Metastatic breast cancer treatment

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Assistant Editor-in-Chief Jack Khouri

## Overview

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With rare exception, metastatic breast cancer is an incurable but treatable illness. Currently, it is managed as a chronic disease, especially the category that is estrogen receptor (ER)-positive with predominantly bone or soft tissue metastasis. Chemotherapy, biologic therapy and endocrine therapy are all considered in the treatment of metastatic breast cancer.

## Principles of therapy

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* The main aims of therapy are prolonging survival, improving quality of life and avoiding treatment-induced toxicity. Given that treatment is palliative, patients should be given treatment holidays in order to reduce drug-induced toxicity.
* HER2 overexpression and hormone receptor status are very important factors that guide therapy and influence prognosis.
* Multiagent chemotherapy regimens don't show significant survival benefit compared to single-drug regimens and augment toxicity.
* Chemotherapy is recommended for patients with ER-negative metastatic breast cancer and those with ER-positive breast cancer resistant to endocrine therapy or associated with visceral disease.
* Trastuzumab (Her2 inhibitor) increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.[1]
* Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 overexpression.[2]

## Chemotherapy

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* The most active single agents are Anthracyclines (Doxorubicin 60-75 mg/m2 IV every 21 days), Taxanes (paclitaxel 175 mg/m2 every 21 days or 80 mg/m2 IV days 1,8,15 every 21 days; docetaxel 60-100 mg/m2 IV every 21 days), Capecitabine (1000-1250 mg/m2 PO twice a day on days 1-14 every 21 days), Gemcitabine (800-1200 mg/m2 IV days 1,8,15 every 28 days), and Vinorelbine (25 mg/m2 weekly or days 1,8,15 every 28 days)
* Bevacizumab (the monoclonal antibody that inhibits VEGF, thus preventing angiogenesis) has been shown to improve the efficacy of taxanes in frontline treatment of patients with metastatic breast cancer.[3] A randomized phase III study showed that the combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased progression free survival when combined with docetaxel as first-line therapy for netastatic breast cancer compared with docetaxel plus placebo.[4]
* Consider using combination chemotherapy to treat patients with advanced breast cancer for whom a greater probability of response is important and who understand and are likely to tolerate the additional toxicity.[5]
* Combination chemotherapy include Gemcitabine combined with paclitaxel and docetaxel combined with capecitabine.
* There is little evidence from trials reported from 2000 to 2007 that major survival differences exist between many commonly employed chemotherapy regimens.[6]

## Endocrine Therapy

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* Endocrine therapy is based on the fact that estrogen receptor-positive tumors are highly estrogen-dependent for growth.
* Endocrine therapy agents for breast cancer are meant to block the effect the estrogen growth effect on breast cancer cells via several mechanisms:
* Blocking the estrogen receptor (eg, Selective Estrogen Receptor Modulators (SERMs) like Tamoxifen)
* Down-regulating and degrading the estrogen receptor (eg, Fulvestrant which is a pure estrogen antagonist)[7]
* Decreasing estrogen synthesis by blocking the enzyme called Aromatase, which converts androgens to estrogens. Aromatase inhibitors include many agents like Anastrozole, Letrozole and Exemestane
* Decreasing estrogen level by:
* Shutting down the hypothalamus-pituitary-ovarian axis by means of GnRH agonists, which block the hypothalamic signal that normally promotes etrogen synthesis by the ovaries
* Ablating the ovaries (oophorectomy)
* Endocrine therapy should be the first-line treatment for ER-positive metastatic breast cancer unless there is significant visceral involovement (the so-called visceral crisis (ie, liver or lung disease)) where first-line chemotherapy should be offered first.
* There is no survival advantage for the combined administration of chemotherapy and endocrine therapy over either single therapy.[8] [9]

The factors that need to be taken into account when considering what endocrine therapy is appropriate for a particular patient include:[5]

* Whether or not they have had previous endocrine therapy (including as an adjuvant)
* If so, which agent
* The extent and duration of any previous response to endocrine therapy
* Menopausal status

### Tamoxifen

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* As mentioned above, Tamoxifen (TAM) is a SERM meaning that its effect on estrogen receptors depends on the target tissue. In fact, TAM inhibits breast cancer growth by competitive blockade of the estrogen receptor in breast tissue. However, it has agonistic activiy in other tissues such as bone, uterus and blood vessels which is responsible for the side effects observed in patients on TAM, such as venous thromboembolism and uterine cancer.
* TAM is the first-line recommended endocrine agent for premenopausal metastatic breast cancer patients and the second-line agent for postmenopausal patients relapsing on/after aromatase inhbitors.
* Small, randomized trials in premenopausal women have found that oophorectomy is not superior to TAM.[10]
* Tamoxifen is a first-line treatment to men with ER-positive advanced breast cancer.[5]
* An oral dose of 20 mg daily is the standard of care.

### Aromatase Inhibitors

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Aromatase Inhibitors (AIs) are drugs that suppress the enzyme aromatase present in many tissue such as the gonads, the adipose tissue, the placenta, and the endometrium. By blocking this enzyme, estrogen synthesis is suppressed and thus the trophic effects of estrogen on the breast tissue are rendered minimal. Aromatase inhibitor therapy is ONLY effective in suppressing estrogen levels in postmenopausal women.[5] Because of that, measurement of serum follicle-stimulating hormone (FSH) levels can help selecting the proper patient population.

