Early discontinuation of endocrine therapy for breast cancer: who is at risk in clinical practice?

Endocrine therapy is the foundation of post-surgical treatment for women with hormone-dependent early breast cancer (Cheung 2007). Clinical trials clearly demonstrate that endocrine therapy halves the risk of recurrence and reduces cancer-related mortality when used for at least five years (ATAC Trialists’ Group 2005; Bliss et al. 2012; Coates et al. 2007; Davies and Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group 2013; Forbes et al. 2008; Gray and aTTom Collaborative Group 2013). Women using endocrine therapy for shorter time periods are at increased risk of recurrence and have higher mortality (Hsieh et al. 2014; McCowan et al. 2008; Swedish Breast Cancer Cooperative Group 1996; Yood et al. 2008). Despite strong empirical support for at least five years of endocrine therapy, early discontinuation of therapy in clinical practice has been reported in many European and North American studies (Hershman et al. 2010; Huiart et al. 2011; McCowan et al. 2008; Owusu et al. 2008; Partridge et al. 2008; van Herk-Sukel et al. 2010). A review of endocrine therapy duration of use outside of clinical trials reported that between 13% and 20% of women had discontinued therapy within one year, and 31%–73% had discontinued within five years (Murphy et al. 2012).

A number of demographic and clinical factors have been associated with early discontinuation including younger and older age (<45 years or >70 years) (Barron et al. 2007; Hershman et al. 2010; Nekhlyudov et al. 2011; van Herk-Sukel et al. 2010), being married (Kimmick et al. 2009), social disadvantage (Nekhlyudov et al. 2011), having a node-negative tumour (Kimmick et al. 2009), not undergoing chemotherapy or mastectomy (Barron et al. 2007; Hershman et al. 2010), and number of comorbidities (Demissie et al. 2001; Hershman et al. 2010; Kimmick et al. 2009; Neugut et al. 2011; van Herk-Sukel et al. 2010). Number of comorbidities has typically been ascertained using the Charlson comorbidity index (Charlson et al. 1987) or number of prescriptions used prior to commencing therapy, and reported associations with persistence to endocrine therapy have been mixed. Endocrine therapy may cause or exacerbate specific conditions including anxiety (Grunfeld et al. 2005; Güth et al. 2011), depression (Grunfeld et al. 2005), hot flashes (Grunfeld et al. 2005; Güth et al. 2011), musculoskeletal pain (Chim et al. 2013; Güth et al. 2011;), osteoporosis (Bell et al. 2013), and vaginal atrophy (Fallowfield et al. 2004). Self-report suggests that these comorbidities are the reason some women discontinue therapy (Murphy et al. 2012) but the role of specific comorbidities has not been examined in observational studies of discontinuation.

A number of observational studies of endocrine therapy duration have ended follow-up when a woman’s initial therapy is discontinued, reflecting the prominence of tamoxifen therapy until the mid-2000’s (Barron et al. 2007; McCowan et al. 2008; Partridge et al. 2003; van Herk-Sukel et al. 2010). There are few data to indicate whether characteristics associated with discontinuation of initial therapy (including initial therapy type) are associated with discontinuation of any endocrine therapy outside of clinical trials. One study of 4917 women with early breast cancer compared characteristics predicting discontinuation of initial therapy and any therapy (van Herk-Sukel et al. 2010). The authors reported that having ≥2 comorbidities was associated with shorter duration of any endocrine therapy but found no association with discontinuation of initial therapy (van Herk-Sukel et al. 2010). Another study compared duration of initial therapy in women commencing with tamoxifen or an aromatase inhibitor (AI: anastrozole, letrozole or exemestane) and reported greater discontinuation for tamoxifen users than those taking AIs at five years (31% vs. 19%) (Huiart et al. 2011).

The aim of this study was to determine duration of use for initial endocrine therapy, and any endocrine therapy by women treated for early breast cancer in clinical practice; and the impact of initial therapy type and specific comorbidities on early discontinuation.

Only 19% of women receiving endocrine therapy for early breast cancer in clinical practice continued to use their initial therapy for five years. When allowing for switching between therapies, the proportion of women using any endocrine therapy for five years, as consistently recommended by clinical trial evidence (ATAC Trialists’ Group 2005; Bliss et al. 2012; Coates et al. 2007; Davies and (ATLAS) (2013); Forbes et al. 2008; Gray and aTTom Collaborative Group 2013), was 42%. These suboptimal persistence rates are similar to discontinuation rates of 31–73% by five years reported elsewhere (Murphy et al. 2012). The extent of early discontinuation of all endocrine therapy observed here suggests that more than half of treated women do not obtain the benefits of endocrine therapy demonstrated in clinical trials (Hsieh et al. 2014; McCowan et al. 2008; Swedish Breast Cancer Cooperative Group 1996; Yood et al. 2008). Given that tamoxifen duration is now recommended to be 10 years based on ATLAS and aTTom data, this suboptimal efficacy is likely to be magnified in the future (Davies and (ATLAS) (2013); Gray and aTTom Collaborative Group 2013).

