For the past two decades, non-adherence to chemoprevention for breast cancer remains a major problem.
The National Surgical Adjuvant Breast and Bowel Project [NSABP] P-1 study evaluated the worth of tamoxifen in decreasing the incidence of contralateral primary breast cancer (BC) in women at high risk. The NSABP P-1 was a prevention trial, where women were randomised into placebo and tamoxifen groups. The study concluded: a significant risk reduction of invasive and non-invasive BC by approximately 50%; a risk reduction of osteoporotic fractures; and a higher incidence of endometrial cancer in the tamoxifen group, but no woman died because it was stage I (localised disease). In NSABP P-1, Fisher and coworkers observed that non-adherence with tamoxifen was highest at a six-month interval following an interruption of accrual in the study. The trial was planned to enrol a large patient cohort to maintain adequate power, despite any potential high rates of tamoxifen non-adherence. Poor adherence undermines clinical trials and their goals.
Day and coworkers conducted a health-related quality of life overview of the NSABP P-1 study. They found that only the tamoxifen arm had a much higher occurrence of vasomotor and gynaecologic symptoms and recommended educating women on tamoxifen’s adverse effects. Followed by Land and coworkers, who conducted a prospective study of the NSABP P-1. The aim was to evaluate if participant-reported outcomes were connected with tamoxifen adherence, and if baseline behavioural risk factors could modify such associations. They concluded that the statistically significant predictors of tamoxifen adherence were: three-month mental component summary; three-month gynaecologic symptoms in moderate alcohol drinkers; baseline vasomotor symptoms only in women assigned to tamoxifen; and three-month sexual symptoms among young women. The strongest association was observed in the three-month other symptoms in both the tamoxifen and placebo arms. Other symptoms were defined as: gastrointestinal, bladder, and musculoskeletal symptoms, weight concerns, chest pain, dry mouth, breast sensitivity, and difficulty breathing. This means women in both arms were misattributing possibly normal symptoms to those of the drug. The three-month interval was a statistically significant predictor of adherence at year 1, which coincides with Smith and co-workers observation.
McCowan and coworkers investigated adherence to tamoxifen after surgery and how this would impact BC-related mortality. They retrospectively evaluated the cohort of women treated with tamoxifen between 1993 and 2002 in the Tayside region of Scotland. The study concluded that a significant proportion of women had low adherence to tamoxifen, and therefore were at a much higher risk of BC related-death. The study also showed that one in two women would not complete the recommended five-year duration of adjuvant tamoxifen treatment.
Smith and coworkers’ study emerges as a grim reminder of the significant effect patient health literacy has on adherence. The International Breast Cancer Intervention Study I (IBIS I) was conducted to evaluate the worth of tamoxifen in chemoprevention in women at high-risk. Both, NSABP P-1 and IBIS I had a tamoxifen arm with 20mg/daily for five years. However, the patient population in IBIS I was women ages 35–70, whereas, the patient population in NSABP P-1 was women >=60 years of age, 35–59 years with a 5-year predicted risk for BC of at least 1.66%, or had a history of lobular carcinoma in situ. Women who experienced natural postmenopausal symptoms (not induced by an anti-oestrogen therapy such as tamoxifen) in the first six months in the placebo arm were found to have mistaken their symptoms to those induced by tamoxifen. In addition, women who experienced nausea and vomiting (not gynaecological or vasomotor symptoms) in both the tamoxifen and placebo arms were less likely to adhere to tamoxifen. These symptoms are not necessarily related to the natural menopause symptoms or tamoxifen administration. These symptoms, in fact, can happen in healthy individuals and could be attributed to something entirely different. It seems that women’s preconceived notions towards tamoxifen or misattributing normal symptoms to those induced by tamoxifen could be linked to this observed notable reduction in long-term tamoxifen adherence, with the highest dropout rates observed at month 8 and 12.
Long-term tamoxifen was shown to be beneficial in laboratory studies[7,8] and in clinical trials[9,10]. Long-term tamoxifen administration can, in fact, prevent BC for up to 20 years. Despite that unequivocal benefit and a 30% reduction in oestrogen receptor-positive early BC incidence in women who take selective oestrogen receptor modulators [SERMs], only 16% take tamoxifen for chemoprevention.
It seems that women’s preconceived notions towards tamoxifen or misattributing normal symptoms to those induced by tamoxifen could be linked to this observed notable reduction in long-term tamoxifen adherence
The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 trial aimed to compare and contrast tamoxifen and raloxifene in regards to toxicity profiles. A study update by Vogel and coworkers noted that adherence was higher among the tamoxifen arm compared with that in the raloxifene arm, although both tamoxifen and raloxifene are SERMs and can cause similar menopausal symptoms. There seems to be a peculiar fear from women towards tamoxifen.
