Available Agents

Current Available Agents

For a complete list of current breast cancer treatments, please see the PDF available at https://oncologynurse-ce.com/wp-content/uploads/2018/05/Breast-Cancer-Treatment.2018.V2.pdf

Endocrine Therapy (ET)

Approximately three out of four breast cancers are positive for either the estrogen or progesterone receptor, and estrogen and/or progesterone are the key drivers of carcinogenesis in these tumors. Endocrine therapy, which acts by lowering estrogen levels and inhibiting the growth of cancer, remains the mainstay systemic treatment for hormone receptor-positive (HR+) breast cancer in the adjuvant, metastatic, and neoadjuvant settings. Selective estrogen receptor modulators (SERMs) are competitive partial agonists of the estrogen receptor (ER). In breast cells, SERMs have an antiestrogen effect, competing with circulating estrogen for binding with the ER, thereby preventing breast cancer growth in HR+ tumors. Commonly used SERMs include tamoxifen and raloxifene.1

Raloxifene is a nonsteroidal agent that binds to ERs, inhibits bone resorption, and does not stimulate the uterine endometrium. A study of postmenopausal women with osteoporosis found that raloxifene increased bone mineral density in the spine and femoral neck and reduced the risk of vertebral fractures.2 Similarly, a large study of women at risk of developing breast cancer found that tamoxifen use decreased the risk of hip, radius, and spinal fractures.3  An additional benefit of tamoxifen may be a reduced risk of cardiovascular disease. A randomized trial of tamoxifen 20 mg/day demonstrated a reduction in total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels.1

Breast Cancer Chemoprevention

Breast cancer is the most frequently diagnosed cancer worldwide, and strategies to reduce the risk of developing breast cancer can have a large impact. The American Society of Clinical Oncology (ASCO) recommends pharmacologic interventions to reduce estrogen receptor-positive (ER+) breast cancer risk in women without a personal history of breast cancer but who are at increased risk of developing the disease.4

An individual’s risk of developing breast cancer can be assessed using the Gail model, the National Cancer Institute breast cancer risk assessment tool. The risk factors used in this model are current age, age at menarche, age at first live birth, number of previous biopsies, and number of first-degree relatives with breast cancer. This tool does not accurately assess risk for women with mutations in the breast cancer 1 (BRCA1) or BRCA2 genes, a personal history of breast cancer, or a history of chest radiation for Hodgkin lymphoma.4 The Gail model can be found at https://bcrisktool.cancer.gov

Healthcare providers are encouraged to discuss the option of chemoprevention with women who are at an increased risk of breast cancer. This includes women aged 35 years or older with a 5-year projected absolute risk of breast cancer of 1.66% or higher based on the Gail model or women diagnosed with lobular carcinoma in situ.5

The following treatment options are recommended.5

For premenopausal women:

  • Tamoxifen 20 mg per day for 5 years

For postmenopausal women, either:

  • Tamoxifen 20 mg per day for 5 years
  • Raloxifene 60 mg per day for 5 years
  • Exemestane 25 mg per day for 5 years

Compared with placebo, tamoxifen use is associated with a significant absolute reduction in breast cancer mortality of 23.9% to 33.1% at 15 years, preventing one breast cancer death for every 11 patients who are treated.6

Aromatase Inhibitors

The enzyme aromatase is responsible for converting androgen into estrogen. There are two classes of third-generation aromatase inhibitors (AIs): nonsteroidal AIs such as anastrozole and letrozole that bind reversibly to aromatase and steroidal exemestane that binds aromatase irreversibly. All third-generation AIs are administered orally on a daily basis. Adverse events with these agents include hot flushes, vaginal dryness, loss of libido, fatigue, arthralgias, joint stiffness, and loss of bone mineral density with increased risk of fracture. AIs have a limited ability to reduce circulating estrogen in premenopausal women and are given only in combination with ovarian suppression to premenopausal women at high risk.7

About one-third of women who receive five years of tamoxifen will eventually relapse, regardless of chemotherapy use. AIs produce a durable response in postmenopausal women previously treated with tamoxifen or endocrine ablative surgery. AIs are preferred for first-line treatment of ER+ metastatic breast cancer and for adjuvant use in postmenopausal women with ER+ breast cancer. AIs can be used in premenopausal women if tamoxifen fails or is contraindicated; however, they must be used in combination with surgical or medical ovarian ablation in this population.7

CDK4/6 in Breast Cancer

Selective cyclin-dependent kinase (CDK) 4/6 inhibitors interrupt tumor growth by arresting cell-cycle progression. When used in combination with endocrine therapy, these novel drugs have demonstrated significant improvements in progression-free survival (PFS) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. There are three oral CDK4/6 inhibitors currently available for the treatment of breast cancer: abemaciclib, palbociclib, and ribociclib.

