Association of Markers of Tumor Aggressivity and Cognition in Women with Breast Cancer Before Adjuvant Treatment: The Thinking and Living with Cancer Study

doi:10.21203/rs.3.rs-1506459/v1

Download PDF

Research Article

Association of Markers of Tumor Aggressivity and Cognition in Women with Breast Cancer Before Adjuvant Treatment: The Thinking and Living with Cancer Study

https://doi.org/10.21203/rs.3.rs-1506459/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Purpose: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of pre-treatment cognition and tumor aggressivity in older breast cancer patients.

Methods: Women diagnosed with non-metastatic breast cancer (n=705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score <54 or having 2 tests <1.5 SD or 1 test <2 SD from the mean APE or LM domain score).

Results: HER2 positivity and the hormone receptor negative/HER2+ molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values <.05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM.

Conclusions: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.

breast cancer

clinicopathological tumor features

cognition

older adults

elderly

Cognitive problems among cancer patients are commonly referred to as cancer-related cognitive decline (CRCD) and have now been well-documented in subsets of adults after treatment of non-central nervous system cancers [1, 2]. CRCD is, in turn, associated with declines in quality of life, work performance and daily functioning of cancer patients [3–5]. Recommendations by the International Cognition and Cancer Task Force [6] to measure pre-treatment baseline cognition have led to several reports of cognitive problems even before starting adjuvant systemic therapy [7–9].

Pre adjuvant systemic-treatment cognitive problems have been attributed to a number of factors, including extant comorbidity burden and frailty [10, 8], biological stress associated with diagnosis and treatment [11, 12], and shared environmental exposures or genetic risk factors for both cancer incidence and cognitive dysfunction [13], while most do not find an association with underlying mood disturbance [7, 2].

There are few clinical studies examining the relationships of adjuvant systemic therapy cognition and tumor features and these have had relatively small samples and inconsistent results [8, 7, 14]. However, it is plausible that tumor features could themselves affect pre-treatment cognition since they may differentially affect the tumor microenvironment, systemic inflammatory and neuroinflammatory responses and/or alter blood brain barrier permeability [15–17]; notably, studies in preclinical models have found behavioral effects of tumor burden that are reversed with anti-inflammatory agents [18]. It has also been suggested that aggressive tumors are the most likely to generate responses that adversely affect cognition, including high levels of systemic inflammation [19]. In previous work from our group, we reported an association of stage of disease with executive dysfunction prior to adjuvant treatment, with stage II to III cancers exhibiting lower executive function compared to those with stage 0 or I disease [8]. Similarly, in another study, higher-stage patients were significantly more likely to be classified as having lower than expected overall cognitive performance than lower stage patients and healthy controls [7]. HER2 positivity, another marker of tumor aggressivity, has also been found to be associated with pre-adjuvant therapy cognition [19].

We use data from the Thinking and Living with Cancer (TLC) study, a large, multisite cohort of patients with breast cancer ages 60 and older [20–22, 10, 23] to test hypotheses about tumor aggressivity and pre-systemic treatment cognition. Our primary hypotheses were that higher tumor stage, and HER2 positivity (and HER2 positive molecular subtypes) would be associated with lower self-reported and objective cognition prior to systemic therapy. In secondary analyses we explored the relationship between other tumor features considered markers of aggressivity (e.g., large tumor size, high grade, lymph node positivity, hormone receptor negativity) and cognition. The results are intended to guide future studies to understand how features of breast tumors may contribute to cognitive problems even prior to systemic adjuvant treatment and ultimately use that knowledge to guide supportive care and surveillance of cognitive function from the point of diagnosis through post-active treatment survivorship.

This Institutional Review Board-approved study (ClinicalTrials.gov Identifier: NCT03451383) has been reported previously [8, 2] and was conducted at six US sites in Los Angeles, New York City, New Jersey, the DC metropolitan area, Indianapolis, and Tampa.

Setting, Population And Data Collection

We included all women with breast cancer recruited between August 1, 2010 and March 1, 2020; none of these women had COVID19 prior to initial enrollment. Eligible patients were 60 years of age or older, newly diagnosed with non-metastatic breast cancer and English-speaking. We excluded those with neurological disorders or any hearing or vision impairment that precluded assessment. Candidate participants with a history of other cancers were excluded if active treatment was recent (< 5 years) or included systemic therapy.

Patients were screened using the Mini-Mental State Examination (MMSE) [24] and the Wide Range Achievement Test, 4th edition (WRAT-4) Word Reading subtest [25]; those with scores of < 24 or < 3rd grade-equivalent reading level, respectively, were ineligible (1 patient). The analytic sample included 705 patients.

Baseline assessments were conducted by trained staff post-surgery and prior to systemic adjuvant treatment (or prior to neo-adjuvant therapy) using an interviewer-administered structured survey and neuropsychological testing [8, 2]. Medical records were abstracted using a structured tool at study enrollment and annually thereafter for tumor features, therapy, and surgery.

