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Young hopefuls

Can aromatase inhibitors become the new Gold standard in breast cancer care?

Breast cancer ranks second only to lung cancer as the leading cause of cancer-related deaths and is the most commonly diagnosed cancer among women, with the exception of non-melanoma skin cancers.

In 2005, more than 1.2 million people worldwide will be diagnosed with breast cancer, according to the World Health Organisation (WHO). Approximately 90 per cent of patients with invasive cancer are diagnosed with localised (stage I or II) disease, which occurs mostly in post menopausal women.

The majority of all breast cancers among post menopausal patients are hormone-dependent, involving tumour growth driven primarily by oestrogen. In this light, the selection of chemotherapy for such patients is based on oestrogen-receptor (ER) status.

Patients with ER-positive tumours often respond well to hormonal therapies targeting the ER signalling pathway and have a better clinical outcome compared to those with ER-negative tumours.

Since the early 1980s, tamoxifen has been the hormonal treatment of choice for patients with all stages of hormone receptor-positive breast cancer. This Gold standard is a selective oestrogen receptor modulator (SERM) that competitively blocks the effect of oestrogen at the ER binding site, particularly in breast tissue.

However, tamoxifen also mimics the action of oestrogen on the cardiovascular, skeletal and reproductive tissues, which causes side effects.

Long-term use of tamoxifen in the adjuvant setting has revealed other disadvantages, including limited duration of efficacy, continued risk of relapse after standard treatment and acquired resistance to the drug.

Aromatase inhibitors

In contrast to tamoxifen, aromatase inhibitors (AIs) reduce circulating levels of oestrogen in the body and also block local oestrogen production in breast tumours.

AIs are compounds that interfere with aromatase, the enzyme present in adi-pose tissue and adrenal glands of post menopausal women that transforms androgens into oestrogens.

Anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin) are third-generation AIs that are proving to be at least equivalent to, and perhaps better than, tamoxifen as first-line treatment for hormone-sensitive metastatic breast cancer, and are effective adjuvant therapies for post menopausal patients with early-stage breast cancer.

Crucially, AIs are also less likely to cause vaginal bleeding, blood clots and uterine cancer in comparison to tamoxifen.

Anastrozole, a non-steroidal AI developed by AstraZeneca, has been approved as an adjuvant treatment for hormone-sensitive early breast cancer in post menopausal women in over 79 countries, including the US, Europe and Japan.

AstraZeneca believes that evidence-based medicine would favour anastrozole as the first-choice adjuvant because it is the most studied AI.

The agent demonstrated significant superiority over tamoxifen in both the adjuvant and adjuvant-switching settings based on results from the Arimidex, tamoxifen Alone or in Combination (ATAC) study and combined data analysis from the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) and Arimidex-Nolvadex 95 (ARNO 95) studies.

Novartis' letrozole has been approved for extended adjuvant treatment of early breast cancer among post menopausal women following standard tamoxifen therapy in more than 57 countries.

Approval was based on data from the MA-17 trial, which showed that the nonsteroidal AI significantly reduced risk of recurrence and improved disease-free survival among patients who completed adjuvant tamoxifen therapy for five years.

Novartis is also seeking Food and Drug Administration (FDA) approval for letrozole as adjuvant treatment in post menopausal women with hormone receptor-positive early breast cancer after surgery.

Findings from the Breast International Group 1-98 (BIG 1-98) trial similarly has shown letrozole to be more beneficial than tamoxifen in the adjuvant setting.

However, data from two parts of the study, in which patients switched from tamoxifen to letrozole (or vice versa), will only become available in 2008.

Exemestane, a steroidal AI developed by Pfizer, has been approved in Europe and New Zealand for the adjuvant treatment of ER-positive early breast cancer after two to three years of initial adjuvant tamoxifen therapy in post menopausal women. It is under FDA review for this in the US.

Results from the Intergroup Exemestane Study (IES) trial showed that switching to exemestane after two to three years of tamoxifen was more effective than continuing with tamoxifen for the full five years. However, Pfizer is still evaluating whether exemestane offers a better treatment option than tamoxifen after surgery - such findings are expected in 2008.

Implications and strategies

In light of the available trial data, three new approaches to adjuvant treatment have emerged and are being evaluated:

(i) Extended adjuvant therapy: undergo tamoxifen therapy for five years after surgery, and then take an aromatase inhibitor for an additional period

(ii) Early sequential adjuvant therapy: begin tamoxifen therapy, and after two to three years switch to an
aromatase inhibitor for the remainder of a five-year treatment period after surgery; and

(iii) Early adjuvant therapy: take an aromatase inhibitor exclusively instead of tamoxifen for five years after surgery.

Up for discussion

The role of AIs in early-stage breast cancer has generated a great deal of discussion among breast cancer experts worldwide.

The American Society of Clinical Oncology panel has recommended that optimal adjuvant hormone therapy for a post menopausal woman with receptor-positive breast cancer includes an AI as initial therapy or after treatment with tamoxifen.

The panel also recommended the risks and benefits of all potential therapies should be carefully considered. This call to action was supported by the St Gallen consensus panel, which confirmed that five-year treatment with an AI is one of the best options to replace tamoxifen for post menopausal women with hormone-sensitive disease to prevent relapse after surgery.

However, tamoxifen is still considered to be the standard hormonal treatment to prevent recurrence among women with hormone-sensitive breast cancer.

Any changes to current guidelines for adjuvant treatment will be based on the availability and maturity of clinical data in the appropriate clinical setting.

Anastrozole is the preferred AI for adjuvant treatment of early-stage breast cancer. This is because it is the only one that has solid clinical evidence of its efficacy and side effects.

The comparative toxicity between the AIs could also influence the decision on which option to take. While all three AIs appear to share broadly similar toxicity profiles, anastrozole does not exhibit seemingly minor increases in cardiac toxicity seen with letrozole and exemestane; the incidence of such side effects could be attributable to chance, but needs careful monitoring.

Risk factors

Clinical studies have consistently shown that AIs were associated with adverse effects, including joint pain, vaginal dryness and dyspareunia, which were bothersome in a small number of patients.

Another side effect appears to be an increased tendency for fractures and it remains unclear if treatment with calcium, vitamin D, and other drugs can prevent this.

Finally, the problem of resistance to AI therapy must be addressed and several treatment strategies have been proposed.

Recent studies on mammary tumour cell lines deprived of oestrogen or exposed to an AI have indicated that targeted agents such as AstraZeneca's fulvestrant (Faslodex), as well as gefitinib (Iressa), Genentech/Roche's trastuzumab (Herceptin) and a variety of farnesyl transferase inhibitors could be used to delay, or even reverse, resistance.

The author
Pipeline was written by Darrell Ng of Wolters Kluwer Health (Adis International), using data derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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