HORMONAL OR ENDOCRINE THERAPY
If your cancer was tested and found to be estrogen and progesterone positive, that means its growth was dependent upon the naturally occurring estrogen and progesterone in your body. The main source of these hormones is in the ovaries. However, there is estrogen throughout a woman’s body. Post menopause, estrogen is converted by androgen and can still “feed” a breast cancer cell. Therefore, it is necessary to eliminate or block as much estrogen as possible in order to keep a woman cancer free.
The advent of endocrine therapy has changed the face of breast cancer dramatically. In premenopausal women, drugs such as Tamoxifen and Evista block the estrogen receptors at the cellular level so cancer is not able to grow.
In post-menopausal women, the use of aromatase inhibitors like Arimidex, Femera and Aromasin, naturally occurring androgens that convert to estrogen, are stopped. These drugs block the aromatase enzymes which make this happen and as a result prevent cancer growth.
Removing a woman’s ovaries has also shown to be a great benefit. One of the discoveries that doctors have made is that the chemotherapy induced menopause is an added benefit of chemotherapy in estrogen/progesterone positive women, because the hormones have been shut down by the chemotherapy drugs. Without the hormones in the body, the cancer cannot grow. A chemically induced menopause can be achieved by drugs such as Lupron and Zoladex. Many pre-menopausal women choose to have their ovaries removed to put them into permanent menopause.
ABOUT THE SIDE EFFECTS....
Many women have no trouble at all with any of these therapies. However some do and to such an extent that they stop treatment. This is a very worrisome thing to many oncologists. Since women are on the "honor system" because they take these drugs at home, it is hard for their doctors to monitor their care. One of the reasons that women are surviving breast cancer longer is because of the advent of these drugs. So everything must be done to manage the side effects and remain on course.
For increased hot flashes, there are drugs like Effexor, an anti-depressant, that can help decrease their frequency. For the joint pain and stiffness, it has been found that women who are found to be vitamin D deficient experience more pain than women who have blood values of vitamin D above 45. Get your vitamin D level tested and then correct it if you are deficient. Not only can it reduce joint pain, it may help prevent breast cancer recurrence.
Bone loss is another concern. New studies have shown that taking bisphosphonates, bone density drugs such as Zometa, can prevent bone loss and it can also help prevent cancer spreading to the bones.
The following is a list of endocrine therapy drugs.
Aromatase inhibitors for post menopausal women only:
Premenopausal and post menopausal women can take:
Tamoxifen* please read warning at bottom of page
Note: The STAR Trial, part of the The NSABP Study of Tamoxifen and Raloxifene, concluded that when directly comparing Evista to Tamoxifen, Evista is as effective as Tamoxifen in reducing the risk of invasive breast cancer, but may be less effective in reducing the risk of noninvasive breast cancers such as ductal carcinoma in situ (DCIS). Evista has less risk of blood clots than Tamoxifen, except in women with coronary artery disease or who are at risk of coronary artery disease. These women should not take Evista because it has been found to increase the risk of blood clots and fatal strokes.
Faslodex was the first estrogen receptor antagonist with its use, estrogen is no longer able stimulate cellular growth. The Food and Drug Administration (FDA) has approved Faslodex for hormone treatment in postmenopausal women who have failed other endocrine therapies.
Side Effects of Endocrine Therapy
Hot flashes, irregular menstrual periods and vaginal discharge or bleeding. There is a small increase in developing blood clots. Tamoxifen increases a woman’s risk of developing uterine cancer. The same risk women taking hormone replacement therapy face.
RISK VS BENEFIT: Uterine cancer can be detected at an early stage and treated quite successfully. The benefit of Tamoxifen in preventing breast cancer outweighs the slight risk of developing uterine cancer.
HOWEVER: All women taking anti-estrogen therapy should go for regular gynecologic examinations.
