26 december 2017:

Dit studierapport: Endocrine Therapy for Early Breast Cancer: Updated Review is zover ik kan vinden de meest recente publicatie over de plaats van hormoontherapie bij borstkanker.

En lees ook dit artikel: 


27 juni 2012: er is zoveel gepubliceerd over hormoonremmers, aromaseremmers enz. voor de behandeling van borstkanker dat het onmogelijk is dat allemaal hier te publiceren. Als u naar oncoline-borstkanker gaat dan staat daar in de NABON nota in ieder geval wat de huidige richtljnen zijn voor borstkanker, maar ook dat is geschreven in medische taal en zeer uitgebreid.

Dit artikel: Construction of a database for the evaluation and the clinical management of patients with breast cancer treated with antiestrogens and/or aromatase inhibitors 

geeft een Engelstalig overzicht van hormoontherapie en aromaseremmers bij borstkanker. Hier het abstract van dit artikel.


SOD Malattie del Metabolismo Minerale ed Osseo, AOU Careggi, Florence, Italy.


Breast cancer, mostly exhibiting an hormone-dependent pathogenesis, is a commonly diagnosed cancer in females.It is well known that sex steroids favor the process of carcinogenesis of breast tissue and anti-hormonal therapy of breast cancer aims to decrease the action of estrogens on this tissue. For this purpose, two different compounds are prevalently used: the Selective Estrogen Receptor Modulators, preventing the cancer cell to interact with estrogens, and Aromatase Inhibitors, inhibiting the tissue conversion of androgens into estrogens. Unfortunately, latter treatments negatively impact on bone mass leading to the onset of osteoporosis. For this purpose, we propose to build a database to afford, to store and analyze information about the effects of treatment with Selective Estrogen Receptor Modulators and/or Aromatase Inhibitors on bone metabolism in patients with breast cancer referred to Our Center. We will focus on the possibility of intervening to reduce the negative effects on bone both by the identification of modifiable risk factors and administration of specific therapies, in order to create a therapeutic, diagnostic standard workup for these diseases.

[PubMed - in process]

Aromatase Inhibitors Vs Tamoxifen: A Changing of the Guard? from Medscape Hematology-Oncology eJournal 
Harold J. Burstein, MD, PhD
Aromatase inhibitors are among several types of hormonal therapies effective in treating women with estrogen receptor (ER)-positive breast cancer. Recent studies have demonstrated the utility of aromatase inhibitors both in women with advanced breast cancer and in women with early-stage breast cancer.
This review will summarize the biology of aromatase inhibitor therapy, and discuss results of trials comparing aromatase inhibitors with tamoxifen and other hormonal agents. Several comprehensive recent reviews of therapy with aromatase inhibitors are also available.[1,2]
Biology and Classification of Aromatase Inhibition
Aromatase inhibitors are drugs that inhibit the activity of the enzyme estrogen synthetase, which converts the androgen androstenedione and testosterone into estrone (E1) and estradiol (E2), respectively. In postmenopausal women, peripheral aromatization of androgens into estrogens takes place in the liver, fat, muscle, skin, and even breast tissues, including malignant breast tumors, giving rise to low levels of circulating estrogen. With use of modern aromatase inhibitors, these levels are further suppressed by 80% to 90%, often to levels of estradiol that are undetectable by older assays.[3]
By contrast, premenopausal women have functioning ovaries that also synthesize estrogens. Aromatase inhibitors are not appropriate for premenopausal patients for a number of reasons. First, higher circulating levels of androgens present in premenopausal women compete with aromatase inhibitors for the aromatase enzyme complex, resulting in less efficient suppression of estrogen production. Second, hypothalamic/pituitary feedback mechanisms in premenopausal women mean that lower serum estrogen levels lead to compensatory changes in the ovary, including upregulation of aromatase enzymes in the ovary, that render aromatase inhibitors ineffective.

For these reasons, clinical trials of aromatase inhibitors have, to date, generally excluded premenopausal women. While some newer aromatase inhibitors may be able to suppress estrogen production in premenopausal women, this approach remains experimental. All data discussed in this review reflect experience with postmenopausal women, only.

Aromatase inhibitors are classified as steroidal (type I) if the chemical structure resembles that of steroidal hormones, and as nonsteroidal (type II) if alternate structures are used to inhibit the aromatase enzyme. Some inhibitors may be "irreversible" in that they bind covalently to the aromatase enzyme, or "reversible" if noncovalent binding occurs.

