NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

ONJ, a complication of bisphosphonate treatment, has been described. In a review of more than 16,000 cancer patients, an increased risk of jaw or facial bone surgery along with an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw with the use of intravenous bisphosphonates was documented. An absolute risk of 5.48 events per 100 patients treated was seen, with an increase in risk associated with an increase in cumulative dose of drug. 429 It is recommended that patients should undergo a dental examination with preventive dentistry prior to initiation of bisphosphonate therapy. Denosumab Women with metastatic breast cancer to bone who are candidates for bisphosphonate therapy may also be considered for treatment with denosumab (category 1). This recommendation is based upon the results of a single randomized trial comparing denosumab to zoledronic acid. 412 All trial patients were recommended to supplement with vitamin D and calcium. Patients on the experimental arm were given 120 mg of denosumab injected subcutaneously every 4 weeks plus intravenous placebo versus the control arm where patients were given an intravenous infusion of 4 mg of zoledronic acid every 4 weeks, and a subcutaneous placebo. In this trial with non-inferiority as the primary endpoint, denosumab was shown to significantly delay time to first SRE by 18% as compared with zoledronic acid (HR, 0.82; 95% CI, 0.71– 0.95; P < .001 for non-inferiority; P = .01 for superiority) and time to first and subsequent SREs (rate ratio, 0.77; 95% CI, 0.66–0.89; P = .001). No difference in time to progression or OS was observed. Adverse event profiles were similar for the two groups, including incidence of ONJ, with a reduced risk of renal-related and acute phase adverse events in the denosumab treatment group. Long-term risks of denosumab treatment are unknown. The optimal duration of treatment with denosumab is not known.

Endocrine Therapy for Stage IV or Recurrent Metastatic Disease Women with recurrent or metastatic disease characterized by tumors that are ER and/or PR positive are appropriate candidates for initial endocrine therapy. Endocrine therapies in postmenopausal women include nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum ER modulators (tamoxifen or toremifene) ER down-regulators (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). After second-line endocrine therapy, little high-level evidence exists to assist in selecting the optimal sequence of endocrine therapy. In premenopausal women, endocrine therapies include selective ER modulators (tamoxifen or toremifene); luteinizing hormone-releasing hormone (LH-RH) agonists (goserelin and leuprolide); surgical or radiotherapeutic oophorectomy; progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). For most premenopausal patients following therapy with tamoxifen, the use of ovarian suppression or ablation in combination with endocrine therapy for premenopausal women is appropriate. After second-line endocrine therapy, little high-level evidence exists to assist in selecting the optimal sequence of endocrine therapy. Endocrine therapy may be active in patients with negative ER and PR determinations, especially on the primary tumor and in soft tissue disease and/or bone-dominant disease. 430-432 Endocrine therapy is also associated with relatively low toxicity. Further false-negative determinations of ER and PR tumor status are not unusual and the hormone receptor status of primary and metastatic sites of disease may differ. The NCCN Breast Cancer Panel recommends consideration of a trial of endocrine therapy for patients with disease characterized as

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