ONCOLOGYEDUCATION.COM ARTICLE SUMMARIES Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

BACKGROUND Based on emerging data from prospective, randomized trials, Clinical Practice Guidelines are being regularly updated. Two important studies now are the basis of a focused update on optimal duration of endocrine treatment with tamoxifen. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

STUDY DESIGN Trials analysed were peer-reviewed phase III RCT’s from medical literature. Meeting abstracts and meta-analyses were also considered. For the current guideline, 5 RCT were included in the analysis. They all looked at length of treatment with tamoxifen 5 years versus indefinitely or 10 years. The ATLAS and the aTTom trial played a major role in the development of these guidelines. Research Question: Which endocrine treatment should be offered to a pre- or perimenopausal patient with breast cancer and for how long? Research Question: Which endocrine treatment should be offered to a postmenopausal patient with breast cancer and for how long? Research Question: What is the appropriate sequence of endocrine therapy? Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

RESULTS – QUESTION 1 Which endocrine treatment should be offered to a pre- or perimenopausal patient with breast cancer and for how long? If the patient remains pre- or perimenpausal or if her menopausal status is unknown after 5 years, tamoxifen should be continued for an additional 5 years If the patient has become postmenopausal she has the option of either switching to an aromatase inhibitor for additional 5 years or continuing with tamoxifen for 10 years altogether According to 3 trials (and more specifically the newer ATLAS and aTTom trials) breast cancer-specific mortality and breast-cancer-specific survival are improved with the extended use of tamoxifen which has now led to the change of the Clinical Practice Guidelines as shown above. Likewise, DFS and RFS along with reduction in contralateral breast cancer incidence are significantly improved. Extended use of tamoxifen is associated with an increase in adverse events. Most notably the cumulative risk of uterine cancer increases from 1.6 to 3.1% when tamoxifen is taken for five additional years. The risk of pulmonary embolism also rises with the extended use of tamoxifen. None of the studies formally evaluated quality of life. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

RESULTS – QUESTION 2 Which endocrine treatment should be offered to a postmenopausal patient with breast cancer and for how long? Tamoxifen for 10 years or an aromatase inhibitor for 5 years? There is so far not enough data supporting to extend endocrine treatment with an aromatase inhibitor beyond 5 years or Tamoxifen for 5 years, followed by an aromatase inhibitor for up to 5 years or Tamoxifen for 2 to 3 years, followed by an aromatase inhibitor for up to 5 years, for a total of endocrine treatment for 7 to 8 years. Postmenopausal women have two choices of endocrine therapy: Tamoxifen or an aromatase inhibitor. Based on the initial choice of hormonal therapy, the current treatment recommendations differ in length of time. The extension of endocrine treatment to up to 10 years when switching Tamoxifen to an AI after 2 to 5 years again seems to be a reasonable extrapolation from the ATLAS and aTTom trials, along with known data from MA.17 study. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

RESULTS – QUESTION 3 What is the appropriate sequence of endocrine therapy? In the postmenopausal woman tamoxifen should be switched to an aromatase inhibitor or vice versa if intolerance develops. If women have initially received 5 years of tamoxifen they should be offered 5 additional years of endocrine treatment (depending on their menopausal status either continue with tamoxifen or – if postmenopausal – alternatively receive up to 5 years of an AI. Like premenopausal women, postmenopausal women should receive additional endocrine treatment if they initially had tamoxifen for 5 years. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

SUMMARY The new ASCO Guidelines on length of endocrine treatment for patients with hormone-sensitive breast cancer are based on trial results on extended use of tamoxifen, most notably the ATLAS and the aTTOm studies. The new ASCO Guidelines now give a number of options for endocrine treatment. The ultimate decision on exact treatment option will depend on number of factors including existing co-morbidities, patient preference, patient tolerability and side- effect profile. It is important to highlight that dose compliance is a significant issue in this setting, and efforts need to be made to ensure appropriate education around compliance and side-effect management to ensure optimal efficacy. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258

COMMENTARY Quality of data regarding “triple-positive” (ER/PR+, HER2+) disease is weak. ASCO committee generally recommends chemotherapy-containing regimens first-line for most patients, followed by endocrine therapy either after chemotherapy or upon progression. Burstein H., et al., Journal of Clinical Oncology, doi: 10.1200/JCO.2013.54.2258