A feasibility study to evaluate the relationships between endocrine symptoms, drug adherence and genetic polymorphisms in breast cancer patients receiving tamoxifen therapy

December 14th, 2017 in ICNN Articles

 A feasibility study to evaluate the relationships between endocrine symptoms, drug adherence and genetic polymorphisms in breast cancer patients receiving tamoxifen therapy 

Carmen WH Chan PhD 1, Ka Ming Chow DN 1, Alexandra McCarthy PhD 2, Judy YW Chan PhD 1 , Mary MY Waye PhD 1 , Stephen KW Tsui PhD 3, Winnie Yeo MBBS, MD 4, K C Choi PhD 1, Winnie KW So PhD 1, Winnie Soo MbChB, FHKAM 4, Christine Miaskowski PhD 5

1 The Nethersole School of Nursing, The Chinese University of Hong Kong
2 School of Nursing, The University of Auckland
3 School of Biomedical Sciences, The Chinese University of Hong Kong
4 Department of Clinical Oncology, The Chinese University of Hong Kong
5 Department of Physiological Nursing, University of California

A common practice to prevent cancer recurrence after treatment is to prescribe
adjuvant tamoxifen, an anti-hormonal therapy, for at least five years.

1 Despite the acknowledged benefits in terms of reduced recurrence rates associated with its use,
adherence to tamoxifen is less than ideal. Approximately 1 in 5 patients who are
prescribed adjuvant tamoxifen do not achieve the optimal adherence threshold of
≥80% during the first year of treatment.

2-3 The most significant factor contributing to non-adherence is the tamoxifen-related endocrine (hormone deprivation) symptom
profile. Symptoms include sudden, severe, and often permanent vasomotor symptoms,
and related insomnia, somatic symptoms, depression and sexual dysfunction.

4-5 Toxicities, and the way that tamoxifen is metabolized, are largely influenced by
individual genetic makeup. Different forms of some genes found in the population
(i.e. polymorphisms) which are involved in the metabolism of tamoxifen (e.g.
CYP3A4 and CYP2D6) may influence the toxicity, side effects, and symptom
experiences of tamoxifen.

6-7 We want to explore if, and how, endocrine symptoms of tamoxifen correlate with both
drug adherence and polymorphisms in genes that regulate the metabolism of 2
tamoxifen in Chinese women with breast cancer. This is a collaborative study among
colleagues from the Chinese University of Hong Kong, University of California at
San Francisco, and the University of Auckland. Our research team comprises
oncology specialists, credentialed oncology nurses, molecular geneticists, a
biostatistician and technical staff. We plan to conduct a cohort study to follow 200
Chinese women over 12 months and assess their clinical symptoms and genetic
variations. Endocrine symptoms and drug adherence will be scored during interviews
with standardized questionnaires including the Greene Climacteric Scale (GCS), the
Functional Assessment of Cancer Therapy-Endocrine subscale (FACT–ES)
questionnaire (Version 4), the Medication Possession Ratio. Polymorphisms in
significant target genes will be determined using commercial assays of saliva samples.
Participants will also maintain a logbook to record their intake of tamoxifen and any
other compounds, such as Chinese medicines, on a daily basis for 12 months.

In the past 3 months, our group has conducted a pilot study and successfully recruited
30 participants (response rate: 68.2%). Based on the data collected to date, some
allelic variations in some candidate SNPs, including ABCB1 rs1128503, UGT2B15
rs4148269, ABCC2 rs717620, CYP3A5 rs776746, CYP1A2 rs2470890, ABCC1
rs35628, CYP2B6 rs3745274, CYP2C19 rs4244285, showed considerably large
differences, with standardized mean differences of > 1 in endocrine-related symptom
score. This pilot study demonstrated the feasibility of recruitment and data collection.
The participants reported that the study design is simple and not time consuming.
This study will be the first to uncover any unique profile or gene(s) that are associated
with tamoxifen-related endocrine symptoms and other important outcomes. We will
pioneer exploration of the associations between genotypes, endocrine symptoms and
drug adherence in Chinese women with breast cancer.

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2005). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15- year survival: an overview of the randomized trials. Lancet 2005; 365: 1687-717.

2. Hershman, D.L., Shao, T., Kushi, L.H., Buono, D., Tsai, W.Y., Fehrenbacher, L., Kwan, M., Gomez, S.L., Neugut, A.I. (2011) Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Research and Treatment 126: 529–537.

3. McCowan, C., Shearer, J., Donnan, P.T. (2008) Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. British Journal of Cancer 99: 1763–1768.

4. Barron, T.I., Connolly, R., Bennett, K., Feely, J., Kennedy, M.J. (2007) Early discontinuation of tamoxifen: a lesson for oncologists. Cancer 109: 832–839.

5. Cluze, C., Rey, D., Huiart, L. (2012) Adjuvant endocrine therapy with tamoxifen in young women with breast cancer: determinants of interruptions vary over time. Annual Oncology 23:882-90.

6. Briest, S., Stearns, V. (2009) Tamoxifen metabolism and its effect on endocrine treatment of breast cancer. Clin Adv Hematol Oncol. 7:185–192.

7. Cronin-Fenton, D.P., Damkier, P., Lash, T.L. (2014) Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncology 10:107–122.