We observed different predictors for discontinuation of initial therapy compared with any endocrine therapy. Women were more likely to discontinue their initial therapy if they commenced with tamoxifen, had pre-existing arthritis, or were newly-treated for anxiety. The finding that women discontinued initial therapy with tamoxifen earlier than women initiated on anastrozole or letrozole is unsurprising given that trial evidence and clinical guidelines support a switch from tamoxifen to an aromatase inhibitor after 2–3 years for post-menopausal women (Baum et al. 2003; National Breast Cancer Centre (NBCC) and National Health and Medical Research Council (NHMRC) 2001; Winer et al. 2005). Given that tamoxifen is the only endocrine therapy recommended for pre- or peri-menopausal, it is more likely that women would switch from tamoxifen to AIs as therapy progresses than the converse (Cheung 2007; NBCC and NHMRC 2001). Switching from tamoxifen to an AI, rather than the converse, is also more likely because our study covers the period before release of the BIG 1–98 results, which supports use of AIs before a switch to tamoxifen in low and intermediate risk women (Viale et al. 2011). It is encouraging to note that initial therapy type did not influence the total duration of endocrine therapy for women in this study, nor did the other predictors of initial therapy discontinuation: pre-existing musculoskeletal pain and newly-treated anxiety.

Our results showed that the women most likely to discontinue any endocrine therapy before five years were those who did not undergo chemotherapy or mastectomy. This finding remained after adjusting for treatment by a medical oncologist. Previous studies have reported that women not undergoing chemotherapy or mastectomy are more likely to discontinue therapy early. A large observational study of 8769 women followed for 4.5 years found that women undergoing chemotherapy before commencing endocrine therapy were significantly less likely to discontinue than other women, and those who had undergone mastectomy were less likely to discontinue than those who had a lumpectomy (Hershman et al. 2010). A shorter-term study (1 year follow-up) of >13,000 women also reported that women with pre-endocrine therapy mastectomy had nearly half the probability of non-adherence compared with women without mastectomy (Sedjo and Devine 2011). It may be that women who undergo more ‘aggressive’ treatments perceive their condition as more serious and their need for endocrine therapy greater, than other women.

Women in this study first treated for hot flashes after commencing endocrine therapy were at higher risk of early discontinuation than other women. Hot flashes were the side-effect women most commonly cited for discontinuing tamoxifen in Swiss (N = 400) and UK studies (N = 110) (Charlson et al. 1987; Neugut et al. 2011). Anecdotally, women describe hot flashes as causing sleep disturbance, difficulty concentrating and decreased quality of life. It is interesting to note that only newly-treated, and not pre-existing, hot flashes were associated with early discontinuation. None of the other pre-existing or newly-treated comorbidites we examined were associated with early discontinuation of any endocrine therapy. We may have underestimated treatment for hot flashes in this group because our data did not include non-PBS supply of medicines which might be used for flushing (such as gabapentin and venlafaxine, which are restricted to use for epilepsy and major depression, respectively) (Australian Government Department of Health 2013a).

It is not clear why women born in NZ or the UK would discontinue endocrine therapy earlier than Australian-born women. All of the women in the study were residents of NSW at recruitment to the 45 and Up Study (2006–2009) and reported a median duration of residence in Australia of 37 years (range 26–47). NZ and the UK are culturally similar to Australia, have comparable public pharmaceutical insurance (Kemp et al. 2010), and NZ and UK immigrants to Australia are the most frequent of any countries (Australian Bureau of Statistics 2013). Therefore we consider it unlikely that social marginalisation or unfamiliarity with the health system underpins this higher discontinuation. Further research with this group of women is needed to understand the increased risk of early discontinuation observed here or indeed see if this represents just a spurious finding.

Less than half of women in this study (42%) completed five years of endocrine therapy for breast cancer. This suboptimal use means that the full benefit of endocrine therapies in reducing recurrence and cancer-related mortality consistently demonstrated in clinical trials may not be realised in practice. Choice of initial endocrine therapy, pre-existing musculoskeletal pain and newly-treated anxiety were related to shorter duration of initial therapy but not early discontinuation of any therapy. Women at greatest risk of stopping any endocrine therapy before the recommended five years were those receiving less aggressive initial treatment (i.e. no chemotherapy or mastectomy), those with newly-treated flashes, and those born in UK or NZ. Strategies are needed to support medicine use and improve outcomes for these women.

^aIn 2011, the purchasing power of 1$US was 1.51 AUS dollars.