New research published in the journal Cancer provides some unexpected good news for survivors of breast cancer on adjuvant endocrine therapy (ET)—contrary to current assumptions, ET may not contribute to cognitive dysfunction (2018; doi:10.1002/cncr.31858).
The results are the latest investigation out of the NCI-funded Mind Body Study (MBS), which assessed the cognitive function of survivors of early-stage breast cancer after primary treatment and found those treated with ET showed no cognitive impairment compared with those who did not receive the therapy, even after 6 years of follow-up.
The study, one of the largest and longest to look at ET's effect on cognition, provides much-needed long-term data—and a glimmer of hope for many battling breast cancer.
New Piece to the Puzzle
The findings add to a growing body of literature aimed at helping clinicians better understand the complex interplay between cancer therapies and cognition. The investigators at UCLA have been studying early-stage, newly diagnosed breast cancer patients recruited immediately after the completion of primary treatment (surgery, adjuvant chemotherapy, radiation therapy) and prior to the initiation of adjuvant ET, if indicated, since 2007.
“We have already published a number of papers on the cohort, but this was the first to look at formal neuropsyschological (NP) testing,” said senior author Patricia Ganz, PhD, Director of Prevention and Control Research at the UCLA Jonsson Comprehensive Cancer Center. “Other reports from the study showed that at baseline prior to starting endocrine therapy, but after chemotherapy with or without radiation, women report problems on self-report questionnaires of cognitive function that can be associated with subtle changes in NP tests.”
One of the earliest MBS reports noted nearly 1 in 5 patients had increased memory and/or executive function complaints after adjuvant treatment with chemotherapy, radiation, or both (J Natl Cancer Inst 2013; doi:10.1093/jnci/djt073).
According to Ganz, “6 months later, for those who started endocrine therapy compared to those who did not, we saw self-reports of increased problems with word finding, and that this was associated with a slowing in psychomotor speed on NP testing” (J Clin Oncol 2014; doi:10.1200/JCO.2014.56.1662). But after following patients for as long as 6 years and assessing cognition with formal NP testing, the data provides some much-needed reassurance for the safety of the treatment.
In the most recent arm of the MBS, the researchers administered both self-reports and in-person NP assessments to 189 study participants and then used linear mixed models to examine the patients' cognitive performance or impairment rates over time.
The results accounted for age, IQ, race, depression, and chemotherapy exposure, and included assessments of learning, memory, attention, visuospatial, executive function, and processing speed.
Of the patients included in the study, 175 were followed for 6 months, 173 presented for a 12-month assessment, and 102 agreed to follow-up NP testing between 3 and 6 years. “We saw all women getting better in terms of their NP testing results and there was no difference between the two groups that we could detect,” said Ganz. For most of the NP testing domains, both groups had similar rates of cognitive improvement the first year and a return to baseline levels by the 3- to 6-year follow-up.
Because patients are commonly on ET for 5-10 years and already often struggle with other treatment complications such as non-adherence and reduced benefit, the results are welcome news.
The findings come as a surprise, however, as the researchers began with the hypothesis that survivors of breast cancer receiving ET after primary treatment would demonstrate diminished cognitive functioning over time compared with those not receiving the therapy.
The assumption was based, in part, on previous MBS data showing patients on ET reported significantly increased language and communication cognitive complaints at 6 and 12 months, which was reflected in diminished improvements in some NP tests, compared with those not receiving ET.
In addition, cognitive impairment is a known side effect of other cancer treatments such as chemotherapy and radiation. In fact, other findings within the MBS have even revealed a possible underlying link between common cancer treatments and NP side effects (Cancer 2018; doi:10.1002/cncr.31777).
“At the 3- to 6-year time point, there were biological changes in DNA damage and telomerase, associated with use of chemotherapy and/or radiation, that were associated with poorer NP executive function,” said Ganz. “So long-term, there may be some lasting effects from the chemotherapy and radiation that we can detect in some women. The story for endocrine therapy is less clear, but it may cause subtle changes in cognitive function that women are able to detect.”
The very mechanisms driving ET would suggest possible NP compromise, as ET agents cross the blood-brain barrier and are known to interfere with the action of estrogen in the brain, according to the study. While the role of endogenous estrogen in the brain is complex, it is believed to be neuroprotective.
Nonetheless, this new study “joins other cross-sectional and longitudinal studies that have similarly failed to find any cognitive effects of ET within the first year after treatment,” according to study authors. Given its large sample size and long follow-up, the study adds significant weight to a new way of thinking.
The MBS researchers also cite a recent meta-analysis of 14 studies specific to the cognitive sequelae of ET that found patients on the therapy had worse verbal learning/memory than controls, but no worse psychomotor efficiency or visuospatial function (Breast Cancer Res Treat 2018; doi:10.1007/s10549-017-4627-4). Such results are far from compelling and only add to the mixed findings plaguing ET research, the MBS researchers write in the study.
One likely cause for the lack of uniform findings is the fact that most research is limited by methodological issues such as small sample size and a short duration of follow-up. In addressing these research concerns in the MBS, the researchers hope their findings provide a clearer picture of the cognitive effects of ET.
Despite overcoming some study design hurdles, the research was not without limitations. The nuances of NP testing may have come into play in the current study, as the practice effects of repeat testing may account for some of the early recovery from the cognitive deficits and the diminishing effects after years of no testing, the authors said in the study. One of the next steps in their research is a careful analysis of self-report measures across all time points.
Work on the Horizon
The study's unexpected results led the authors to look closely at the study design and offer careful interpretation. While the results go a long way to ease patients' fears, the researchers know more work is needed to better understand the complex interplay of various treatments and their effect on each patient.
For example, the study found that those who consented to the 3- and 6-year follow-up presented with better executive function at baseline. Those unwilling to undergo formal NP testing long-term may be more cognitively vulnerable or more likely to be receiving ET, the authors speculate, and the longitudinal nature of the study may miss that crucial data.
The authors admit their study did not hone in on specific subgroups of patients such as menopausal status or prior hormone replacement therapy, instead taking a broader approach to the question of cognition and long-term ET. More studies focused on these vulnerable subgroups would help uncover the risks ET poses to brain health for specific patient populations.
But for now, “this [study] provides some reassurance to the many thousands of women receiving these medications who may be concerned about cognitive effects,” the study concludes.
Rebecca Hepp is a contributing writer.