Assessing Predictors of Tamoxifen Nonadherence in Patients with Early Breast Cancer

Emilia Montagna, Paola Zagami, Marianna Masiero, Ketti Mazzocco, Gabriella Pravettoni, Elisabetta Munzone, Emilia Montagna, Paola Zagami, Marianna Masiero, Ketti Mazzocco, Gabriella Pravettoni, Elisabetta Munzone

Abstract

Adjuvant endocrine therapy (AET) is generally proposed to all patients with hormone receptor-positive breast cancer to reduce the risk of recurrence and death. Adherence to therapy is crucial. However, non-adherence to AET is common, with estimates of up to 50% of patients not successfully completing a five-year course of treatment, and it is significantly associated with lower survival rates and a higher risk of recurrence. Currently, no gold standard is available to assess adherence. Several studies, most of them retrospective in nature, have used both direct and indirect methods to monitor the adherence to therapy in breast cancer. The indirect method is more widely used, and it is based on pharmacy prescription refills and patient administered questionnaires. On the other hand, direct methods such as a measurement of the level of the drug or its metabolites in blood or urine are much more precise, but more expensive and not routinely implemented. In this review, we analyzed the results of the major studies focused on the adherence to tamoxifen in breast cancer patients. We identified several factors associated with poor adherence, such as the side effects of therapy, the lack of shared decision-making between the physician and patient, the context in which the discussion takes place, and whether the patients are enrolled in a clinical trial. Moreover, we discussed possible methods to improve adherence to adjuvant therapy in breast cancer.

Keywords: adherence; adjuvant endocrine therapy; breast cancer; tamoxifen.

Conflict of interest statement

Drs Elisabetta Munzone reports advisory roles for Pierre Fabre, Genomic Health, and Eisai, and travel grants from Roche and Pfizer, outside the submitted work. The authors report no other potential conflicts of interest for this work.

© 2021 Montagna et al.

Figures

Figure 1
Figure 1
Factors associated to non-adherence to Tamoxifen in breast cancer patients.

