JNCI J Natl Cancer Inst (2015) 107(7): djv099 doi:10.1093/jnci/djv099 First published online April 16, 2015 Article
article
Elucidating Pretreatment Cognitive Impairment in Breast Cancer Patients: The Impact of Cancer-Related Post-Traumatic Stress
Correspondence to: Kerstin Hermelink, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Klinikum der Universität München Marchioninistr, 15, D-81377 München, Germany (e-mail: [email protected]).
Abstract Background: Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress. Methods: Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients’ risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided. Results: The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment. Conclusion: Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress.
Received: October 6, 2014; Revised: February 3, 2015; Accepted: March 12, 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 13
article
Affiliations of authors: Breast Center, Department of Gynecology and Obstetrics (Campus Grosshadern), CCCLMU University Hospital of Munich, Munich, Germany (KHe, VV, JK, FN, SH, NH); Breast Center, Department of Gynecology and Obstetrics (Campus Innenstadt), CCCLMU University Hospital of Munich, Munich, Germany (RW, KHä); Department of Psychology, Division of Psychological Methods and Assessment, Ludwig Maximilian University of Munich, Munich, Germany (MBü); Department of Psychology, Division of Neuropsychology, Ludwig Maximilian University of Munich, Munich, Germany (KM); Institute for Clinical Radiology, CCCLMU University Hospital of Munich, Munich, Germany (DRD, SG); Breast Center, Department of Gynecology, Red Cross Hospital, Munich, Germany (MBr); Breast Center, Department of Gynecology and Obstetrics, Dritter Orden Hospital, Munich, Germany (FEvK); Breast Center, Department of Gynecology and Obstetrics, District Hospital of Ebersberg, Ebersberg, Germany (SH); Breast Center, Department of Gynecology and Obstetrics, Hospital of Landshut, Landshut, Germany (IB); Breast Center, Department of Gynecology and Obstetrics, Helios Amper Hospital Dachau, Dachau, Germany (GD); Department of Psychosomatic Medicine and Psychotherapy, Division of Psychosocial Oncology, Roman Herzog Comprehensive Cancer Center, Technical University of Munich, Munich, Germany (PH).
Downloaded from http://jnci.oxfordjournals.org/ by guest on September 21, 2015
Kerstin Hermelink, Varinka Voigt, Judith Kaste, Franziska Neufeld, Rachel Wuerstlein, Markus Bühner, Karin Münzel, Dorothea Rjosk-Dendorfer, Susanne Grandl, Michael Braun, Franz Edler von Koch, Kristin Härtl, Stephan Hasmüller, Ingo Bauerfeind, Gerlinde Debus, Peter Herschbach, Nadia Harbeck
2 of 13 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 7
Methods Participants Women newly diagnosed with stage 0 to IIIc breast cancer (66) at six breast centers in the area of Munich, Germany, from January 2011 to August 2013 were eligible for participation if they met the following criteria: age 18 to 65 years, fluent in German, free of substance abuse, without a history of neurological or psychotic disorder, and no prior systemic treatment for cancer. To assure that case patients and control patients did not differ in any systematic way except for the presence of cancer, only women who had had breast imaging at one of the participating breast centers were eligible for the control group. The same criteria as for case patients were applied to control patients, with the addition that control patients must neither have suffered from any malignant disease nor require further imaging, biopsy, or treatment for any breast disease. Written informed consent was obtained from all participants. Cognicares was approved by the ethics committee of the Ludwig Maximilian University of Munich and is registered at ClinicalTrials.gov, registration number NCT01264562 (67).
Enrollment and Assessment Proceedings Physicians at participating breast centers informed potentially eligible women briefly about the study. Patients who agreed to their contact information being forwarded to Cognicares staff were then contacted, fully informed, and asked to participate if eligibility criteria were met. Enrollment proceedings were the same for case patients and control patients. Participants underwent a two- to two and a half–hour assessment session that was scheduled a minimum of one week after a negative mammogram for control patients and before any local or systemic intervention (except biopsy of the tumor or sentinel lymph nodes) for case patients. Participants were compensated with 15 Euro. All assessments were conducted by master’s-level psychologists who had received expert training on neuropsychological testing and PTSD diagnostics.