While there are theoretical arguments as to which aromatase inhibitor strategy (steroidal/nonsteroidal; reversible/irreversible) is optimal, all currently available agents suppress estrogen synthesis to comparable degrees in postmenopausal women, and clinical data are not available supporting the use of one type of aromatase inhibitor over another.

The first-generation aromatase inhibitor aminoglutethimide was approved for treatment of advanced breast cancer in the 1970s. Aminoglutethimide inhibited corticosteroid synthesis in the adrenal gland as well as estrogen production, and for this reason necessitated supplemental hydrocortisone therapy. Other side effects of aminoglutethimide included lethargy, vertigo, rash, and mood disturbance. Second-generation aromatase inhibitors include agents such as formestane and fadrozole. While these older drugs have been used in many important clinical trials, including tests of principle for single-agent and combination-agent therapy, their clinical applications are principally of historical interest.

Presently, there are 3 orally available third-generation aromatase inhibitors approved for use in the United States -- the reversible, nonsteroidal agents anastrozole and letrozole, and the irreversible steroidal inhibitor exemestane. Because of their approvals for clinical use, ease of administration, potency, and the large body of available clinical data, these 3 drugs will be the focus of the remainder of this review.
Aromatase Inhibitors for Metastatic Breast Cancer: Tamoxifen-Refractory Patients
Third-generation aromatase inhibitors were initially evaluated in patients with hormone-refractory breast cancer, usually patients with ER-positive tumors resistant to tamoxifen therapy. After initial demonstrations of clinical activity in phase 1 and 2 studies, aromatase inhibitors were then evaluated in randomized phase 3 trials as second-line agents, usually against megestrol acetate, a common second-line hormonal treatment option.
Results of 4 representative randomized trials of aromatase inhibitors vs megestrol acetate or aminoglutethimide as second-line therapy are shown in Table 1.[4-7]

Because of differences in patient populations and treatment evaluations, it is not meaningful to compare results from these studies vs each other. However, certain clear trends emerge from the major findings. In each instance, third-generation aromatase inhibitor therapy proved at least as effective as megestrol acetate or aminoglutethimide, and, in all instances, trends for response rate, time to progression, and survival tended to favor the newer aromatase inhibitors.

Side-effect profiles were generally comparable, with patients experiencing more menopausal symptoms (hot flashes) with aromatase inhibitors, but less weight gain. Formal quality-of-life studies, when completed, tended to favor use of aromatase inhibitors. Based on this collective experience, aromatase inhibitors rapidly became the preferred second-line therapy for patients with ER-positive metastatic breast cancer, refractory to tamoxifen.

The utility of treatment with 1 third-generation aromatase inhibitor after prior aromatase inhibitor therapy remains unclear. There are 2 reports on the efficacy of the steroidal inhibitor exemestane following other nonsteroidal aromatase inhibitor treatment. Among 80 patients previously treated with aminoglutethimide, exemestane led to objective response in 26% of women.[8]

In a second, larger report, a total of 241 patients received exemestane after progressing on aminoglutethimide (n = 136) or other aromatase inhibitor (n = 105).[9] Objective responses were seen in 8% of patients previously treated with aminoglutethimide, and 4.8% of patients previously treated with a third-generation nonsteroidal aromatase inhibitor. These results suggest that some noncross-resistance for different aromatase inhibitors may exist, though the absolute magnitude of such clinical benefit may be quite modest. More trials are clearly needed to answer this compelling question.

Aromatase Inhibitors for Metastatic Breast Cancer: First-Line Trials Against Tamoxifen
Based on the utility of aromatase inhibitors as treatment for tamoxifen-refractory breast cancer, a number of randomized trials proceeded to compare aromatase inhibitors vs tamoxifen. Several of these trials are summarized in Table 2.
Again, the particular features of these trials do not allow comparison between the studies. Within each study, however, familiar patterns can be discerned. Response rates to aromatase inhibitor therapy tend to be at least as good as with tamoxifen, with time to progression being generally comparable. When differences do exist, they tend to favor up-front use of aromatase inhibitors. However, dramatic survival differences have not been observed in these trials, perhaps in part because of crossover therapy with the other agent.

