane group but gynecologic symptoms, vaginal bleeding, muscular cramps and thromboembolic events were more common in tamoxifen group. Fractures were reported more frequently in exemestane group (3.1% versus 2.3%) but without reaching statistical significance. This study has shown the advantage of utilizing AIs (exemestane) after tamoxifen in a sequential manner. In addition to improved DFS, more importantly distant disease free survival was significantly better in patients treated with exemestane.The last study was presented at San Antonio Breast meeting in 2003 and published in the abstract form. The Italian Tamoxifen Arimidex trial (ITA) used anastrozole after two to three years of initial tamoxifen to complete a total of five years of therapy [16]. The competitor arm had women treated with tamoxifen for five years. A total of 426 women, all axillary lymph node positive, were randomized on this trial. Initial results after a median follow-up of two years showed a significant benefit in anastrozole group with hazard ratio of 0.36 for risk of relapse (95% confidence interval = 0.17 to 0.75; p value = 0.006). The hazard ratio of death was 0.18 (CI = 0.02-1.57; p value = 0.07). Although serious adverse events were reported more frequently in patients on Tamoxifen arm, the detailed results from this study are awaited.How can we apply these results to our adjuvant therapy decision-making in postmenopausal women with breast cancer? The pertinent issues are now discussed under the following sub-headings:The first question is which AI to use and in which situation. The following two approaches are considered and discussed as below.

Timeline approach

These trials have used three landmarks on the treatment timeline for breast cancer patients (( figure 1 )). Considering the evidence based medicine approach, each trial has proved the superiority of a particular AI at one particular time point in the adjuvant phase of treatment. Thus logically, an individual patient would be best treated with a particular AI proven efficacious at that treatment time. Taking this approach, anastrozole appears best for patients starting the adjuvant hormonal therapy. Patients who have completed five years of adjuvant tamoxifen will be best suited to start Letrozole and the patients who have been on tamoxifen for two or three years will benefit from switching over to exemestane.
Table 1 Summary of adjuvant AI trials

Trial

ATAC

MA-17

IES

ITA

Plan of treatment

Anastrozole alone, tamoxifen alone, anastrozole + tamoxifen for 5 yrs

Tamoxifen for 5 yrs then letrozole or placebo for 5 yrs

Tamoxifen for 5 yrs vs. tamoxifen for 2-3 yrs then exemestane for 2-3 yrs

Tamoxifen for 5 yrs vs. tamoxifen for 2-3 yrs then anastrozole for 2-3 yrs

No. of patients

9,366

5,157

4,742

426

Median follow-up (at the time of analysis)

47 months (6% patients completed randomized treatment; 47% patients completed at least 4 yrs)

30 months (< 1% patients completed randomized treatment)

30.6 months (> 90% patients completed randomized treatment)

36 months (all patients completed randomized treatment)

ER-positive (%)

84% (8% unknown)

98% (2% unknown)

81% (17% unknown)

86% (tamoxifen, 14% unknown) vs 91% (anastrozole, 8% unknown)

Tumor size < 2 cm

63.9%

57%

Unknown

44-49%

Node-positive (%)

35% (5% unknown)

46% (4% unknown)

44% (4% unknown)

100%

Chemotherapy

22%

46%

32%

67%

Improvement in absolute risk of recurrence

2.4% for anastrozole

Estimated at 4 yr: 6%

4.7% for exemestane

10% for anastrozole

Overall survival reported to date

No difference

No difference

No difference

No difference

Treatment withdrawals

More with tamoxifen

Equal in both arms

More with exemestane

Equal in both arms

Comments

DFS benefit consistent and increasing with time

Unblinding and cross-over may not reveal safety, optimal duration and efficacy etc.