Measures

We use the protocol-specified primary cognitive outcomes: self-reported cognition measured using the Functional Assessment of Cancer Therapy – Cognition, Perceived Cognitive Impairment scale (FACT-Cog PCI) [26], and objective performance on the attention, processing speed, and executive function domain (APE; 6 tests) and learning and memory domain (LM; 5 tests) [8, 2]. The PCI is an 18-item scale often used in clinical trials and had excellent reliability in our cohort (Cronbach’s alpha = .94). Scores range from 0–72, with higher scores representing better cognitive function; a 3 to 5 point difference in scores is considered a meaningful difference and a score of < 54 corresponds to mild cognitive impairment and is considered a clinically meaningful cut-point [27]. For the APE and LM domains, results are transformed into z-scores based on age- and education-matched non-cancer control baseline means and standard deviations [2]. Z-scores have a mean of zero and range from − 3 standard deviations (SD) to + 3 SD. A positive score indicates better than average cognition and a negative score reflects worse than average scores. Domain-level impairment was defined based on having two tests in the domain < 1.5 SD or 1 test < 2 SD from the mean.

The primary tumor features of interest were stage of disease and HER2 status based on past reports and the association of these tumor features with aggressivity of disease [19]; other tumor features were secondary independent variables. For stage of disease, American Joint Committee on Cancer (AJCC) v6 stage (in place at the start of the cohort) was categorized as pathological stage 0/I vs. II/III. For HER2 status, cases were considered positive (vs. negative) if there was either a score of 3 + on HER2 IHC, a positive result on HER2 FISH, or the patient went on to receive trastuzumab treatment.

Hormone receptor (HR) status was categorized as positive if either estrogen (ER) and/or progesterone receptors (PR) were positive, otherwise hormone receptor status was negative. We also examined molecular subtype based on combinations of hormone receptor and HER2 status (i.e., HR+/HER2-, HR+/HER2+, HR-/HER2 + and HR-/HER2- [triple negative]). Tumor grade was reported as low vs. moderate and high. Lymph nodes were considered positive for any positive nodes on sentinel node or full axillary dissection. Tumor pathological size was characterized as < 2 cm or 2 + cm.

Potential pre-systemic therapy covariates that might affect the associations between cognition and tumor features included age, cognitive reserve (measured by WRAT-4 [25] scores), race, recruitment site, surgery type (mastectomy vs. breast conservation) and number of comorbid illnesses. We also examined other potential covariates, including reactive mood that might be associated with knowledge of a more aggressive disease and need for additional adjuvant treatment, using the STAI-State (score of 45 or more) [28] or CES-D (score of 16 or more) [29]. Finally, since larger or more advanced stage tumors may reflect access barriers not fully captured by social determinants like race and cognitive reserve, we explored years of education, usual occupation, and Medicaid status as possible covariates.

Statistical Analysis

We estimated the association of stage of disease or HER2 and self-reported cognition scores and objective performance on APE and LM domains in unadjusted linear regression models. Adjusted self-reported cognitive scores and objective performance (or rates of impairment) on APE and LM domains were estimated in multivariable linear regression models controlling for age, race, and recruitment site.

In secondary analyses, associations of HER2 + molecular subtypes and cognitive impairment rates were tested using ANCOVA or Chi-square tests. In other secondary analyses we used similar analyses to explore the association of self-reported and objective cognitive scores or impairment and other tumor markers.

In all analyses, we tested whether additional variables might have confounded the association of specific tumor features and cognition through socioeconomic status or barriers to treatment (e.g., years of education, Medicaid status). Finally, since self-reported depression and anxiety were variably associated with tumor features and cognition, these were considered in secondary analyses.

Since stage of disease and HER2 status were our a priori primary hypotheses, results for each were considered significant at a two-sided p-value < 0.05. For secondary tumor features, no multiplicity correction was performed, and we report these results as exploratory for hypothesis generating purposes.

All analyses were conducted using SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA).

Participants

Patients were on average 68 years old (SD 5.8, range 60–98), well-educated (mean years of education 15.3 [SD 2.2]), and predominantly white (79.1%) (Table 1). The majority of patients had tumors that were HER2 negative (89.3%), hormone receptor positive (88.6%), < 2 cm tumor size (71.5%) and/or Stage 0/1 (72.6%) (Table 1). Tumor features were not related to sociodemographic, mood or other covariates except for small differences in racial group and minor variation in education by tumor size (Online materials, Table 1); race is included in all adjusted models of cognition and tumor features.