Measures Assessments comprised a one-hour neuropsychological test battery, PTSD diagnostics, self-report measures of cognitive functioning and psychological morbidity, a test of premorbid intelligence, and demographic and medical data (Table 1) that were additionally extracted from medical records. The neuropsychological battery consisted of the tests recommended by the International Cognition and Cancer Task Force (ICCTF) (26,68) or their validated German counterparts (69,70) and additional paper-and-pencil (71) and computerized tests (72) found to be sensitive for cancer-related cognitive impairment (73). Twenty indices of cognitive functioning were chosen from the tests (Table 2). The selection of indices was premeditated prior to any analyses and guided by the aim to obtain finegrained information but to avoid redundancy. The validated German version of the Structured Clinical Interview for DSM-IV (SCID) (65) was used for diagnosis of stress disorder and stress symptoms. If control patients endorsed more than one potentially traumatic event, the event rated as the worst by the participant was inquired. If cancer patients
Downloaded from http://jnci.oxfordjournals.org/ by guest on September 21, 2015
article
There is no doubt that problems of cognitive functioning can considerably afflict patients with breast cancer (1,2) or other noncentral nervous system cancers (3). When neuropsychological studies started to demonstrate cognitive impairment in subgroups of cancer patients, the deficits were initially almost entirely attributed to neurotoxic effects of chemotherapy (4). This view was questioned when an increasing number of studies found evidence of pretreatment cognitive impairment. Already before adjuvant treatment, and even before surgery (5–7) or definite diagnosis (8), breast cancer patients were observed to perform poorly on neuropsychological tests in comparison with published normative data (6,9–12) or healthy control patients (7,9,13,14). In recent years, neuroimaging studies detected abnormalities of brain activation patterns during cognitive tasks in chemotherapy-naïve patients with breast cancer (15–19). Although not all studies have found evidence of cognitive deficits in cancer patients before chemotherapy (20–22), pretreatment cognitive impairment is now widely accepted and has changed thinking (23–26) about the phenomenon once named chemobrain. Clearly, other factors than only chemotherapy neurotoxicity may cause cognitive dysfunction in cancer patients, and part of them seem to exert their influence before the start of treatment. Hypotheses regarding cancerassociated cognitive deficits include shared vulnerability for cancer and cognitive impairment, and biological effects of the cancer itself (27–31). While psychological factors have usually been taken into account as confounders, a causative role of these factors for cognitive impairment in cancer patients has rarely been examined in hypothesis-driven investigations (32,33). The Cognition in Breast Cancer Patients: The Impact of Cancer-Related Stress (Cognicares) study was designed to test the hypothesis that cognitive impairment in breast cancer patients is mediated by cancer-related post-traumatic stress that is manifest in symptoms of post-traumatic stress disorder (PTSD). There is substantial evidence that PTSD is associated with cognitive impairment (34–42). Functional and structural brain abnormalities in patients with PTSD are well established (43, 44), among them aberrant activation patterns during a cognitive task (45,46), decreased volumes of the hippocampus (47–50) or other brain regions (51), white matter atrophy (52), and pronounced effects of aging on the brain (52). PTSD predicts cognitive impairment and brain abnormalities independently of depression or other psychological morbidity (35,37,40,52). In animal models, stress had extensive effects on the brain, most prominently suppression of adult hippocampal neurogenesis (53–55). The prevalence of clinician-diagnosed full PTSD is low in breast cancer patients, with rates ranging from 2.4% to 6% (56–60) and only sporadically higher rates of up to 16% (61). Nevertheless, PTSD symptoms that do not meet the criteria of a full diagnosis are a frequent consequence of breast cancer (62,63), especially shortly after diagnosis (64). In the prospective, longitudinal, multisite Cognicares study, PTSD symptoms are assessed with the Structured Clinical Interview for DSM-IV (SCID) (65). Cognitive functioning is measured with traditional and computerized neuropsychological tests in breast cancer patients and in matched cancerfree control patients. Here, we report the findings of the initial assessment conducted prior to any local or systemic cancer treatment.
