Identifying pre-surgical risk factors of longitudinal changes in cancer-related cognitive impairment in patients with breast cancer

Background
Cancer-related cognitive impairment (CRCI) is a common symptom in patients with breast cancer. Approximately 75% of breast cancer patients experience cancer related cognitive impairment (CRCI) prior to, during, or after treatment. CRCI remains a significant long-term problem for about 35% of cancer survivors. CRCI may interfere with patients’ self-care activities, such as ability to adhere to treatment, manage side effects, and re-integrate into the workforce, which can have a negative impact on their quality of life. The Attentional Function Index (AFI) is a subjective measurement commonly used to assess attentional function and includes three subscales, namely effective action, attentional lapses, and interpersonal effectiveness. In our previous study of 397 women with breast cancer, three groups of patients with distinct CRCI profiles (i.e., High, Moderate, and Low-moderate attentional function) were identified. While the three classes were significantly different in demographic and clinical characteristics using the total AFI scores, little is known about how other pre-surgical psychological and physical symptom and genetic biomarker characteristics are associated with the distinct profiles of CRCI.
Aims
The overall aims of this dissertation were threefold: 1) to expand on our previous work and evaluate for the differences among the three latent classes in the severity of psychological (ie, anxiety, depression) and physical (ie, fatigue, decrements in energy, sleep disturbance, and pain) symptoms prior to surgery. 2) to identify distinct cognitive profiles for each of the AFI subscales, and then to determine the differences in demographic, clinical, and pre-surgical psychological and physical symptoms among the subgroups. 3) to evaluate for associations between CRCI subgroup membership and single nucleotide polymorphisms among 15 genes involved in catecholaminergic and serotonergic neurotransmission.
Methods
This PhD dissertation is based on the B-CaSS study. This descriptive, prospective, longitudinal study observational study included 398 female breast cancer patients, who were screened for the aforementioned risk factors prior to surgery. Longitudinal changes of CRCI were measured with the Attentional Function Index (AFI) from prior to surgery through 6 months after surgery (ie, baseline, 1, 2, 3, 4, 5, and 6 month). Growth mixture modeling (GMM) and Latent Class Growth Analyses (LCGA) were used to identify distinct CRCI profiles. Parametric and non-parametric statistics were used to determine differences of the aforementioned pre-surgical risk factors among the distinct profiles. Logistic regression analyses were used to identified significant differences between genotype frequencies and the extreme attentional function classes comprised of 296 patients (ie, High class [n=165] and Low-moderate class [n=131].
Results
Our results found: 1) significant differences of the severity level of trait and state anxiety, depression, fatigue, and sleep disturbance among the three classes (i.e., High < Moderate< Low-moderate). 2) Three latent classes were identified for the effective action subscale. Four latent classes were identified for the attentional lapses subscale. Two latent classes were identified for the interpersonal effectiveness subscale. Across the three subscales, lower functional status, higher level of anxiety, depression, fatigue, and sleep disturbance, and worse decrements in energy were associated with worse cognitive performance. 3) Genotypes in 5 genes were associated with membership in the Low-moderate attentional class: alpha-1D adrenergic receptor (ADRA1D) rs2326478, beta-2 adrenergic receptor (ADRB2) rs1042718, solute like carrier family 6 member 2- noradrenaline transporter (SLC6A2) rs47958, 5-hydroxytryptamine receptor 3A (HTR3A) rs10160548, and solute like carrier family 6 member 4- serotonin transporter (SLC6A4) rs8076005.
Conclusions
Our findings suggest that women with clinically meaningful levels of persistent CRCI have a relatively high symptom burden prior to surgery. Pre-surgery symptoms (i.e., anxiety, depression, fatigue, sleep disturbance) and other modifiable characteristic (e.g., lower functional status) may be potential targets for personalized interventions. Additionally, variability in genes within the catecholaminergic and serotonergic pathways may explain variability in development and severity of CRCI in women with breast cancer.