Table 1

Characteristics of Older Patients with Non-Metastatic Breast Cancer at Enrollment, Prior to Systemic Therapy (n = 705)
	Percent (n) or mean (SD)
Age	68.0 (5.8), range 60–98
Race*
White, non-Hispanic	79% (558)
Non-White	18% (124)
Hispanic	3% (23)
Years of education	15.3 (2.2)
Number of comorbidities	2.8 (2.0)
Surgery
Mastectomy	32.6% (228)
Lumpectomy	67.4% (471)
Time from surgery to enrollment, days	44.2 days (51.4)
STAI-A Anxiety above cutoff (> 44)**	6.1% (40)
CES-D score indicting depression (≥ 16) ^†	12.6% (81)
HER2 Positivity^‡
Negative	89.3% (552)
Positive	10.7% (66)
Hormone Receptor status^❡
Positive	88.6% (620)
Negative	11.4% (80)
Triple negative status (ER-, HER2-, PR-)
Not triple negative	91.9% (634)
Triple negative	8.1% (56)
Tumor Grade
Low	20.1% (110)
Moderate	61.1% (334)
High	18.8% (103)
Lymph node
Negative	82.2% (560)
Positive	17.8% (121)
Tumor size
<2 cm	71.5% (487)
2 + cm	28.5% (194)
AJCC v. 6 Stage
Stage 0/II	72.6% (504)
Stage II/III	27.4% (190)
* non-White includes Black and Asian
** Scores on the State-Trait Anxiety Inventory range from 20 to 80, with higher scores reflecting more anxiety. A cut point of > 44 is used to define clinical anxiety.
^† Scores on the Center for Epidemiologic Studies Depression Scale range from 0–60, with higher scores representing more depressive symptoms; a cut point of 16 is used to define clinical depression.
^‡ HER2 positivity was defined as scoring 3 + on HER2 IHC, or tested positive on HER2 FISH, or going on to receive Herceptin treatment.
^❡ Hormone receptor positive was defined as being estrogen receptor (ER) positive and/or progesterone receptor (PR) positive.

Association of Tumor Features with Pre-systemic Therapy Cognition

Objective Cognitive Performance

As predicted, higher stage of disease was associated with lower attention, processing speed, and executive functioning (APE) domain scores in unadjusted models (p < 0.001) and this relationship persisted in models adjusted for age, race, and site: patients with stage II/III tumors had worse APE performance than those with stage 0/I tumors (-0.369 [0.048] vs. -0.222 [0.033], p = 0.005). HER2 positivity or having a HER2 positive molecular subtype was not associated with APE or LM scores or impairment rates in unadjusted or adjusted models (Tables 2 and 3a, b).

Table 2

Crude and Adjusted¹ Enrollment, Pre-systemic Therapy Cognitive Function by Tumor Characteristics among Older Patients with Non-Metastatic Breast Cancer
	FACT-Cog PCI Score²				Attention, Processing Speed, Executive Function³				Learning and Memory³
	Unadjusted		Adjusted		Unadjusted		Adjusted		Unadjusted		Adjusted
Stage
Stage 0/1	60.9 (0.5)	p = 0.452	61.0 (0.6)	p = 0.171	− .052 (0.029)	p = < .001	− .222 (0.033)	p = 0.005	− .041 (0.037)	p = 0.699	− .295 (0.042)	p = 0.733
Stage 2/3	60.2 (0.8)		59.7 (0.9)		− .242 (0.047)		− .369 (0.048)		− .069 (0.061)		− .272 (0.061)
HER2⁴
Negative	61.2 (0.5)	p = 0.008	60.9 (0.6)	p = 0.023	− .113 (0.028)	p = 0.946	− .284 (0.034)	p = 0.786	− .052 (0.035)	p = 0.170	− .322 (0.042)	p = 0.292
Positive	57.3 (1.4)		57.6 (1.4)		− .107 (0.081)		− .262 (0.079)		− .201 (0.102)		− .428 (0.098)
Tumor size
< 2 cm	61.3 (0.5)	p = 0.024	61.2 (0.6)	p = 0.021	− .063 (0.029)	p = 0.008	− .238 (0.034)	p = 0.074	− .038 (0.038)	p = 0.669	− .301 (0.043)	p = 0.595
2 + cm	59.1 (0.8)		59.0 (0.9)		− .210 (0.046)		− .331 (0.047)		− .068 (0.060)		− .267 (0.059)
Hormone receptor
Positive	61.0 (0.5)	p = 0.034	60.9 (0.6)	p = 0.131	− .100 (0.026)	p = 0.534	− .265 (0.031)	p = 0.915	− .026 (0.033)	p = 0.043	− .272 (0.039)	p = 0.163
Negative	58.2 (1.3)		58.9 (1.3)		− .148 (0.073)		− .257 (0.070)		− .227 (0.093)		− .400 (0.088)
Grade
Low	61.2 (1.0)	p = 0.562	61.7 (1.4)	p = 0.545	− .039 (0.062)	p = 0.609	− .140 (0.078)	p = 0.439	− .003 (0.079)	p = 0.352	− .096 (0.098)	p = 0.310
Moderate	60.3 (0.6)		60.7 (1.2)		− .109 (0.036)		− .224 (0.064)		0.018 (0.045)		− .122 (0.079)
High	59.6 (1.1)		60.1 (1.5)		− .076 (0.064)		− .182 (0.080)		− .117 (0.082)		− .241 (0.100)
Lymph node
Negative	60.9 (0.5)	p = 0.907	60.8 (0.6)	p = 0.946	− .097 (0.028)	p = 0.588	− .262 (0.032)	p = 0.528	− .043 (0.035)	p = 0.990	− .281 (0.040)	p = 0.805
Positive	60.8 (1.0)		60.9 (1.1)		− .133 (0.059)		− .301 (0.060)		− .044 (0.076)		− .300 (0.075)
1. Unadjusted scores for each individual categorical tumor characteristic were calculated from simple linear regression models, with significance testing based on Type III tests. Adjusted cognitive scores for each individual categorical tumor characteristic were controlled for age, race, and recruitment site in linear regression models.
2. Scores on the FACT-Cog perceived cognitive impairment scale range from 0–72, with higher scores represent better cognitive function.
3. Z-scores for neurological tests within each domain range from − 3 to + 3, with a mean of 0. A positive score indicates better cognitive performance and a negative score reflects worse than average scores.
4. HER2 positivity was defined as scoring 3 + on HER2 IHC, or tested positive on HER2 FISH, or receiving Herceptin treatment.