References

    1. Lemstra M, Nwankwo C, Moraros BY. Primary nonadherence to chronic disease medications: a meta-analysis. J Patient Prefer Adherence. 2018;12:721–731. doi:10.2147/PPA.S161151
    1. McHorney CA, Schousboe JT, Cline RR, Weiss TW. The impact of osteoporosis medication beliefs and side-effect experiences on non-adherence to oral bisphosphonates. Curr Med Res Opin. 2007;23:3137–3152. doi:10.1185/030079907X242890
    1. Mohiuddin AK. Risks and reasons associated with medication non-adherence. J Clin Pharm. 2019;1:50–53.
    1. Kardas P, Aguilar-Palacio I, Almada M, et al. The need to develop standard measures of patient adherence for big data: viewpoint. Med Internet Res. 2020;22:1–11.
    1. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–1717. doi:10.1016/S0140-6736(05)66544-0
    1. The Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–784. doi:10.1016/S0140-6736(11)60993-8
    1. Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early stage breast cancer the st gallen international consensus guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30(10):1541–1557. doi:10.1093/annonc/mdz235
    1. Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194–1220. doi:10.1093/annonc/mdz173
    1. Ruhstaller T, Giobbie-Hurder A, Colleoni M, et al. Adjuvant letrozole and tamoxifen alone or sequentially for postmenopausal women with hormone receptor-positive breast cancer: long-term follow-up of the BIG 1–98 trial. J Clin Oncol. 2019;37(2):105–114. doi:10.1200/JCO.18.00440
    1. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107–108. doi:10.1056/NEJMoa1404037
    1. Metzger Filho O, Giobbie-Hurder A, Mallon E, et al. Relative effectiveness of letrozole compared with tamoxifen for patients with lobular carcinoma in the BIG 1–98 trial. J Clin Oncol. 2015;33(25):2772–2779. doi:10.1200/JCO.2015.60.8133
    1. 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;381:805–816. doi:10.1016/S0140-6736(12)61963-1
    1. Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005;97:1262–1271. doi:10.1093/jnci/dji250
    1. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209–219. doi:10.1056/NEJMoa1604700
    1. Colleoni M, Luo W, Karlsson P, et al. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, Phase 3 trial. Lancet Oncol. 2018;19:127–138. doi:10.1016/S1470-2045(17)30715-5
    1. Chlebowski RT, Geller ML. Adherence to endocrine therapy for breast cancer. Oncol. 2006;71:1–9. doi:10.1159/000100444
    1. Hadji P. Improving compliance and persistence to adjuvant tamoxifen and aromatase inhibitor therapy. Critic Rev Oncol Hematol. 2010;73:156–166. doi:10.1016/j.critrevonc.2009.02.001
    1. Dogrell SA. Adherence to oral endocrine treatments in women with breast cancer: can it be improved? Breast Cancer Res Treat. 2011;129:299–308. doi:10.1007/s10549-011-1578-z
    1. Gotay C, Dunn J. Adherence to long-term adjuvant hormonal therapy for breast cancer. Expert Rev Pharmacoeco Outcomes Res. 2011;11(6):709–715. doi:10.1586/erp.11.80
    1. Verma S, Madarnas Y, Sehdev S, Martin G, Bajcar J. Patient adherence to aromatase inhibitor treatment in the adjuvant setting. Curr Oncol. 2011;18(Supplement 1):S3–S9. doi:10.3747/co.v18i0.899
    1. Banning M. Adherence to adjuvant therapy in post-menopausal breast cancer patients: a review. Eur J Cancer Care. 2012;21:10–19. doi:10.1111/j.1365-2354.2011.01295.x
    1. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21(4):602–606. doi:10.1200/JCO.2003.07.071
    1. van Herk-sukel MPP, van Del Poll-franse LV, Voogd AC, Nieuwenhuijzen GAP, Coebergh JWW, Herings RMC. Half of breast cancer patients discontinue tamoxifen and any endocrine treatment before the end of the recommended treatment period of 5 years: a population-based analysis. Breast Cancer Res Treat. 2010;122:843–851. doi:10.1007/s10549-009-0724-3
    1. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8769 early-stage breast cancer patients. J Clin Oncol. 2010;28(27):4120–4128. doi:10.1200/JCO.2009.25.9655
    1. Cavazza M, Banks H, Ercolanoni M, et al. Factors influencing adherence to adjuvant endocrine therapy in breast cancer-treated women: using real-world data to inform a switch from acute to chronic disease management. Breast Cancer Res Treat. 2020;183:189–199. doi:10.1007/s10549-020-05748-6
    1. Lash TL, Fox MP, Westrup JL, et al. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat. 2006;99(2):215–220. doi:10.1007/s10549-006-9193-0
