TNF-Alpha Activity Eyed for Role in ‘Chemo Brain’

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.

CHICAGO – Circulating tumor necrosis factor appears to play a role in the cognitive dysfunction called "chemo brain" that some women experience after receiving chemotherapy as part of their primary treatment for newly diagnosed breast cancer.

Preliminary data on 93 women in a prospective observational cohort study show that women who underwent chemotherapy had higher levels of circulating tumor necrosis factor (TNF) than did similar women who had not received chemotherapy as part of their primary treatment.

The chemotherapy group also started the study with worse quality of life and poorer cognitive function, compared with patients who did not have chemotherapy before enrolling in the study. None of the women had started endocrine therapy at that point.

"These effects are specific to TNF and were not associated with other biomarkers of inflammation studied," Dr. Patricia A. Ganz reported at the annual meeting of the American Society of Clinical Oncology.

TNF may, therefore, represent a biologic target for pharmacologic therapy, as well as a biomarker that could help identify patients at increased risk for so-called "chemo brain," cognitive complaints during adjuvant chemotherapy that can persist for years afterward in up to 25% of breast cancer survivors, according to Dr. Ganz, director of prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

The study is thought to be among the first to comprehensively examine the relationship between inflammatory markers and cognitive changes in breast cancer patients, she said. It was suggested in part by a study of doxorubicin exposure in an animal model, which found systemic increases in the proinflammatory cytokine TNF-alpha. This cytokine is able to cross the blood-brain barrier and accumulate in the central nervous system (Neurobiol. Dis. July 2006;23:127-39).

The current study enrolled 191 women within 3 months of completion of primary therapy (surgery, radiation, and/or chemotherapy), and prior to initiating endocrine therapy for recently diagnosed breast cancer. All women underwent comprehensive assessments at baseline, 6 months, and 12 months after enrollment. A subset of 16 women also participated in a PET scan substudy and had brain scans at baseline and 12 months later.

The longitudinal data reported by Dr. Ganz was based on the first 93 women with complete cytokine assessments: 49 women who received chemotherapy and 44 women who did not have chemotherapy as part of their primary treatment. Similar proportions of both groups had undergone mastectomy (28% overall) and radiotherapy (76% overall) during primary treatment; 72% of the total population went on to receive endocrine therapy. The women had a mean age of 51 years and were enrolled an average of 7 months after diagnosis of breast cancer.

At baseline, the postchemotherapy group reported significantly poorer quality of life and functioning on several standardized measures, including the SF36 physical and mental component summary scales, sleep, fatigue, and depression.

Self-reported measures of cognitive complaints, including the multidimensional Patients Assessment of Own Functioning Inventory, also suggested that they had greater memory impairments. A significant correlation was found between the memory subscale score in the chemotherapy group (correlation with log r = 0.33, P = .05).

Fasting blood specimens were tested for four inflammatory markers: interleukin-1 receptor antagonist, interleukin-6, C-reactive protein, and soluble TNF receptor type II (sTNFRII), which provides a stable assessment of TNF-alpha activity.

Only sTNFRII was significantly increased in the chemotherapy-treated group (2,492.5 pg/mL vs. 2,115.6 pg/mL in the other patients, P = .007). Over the course of the year, it decreased to the point where the difference between groups was no longer significant.

In the 16 patients with complete PET scan data, soluble TNF receptor level at baseline was negatively correlated with metabolic activity in the inferior frontal gyrus in chemotherapy-treated patients (P = .04). Patients with higher levels of TNF receptor had lower levels of metabolic activity. This also improved over 12 months.

Finally, genetic analysis suggests that the GG allele of the TNF-alpha 308 single nucleotide polymorphism was associated with more cognitive complaints. It may enhance the patient’s vulnerability to cognitive complaints and cognitive dysfunction.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) said, "The strengths of this study include its prospective longitudinal design as well as the examination of potential biological mechanisms, including inflammation, genetic polymorphisms, and cerebral function."

She described examination of biomarkers and mechanisms as important in supportive care research, and expressed optimism that this type of research has only just begun.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Ganz and Dr. Mustian said they had no relevant relationships.