In secondary analyses, larger tumor size was associated with lower APE performance in unadjusted models (p = 0.008), but this association decreased to marginal significance in models adjusted for age, race, and site (p = 0.074). Hormone receptor negativity was associated with lower LM performance in unadjusted models (p = 0.043), but this association did not persist in models adjusted for age, race, and site (p = 0.163) (Table 2). Measures of mood were variably associated with tumor features (Online materials, Table 1). However, with the exception of the association of tumor size and APE performance, when depression or anxiety were added to models all other associations between tumor features and objective cognition remained either significant or marginally significant with similar magnitude of effects (Online materials Tables 2a and 2b).

Self-Reported Cognition

As predicted, HER2 positivity (p = 0.008) was associated with self-reported cognition and this relationship remained after adjustment for age, race, and site (p = 0.02) (Table 2). Patients with HER2+ (vs. HER2-) tumors had a higher rate of self-reported cognitive scores at or below the cut-point indicating impairment (30% vs. 19%, p = 0.049) (Fig. 1). When considering combinations of tumor features based on common molecular subtypes (Table 3), patients with the HR-/HER2 + molecular subtype tumors had significantly and clinically meaningfully lower self-reported cognitive scores (50.9 vs. 59.7–61.0 in other subtypes, p = 0.006) (Table 3a). Patients with HR-/HER2 + molecular subtype tumors also had the highest level of impairment (37.5% vs. 18.9–28.3% for other subtypes) but this difference was not statistically significant (Table 3b). Stage of disease was not associated with self-reported cognition.

Table 3. Pre-systemic Therapy Cognition by Molecular Sub-type among Older Patients with Non-Metastatic Breast Cancer

a. Mean (SE) Adjusted Baseline Cognitive Scores By Molecular Subtype

Mean scores	HR+, HER2- (n=493)	HR+, HER2+ (n=51)	HR-, HER2+ (n=15)	HR-, PR-, HER2- (triple negative) (n=56)	p-value¹
Self-reported cognitive problems (FACT cog PCI)*	60.8 (0.7)	59.7 (1.6)	50.9 (2.8)	61.0 (1.5)	0.006
APE z-score **	-.296 (0.036)	-.237 (0.090)	-.350 (0.159)	-.197 (0.084)	0.621
LM z-score **	-.306 (0.045)	-.377 (0.112)	-.578 (0.199)	-.430 (0.104)	0.370

Adjusted for age, race, site; p values based on ANCOVA.

b. Mean rates of baseline cognitive impairment by molecular subtype

Percent impaired	HR+, HER2- (n=460)	HR+, HER2+ (n=46)	HR-,HER2+ (n=14)	HR-, PR-, HER2- (triple negative) (n=53)	p-value²
Self-reported cognitive problems (FACT cog PCI)*	19.4%	28.3%	35.7%	18.9%	0.245
APE domain**	17.2%	15.7%	20.0%	10.7%	0.636
LM domain**	14.2%	7.8%	13.3%	23.2%	0.150

p-values based on Chi-square tests.

*Scores on the FACT-Cog perceived cognitive impairment scale range from 0-72, with higher scores represent better cognitive function. 3-5 point differences are considered clinically meaningful and a score of <54 is considered impaired.

** Z-scores for neuropsychological tests within each domain range from -3 to +3, with a mean of 0. A positive score indicates better cognitive performance and a negative score reflects worse than average scores. Having one of the tests within the domain with a score of <2SD from the mean or two tests <1.5 SD from the mean are considered impairment.

In secondary analyses, additional markers of tumor aggressiveness were also significantly associated with having more perceived cognitive problems, including hormone receptor negativity and larger tumor size (p = 0.02) (Table 2), but only larger tumor size (p = 0.02) remained significantly associated with having more perceived cognitive problems in models adjusted for age, race, and site (Table 2). Having a larger (vs. smaller) tumor was also associated with higher adjusted self-reported rates of pre-systemic therapy cognitive impairment (28% vs. 18%, p = 0.006) (Fig. 1). Associations between tumor features and self-reported cognition remained either significant or marginally significant with similar magnitude of effects considering mood (Online materials Tables 2a and 2b).