The side effect profiles of aromatase inhibitors and tamoxifen have been generally comparable, with roughly equivalent rates of menopausal symptoms (hot flashes, vaginal dryness), gastrointestinal disturbance, and weight gain. Some but not all studies have suggested that aromatase inhibitor therapy may be associated with a reduced rate of thromboembolic events (stroke, deep venous thrombosis) compared with tamoxifen.

The collective data from these trials support the use of aromatase inhibitors as first-line or second-line therapy for ER-positive, metastatic breast cancer in postmenopausal women. It is important to note that the size of these clinical trials and consistency of the findings in the second-line and first-line trials of advanced disease, have both set the stage for the randomized adjuvant studies, following clinical familiarity and acceptance of these drugs.

Aromatase Inhibitors in the Adjuvant Setting: Available Data
Two large studies have now reported experience with aromatase inhibitors in the adjuvant setting. The most relevant study, the ATAC trial, was a traditional randomized trial for women with operable breast cancer. The second study, a neoadjuvant trial comparing tamoxifen with letrozole as preoperative therapy, does not have data on long-term disease outcomes. While data from these trials are of recent vintage, the large scale of the ATAC study in particular (it is the largest prospective treatment study in cancer medicine) makes the results quite powerful.
The ATAC study, supported by AstraZeneca, the manufacturer of both tamoxifen and anastrozole, was an international effort, recruiting patients from 29 countries, and representing the largest randomized trial ever reported among cancer patients. More than 9000 women were enrolled on the study between July 1996 and March 2000. An original accrual goal of approximately 6000 patients was extended to more than 9000 when it was clear that the event rate among the initial 6000 was relatively low.

Eligible women were postmenopausal, and had ER-positive or unknown early stage breast cancer. Patients were randomized to 3 treatment arms: anastrozole, tamoxifen, or both, and the study was placebo-controlled. The major findings of the ATAC trial are summarized in Table 3. Data were presented with median follow-up of 2.5 years, representing 1079 events, and 766 events among women with ER-positive tumors.

Overall, there was a statistically significant reduction in events for anastrozole compared with tamoxifen (hazard ratio 0.83), but not for combination therapy compared with tamoxifen (HR 1.02). This translated into an absolute difference in event recurrence of approximately 1.5% at 42 months follow-up. Most patients had a very good prognosis, with an actuarial event-free survival at 3.5 years of 90% or better.

Among women with ER-positive tumors, the HR for events was 0.78 in favor of anastrozole compared with tamoxifen or combination therapy. There was an approximately 60% reduction in the incidence of contralateral breast cancer among women on anastrozole vs tamoxifen or the combination. Given the large size of the study, these differences were highly statistically significant.

The side effect profiles of therapy differed slightly. Women taking anastrozole were less likely to report hot flashes, weight gain, vaginal bleeding or dryness, or to have endometrial cancer or thromboembolic events. Women on tamoxifen reported fewer arthralgia symptoms and had fewer bone fractures, including fewer fractures in the hip, spine, and wrist, which are common sites for osteoporotic fractures.

There are several points to consider when reviewing these preliminary data:
The initial events reported include nonbreast cancer deaths (which greatly outnumbered breast cancer deaths) and contralateral breast cancers. The reduction in contralateral breast cancer risk seen with anastrozole contributes a disproportionate benefit to the anastrozole arm when measuring event-free survival. The occurrence of distant metastases also tended to favor anastrozole, but the differences were smaller between the groups. Thus, the effect of anastrozole vs tamoxifen on the natural history of the primary breast cancer may be more modest than suggested by the aggregate data.

There were very few reported breast cancer deaths -- 5 among 9366 patients. There were no differences in the numbers of breast cancer or nonbreast cancer deaths between the groups.

It is not clear why the combination therapy arm yielded results similar to tamoxifen as opposed to anastrozole. It was hypothesized that in the very low estrogen environment achieved in postmenopausal women treated with aromatase inhibitors, tamoxifen may paradoxically act as an estrogen agonist.

In addition, several significant "caveats" need to be borne in mind when considering whether to use anastrozole in preference to tamoxifen. This is but a single trial, albeit a very large one. Confirmatory trials are currently underway (see below).
The optimal duration for adjuvant aromatase inhibitor therapy is not known. The 5 years of therapy proposed in ATAC were designed to mirror the current recommendation for tamoxifen. However, that duration of tamoxifen therapy was derived through randomized trials comparing 1, 2, 5, and 5+ years of treatment. The follow-up in the ATAC study remains quite short, the number of cancer-related events relatively low, and there are minimal data for women having taken 5 years of anastrozole. Finally, the longer-term side effects of that therapy, perhaps including osteoporosis, are not yet known.