Joint pain and decreased bone density
Women who took Tamoxifen for 2 – 3 years and then switched to Aromasin showed a marked improved survival. However, they also showed a minor loss of bone density. After almost five years of follow-up, bone fractures had occurred in 7% of women who switched to Aromasin and 5% of women who remained on Tamoxifen.
RISK VS BENEFIT: Women survive longer on aromatase inhibitors and their five year bone fractures rate is 7%. If they remain on Tamoxifen, their survival is shorter and their bone fracture rate is 5%.
The benefit of switching to an aromatase inhibitor outweighs the risk of remaining on Tamoxifen
Who benefits from Endocrine Therapy?
The use of hormonal therapy appears to benefit all women with hormone receptor-positive early-stage breast cancer. It significantly reduces the risk of cancer recurrence.
In women with ductal carcinoma in situ (DCIS) research has shown that the use of Tamoxifen after surgery and radiation was more effective for preventing breast cancer recurrence in patients with DCIS than surgery and radiotherapy alone.
Women with metastatic breast cancer benefit from initial treatment with hormonal therapy. Should it recur, metastatic women benefit from switching to a different endocrine therapy.
It can be used in the following ways: to treat newly diagnosed metastatic disease; to treat metastatic disease that once was treated with Tamoxifen; to treat metastatic disease that was once treated with another aromatase inhibitor.
NOTE: A clinical trial directly compared Femara and Tamoxifen as initial hormonal therapy in postmenopausal women with metastatic breast cancer. The results of the trial showed that Femara is superior to Tamoxifen.
Femara and Arimidex were compared among postmenopausal women with advanced breast cancer . Overall, treatment response was higher in patients treated with Femara (19.1% response rate) than in patients treated with Arimidex (12.3% response rate). Survival was similar in the two treatment groups.
BENEFITS OF ENDOCRINE THERAPY
Tamoxifen may help to lower blood cholesterol and reduce the rate of bone loss (osteoporosis). Two clinical studies have reported that women treated with Tamoxifen had a lower risk of cardiac disease than women not treated with Tamoxifen. Evista is FDA-approved for the prevention and treatment of osteoporosis.
Recent study findings
Aromasin and Faslodex are approved for treatment of women with metastatic breast cancer that has stopped responding to Tamoxifen.
Aromasin: Research indicates that Aromasin appears to be superior to Tamoxifen. In a recent study, women treated with Aromasin had nearly 3 times more anti-cancer responses than those treated with Tamoxifen (41% versus 17%).
Faslodex: Faslodex appears to be an effective first-line endocrine therapy. Research indicates that Faslodex was superior to Tamoxifen , 44% versus 30%, respectively
Being diagnosed with estrogen and progesterone positive cancer has its benefits. Women are living longer because of the many weapons in their arsenal post treatment. The use of endocrine therapy has changed the landscape of breast cancer survival… in OUR favor.
Please refer to these Resources to read the actual studies
Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in Nolvadex®-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. Journal of the National Cancer Institute 1994;86:527-537.
Davidson NE, Osborne CK. Adjuvant Endocrine Therapy for Early-stage Breast Cancer. In: Govindan R, ed. American Society of Clinical Oncology 2007 Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2007:96-99.
Goss P, Ingle J, 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. Journal of the National Cancer Institute. 2005; 97: 1262-1271.
Coombes RC, Paridaens R, Jassem J et al. First Mature Analysis of the Intergroup Exemestane Study: a Randomized Trial in Disease-free, Postmenopausal Patients with Early Breast Cancer Randomized to Continue Tamoxifen or to Switch to Exemestane Following an Initial 2-3 Years of Adjuvant Tamoxifen. Presented at the 2006 ASCO Annual Meeting. Abstract #LBA527.
Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trial after Completion of 5 Years’ Adjuvant Treatment for Breast Cancer. The Lancet. 2005;365:60-2.
Vogel VG, Costantino JP, Wickerham DL et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association. 2006;295:(doi:10.1001/jama.295.23.joc60074).
Vogel VG, Costantino JP, Wickerham DL et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association. 2006; 295:2727-41.
