Measuring serum levels of tamoxifen among premenopausal women being treated for invasive breast cancer identified a “worryingly high proportion of patients, one in six, who were nonadherent to therapy at only 1 year after treatment prescription,” researchers reported in the Journal of Clinical Oncology.¹ Nonadherence to tamoxifen, as measured by serum assessment at 1 year, was higher than self-reported nonadherence and “emerged as a marker of poorer outcomes regardless of other main prognostic factors, suggesting the risk of recurrence increases as soon as patients start to be nonadherent,” the authors noted.

At a median follow-up of 24.2 months after tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter distant disease–free survival (adjusted hazard ratio = 2.31; 95% confidence interval = 1.05–5.06; P = .036). At 3 years’ follow-up, 95.4% of patients whose serum assessments at 1 year had shown them to be adherent to tamoxifen were alive without distant recurrence, compared with 89.5% of nonadherent patients.

Ann H. Partridge, MD, MPH, FASCO

Although the side effects of tamoxifen cause some women to interrupt or discontinue taking it, study coauthor Ann H. Partridge, MD, MPH, FASCO, stressed in an interview with The ASCO Post that tamoxifen is “effective therapy, not 100% effective, but it does cut the risk on average in half. It improves mortality by 30%. It is our job to help people tolerate that effective therapy. Patients who do not take it do not receive those benefits.” Dr. Partridge is Professor of Medicine at Harvard Medical School and Vice Chair of Medical Oncology at Dana-Farber Cancer Institute, Boston.

Subset of Women in the CANTO Trial

Researchers analyzed data from a subset of women participating in the large prospective CANTO trial (ClinicalTrials.gov identifier NCT01993498), which enrolled patients across France from 2012 to 2018. Patients in that trial had to be at least 18 years old, with a primary diagnosis of invasive stage cT0–cT3, cN0–3 breast cancer and no previous treatment of current breast cancer.

The adherence analysis included only those who were premenopausal at diagnosis, had hormone receptor–positive breast cancer, “were prescribed and agreed to take adjuvant tamoxifen,” and had serum assessment 1 year from when tamoxifen was prescribed. The median time from tamoxifen prescription to serum assessment was 16.2 months.

Among the 1,177 women selected, 66.9% had breast-conservation surgery vs 33.1% who had mastectomy, and more than 90% received radiotherapy. The median age of the women was 45 years. “Young women historically, especially with hormone-sensitive breast cancer, seem to be at a little higher risk on average of having breast cancer recurrence,” Dr. Partridge commented.

“This is one of the first large, national cohort studies to show the effect of nonadherence on mortality,” Dr. Partridge noted. “It confirms this is not just a problem unique to France or the United States. It is a universal problem for a substantial minority of patients, who we need to support better.”

Adherence Underreported by Patients

The predefined threshold for biochemical nonadherence was a tamoxifen serum level less than 60 ng/mL. At the 1-year measurement, serum levels ranged from less than 6 to 298 ng/mL (median, 110 ng/mL). Patient self-reports on adherence were obtained through semistructured interviews with clinical research nurses at the time of the blood draws. “Patients were considered as having declared nonadherence if they mentioned one of the following conditions: no ongoing hormone therapy, treatment interruption, or treatment discontinuation during the year before assessment,” the authors explained. Although the consent form noted that there could be serum assessment of drugs, including hormonal therapy, it is not clear whether study participants were aware of that at the time of the blood draws.

Serum assessment of tamoxifen identified 16.0% of patients who were below the adherence threshold, higher than the patient-reported nonadherence rate of 12.3%. “Of 188 patients who were biochemically nonadherent, 104 (55.3%) stated they had been regularly taking tamoxifen over the past year,” the researchers reported. None of the patients identified as biochemically nonadherent were exposed to any of the drugs that may interfere with tamoxifen serum levels, they noted.

At least some of the differences between the serum assessments and patient self-reports could be due to patients just wanting to be perceived as good patients. “It is a social construct,” Dr. -Partridge commented. “Nonadherence is associated with being a bad patient. People want to be socially acceptable.”

Multiple Reasons for Nonadherence

Among the 145 study participants who self-reported nonadherence, 57 mentioned toxicity. However, most gave no personal or medical reason, despite being questioned by the clinical research nurses about the reasons for treatment interruption or discontinuation.

“There are multiple reasons for nonadherence,” Dr. Partridge explained. “Most people focus on the side effects, but there are other factors, too.” They include financial issues, basic access to treatment, and lack of understanding about risks of recurrence. “There is a model for adherence, called the biopsychosocial model, which tells you how complicated this is,” Dr. Partridge said.

