Arimidex.jpg (8892 bytes) Hormonal Therapy in Breast Cancer

It used to be quite simple to use hormonal therapy, patients would get Nolvadex (tamoxifen) then if they progressed they would receive Megace (megestrol) then aminoglutethamide then finally testosterone.}

 Now the aromatase inhibitors (Femara, Aromasin and Arimidex) have been shown to be superior to Tamoxifen (go here and see review #1 of new drugs, review #2, review #3, review #4 , review #5 and the section on hormone receptors.) An old technique was radiation ablation of the ovary (see here)

 
There are now several categories that include:

  - aromatase inhibitors : Femara (letrozole), Aromasin (exemestine) or Arimidex (anastrazole)
  - other anti-estrogen drugs like Faslodex (fulvestrant)
  - or selective estrogen receptor modulators or SERMS :Fareston (toremifine), Evista (raloxifene), Nolvadex (tamoxifen)

A discussion of these is noted in the abstract section. (The NCCN guidelines (go here for adjuvant and here for metastatic) now recognize the aromatase inhibitors as an alternative to Tamoxifen for adjuvant hormonal therapy and as first line therapy for metastatic or recurrent disease.)

for more on tamoxifen go here and more on Femara go here and more on Arimidex go here and more on Faslodex (fulvestrant) go here, and reviews of aromatase inhibitors by Smith and by Buzdar.   Also both Tamoxifen and Evista can be used to prevent breast cancer (go here)

In 1977 the FDA approved tamoxifen (Nolvadex) as hormonal therapy for breast cancer. Over the years is was determined that women whose breast cancer cells were sensitive to hormonal therapy (i.e. have positive estrogen/progesterone receptors) would likely respond to tamoxifen. Initially this drug was thought of as an anti-estrogen but it became clear that had both anti-estrogen effects and well a mimic of estrogen effects and later was reclassified as a SERM (selective estrogen receptor modulator) a class which also includes Fareston and Evista. The good thing about the estrogen effect was that Tamoxifen would prevent osteoporosis, the bad thing was that it would increase the risk of blood clots and uterine cancer. Also tumors would become resistant to tamoxifen. The newer SERM's (Fareston and Evista) may not increase the risk of endometrial cancer and are being studied.

The next improvement was drugs that would prevent the body from making estrogen by blocking the enzyme aromatase (found in fat, muscle and liver) that converts androgens from the adrenal gland  into estrogens (estrone and estradiole.) These drugs (aromatase inhibitors) which include Femara, Aromasin and Arimidex are more effective than Tamoxifen and produce no estrogen effect so they do not increase the risk of blood clots or uterine cancer. These drugs are being intensively studied and are likely to replace Tamoxifen in postmenopausal women. (They are not effective in premenopausal women because that aren't strong enough block production of estrogen from the ovaries. Another drug like Zoladex (chemical name: goserelin acetate)  may shut down the ovaries in premenopausal women.) Also another new class of drugs are true anti-estrogens (Faslodex) which also appears to be superior to Tamoxifen. Read the many links above.

In postmenopausal women who are candidates for adjuvant hormone therapy... there is more evidence that Arimidex is better than Tamoxifen with 13% better disease-free survival, 14% lower risk of metastases and 42% lower risk of cancer developing on the other breast...see below

Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer

ATAC Trialists' Group*   Lancet. Volume 364, Number 9451 11 December 2004

The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor-positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0·87, 95% CI 0·78-0·97, p=0·01) and time-to-recurrence (402 vs 498, 0·79, 0·70-0·90, p=0·0005), and significantly reduced distant metastases (324 vs 375, 0·86, 0·74-0·99, p=0·04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0·01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.

Optimizing Adjuvant Endocrine Therapy in Postmenopausal Women With Early-Stage Breast Cancer: A Decision Analysis
Rinaa S. Punglia, JCO Aug 1 2005: 5178–5187.

The optimal adjuvant endocrine strategy for postmenopausal breast cancer is unknown. Options include the antiestrogen tamoxifen, estrogen deprivation with aromatase inhibitors, and sequential therapy with tamoxifen and then an aromatase inhibitor. We developed Markov models to simulate 10-year disease-free survival among postmenopausal women with hormone receptor–positive breast cancer. The treatment strategies analyzed were 5 years of tamoxifen alone, 5 years of an aromatase inhibitor alone, and sequential treatment consisting of tamoxifen with cross over to an aromatase inhibitor at 2.5 or 5 years. Risk estimates were derived from reported randomized clinical trials.

RESULTS: Sequential therapy with tamoxifen followed by cross over to an aromatase inhibitor at 2.5 years yielded a modest improvement in disease-free survival compared with planned aromatase inhibitor monotherapy. At 10 years, the cross-over strategy yielded absolute disease-free survival rates of 83.7% and 67.6% for node-negative and node-positive patients, respectively, compared with 82.6% and 65.5%, respectively, for aromatase inhibitor monotherapy, which is a 6% relative risk reduction. Sequential therapy improved disease-free survival estimates by year 6 after treatment initiation. Later cross over from tamoxifen to an aromatase inhibitor at 5 years did not further improve 10-year disease-free survival estimates. Sensitivity analyses suggest that sequential treatment strategies optimized 10-year disease-free and distant disease–free survival independent of the degree of the beneficial carryover effect after aromatase inhibitor therapy or the ratio of local to distant tumor recurrence.

CONCLUSION: Modeling estimates suggest that sequential adjuvant therapy with tamoxifen followed by an aromatase inhibitor after 2.5 years yields improved outcomes compared with either drug alone or cross-over treatment after 5 years of tamoxifen.