To our knowledge this is the largest study of the association between breast cancer molecular and clinicopathological tumor features and pre-systemic therapy cognition in older patients with breast cancer. Our results indicated that higher stage of disease and HER2 positivity were associated with cognition: higher stage of disease was associated with worse performance on measures of attention, processing speed, and executive dysfunction and HER2 positivity was associated with significantly more self-reported cognitive problems and higher rates of clinically meaningful cognitive impairment. Among other markers of tumor aggressiveness, larger tumor size was associated with self-reported cognitive dysfunction. Taken together, our results suggest that aggressive tumor features like stage of disease, HER2 positivity, and tumor size may have systemic effects that impact cognition.

These results confirm the limited previous reports from largely younger patients and smaller samples that suggest a role for higher tumor stage/later stage [8, 7] and HER2 status [19] in pre-systemic treatment cognition. However, not all past studies have observed associations between tumor features and cognition, but these may have been limited in power due to small sample sizes [14]. Our results from a large cohort add new data from older patients with breast cancer. While older patients are less likely to have aggressive, poor prognosis tumors than younger patients, when they do have these tumor types, they may be more likely to report cognitive problems than other age groups because older patients often have diminished age-related cognitive reserve and limited ability to compensate for even small cognitive changes. Ways to test these ideas further include new cohort studies, use of pooled existing data, measuring self-reported cognition in clinical trials and increasing the representation of older patients in those trials.

Since the tumor features we identified as associated with cognition are known to be highly intercorrelated and related to tumor aggressiveness [30], it is possible that there is a final common pathway for their effect on cognition. Chronic, heightened inflammatory responses to larger, more aggressive tumors may be one potential pathway affecting pre-systemic therapy cognition via peripheral inflammation and neuroinflammation [31, 18]. This seems plausible given evolving evidence about the role of inflammation in post-treatment cognitive problems [32–35], which are thought to be due to peripheral inflammation crossing the blood brain barrier and promoting neuroinflammation [13]. Alternatively, since HER2 is encoded by ERBB2 and ERBB2 plays a role in central and peripheral nervous system development and adult cognition [36], this may be another pathway of effect for higher stage of disease and tumor size seen with HER2 positive tumors. Alternative pathways are also plausible since a subset of features associated with aggressivity were not associated with cognitive outcomes, such as triple negative status, although this is a less common subtype in older age, limiting our power. As data evolve, it will be useful to examine whether different tumor features influence cognition via multiple, separate, and distinct pathways or through a final, common pathway.

Other factors have been proposed to contribute to cognitive problems after surgery but before systemic therapy, including effects of general anesthesia [37, 38], genotype [39], and differential inflammatory effects related to extent of resection [40]. This latter effect has been particularly pronounced in pre-clinical models with aged animals [41]. However, we did not find a difference in cognition by surgery type in the current study and previous work associating anesthetic dose with pre-systemic therapy cognition also failed to find an association [7].

Other possible contributors to the relationships of aggressive tumor features and cognition we observe include anxiety and depression in reaction to facing treatment for an aggressive cancer or sociodemographic factors creating barriers to screening, diagnosis and/or access to treatment. However, models including measures of mood showed a persistence or minimal attenuation of the association between aggressive tumor features and cognition. Race was included in all models and did not attenuate effects. Other socioeconomic factors were not related to tumor features; on the contrary, larger tumor size and stage were found to be associated with higher levels of education. Given the relatively small number of older patients with aggressive tumor features and the limited socioeconomic and demographic diversity of our cohort it will be important to conduct future studies to explore the multi-level inter-relationships between life course experiences, coping styles, tumor characteristics and cognition.

Understanding pre-systemic therapy mechanisms and factors associated with cognitive problems may be useful in identifying those patients who are at heightened risk for further cognitive decline and could suggest interventions to treat early cognitive issues and/or prevent additional decline while undergoing life-saving systemic therapy. This is especially important because aggressive tumors require extensive treatments that may also impact longer-term cognition after active therapy. Identifying cognitive vulnerability is especially important in older adults who are already at risk for age-related cognitive decline and can alert clinicians to the potential need to evaluate cognitive function and ability to complete complex treatment regimens. Our findings also underscore the importance of screening older adults with cancer for cognitive problems at all phases of care, from diagnosis to survivorship, using geriatric assessments or other approaches [42]. It will also be important to determine if pre-systemic therapy cognitive problems resolve over time or are a harbinger of continued declines.

The TLC study is the largest study examining cognition in older patients with breast cancer to date. We found consistent results suggesting that features related to tumor aggressiveness are associated with pre-systemic therapy objective and self-reported and cognitive problems. There are also caveats that should be considered in evaluating our results. The current sample is composed of largely white, well-educated participants and should be replicated in other populations to assess generalizability. While stage of disease and HER2 status were hypothesized to be associated with cognitive function, our secondary analyses explored several other tumor features and may have increased risk for Type 1 error. Additionally, we did not have the power to test for the role of genetic factors like APOE4 positivity or interactions between tumor features and APOE4 positivity since this was only seen in about one-fifth of our sample. Finally, we did not have any data on earlier life exposures that may have affected pre-systemic therapy cognition. These will be important areas to consider when designing new studies of cognition and cancer.