Neoadjuvant use of aromatase inhibitors has also been evaluated in a large, prospective, randomized comparison with tamoxifen. In this trial, postmenopausal women with ER- and/or PR-positive primary breast tumors were randomized to 4 months of preoperative therapy with either letrozole or tamoxifen. The major findings are shown in Table 4.

This trial demonstrated that aromatase inhibitor therapy achieved a higher rate of clinical response in the neoadjuvant setting, with an important clinical consequence: a greater likelihood of breast-conserving surgery

Aromatase Inhibitors in the Adjuvant Setting: Ongoing Trials
The results of the ATAC study and the neoadjuvant trial with letrozole are very provocative, and clearly justify further exploration of aromatase inhibitors as both adjuvant treatments and as preventive agents for women at risk for breast cancer. Several large randomized trials are still underway, and clinicians with patients interested in aromatase inhibitor therapy should encourage appropriate patients to consider participation in these trials.
The BIGFEMTA study is a 4-arm trial comparing 5 years of tamoxifen, 5 years of letrozole, or sequenced therapy of 2 ‡ 3 years each starting with either tamoxifen or letrozole. In the ARNO trial, women receive 2 years of tamoxifen followed by randomization to 3 years of either anastrozole or tamoxifen. In the ICCG trial, women receive 3 years of tamoxifen followed by 2 years of either tamoxifen or exemestane.

A number of trials are evaluating the use of aromatase inhibitor therapy beyond the standard 5 years of tamoxifen. In the past, continuation of tamoxifen therapy beyond 5 years has not been shown to improve clinical outcomes. The Canadian cooperative group is leading a trial of letrozole vs placebo for women who remain free of recurrence through 5 years of tamoxifen, and the NSABP is studying exemestane vs placebo for a similar group of patients.

These studies have taken on particular urgency in the wake of recent reports. Questions of sequencing, duration, and combination therapy remain to be explored. As with many important scientific advances, more questions arise than may be answered only by new data.

Aromatase Inhibitors in the Adjuvant Setting: For Whom?
Based on the preliminary results of the ATAC study, many postmenopausal patients will be interested in discussing aromatase inhibitor therapy as an option for treatment of ER-positive, early-stage breast cancer. What counsel can physicians provide such patients?
There has been a temptation to try to use the ATAC study to define a new "gold standard" suitable for all patients. A better strategy is probably to try to understand the ATAC data, and use the information to help individual patients make informed choices. It is important to recall that the recommendations for tamoxifen are built upon survival differences based on collective analyses of 55 randomized trials begun in the 1980s with a total of more than 36,000 patients and long follow-up.

As yet, there is no survival advantage known for use of an aromatase inhibitor vs tamoxifen among postmenopausal women. Thus, the data from the ATAC trial are provocative and may yet demonstrate long-term superiority vs tamoxifen, but they are currently not definitive yet.

A particular concern is the lack of long-term follow-up for both efficacy and safety. While aromatase inhibitors are generally well tolerated, there are concerns about late side effects, including the possibility of osteoporosis, which may be significant in women with very favorable breast cancer prognoses.

As discussed above, the ATAC trial does not address questions of sequences of hormonal therapy, nor of durations of therapy, and additional confirmatory trials will be available in the near future. Nonetheless, patients will undoubtedly be interested in advances in hormone therapy, and the ATAC study. Appropriate patients can be encouraged to participate in ongoing trials of various hormonal options.

Aromatase inhibitor therapy may be a reasonable option for some patients, including those particularly concerned about or at risk for thromboembolic disease, or bothered by menopausal symptoms, or for patients who prove intolerant of tamoxifen. By contrast, women with osteoporosis or osteopenia, or women who are particularly concerned about bone mineral density, may be cautious about choosing aromatase inhibitor therapy.

Presented with the available results, women should be able to make an informed decision after considering the potential benefits and risks of treatment with aromatase inhibitor or tamoxifen.

Funding Information
Harold J. Burstein, MD, PhD, has received grants for educational activities from Novartis and AstraZeneca.

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