    1. Brett J, Boulton M, Fenlon D, et al. Adjuvant endocrine therapy after breast cancer: a qualitative study of factors associated with adherence. Patient Prefer Adherence. 2018;12:291–300. doi:10.2147/PPA.S145784
    1. Ziller V, Kalder M, Albert US, et al. Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer. Ann Oncol. 2009;20:431–436. doi:10.1093/annonc/mdn646
    1. Wassermann J, Gelber SI, Rosenberg SM, et al. Nonadherent behaviors among young women on adjuvant endocrine therapy for breast cancer. Cancer. 2019;125:3266–3274.
    1. Yusufov M, Nathan M, Wiley A, et al. Predictors of increased risk for early treatment non-adherence to oral anti-estrogen therapies in early-stage breast cancer patients. Breast Cancer Res Treat. 2021;185:53–62.
    1. He W, Fang F, Varnum C, Eriksson M, Hall P. Predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer. J Clin Oncol. 2015;33(20):2262–2269. doi:10.1200/JCO.2014.59.3673
    1. Pistilli B, Paci A, Ferreira AR, et al. Serum detection of nonadherence to adjuvant tamoxifen and breast cancer recurrence risk. J Clin Oncol. 2020;24:2762–2772. doi:10.1200/JCO.19.01758
    1. Cahir C, Dombrowski SU, Kelly CM, Kennedy MJ, Bennett K, Sharp L. Women’s experiences of hormonal therapy for breast cancer: exploring influences on medication-taking behaviour. Support Care Cancer. 2015;23(11):3115–3130. doi:10.1007/s00520-015-2685-x
    1. Moon Z, Moss‐Morris R, Hunter MS, Hughes LD. More than just side‐effects: the role of clinical and psychosocial factors in non‐adherence to tamoxifen. British J Health Psychol. 2017;22(4):998–1018. doi:10.1111/bjhp.12274
    1. Vaughn J, Ammerman C, Stein J. Delay discounting as a predictor of adjuvant endo-crine therapy adherence among breast cancer survivors. J Clin Oncol. 2020;38(15):e24172–e24172.
    1. Moon Z, Moss-Morris R, Hunter MS, Norton S, Hughes LD. Nonadher-ence to ta-moxifen in breast cancer survivors: a 12 month longitudinal analysis. Health Psychol. 2019;38(10):888–899. doi:10.1037/hea0000785
    1. Pan Y, Heisig SR, von Blanckenburg P, et al. Facilitating adherence to endocrine therapy in breast cancer: stability and predic-tive power of treatment expectations in a 2-year prospective study. Breast Cancer Res Treat. 2018;168(3):667–677. doi:10.1016/j.pec.2004.10.005
    1. Fink AK, Gurwitz J, Rakowski W, Guadagnoli E, Silliman RA. Patient beliefs and Tamoxi-fen discontinuance in older women with estrogen receptor—positive breast cancer. J Clin Oncol. 2004;22(16):3309–3315.
    1. Cluze C, Rey D, Huiart L, et al. Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: de-terminants of interruptions vary over time. Ann Oncol. 2012;23(4):882–890. doi:10.1093/annonc/mdr330
    1. Kahn KL, Schneider EC, Malin JL, Adams JL. Patient centered experiences in breast cancer: predicting long-term adherence to tamoxifen use. Med Care. 2007;45(5):431–439.
    1. Liu Y, Malin JL, Diamant AL, Thind A, Maly RC. Adherence to adjuvant hormone therapy in low-income women with breast cancer: the role of provider-patient communication. Breast Cancer Res Tr. 2012;137:829–836. doi:10.1007/s10549-012-2387-8
    1. Chlebowski RT, Kim J, Haque R. Adherence to endocrine therapy in breast cancer adjuvant and prevention settings. Cancer Prev Res. 2014;7(4):378–387. doi:10.1158/1940-6207.CAPR-13-0389
    1. Murphy CC, Bartholomew LK, Carpentier MY, Bluethmann SM, Vernon SW. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat. 2012;134(2):459–478. doi:10.1007/s10549-012-2114-5
    1. 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
    1. Makubate B, Donnan PT, Dewar JA, Thompson AM, McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer. 2013;108(7):1515–1524. doi:10.1038/bjc.2013.116
    1. Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126(2):529–537. doi:10.1007/s10549-010-1132-4
    1. Wheeler SB, Spencer J, Pinheiro LC, et al. Endocrine therapy non-adherence and discontinuation in black and white women. J Natl Cancer Inst. 2019;111(5):498–508. doi:10.1093/jnci/djy136
    1. Neugut AI, Hillyer GC, Kushi LH, et al. Non-initiation of adjuvant hormonal therapy in women with hormone receptor-positive breast cancer: the breast cancer quality of care study (BQUAL). Breast Cancer Res Treat. 2012;134(1):419–428. doi:10.1007/s10549-012-2066-9
    1. Montagna E, Pagan E, Bagnardi V, et al. Evaluation of endocrine therapy and patients preferences in early breast cancer: results of Elena study. Breast Cancer Res Treat. 2020;184:783–795. doi:10.1007/s10549-020-05900-2
    1. Bergqvist J, Lundström S, Wengström Y, et al. Patient interactive digital support for women with adjuvant endocrine therapy in order to increase compliance and quality of life. Support Care Cancer. 2021;29(1):491–497. doi:10.1007/s00520-020-05476-z