“This study provides important insights on the complexity of nonadherence,” the authors noted. “We found that sicker, nonpartnered patients and those with higher symptom burdens, including more severe fatigue and musculoskeletal symptoms, had a higher likelihood of being nonadherent to therapy.” In addition to previously known barriers related to social and clinical characteristics, “patients who did not receive adjuvant chemotherapy were also more likely not to be adherent to tamoxifen in our analysis,” the authors continued. “We hypothesize that these patients are less aware of the health risks related to their disease and misconceive the beneficial impact of adjuvant endocrine therapy on breast cancer outcomes.”

The duration of tamoxifen therapy can also be a deterrent. “Chronically tolerating anything is much more difficult than tolerating something short term,” Dr. Partridge said. “The more immediate the threat, the more adherent patients are.” A person taking a medication for metastatic cancer, especially if the patient is symptomatic, is more likely to be more adherent than a person who is taking a medication for prevention.”

Fertility Concerns

Young women who have not completed their families when they are diagnosed with breast cancer and advised to go on hormone therapy for 5 to 10 years “have a conundrum: optimize breast cancer care or optimize your family,” Dr. Partridge noted, and it may be a reason why many women seek second opinions.

With invasive breast cancer, the risk of recurrence argues against delaying tamoxifen therapy, but the POSITIVE trial (NCT02308085) is looking at interrupting endocrine therapy for a relatively short period to accommodate pregnancy. “We finished accrual this past December,” with just over 500 patients, Dr. Partridge reported.

“This is one of the first large, national cohort studies to show the effect of nonadherence on mortality.”

— Ann H. Partridge, MD, MPH, FASCO

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Women on the study take at least 18 months of endocrine therapy after diagnosis of early hormone-sensitive breast cancer. They take no more than 30 months, Dr. Partridge explained. Then, they wait 3 months “to get the tamoxifen or aromatase inhibitor out of their system” before trying to achieve a pregnancy. The study protocol allows up to 2 years’ interruption for pregnancy, delivery, breastfeeding, or failure to conceive (NCT02308085). Then, women resume treatment and complete the full duration of endocrine therapy.

“We are studying whether or not an interruption in endocrine therapy is safe, because the risk of hormone-sensitive breast cancer can last for over 20 years. Only approximately half the risk is in the first 5 years,” Dr. Partridge said. “Can we interrupt therapy for a relatively short period, 1 or 2 years, to achieve a pregnancy? Then, let the woman get back on and take a full course, 5 to 10 years, and might that be just as good as taking it straight through?”

Emerging Interventions

The study report concluded: “Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes.”

“Checking labs serially on patients is something they would have to agree to if they wanted to be monitored in that way, and maybe some people want that, so they have some kind of accountability,” Dr. -Partridge commented. “Monitoring of the blood in that manner, however, is more typically used for research. How it would be implemented to use it as an actual clinical tool to improve adherence would certainly depend on the person and would be an extreme and potentially burdensome measure.”

The authors called for the development of other targeted interventions that may facilitate adherence to tamoxifen therapy and have the potential to improve breast cancer outcomes. Some interventions are already in development, including motivational interviewing using a personal and tailored approach (but remotely during the COVID-19 era) to help patients overcome barriers to tamoxifen adherence.

A review of studies evaluating interventions to improve adherence to oral antineoplastic agents found “few have been rigorously tested.” Published in the Journal of the National Cancer Institute and coauthored by Dr. Partridge, the review noted, “The nascent literature suggests those that are pharmacist directed and use regular monitoring show promise, though additional prospective studies are needed.”²

Dr. Partridge said that better supportive care medicine is needed, along with developing hormone therapies that patients can tolerate better and/or administering agents along with the hormone therapy to help prevent or lessen some of the symptoms. It is also important, she noted, to make sure all patients who need therapy or other medications have access to them. 

DISCLOSURE: Dr. Partridge has received royalties for coauthoring the breast cancer survivorship section of UpToDate and has been reimbursed for travel, accommodations, or other expenses by Novartis.

REFERENCES

1. Pistilli B, et al: Serum detection of nonadherence to adjuvant tamoxifen and breast cancer recurrence risk. J Clin Oncol. June 22, 2020 (early release online).

2. Rosenberg SM, et al: Inventions to enhance adherence to oral antineoplastic agents: A scoping review. J Natl Cancer Inst 112:443-465, 2020.