Fractures and osteoporosis found more in Exemestane arm as were treatment withdrawals

Relatively Small number of patients. All were node-positive therefore earlier and prominent difference


Table 2 Adverse events in AIs adjuvant therapy trials

Toxicity (%)

ATAC (A vs T)

MA-17 (L vs P)

IES (E vs T)

ITA (A vs T)

Endometrial cancer

0.1 vs 0.7 a

NA

NA

NA

Vaginal bleeding

4.8 vs 8.7 a

4.3 vs 6 a

4 vs 5.5 a

NA

Cerebrovascular events

1.1 vs 2.3 a

4.1 vs 3.6

NA

NA

Thromboembolism

2.2 vs 3.8 a

NA

1.3 vs 2.4 a

1.8 vs 1.3

Hot flashes

35 vs 40 a

47.2 vs 40.5 a

42 vs 39.6

Musculoskeletal disorders

30.3 vs 23.7 a

NA

NA

7.2 vs 5.8

Fractures

7.1 vs 4.4 a

3.6 vs 2.9

NA

0.9 vs 0.9

Arthralgia

NA

21.3 vs 16.3 a

5.4 vs 3.6 a

NA

Myalgia

NA

11.8 vs 9.5 a

NA

Diarrhea

NA

NA

4.3 vs 2.3 a

NA

Gynecologic symptoms

NA

NA

5.8 vs 9 a

6.3 vs 4

Osteoporosis

NA

5.8 vs 4.5 (self reported)

7.4 vs 5.7 a

NA

Gastrointestinal symptoms

NA

NA

NA

6.3 vs 1.3 a

aStatistically significant.

Extrapolated approach

Is it reasonable to consider that the AIs exert their effect as a class of drugs? Based on this assumption, could we replace tamoxifen or anastrozole with letrozole or exemestane and use them at time points different than how they were used in their respective trials? Following the evidence from the published trials, this does not appear to be an acceptable approach. The results from different adjuvant hormonal therapy trials using exemestane and letrozole are awaited and will provide the answer to this question. It certainly seems possible that AIs with their demonstrated superiority in metastatic setting will continue to enjoy similar importance in adjuvant stage of treatment.

Is sequential therapy better?

Sequential therapy will utilize the maximum therapeutic benefit of tamoxifen and then a continued (and perhaps a better) coverage by an AI. There is certainly a hint from both ITA (anastrozole) and IES (exemestane) study that AIs after an initial use of tamoxifen provide additional benefit of disease free survival compared to tamoxifen alone. In addition, distant disease free survival seen in IES trial is an important finding and perhaps a better marker for overall efficacy [17]. It is possible that the results of adjuvant trials with letrozole and or exemestane may provide even superior results compared to sequential therapy (IES/ITA trials) and may become the standard therapy. At present, it certainly seems better to switch patients who have completed two to three years of tamoxifen to exemestane (based on IES trial results). The result from Big Femta trial specifically (comparing letrozole with tamoxifen both in a head to head and in a cross over design) may shed more light on this issue and possibly in a more conclusive manner.

Selection of patients

The American Society of Clinical Oncology (ASCO) technology assessment report recommended AIs to reduce the risk of recurrence for postmenopausal women with hormone receptor positive breast cancer [18]. This report has noted that the only subgroup to achieve a survival advantage comprised of lymph node positive patients in MA-17 study. Many postmenopausal breast cancer patients will have a relatively small risk of recurrence to begin with and with adjuvant treatment this risk may significantly decrease. Therefore it may appear attractive to just treat patients with AIs only if they have a high-risk disease. However, the trials using AIs did not include only high-risk patients. In fact, majority of participating patients were lymph node negative or with tumors less than or equal to 2 cms (table 1). Therefore we recommend discussing risks and benefits of the treatment with AIs with all women considered eligible for ATAC, EIS and MA.17 trials, or who are considered eligible for adjuvant tamoxifen therapy.

Any role of tamoxifen?

Is there now a role for adjuvant tamoxifen? The efficacy and side effects of tamoxifen are extremely well known and discussing the use of tamoxifen with the patients in an adjuvant setting is quite easy.

Although the results of adjuvant trials with AIs are showing improved DFS but there has been no survival advantage evident. In addition, due to a lack of long term follow up or cross over of treatments, the toxicities related to AIs are not well defined. Therefore, it is difficult to discuss the exact risk-benefit ratio and have a balanced picture for the patients to decide about using AIs and not to use tamoxifen.

From a global angle however, it appears that AIs are at least as effective as tamoxifen (considering the overall survival) or better (considering DFS). These agents lack the more serious side effects of tamoxifen and have an overall better toxicity profile. Certainly more time is needed to draw absolute conclusions but at present AIs appear a better choice in adjuvant therapy plans for postmenopausal women with breast cancer.