In phase 3 clinical trials, abemaciclib plus anti-estrogen therapies showed improved PFS over endocrine therapy alone. In the MONARCH-2 trial, abemaciclib plus fulvestrant increased median PFS (16.4 months) when compared with fulvestrant monotherapy (9.3 months) in premenopausal and postmenopausal women who progressed on endocrine therapy.8 The MONARCH-3 trial found that abemaciclib plus letrozole or anastrozole improved median PFS over endocrine-based therapy alone as first-line treatment in postmenopausal women with metastatic breast cancer (hazard ratio [HR] = 0.54; P= .000021).9 In the MONARCH-1 trial, an objective response rate of 19.7% and a clinical benefit rate (complete response + partial response + stable disease ≥6 months) of 42.4% were observed with abemaciclib monotherapy in women with metastatic disease who had progressed on or after prior endocrine therapy and had one or two chemotherapy regimens in the metastatic setting.10

The efficacy and safety of palbociclib was evaluated in several large clinical trials. The PALOMA-2 trial showed improved PFS for palbociclib plus letrozole over letrozole alone in postmenopausal women with previously untreated HR+/HER2– advanced breast cancer.11 The PALOMA-3 trial investigated the combination of palbociclib plus fulvestrant versus placebo plus fulvestrant in pre- and postmenopausal women with HR+/HER2– advanced breast cancer who had progressed during previous endocrine therapy. Patients on combination therapy had a significantly longer PFS than patients on endocrine monotherapy (HR = 0.46; P <.0001).12

The MONALEESA-2 trial evaluated the efficacy of ribociclib plus letrozole versus letrozole monotherapy in treatment-naïve postmenopausal women with HR+/HER2– advanced breast cancer. The MONALEESA-7 trial investigated ribociclib plus goserelin versus placebo plus goserelin, with both groups also receiving either tamoxifen or a non-steroidal aromatase inhibitor (letrozole or anastrozole) in premenopausal women. Ribociclib plus endocrine therapy showed significantly improved PFS in both studies.13,14 In MONALEESSA-3, ribociclib plus fulvestrant significantly increased median PFS compared with placebo plus fulvestrant in postmenopausal women with advanced cancer who were treatment-naïve or had received up to one line of prior endocrine therapy in the advanced setting (HR = 0.593; P <.001).15

Oral Anticancer Agents

Use of oral oncolytic agents is growing and will continue to increase with the development and approval of targeted therapies. Advantages of oral oncolytic agents include:

  • Convenience, with no associated intravenous (IV) complications
  • Fewer trips to physician’s office/clinic
  • Some evidence that adverse events are less severe than with IV therapy

As with all self-administered medications, oral oncolytic agents have potential disadvantages, including:

  • Increased risk of medication errors with self-administration
  • Decreased effectiveness with inconsistent administration
  • Drug-to-drug interactions
  • Barriers such as nonadherence, nausea/vomiting, lack of patient education, toxicity profile, dysphagia, odynophagia, and cost

Oral oncolytic agents require less contact with the cancer-care team, decreasing the potential for face-to-face problem-solving. Education provided by oncology nurses may help minimize the risk of nonadherence and medication errors, leading to improved patient outcomes and quality of life.

References

 

  1. Grey AB, Stapleton JP, Evans MC, Reid IR. The effect of the anti-estrogen tamoxifen on cardiovascular risk factors in normal postmenopausal women. J Clin Endocrinol Metab. 1995:80:3191-3195. Abstract at ncbi.nlm.nih.gov/pubmed/?term=grey%5B1au%5D+AND+1995%5Bdp%5D+AND+3191-
  2. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes of Raloxifene Evaluation (MORE) investigators. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial.  1999;282:637-645. Available at https://jamanetwork.com/journals/jama/fullarticle/191242
  3. Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst.1998;90:1371-1388. Available at https://academic.oup.com/jnci/article/90/18/1371/897928
  4. National Cancer Institute. The Breast Cancer Risk Assessment Tool. Available at https://bcrisktool.cancer.gov Accessed 12/4/18.
  5. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol.2013;31:2942-2962. Available at https://ascopubs.org/doi/pdf/10.1200/JCO.2013.49.3122
  6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of randomised trials.  2005;365:1687-1717. Abstract at www.ncbi.nlm.nih.gov/pubmed/?term=Lancet%5Bta%5D+AND+2005%5Bdp%5D+AND+1687-
  7. Fabian CJ. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer. Int J Clin Pract.2007;61:2051-2063. Available at https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-1241.2007.01587.x
  8. Sledge GW Jr, Toi M, Neven P, et al. MONARCH-2: abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol.2017;35:2875-2884. Available at https://ascopubs.org/doi/pdf/10.1200/JCO.2017.73.7585
  9. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646. Available at https://ascopubs.org/doi/pdf/10.1200/JCO.2017.75.6155
  10. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2– metastatic breast cancer. Clin Cancer Res. 2017;23:5218-5224. Available at https://clincancerres.aacrjournals.org/content/23/17/5218.full-text.pdf
  11. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med.2016;375:1925-1936. Available at nejm.org/doi/pdf/10.1056/NEJMoa1607303?articleTools=true
  12. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425-439. Abstract at ncbi.nlm.nih.gov/pubmed/?term=cristofanilli%5B1au%5D+AND+2016%5Bdp%5D+AND+425
  13. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med.2016;375:1738-1748. Available at nejm.org/doi/10.1056/NEJMoa1609709?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov
  14. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol.2018;19:904-915. Abstract at ncbi.nlm.nih.gov/pubmed/?term=tripathy%5B1au%5D+AND+2018%5Bdp%5D+AND+904
  15. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESSA-3. J Clin Oncol. 2018;36:2465-2472. Available at https://ascopubs.org/doi/pdf/10.1200/JCO.2018.78.9909

 

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