In summary, several breast cancer tumor features associated with aggressive disease were found to be significantly associated with pre-systemic treatment cognition, with the most significant effects found for stage of disease, HER2 positivity, including the HER2+/HR- subtype, and tumor size. These findings expand the scope of potential cancer-related cognitive decline mechanisms beyond systemic chemotherapy and hormonal therapies. Until new data become available, our results suggest that cognitive function should be evaluated prior to and during clinically indicated systemic therapies to provide early supportive care and symptom management for older patients.

Funding: This research was supported by the National Cancer Institute at the National Institutes of Health grants R01CA129769 and R35CA197289 to JM. This study was also supported in part by the National Cancer Institute at the National Institutes of Health grant P30CA51008 to Georgetown-Lombardi Comprehensive Cancer Center for support of the Biostatistics and Bioinformatics Resource and the Non-Therapeutic Shared Resource. The work of AJS and BCM was supported in part by the National Institute on Aging, National Library of Medicine, and National Cancer Institute at the National Institutes of Health grants P30AG10133, R01AG19771, R01LM01136, and R01CA244673. TAA and JCR were supported in part by National Cancer Institute at the National Institutes of Health grants R01 CA218496, R01CA172119, R03CA249548, and P30CA008748. The work of JC was supported in part by the American Cancer Society Research Scholars grant 128660-RSG-15-187-01-PCSM and the National Cancer Institute at the National Institutes of Health grant R01CA237535. HJC was supported in part by the National Institute of Aging at the National Institutes of Health grant P30AG028716 for the Duke Pepper Center. SKP was supported in part by the American Cancer Society Research Scholars grant RSG-17-023-01-CPPB.

Role of the funders: The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Competing Interests/Disclosures: Asma Dilawari has served on the Cardinal Health oncology summit advisor board, 2019. Claudine Isaacs has served as a consultant for Genentech, Seattle Genetics, PUMA, Novartis, AstraZeneca, Sanofi, and Pfizer, and received support for research (to institution) from Pfizer and Tesaro/GSK. Heather Jim has consulted for RedHill BioPharma, Janssen Scientific Affairs, and Merck, and has received grant funding from Kite Pharma. The other authors declare that they have no conflict of interest.

Disclaimer: The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.

Acknowledgements: The work of Paul Jacobsen was done while he was at Moffitt Cancer Center. We would like to thank the participants in the TLC study for their sharing of their time and experiences; without their generosity this study would not have been possible. We are also indebted to Sherri Stahl, Naomi Greenwood, Margery London, and Sue Winarsky who serve as patient advocates from the Georgetown Breast Cancer Advocates for their insights and suggestions on study design and methods to recruit and retain participants. We thank the TLC study staff who contributed by ascertaining, enrolling and interviewing participants.

Author contributions: James C. Root was responsible for investigation, supervision and writing. Xingtao Zhou was responsible for formal analysis, data curation and writing. Jaeil Ahn was responsible for supervision, methodology, formal analysis, data curation and writing. Brent J. Small was responsible for supervision, methodology, formal analysis, data curation and writing. Wanting Zhai was responsible for formal analysis, data curation and writing. Traci Bethea was responsible for conceptualization and writing. Judith Carroll was responsible for conceptualization and writing. Harvey Jay Cohen was responsible for conceptualization and writing and editing. Asma Dilawari was responsible for conceptualization and writing. Martine Extermann was responsible for conceptualization and writing. Deena Graham was responsible for investigation, resources and writing. Paul B. Jacobsen was responsible for investigation and writing. Heather Jim was responsible for investigation, resources, writing, project administration and funding acquisition. Claudine Isaacs was responsible for conceptualization and writing. Brenna C. McDonald was responsible for investigation and writing. Zev Nakamura was responsible for conceptualization and writing. Sunita K. Patel was responsible for investigation, resources, writing and project administration. Kelly Rentscher was responsible for conceptualization and writing. Andrew J. Saykin was responsible for investigation, resources, writing, project administration and funding acquisition. Kathleen van Dyk was responsible for conceptualization and writing. Jeanne S. Mandelblatt was responsible for conceptualization, investigation, resources, writing and editing, supervision, project administration and funding acquisition. Tim Ahles was responsible for conceptualization, investigation, resources, writing, project administration and funding acquisition.

Data Availability: The data collected for the Thinking and Living with Cancer (TLC) Study used in this publication were supported by funding from the National Institutes of Health. The data are available for sharing under NIH-compliant TLC Study agreements. Please contact the corresponding author for requests.

Ethics Approval: This Institutional Review Board-approved study (ClinicalTrials.gov Identifier: NCT03451383) has been reported previously [8, 2] and was conducted at six US sites in Los Angeles, New York City, New Jersey, the DC metropolitan area, Indianapolis, and Tampa.

Consent to Participate: Informed consent was obtained from all individual participants included in the study.