Some patients may still opt for tamoxifen, especially who have a relatively low risk of recurrence and/or less likelihood of developing serious side effects (for example a patient with hysterectomy). Patients with severe osteoporosis or arthritis, especially with a low risk of recurrence, may be better off with tamoxifen. In addition, personal preference and cost may be other factors in choosing tamoxifen. The field of adjuvant hormonal therapy is in rapid flux and therefore it may seem reasonable in a few cases to just start with tamoxifen and reconsider the options when further trial results are available.

Follow up of patients on AIs

A decision to use an AI should only be made after a full discussion of the benefits and risks of treatment and an appropriate plan of follow up. We usually recommend that all women starting adjuvant AIs should have a baseline bone density test with follow up testing every one or two years. Patients with no prior history of osteopenia or fragility fracture should be started on calcium 1500 mg and vitamin D 800U daily. Furthermore at least 30 minutes of physical activity three times a week is recommended. Those with documented osteopenia or osteoprosis or with prior fragility fracture should be started on an oral bisphosphonate.

Is economy a possible problem?

AIs are more expensive than tamoxifen. On the other hand, several papers have described AIs as cost-effective compared to other medical interventions. Therefore the cost consideration should not pose any significant problem in using Ais [19,20].

Quality of life

The results of two different trials show that the quality of life appears unaffected with the use of AI compared to tamoxifen or placebo, in the women who participated in the adjuvant AI trials [12,21]. The relatively low toxicity profile of AIs observed in these trials is apparently not significant in magnitude compared to placebo or tamoxifen, to affect the quality of life. However, the quality of life can be dependent on several related and unrelated factors to the therapy used and therefore may not reflect the sole impact from AIs. As an example, women treated with anastrazole in ATAC trial significantly less often felt hot flashes and vaginal discharge. But these women experienced vaginal dryness, dysparuenia and loss of interest in sex more frequently [22].

Postmenopausal status

AIs are only indicated for postmenopausal women. The use of AIs in premenopausal women may induce an initial drop in estrogen levels followed by a feed back increased secretion of gonadotropic hormones and eventually raise the total estrogen levels. The IES trial used stringent criteria to ascertain postmenopausal status (age > 55 years with amenorrhea > 2 years or amenorrhea > 1 year at the time of diagnosis). The ATAC and MA-17 trials included women who were initially premenopausal but became amenorrhic after chemotherapy, for more than one year or had postmenopausal range follicle stimulating hormone (FSH) with less than one year of amenorrhea. Such women were small in number in both these trials and a generalized approach to routinely treat such women with uncertain menopausal status with AIs is clinically concerning.

HER-2/Neu and AIs

In the ATAC trial a subgroup analysis for patients with ER+ but PR- tumors found that these patients had a significantly prolonged time to recurrence when treated with tamoxifen [23]. The hazard ratio for ER+/PR- was 0.43 with anastrozole compared to 0.84 if the tumors were ER+/PR+. This is a retrospective analysis but with a large number of patients. It remains as an interesting point to be considered for patients chosen to be treated with an initial AI.

Several studies have pointed out lower response of hormonal therapy, particularly tamoxifen, in breast cancer patients in whom HER-2/neu is over-expressed [24,25]. Although this effect was not seen in other studies [26,27], AIs tend to be favored by the oncologists in such patients. At present, with all the published studies, a decision to use specific hormonal therapy based on the HER-2/neu status is not justified [28].

Conclusion

It is an exciting time period for oncology to see the rapidly changing face of the adjuvant therapy for breast cancer patients. Although tamoxifen remains as a standard therapy, the results from AI trials provide compelling evidence that AIs have emerged as superior hormonal agents and offer significant advantage over tamoxifen. It is expected that with the support of completed AIs trial data, these agents will be used more frequently in the adjuvant setting. As patients are now better educated through media and the Internet, the demand for the AIs has significantly increased. We have certainly seen this to be the case at our cancer centre. The long term follow up of completed trials and the results from the ongoing AI trials are eagerly awaited and will help present a better risk-benefit picture to our breast cancer patients.

Acknowledgements

We appreciate the secretarial skills of Ms. Mahnoor Jawaid in preparation of this manuscript.

References

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