    1. Guth U, Huang DJ, Schotzau A, et al. Target and reality of adjuvant endocrine therapy in postmenopausal patients with invasive breast cancer. Br J Cancer. 2008;99:428–433. doi:10.1038/sj.bjc.6604525
    1. Presant CA, Bosserman L, Young T, et al. Aromatase inhibitor-associated arthralgia and/or bone pain: frequency and characterization in non-clinical trial patients. Clin Breast Cancer. 2007;7(10):775–778. doi:10.3816/CBC.2007.n.038
    1. Hewitt ME, Greenfield S, Stovall E. From cancer patient to cancer survivor: lost in transition. Washington, D.C: National Academies Press; 2006. Available from:.
    1. Underwood M, Townsend JS, Stewart SL et al. Surveillance or demographic characteristics and health behaviors among adult cancer survivors—behavioral risk factor surveillance system, United States, 2009. centers for disease control and prevention (cdc) mmwr: morbidity and mortality weekly report. 2012; Available from: . Accessed August3, 2021.
    1. Bargon CA, Batenburg MCT, van Stam LE, et al. Impact of the COVID-19 pandemic on patient-reported outcomes of breast cancer patients and survivors. JNCI Cancer Spectr. 2020;5(1):pkaa104. doi:10.1093/jncics/pkaa104
    1. Demissie S, Silliman RA, Lash TL. Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. J Clin Oncol. 2001;19(2):322–328. doi:10.1200/JCO.2001.19.2.322
    1. Grunfeld EA, Hunter MS, Sikka P, Mittal S. Adherence beliefs among breast cancer patients taking tamoxifen. Patient Educ Couns. 2005;59:97–102.
    1. Ma AMT, Barone J, Wallis AE, et al. Noncompliance with adjuvant radiation, chemotherapy, or hormonal therapy in breast cancer patients. Am J Surg. 2008;196:500–504. doi:10.1016/j.amjsurg.2008.06.027
    1. Owusu C, Buist DSM, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer. J Clin Oncol. 2008;26(4):549–555. doi:10.1200/JCO.2006.10.1022
    1. Rae JM, Sikora MJ, Henry NL, et al. Cytochrome P450 2D6 activity predicts discontinuation of tamoxifen therapy in breast cancer patients. Pharmacogenomics. 2009;9(4):258–264. doi:10.1038/tpj.2009.14
    1. Dezentje VO, van Blijderveen NJC, Gelderblom H, et al. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol. 2010;28(14):2423–2429. doi:10.1200/JCO.2009.25.0894
    1. Thompson AM, Johnson A, Quinlan P, et al. Comprehensive CYP256 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Res Treat. 2011;125:279–287. doi:10.1007/s10549-010-1139-x
    1. Huiart L, Bouknik A, Rey D, et al. Early discontinuation of tamoxifen intake in younger women with breast cancer: is it time to rethink the way it is prescribed? Eur J Cancer. 2012;48(13):1939–1946. doi:10.1016/j.ejca.2012.03.004
    1. Kimmick G, Anderson R, Camacho F, Bhosle M, Hwang W, Balkrishman R. Adjuvant hormonal therapy use among insured, low-income women with breast cancer. J Clin Oncol. 2009;27(21):3445–3451. doi:10.1200/JCO.2008.19.2419
    1. Schwartzberg LS, Cobb P, Senecal F, et al. Initial treatment and changes in adjuvant endocrine therapy for early stage breast cancer. Breast. 2009;18(2):78–83. doi:10.1016/j.breast.2009.01.002
    1. Dittmer C, Roeder K, Hoellen F, Salehin D, Thill M, Fischer D. Compliance to adjuvant therapy in breast cancer patients. Eur J Gynecol Oncol. 2011;32(3):280–282.
    1. Guth U, Myrick ME, Schotzau A, Kilic N, Schmid SM. Drug switch because of treatment-related adverse side effects in endocrine adjuvant breast cancer therapy: how often and how often does it work? Breast Cancer Res Treat. 2011;129:799–807.
    1. Nekhlyudov L, Lingling L, Ross-Degnan D, Wagner AK. Five-year patterns of adjuvant hormonal therapy use, persistence, and adherence among insured women with early-stage breast cancer. Breast Cancer Res Treat. 2011;130:681–689. doi:10.1007/s10549-011-1703-z
    1. Wigertz A, Ahlgren J, Holmqvist M, et al. Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study. Breast Cancer Res Treat. 2012;133(1):367–373. doi:10.1007/s10549-012-1961-4
    1. Weaver KE, Camacho F, Hwang W, Anderson R, Kimmick G. Adherence to adjuvant hormonal therapy and its relationship to breast cancer recurrence and survival among low-income women. Am J Clin Oncol. 2013;36(2):181–187. doi:10.1097/COC.0b013e3182436ec1
    1. Corter, AL., Broom R, Porter D, Harvey V, Findlay M. (2018). Predicting nonadherence to adju-vant endocrine therapy in women with early stage breast cancer. Psycho‐oncology. 2018;27(9): 2096–2103.

Source: PubMed

3
Sottoscrivi