Consent to Publish: The authors affirm that human research participants provided informed consent for publication

Janelsins MC, Heckler CE, Peppone LJ, Mohile SG, Mustian KM, Ahles T et al (2017) Longitudinal assessment of cancer-related cognitive impairment (CRCI) up to six-months post-chemotherapy with multiple cognitive testing methods in 943 breast cancer (BC) patients and controls. J Clin Oncol 35(15suppl):10014. doi:10.1200/JCO.2017.35.15_suppl.10014
Mandelblatt JS, Small BJ, Luta G, Hurria A, Jim H, McDonald BC et al (2018) Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study. J Clin Oncol JCO1800140. doi:10.1200/JCO.18.00140
Selamat MH, Loh SY, Mackenzie L, Vardy J (2014) Chemobrain experienced by breast cancer survivors: a meta-ethnography study investigating research and care implications. PLoS ONE 9(9):e108002. doi:10.1371/journal.pone.0108002
Von Ah D, Habermann B, Carpenter JS, Schneider BL (2013) Impact of perceived cognitive impairment in breast cancer survivors. Eur J Oncol nursing: official J Eur Oncol Nurs Soc 17(2):236–241. doi:10.1016/j.ejon.2012.06.002
Ahles TA, Root JC (2018) Cognitive Effects of Cancer and Cancer Treatments. Ann Rev Clin Psychol 14:425–451. doi:10.1146/annurev-clinpsy-050817-084903
Wefel JS, Vardy J, Ahles T, Schagen SB (2011) International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 12(7):703–708. doi:10.1016/S1470-2045(10)70294-1
Ahles TA, Saykin AJ, McDonald BC, Furstenberg CT, Cole BF, Hanscom BS et al (2008) Cognitive function in breast cancer patients prior to adjuvant treatment. Breast Cancer Res Treat 110(1):143–152
Mandelblatt JS, Stern RA, Luta G, McGuckin M, Clapp JD, Hurria A et al (2014) Cognitive impairment in older patients with breast cancer before systemic therapy: is there an interaction between cancer and comorbidity? J Clin Oncol 32(18):1909–1918. doi:10.1200/JCO.2013.54.2050
Wefel JS, Vidrine DJ, Veramonti TL, Meyers CA, Marani SK, Hoekstra HJ et al (2011) Cognitive impairment in men with testicular cancer prior to adjuvant therapy. Cancer 117(1):190–196. doi:10.1002/cncr.25298
Mandelblatt JS, Zhou X, Small BJ, Ahn J, Zhai W, Ahles T et al (2021) Deficit Accumulation Frailty Trajectories of Older Breast Cancer Survivors and Non-Cancer Controls: The Thinking and Living with Cancer Study. J Natl Cancer Inst. doi:10.1093/jnci/djab003
Hermelink K, Voigt V, Kaste J, Neufeld F, Wuerstlein R, Buhner M et al (2015) Elucidating pretreatment cognitive impairment in breast cancer patients: the impact of cancer-related post-traumatic stress. J Natl Cancer Inst 107(7). doi:10.1093/jnci/djv099
Andreotti C, Root J, Ahles T, McEwen B, Compas B (2014) Cancer, coping, and cognition: a model for the role of stress reactivity in cancer-related cognitive decline.Psycho‐Oncology:1099–611
Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7(3):192–201
Lange M, Giffard B, Noal S, Rigal O, Kurtz JE, Heutte N et al (2014) Baseline cognitive functions among elderly patients with localised breast cancer. Eur J Cancer 50(13):2181–2189. doi:10.1016/j.ejca.2014.05.026
Mampay M, Flint MS, Sheridan GK (2021) Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers. Br J Pharmacol. doi:10.1111/bph.15571
Kim J, Chuang HC, Wolf NK, Nicolai CJ, Raulet DH, Saijo K et al (2021) Tumor-induced disruption of the blood-brain barrier promotes host death. Dev Cell 56(19):2712–21e4. doi:10.1016/j.devcel.2021.08.010
Chen SL, Cai GX, Ding HG, Liu XQ, Wang ZH, Jing YW et al (2020) JAK/STAT signaling pathway-mediated microRNA-181b promoted blood-brain barrier impairment by targeting sphingosine-1-phosphate receptor 1 in septic rats. Ann Transl Med 8(21):1458. doi:10.21037/atm-20-7024
Walker AK, Chang A, Ziegler AI, Dhillon HM, Vardy JL, Sloan EK (2018) Low dose aspirin blocks breast cancer-induced cognitive impairment in mice. PLoS ONE 13(12):e0208593. doi:10.1371/journal.pone.0208593
Koleck TA, Bender CM, Sereika SM, Ryan CM, Ghotkar P, Brufsky AM et al (2017) Associations between pathologic tumor features and preadjuvant therapy cognitive performance in women diagnosed with breast cancer. Cancer Med 6(2):339–348. doi:10.1002/cam4.964
Kobayashi LC, Cohen HJ, Zhai W, Zhou X, Small BJ, Luta G et al (2020) Cognitive function prior to systemic therapy and subsequent well-being in older breast cancer survivors: Longitudinal findings from the Thinking and Living with Cancer Study. Psychooncology 29(6):1051–1059. doi:10.1002/pon.5376
Mandelblatt JS, Small BJ, Luta G, Hurria A, Jim H, McDonald BC et al (2018) Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study. J Clin Oncol 36(32):Jco1800140. doi:10.1200/jco.18.00140