Pagani and coworkers evaluated the usage data of tamoxifen and toremifene (a SERM) from two International Breast Cancer Study Group studies. They wanted to study how adherence would impact SERMs efficacy. They concluded that women who did not complete a four-year course of SERM treatment did not achieve the full therapeutic benefit, and that more patient education has to be integrated.
In IBIS II, the aim was to evaluate the worth of anastrozole [an aromatase inhibitor] in preventing breast cancer in high-risk women. Almost 64% of women taking anastrozole reported musculoskeletal symptoms which can be induced by anastrozole. However, in the placebo arm, a similar percentage of 58% reported the same symptoms, although they are not on anastrozole. Women in the placebo arm are, again, misattributing normal symptoms to those of the drug.
Chlebowski and co-workers conducted a comprehensive literature review on adherence to oral endocrine therapies in breast cancer. They concluded that only half had completed the recommended five-year therapy. Patient’s perception of a low recurrence risk, adverse effects, age extremes, medication cost, lack of social support, and suboptimal patient-physician communication were recognised as important factors contributing to non-adherence.
In the UK, the NHS loses £500m a year due to medication non-adherence. The question remains: how can doctors and patients harness health literacy as a powerful tool in achieving medication adherence, prevention, cure, strengthen clinical trials and decrease the devastating financial losses bleeding still from our healthcare systems?
Fellow of Breast Medical Oncology/The University of Texas MD Anderson Cancer Center
Dr V. Craig Jordan, OBE, Dallas/Ft. Worth Living Legend Professor of Cancer Research for his mentorship and support during my fellowship training at MD Anderson Cancer Center. This year is his 70th birthday and my paper is dedicated to him.
This work was supported by Cancer Center Support Grant CA016672 awarded to the MD Anderson Cancer Center.
1. Fisher B, Costantino 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 Nat Cancer Inst 1998;90(18):1371–1388. PMID: 9747868
2. Breckenridge A, Aronson JK, Blaschke TF et al. Poor medication adherence in clinical trials: consequences and solutions. Nat Rev Drug Discov 2017;16(3):149–150. doi: 10.1038/nrd.2017.1
3. Day R, Ganz PA, Costantino JP et al. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17(9):2659–2669. doi: 10.1200/JCO.19126.96.36.19959
4. Land SR, Walcott FL, Liu Q et al. Symptoms and QOL as predictors of chemoprevention adherence in NRG oncology/NSABP Trial P-1. J Nat Cancer Inst 2016;108(4). doi: 10.1093/jnci/djv365
5. Smith SG, Sestak I, Howell A et al. Participant-reported symptoms and their effect on long-term adherence in the International Breast Cancer Intervention Study I (IBIS I). J Clin Oncol 2017:JCO2016717439. doi: 10.1200/JCO.2016.71.7439
6. McCowan C, Shearer J, Donnan PT et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008;99(11):1763–1768. doi: 10.1038/sj.bjc.6604758
7. Jordan VC. Laboratory studies to develop general principles for the adjuvant treatment of breast-cancer with antiestrogens – problems and potential for future clinical applications. Breast Cancer Res Tr 1983;3:S73–S86. PMID: 6423014
8. Jordan V. Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy. Endocr Relat Cancer 1978:49–55.
9. Davies C, Pan H, Godwin J et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381(9869):805–816. doi: 10.1016/S0140-673661963-1
10. Gray RG, Rea D, Handley K et al. aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol 2013;31(18). doi: 10.1016/S0140-673661963-1
11. Cuzick J, Sestak I, Cawthorn S et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 2015;16(1):67–75. doi: 10.1016/S1470-204571171-4
12. Cuzick J, Sestak I, Bonanni B et al. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 2013;381(9880):1827–1834. doi: 10.1016/S0140-673660140-3
13. Smith SG, Sestak I, Forster A et al. Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis. Ann Oncol 2016;27(4):575–590. doi: 10.1093/annonc/mdv590
14. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther 2009;9(1):51–60. doi: 10.1586/14737188.8.131.52
15. Vogel VG, Costantino JP, Wickerham DL et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev Res (Phila) 2010;3:696-706. doi: 10.1158/1940-6207.CAPR-10-0076
16. Pagani O, Gelber S, Colleoni M et al. Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93. Breast Cancer Res Treat 2013;142(2):455–459. doi: 10.1007/s10549-013-2757-x
17. Cuzick J, Sestak I, Forbes JF et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2014;383(9922):1041-1048. doi: 10.1016/S0140-673662292-8
18. Chlebowski RT, Kim J & Haque R. Adherence to endocrine therapy in breast cancer adjuvant and prevention settings. Cancer Prev Res (Phila) 2014;7:378-87. doi: 10.1158/1940-6207.CAPR-13-0389
19. Hagan P. The true cost of medication non-adherence. Omnicell UK — Adherence Let’s Take Care of It Campaign; 2015. Available at: http://www.letstakecareofit.com/wp-content/uploads/2015/10/The-True-Cost-of-Medication-Non-Adherence-Report.pdf (accessed October 2017)