K. Hermelink et al. | 3 of 13
Table 1. Demographic and clinical characteristics Individually matched case patients (n = 60) P vs control patients*
P vs control patients*
.97 52.6 (7.8) 27.3 to 64.9
52.6 (7.7) 25.2 to 65.4
.13 50.4 (9.1) 21.8 to 65.7
1.00 7 (11.7%) 30 (50.0%) 9 (15.0%) 14 (23.3%)
7 (11.7%) 30 (50.0%) 9 (15.0%) 14 (23.3%)
.20 29 (17.5%) 59 (35.5%) 23 (13.9%) 55 (33.1%)
.78 115.4 (13.4)
115.8 (13.1)
.19 112.6 (13.7)
.01 50 (83.3%) 10 (16.7%)
38 (63.3%) 22 (36.7%)
44 (73.3%) 16 (26.7%)
45 (75.0%) 15 (25.0%) . 54 (90.0%) 6 (10.0%)
.01 110 (66.3%) 56 (33.7%)
.84
58 (96.7%) 2 (3.3%) 35.7 (26.6) -
.27 133 (80.1%) 33 (19.9%)
.14
.08 148 (89.2%) 18 (10.8%)
4 (6.7%) 30 (50.0%) 21 (35.0%) 5 (8.3%)
14 (8.4%) 66 (39.8%) 69 (41.6%) 17 (10.2%)
17.7 (11.2) 8
17.0 (11.0) 15 .67
23 (38.3%) 31 (51.7%) 6 (10.0%)
22 (36.7%) 35 (58.3%) 3 (5.0%)
47 (78.3%) 13 (21.7%)
47 (78.3%) 13 (21.7%)
.21 83 (50.0%) 75 (45.2%) 8 (4.8%)
1.00
.29 140 (84.3%) 26 (15.7%)
.53 43 (71.7%) 17 (28.3%)
46 (76.7%) 14 (23.3%)
57 (95.0%) 3 (5.0%)
54 (90.0%) 6 (10.0%)
60 (100%) 0 (0%)
57 (95.0%) 3 (5.0%)
0.4 (1.1)
4.2 (4.0)
.52 126 (75.9%) 40 (24.1%)
.30
.77 156 (94.0%) 10 (6.0%)
.08
.14 160 (96.4%) 6 (3.6%)
article
Elucidating Pretreatment Cognitive Impairment in Breast Cancer Patients: The Impact of Cancer-Related Post-Traumatic Stress
Correspondence to: Kerstin Hermelink, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Klinikum der Universität München Marchioninistr, 15, D-81377 München, Germany (e-mail: [email protected]).
Abstract Background: Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress. Methods: Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients’ risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided. Results: The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment. Conclusion: Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress.
Received: October 6, 2014; Revised: February 3, 2015; Accepted: March 12, 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
1 of 13
article
Affiliations of authors: Breast Center, Department of Gynecology and Obstetrics (Campus Grosshadern), CCCLMU University Hospital of Munich, Munich, Germany (KHe, VV, JK, FN, SH, NH); Breast Center, Department of Gynecology and Obstetrics (Campus Innenstadt), CCCLMU University Hospital of Munich, Munich, Germany (RW, KHä); Department of Psychology, Division of Psychological Methods and Assessment, Ludwig Maximilian University of Munich, Munich, Germany (MBü); Department of Psychology, Division of Neuropsychology, Ludwig Maximilian University of Munich, Munich, Germany (KM); Institute for Clinical Radiology, CCCLMU University Hospital of Munich, Munich, Germany (DRD, SG); Breast Center, Department of Gynecology, Red Cross Hospital, Munich, Germany (MBr); Breast Center, Department of Gynecology and Obstetrics, Dritter Orden Hospital, Munich, Germany (FEvK); Breast Center, Department of Gynecology and Obstetrics, District Hospital of Ebersberg, Ebersberg, Germany (SH); Breast Center, Department of Gynecology and Obstetrics, Hospital of Landshut, Landshut, Germany (IB); Breast Center, Department of Gynecology and Obstetrics, Helios Amper Hospital Dachau, Dachau, Germany (GD); Department of Psychosomatic Medicine and Psychotherapy, Division of Psychosocial Oncology, Roman Herzog Comprehensive Cancer Center, Technical University of Munich, Munich, Germany (PH).