Mandelblatt JS, Zhai W, Ahn J, Small BJ, Ahles TA, Carroll JE et al (2020) Symptom burden among older breast cancer survivors: The Thinking and Living With Cancer (TLC) study. Cancer 126(6):1183–1192. doi:10.1002/cncr.32663
Van Dyk K, Zhou X, Small BJ, Ahn J, Zhai W, Ahles T et al (2021) Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. JNCI Cancer Spectr 5(2):pkab013. doi:10.1093/jncics/pkab013
Folstein MF, Folstein SE, McHugh PR (1975) "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198
Wilkinson GS, Robertson GJ (2006) WRAT4: Wide Range Achievement Test. Psychological Assessment Resources, Lutz, FL
Wagner LI, Lai JS, Cella D, Sweet J, Forrestal S (2004) Chemotherapy-related cogntive deficits: Development of the FACT-Cog instrument.Annals of Behavioral Medicine. p.s10
Dyk KV, Crespi CM, Petersen L, Ganz PA (2020) Identifying Cancer-Related Cognitive Impairment Using the FACT-Cog Perceived Cognitive Impairment. JNCI Cancer Spectr 4(1):pkz099. doi:10.1093/jncics/pkz099
Spielberger CD, Gorsuch RL, Lushene RE (1970) Manual for the Stait-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA
Radloff LS (1977) The CES-D scale a self-report depression scale for research in the general population. Appl Psychol Meas 1(3):385–401
Banin Hirata BK, Oda JM, Losi Guembarovski R, Ariza CB, de Oliveira CE, Watanabe MA (2014) Molecular markers for breast cancer: prediction on tumor behavior. Dis Markers 2014:513158. doi:10.1155/2014/513158
Sankowski R, Mader S, Valdes-Ferrer SI (2015) Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci 9:28. doi:10.3389/fncel.2015.00028
Chae JW, Ng T, Yeo HL, Shwe M, Gan YX, Ho HK et al (2016) Impact of TNF-alpha (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients. PLoS ONE 11(10):e0164204. doi:10.1371/journal.pone.0164204
Jehn CF, Kuhnhardt D, Bartholomae A, Pfeiffer S, Schmid P, Possinger K et al (2010) Association of IL-6, hypothalamus-pituitary-adrenal axis function, and depression in patients with cancer. Integr Cancer Ther 9(3):270–275. doi:10.1177/1534735410370036
Bagnall-Moreau C, Chaudhry S, Salas-Ramirez K, Ahles T, Hubbard K (2019) Chemotherapy-Induced Cognitive Impairment Is Associated with Increased Inflammation and Oxidative Damage in the Hippocampus. Mol Neurobiol. doi:10.1007/s12035-019-1589-z
Meyers CA, Albitar M, Estey E (2005) Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104(4):788–793. doi:10.1002/cncr.21234
Birchmeier C (2009) ErbB receptors and the development of the nervous system. Exp Cell Res 315(4):611–618. doi:10.1016/j.yexcr.2008.10.035
Hovens IB, Schoemaker RG, van der Zee EA, Heineman E, Izaks GJ, van Leeuwen BL (2012) Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives. Brain Behav Immun 26(7):1169–1179. doi:10.1016/j.bbi.2012.06.004
Belrose JC, Noppens RR (2019) Anesthesiology and cognitive impairment: a narrative review of current clinical literature. BMC Anesthesiol 19(1):241. doi:10.1186/s12871-019-0903-7
Li W, Zhang Q, Cai Y, Chen T, Cheng H (2022) The COMT Genetic Factor Regulates Chemotherapy-Related Prospective Memory Impairment in Survivors With HER2-/+ Breast Cancer. Front Oncol 12:816923. doi:10.3389/fonc.2022.816923
Alam A, Hana Z, Jin Z, Suen KC, Ma D (2018) Surgery, neuroinflammation and cognitive impairment. EBioMedicine 37:547–556. doi:10.1016/j.ebiom.2018.10.021
Li Z, Liu F, Ma H, White PF, Yumul R, Jiang Y et al (2017) Age exacerbates surgery-induced cognitive impairment and neuroinflammation in Sprague-Dawley rats: the role of IL-4. Brain Res 1665:65–73. doi:10.1016/j.brainres.2017.04.004
Pergolotti M, Battisti NML, Padgett L, Sleight AG, Abdallah M, Newman R et al (2020) Embracing the complexity: Older adults with cancer-related cognitive decline-A Young International Society of Geriatric Oncology position paper. J Geriatr Oncol 11(2):237–243. doi:10.1016/j.jgo.2019.09.002

StageandHER2supplemental.docx

Download PDF

Reviews received at journal
14 Apr, 2022
Reviewers invited by journal
13 Apr, 2022
Editor assigned by journal
12 Apr, 2022
First submitted to journal
30 Mar, 2022

You are reading this latest preprint version

Association of Markers of Tumor Aggressivity and Cognition in Women with Breast Cancer Before Adjuvant Treatment: The Thinking and Living with Cancer Study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Setting, Population And Data Collection

Measures

Statistical Analysis

Results

Participants

Objective Cognitive Performance

Self-Reported Cognition

Discussion

Declarations

References

Supplementary Files

Status:

Version 1