OncologySTAT has released this very important discussion about CYP2D6 enzyme and tamoxifen. Be aware that there are drugs you may be taking that could render Tamoxifen powerless, leaving you vulnerable for breast cancer recurrence.
Dr. Matthew P. Goetz: Tamoxifen Metabolism, Endoxifen, and CYP2D6 Polymorphism
2010 Jun 15, Interview by L Scott Zoeller
Tamoxifen is a prodrug, and it is converted in part by cytochrome P450 2D6 (CYP2D6)−mediated oxidation into its most active metabolite, endoxifen.
OncologySTAT: Would you describe the results of your work surrounding the pharmacogenetics of tamoxifen biotransformation and CYP2D6 metabolism? Why is this clinically relevant?
Dr. Goetz: Endoxifen is the most abundant, active metabolite of tamoxifen. A key question is whether genetic and drug-induced variability in the CYP2D6 enzyme (and other enzymes that are responsible for tamoxifen activation and elimination) contributes to tamoxifen’s overall activity. This is generating a lot of interest and research right now.
A second important question is, How much endoxifen is necessary for the inhibition of estrogen-stimulated growth? In vitro, it appears that the higher the endoxifen concentrations, the greater the inhibition of estrogen-stimulated growth.
Following the seminal work of Dr. Flockhart and colleagues, who characterized endoxifen and described the role of CYP2D6 in the metabolic activation to endoxifen, we collaborated with this group and published a retrospective analysis of a prospective trial demonstrating an association between CYP2D6 genotype and clinical outcomes with tamoxifen and a subsequent analysis regarding the potential effect of CYP2D6 inhibitors.
However, we were very interested in why endoxifen may be different from the other metabolites of tamoxifen. Our group performed in vitro experiments using pharmacologic concentrations comparable to those in humans taking tamoxifen at a dose of 20 mg/day. In these experiments, we described that endoxifen may degrade ER-alpha, and that furthermore, endoxifen’s effect on ER degradation, transcription, and inhibition of proliferation was concentration dependent, with minimal effects at low endoxifen concentrations observed in CYP2D6 poor metabolizers (20 nmol/L), but significantly greater effects occurred at concentrations observed in intermediate metabolizers (40 to 60 nmol/L) and extensive metabolizers (80 to 100 nmol/L).
In contrast to the in vitro setting, there are no clinical outcome data which relate variability in endoxifen concentrations with disease recurrence. With regard to CYP2D6 genotype, some, but not all, studies have suggested that CYP2D6 poor metabolizers, who have lower endoxifen concentrations, have higher rates of recurrence when treated with tamoxifen in the adjuvant setting for 5 years. One of the largest published studies was a pooled analysis of more than 1300 postmenopausal patients from Germany and the United States who were treated with tamoxifen 20 mg/day for a total of 5 years with no adjuvant chemotherapy. In this analysis, CYP2D6 poor metabolizers had about a two-fold higher risk of recurrence than did extensive metabolizers.
However, the International Tamoxifen Pharmacogenomics Consortium presented data on more than 2800 patients and demonstrated no association between CYP2D6 gentoype and clinical outcome. An additional study presented at ASCO this year demonstrated no association between CYP2D6 genotype and clinical outcome in a subset of 747 Dutch patients who were enrolled in the TEAM trial and who were administered tamoxifen for 2.5 years.
Thus, in the postmenopausal setting, the question is whether the pharmacogenetics of tamoxifen, in terms of CYP2D6, are still important to the way we practice in 2010. Hopefully, the answer to these questions will be forthcoming in the next year, when the results of some large head-to-head trials comparing tamoxifen with aromatase inhibitors are reported.
OncologySTAT: Is there an optimal time when genotyping should be done for a patient with breast cancer?
Dr. Goetz: We need more data to answer that question. First, validation is needed from the large head-to-head studies in which tamoxifen was administered at a dose of 20 mg/day for 5 years. If the relationship holds in these studies, we would then need to determine if a similar association exists in patients embarking on a switching regimen (2 to 3 years of tamoxifen followed by an aromatase inhibitor).