Downloaded from http://jnci.oxfordjournals.org/ by guest on September 21, 2015
Kerstin Hermelink, Varinka Voigt, Judith Kaste, Franziska Neufeld, Rachel Wuerstlein, Markus Bühner, Karin Münzel, Dorothea Rjosk-Dendorfer, Susanne Grandl, Michael Braun, Franz Edler von Koch, Kristin Härtl, Stephan Hasmüller, Ingo Bauerfeind, Gerlinde Debus, Peter Herschbach, Nadia Harbeck
2 of 13 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 7
Methods Participants Women newly diagnosed with stage 0 to IIIc breast cancer (66) at six breast centers in the area of Munich, Germany, from January 2011 to August 2013 were eligible for participation if they met the following criteria: age 18 to 65 years, fluent in German, free of substance abuse, without a history of neurological or psychotic disorder, and no prior systemic treatment for cancer. To assure that case patients and control patients did not differ in any systematic way except for the presence of cancer, only women who had had breast imaging at one of the participating breast centers were eligible for the control group. The same criteria as for case patients were applied to control patients, with the addition that control patients must neither have suffered from any malignant disease nor require further imaging, biopsy, or treatment for any breast disease. Written informed consent was obtained from all participants. Cognicares was approved by the ethics committee of the Ludwig Maximilian University of Munich and is registered at ClinicalTrials.gov, registration number NCT01264562 (67).
Enrollment and Assessment Proceedings Physicians at participating breast centers informed potentially eligible women briefly about the study. Patients who agreed to their contact information being forwarded to Cognicares staff were then contacted, fully informed, and asked to participate if eligibility criteria were met. Enrollment proceedings were the same for case patients and control patients. Participants underwent a two- to two and a half–hour assessment session that was scheduled a minimum of one week after a negative mammogram for control patients and before any local or systemic intervention (except biopsy of the tumor or sentinel lymph nodes) for case patients. Participants were compensated with 15 Euro. All assessments were conducted by master’s-level psychologists who had received expert training on neuropsychological testing and PTSD diagnostics.
Measures Assessments comprised a one-hour neuropsychological test battery, PTSD diagnostics, self-report measures of cognitive functioning and psychological morbidity, a test of premorbid intelligence, and demographic and medical data (Table 1) that were additionally extracted from medical records. The neuropsychological battery consisted of the tests recommended by the International Cognition and Cancer Task Force (ICCTF) (26,68) or their validated German counterparts (69,70) and additional paper-and-pencil (71) and computerized tests (72) found to be sensitive for cancer-related cognitive impairment (73). Twenty indices of cognitive functioning were chosen from the tests (Table 2). The selection of indices was premeditated prior to any analyses and guided by the aim to obtain finegrained information but to avoid redundancy. The validated German version of the Structured Clinical Interview for DSM-IV (SCID) (65) was used for diagnosis of stress disorder and stress symptoms. If control patients endorsed more than one potentially traumatic event, the event rated as the worst by the participant was inquired. If cancer patients
Downloaded from http://jnci.oxfordjournals.org/ by guest on September 21, 2015
article