* A Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women concluded that letrozole was superior to tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.[11]
* In a randomized, double-blind, multicenter study designed to evaluate anastrozole (an AI), it was found that there was a significant increase in time to progression and a lower incidence of thromboembolic events and vaginal bleeding with anastrozole. These findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with advanced breast cancer.[12]

Offer an AI to: [5]

* postmenopausal women with ER-positive breast cancer and no prior history of endocrine therapy
* postmenopausal women with ER-positive breast cancer previously treated with tamoxifen

All aromatase inhibitors appear to be equally effective in terms of primary outcome (overall survival).

The most commonly used AIs are the following:

* Letrozole (Femara): 2.5 mg PO daily
* Anastrozole (Arimidex): 1 mg PO daily
* Exemestane (Aromasin) 25 mg PO daily

### Ovarian suppression with GnRH agonists

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Ovarian suppression is indicated for premenopausal and perimenopausal women who have previously been treated with tamoxifen and then experience disease progression.[5] The combination of a GnRH agonist and tamoxifen is superior to GnRH agonist alone in premenopausal women with advanced breast cancer. Therefore, if a premenopausal woman with advanced breast cancer is thought to be suitable for endocrine treatment, the combination of a GnRH agonist plus tamoxifen be considered as the new standard treatment.[13]

### Fulvestrant: The antiestrogen agent

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Fulvestrant (Faslodex) is an estrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects.[14] Fulvestrant is an effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy including Tamoxifen.[15][16]

## Biologic Therapy: Trastuzumab and Lapatinib

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* Monotherapy with trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 overexpression.
* Trastuzumab combination therapy with a taxane, vinorelbine, or platinum (carboplatin or cisplatin) has higher response rates than monotherapy. For instance, paclitaxel and trastuzumab have shown higher response rates (41% vs. 17%), time to progression (6.9 vs 3.0 months) and a trend toward overall survival (22.1 vs 18.4 months) compared to paclitaxel alone.[1]
* Concurrent administration of trastuzumab and anthracyclines is not recommended due to enhanced cardiotoxicity.[1]
* Trastuzumab lacks CNS penetration. Consequently, brain metastases tend to progess when a patient is on trastuzumab though the disease is controlled systemically.
* For patients who are receiving treatment with trastuzumab for advanced breast cancer, it can be discontinued at the time of disease progression outside the central nervous system. Do not discontinue trastuzumab if disease progression is within the central nervous system alone.[5]
* Lapatinib is a HER2 and EGFR receptor tyrosine kinase inhibitor and is given orally (vs trastuzumab which is given IV).
* Lapatinib in combination with trastuzumab significantly improved progression-free survival versus lapatinib alone in trastuzumab-refractory metastatic breast cancer, thus offering a chemotherapy-free option with an acceptable safety profile to patients with Her2-positive metastatic breast cancer.[17]
* Lapatinib and capecitabine have shown to be superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.[18] Consequently, if progression of disease occurs, Lapatinib and capecitabine are recommended concomitantly.

To read about early stage breast cancer chemotherapy treatment, go to breast cancer chemotherapy

## References

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1. ↑ 1.0 1.1 1.2 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344 (11):783-92. DOI:10.1056/NEJM200103153441101 PMID: 11248153
2. ↑ Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L et al. (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20 (3):719-26. PMID: 11821453
3. ↑ Alvarez RH, Guarneri V, Icli F, Johnston S, Khayat D, Loibl S et al. (2011) Bevacizumab Treatment for Advanced Breast Cancer. Oncologist ():. DOI:10.1634/theoncologist.2011-0113 PMID: 21976315
4. ↑ Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P et al. (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20):3239-47. DOI:10.1200/JCO.2008.21.6457 PMID: 20498403
5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 [[]]. PMID 21901868. Missing or empty `|title=` (help); `|access-date=` requires `|url=` (help)
6. ↑ Wilcken N, Dear R (2008) Chemotherapy in metastatic breast cancer: A summary of all randomised trials reported 2000-2007. Eur J Cancer 44 (15):2218-25. DOI:10.1016/j.ejca.2008.07.019 PMID: 18722111
7. ↑ Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N (2005) Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Mol Cell Endocrinol 239 (1-2):27-36. DOI:10.1016/j.mce.2005.04.008 PMID: 15950373
8. ↑ Stockler M, Wilcken NR, Ghersi D, Simes RJ (2000) Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat Rev 26 (3):151-68. DOI:10.1053/ctrv.1999.0161 PMID: 10814559
9. ↑ Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V et al. (1998) Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 16 (10):3439-60. PMID: 9779724
10. ↑ Buchanan RB, Blamey RW, Durrant KR, Howell A, Paterson AG, Preece PE et al. (1986) A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol 4 (9):1326-30. PMID: 3528402
11. ↑ Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A (2003). "Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 21 (11): 2101–9. doi:10.1200/JCO.2003.04.194. PMID 12775735. Retrieved 2011-12-02. Unknown parameter `|month=` ignored (help)CS1 maint: Multiple names: authors list (link)
12. ↑ Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A et al. (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol 18 (22):3758-67. PMID: 11078488
13. ↑ Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R et al. (2001) Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 19 (2):343-53. PMID: 11208825
14. ↑ Osborne CK, Wakeling A, Nicholson RI (2004) Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 90 Suppl 1 ():S2-6. DOI:10.1038/sj.bjc.6601629 PMID: 15094757
15. ↑ Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR et al. (2002) Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20 (16):3396-403. PMID: 12177099
16. ↑ Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S et al. (2002) Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20 (16):3386-95. PMID: 12177098
17. ↑ Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M et al. (2010) Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28 (7):1124-30. DOI:10.1200/JCO.2008.21.4437 PMID: 20124187
18. ↑ Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (26):2733-43. DOI:10.1056/NEJMoa064320 PMID: 17192538

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