The clinical questions that may arise include the following: Should a patient who is a CYP2D6 poor metabolizer be treated with a different schedule (for example, 2 years of tamoxifen followed by an aromatase inhibitor) or a different dose (for example, 40 mg) or an altogether different drug (an aromatase inhibitor)? For the premenopausal setting, we don’t have any data. We especially need more data in this setting because there is no approved alternative to tamoxifen. Although the data in support of utilizing an aromatase inhibitor along with ovarian function suppression suggest that this may be a reasonable alternative to women receiving tamoxifen plus ovarian function suppression (based on the ABCSG 12 trial), we lack data with regard to CYP2D6 metabolism that would support the routine use of genotyping in this scenario.
OncologySTAT: Endoxifen is currently being developed as a drug by the National Cancer Institute (NCI). What is the evidence surrounding the importance of endoxifen in this setting?
Dr. Goetz: More than 1 year ago, the Developmental Therapeutics Program (DTP) branch of NCI made the decision to develop endoxifen as a drug for the treatment of ER-positive breast cancer. This decision was very important, given that endoxifen was unlikely to be developed by industry because of the lack of intellectual property protection. Since then, DTP has synthesized and formulated endoxifen (hydrochloride salt), and pharmacology studies from NCI animal studies have been analyzed here at the Mayo Clinic, headed by Dr. Matthew Ames and his laboratory. We expect the Investigational New Drug application will be filed later this year, with phase I studies in patients with advanced cancer expected to commence soon thereafter. The Mayo study is being done with support from the NCI Cancer Therapy Evaluation Program and the Mayo NCI phase I grant.
While it is much too early to know whether endoxifen will be a useful alternative to tamoxifen, the in vitro studies clearly demonstrate superiority for endoxifen compared with tamoxifen. However, there are important questions with regard to not only efficacy but also toxicity. Notably, the clinical studies performed by Dr. Flockhart and the COBRA group have not necessarily supported a relationship between CYP2D6 and changes in bone mineral density in women taking tamoxifen. Furthermore, we have no data on whether endoxifen has agonist or antagonist effects at the level of the uterus. As we study endoxifen, it will be very important to determine not only whether endoxifen is a more effective drug than tamoxifen but also whether the toxicity profile is acceptable.
OncologySTAT: For patients being treated with tamoxifen, what are the implications of concurrent treatment with selective serotonin reuptake inhibitors (SSRIs)? SSRIs are used in more than 50% of postmenopausal women for the treatment of hot flashes, and these drugs are known to inactivate CYP2D6.
Dr. Goetz: The studies on CYP2D6 inhibitors have also been controversial. A recent study from the Netherlands looked at clinical outcomes among patients who were taking tamoxifen and SSRIs. This group demonstrated no association between the concurrent use of SSRIs and clinical outcomes with tamoxifen.
In contrast, another study suggested that patients who were taking the potent CYP2D6 inhibitor paroxetine (but not other potent CYP2D6 inhibitors) had a higher risk of death from breast cancer.
The risk of breast cancer death was related to the length of overlap of paroxetine with tamoxifen, with the greatest risk in patients having the longest overlap (1.9-fold higher risk of breast cancer death compared with patients not taking paroxetine).
Aubert presented a study at ASCO last year that has been widely referenced, although it has not been published yet. Results from this study suggested that patients taking potent (but not weak) CYP2D6 inhibitors had a significantly higher risk of breast cancer recurrence.
Overall, the data suggest that patients who are taking potent CYP2D6 inhibitors may have a higher risk of breast cancer recurrence. Therefore, we recommend that practitioners avoid co-prescribing potent CYP2D6 inhibitors for patients being treated with tamoxifen. If a patient must take one of the potent CYP2D6 inhibitors, the duration of treatment should be as short as possible.