There is no doubt that problems of cognitive functioning can considerably afflict patients with breast cancer (1,2) or other noncentral nervous system cancers (3). When neuropsychological studies started to demonstrate cognitive impairment in subgroups of cancer patients, the deficits were initially almost entirely attributed to neurotoxic effects of chemotherapy (4). This view was questioned when an increasing number of studies found evidence of pretreatment cognitive impairment. Already before adjuvant treatment, and even before surgery (5–7) or definite diagnosis (8), breast cancer patients were observed to perform poorly on neuropsychological tests in comparison with published normative data (6,9–12) or healthy control patients (7,9,13,14). In recent years, neuroimaging studies detected abnormalities of brain activation patterns during cognitive tasks in chemotherapy-naïve patients with breast cancer (15–19). Although not all studies have found evidence of cognitive deficits in cancer patients before chemotherapy (20–22), pretreatment cognitive impairment is now widely accepted and has changed thinking (23–26) about the phenomenon once named chemobrain. Clearly, other factors than only chemotherapy neurotoxicity may cause cognitive dysfunction in cancer patients, and part of them seem to exert their influence before the start of treatment. Hypotheses regarding cancerassociated cognitive deficits include shared vulnerability for cancer and cognitive impairment, and biological effects of the cancer itself (27–31). While psychological factors have usually been taken into account as confounders, a causative role of these factors for cognitive impairment in cancer patients has rarely been examined in hypothesis-driven investigations (32,33). The Cognition in Breast Cancer Patients: The Impact of Cancer-Related Stress (Cognicares) study was designed to test the hypothesis that cognitive impairment in breast cancer patients is mediated by cancer-related post-traumatic stress that is manifest in symptoms of post-traumatic stress disorder (PTSD). There is substantial evidence that PTSD is associated with cognitive impairment (34–42). Functional and structural brain abnormalities in patients with PTSD are well established (43, 44), among them aberrant activation patterns during a cognitive task (45,46), decreased volumes of the hippocampus (47–50) or other brain regions (51), white matter atrophy (52), and pronounced effects of aging on the brain (52). PTSD predicts cognitive impairment and brain abnormalities independently of depression or other psychological morbidity (35,37,40,52). In animal models, stress had extensive effects on the brain, most prominently suppression of adult hippocampal neurogenesis (53–55). The prevalence of clinician-diagnosed full PTSD is low in breast cancer patients, with rates ranging from 2.4% to 6% (56–60) and only sporadically higher rates of up to 16% (61). Nevertheless, PTSD symptoms that do not meet the criteria of a full diagnosis are a frequent consequence of breast cancer (62,63), especially shortly after diagnosis (64). In the prospective, longitudinal, multisite Cognicares study, PTSD symptoms are assessed with the Structured Clinical Interview for DSM-IV (SCID) (65). Cognitive functioning is measured with traditional and computerized neuropsychological tests in breast cancer patients and in matched cancerfree control patients. Here, we report the findings of the initial assessment conducted prior to any local or systemic cancer treatment.
K. Hermelink et al. | 3 of 13
Table 1. Demographic and clinical characteristics Individually matched case patients (n = 60) P vs control patients*
P vs control patients*
.97 52.6 (7.8) 27.3 to 64.9
52.6 (7.7) 25.2 to 65.4
.13 50.4 (9.1) 21.8 to 65.7
1.00 7 (11.7%) 30 (50.0%) 9 (15.0%) 14 (23.3%)
7 (11.7%) 30 (50.0%) 9 (15.0%) 14 (23.3%)
.20 29 (17.5%) 59 (35.5%) 23 (13.9%) 55 (33.1%)
.78 115.4 (13.4)
115.8 (13.1)
.19 112.6 (13.7)
.01 50 (83.3%) 10 (16.7%)
38 (63.3%) 22 (36.7%)
44 (73.3%) 16 (26.7%)
45 (75.0%) 15 (25.0%) . 54 (90.0%) 6 (10.0%)
.01 110 (66.3%) 56 (33.7%)
.84
58 (96.7%) 2 (3.3%) 35.7 (26.6) -
.27 133 (80.1%) 33 (19.9%)
.14
.08 148 (89.2%) 18 (10.8%)
4 (6.7%) 30 (50.0%) 21 (35.0%) 5 (8.3%)
14 (8.4%) 66 (39.8%) 69 (41.6%) 17 (10.2%)
17.7 (11.2) 8
17.0 (11.0) 15 .67
23 (38.3%) 31 (51.7%) 6 (10.0%)
22 (36.7%) 35 (58.3%) 3 (5.0%)
47 (78.3%) 13 (21.7%)
47 (78.3%) 13 (21.7%)
.21 83 (50.0%) 75 (45.2%) 8 (4.8%)
1.00
.29 140 (84.3%) 26 (15.7%)
.53 43 (71.7%) 17 (28.3%)
46 (76.7%) 14 (23.3%)
57 (95.0%) 3 (5.0%)
54 (90.0%) 6 (10.0%)
60 (100%) 0 (0%)
57 (95.0%) 3 (5.0%)
0.4 (1.1)
4.2 (4.0)
.52 126 (75.9%) 40 (24.1%)
.30
.77 156 (94.0%) 10 (6.0%)
.08
.14 160 (96.4%) 6 (3.6%)
