the effects of stress management on adaptation and

The Effects of Stress Management on Adaptation

and Biobehavioral Processes in Women Undergoing

Treatment for Non-Metastatic Breast Cancer

Michael H. Antoni, Ph.D.

Department of Psychology

Div of Health Psychology

Director, Center for Psycho-

Oncology

Leader, Biobehavioral Oncology

Research Program, Sylvester

Cancer Center

University of Miami

Acknowledgments NCI

R01 CA64710

NCI R01CA131451

P50CA84944

Sylvester Cancer Center

• Robert Derhagopian, MD

• Frederick L. Moffat, MD

• Tammy Enos Sifre, PhD

• Kristin Kilbourn, PhD

• Susan Alferi Fox, PhD

• Patti Arena, PhD

• Jessica Lehman, PhD

• Amy Boyers, PhD

• Jennifer Culver, PhD

• Susan Yount, PhD

• Suzanne Harris, PhD

• Dean Cruess, PhD.

• Stefan Gluck, MD, Ph.D.

• Bonnie McGregor, PhD

• Alicia Price, PhD

• Vida Petronis, PhD

• Roselyn Smith-Gonas, PhD

• Kurrie Wells, MS

• Cassy Vaughn, MS

• Kenya Urcuyo, MS

• Sophie Guellati, PhD

• Sarah Wimberly, Ph.D.

• Aisha Kazi, Ph.D.

• Kristin Phillips, Ph.D.

• Janny Rodriguez, MEd

• Nicole Whitehead, Ph.D.

• Jarrard Goodwin, M.D.

• Bonnie B. Blomberg, Ph.D., Microbiology/Immunology, University of Miami School of Medicine, Miami

• Suzanne Lechner, Ph.D., Psychiatry, University of Miami School of Medicine, Miami

• Charles S. Carver, Ph.D., Psychology, University of Miami, Coral Gables

• Susan Lutgendorf, PhD, Psychology, University of Iowa, Iowa City, IA

• Steven W. Cole, PhD, Medicine, UCLA, Los Angeles, California

Biobehavioral Oncology (BBO) Research: Testing Theory-generated Multi-

Level Interventions and Biobehavioral Mechanisms Across the Cancer

Continuum

Prevention Detection Diagnosis & Treatment

Early Survivorship

Late Efects Longer-term Survivorship

Cancer Continuum

Targ

et P

op

ula

tio

ns

Patients/ Survivors

Family

Community

Methodology

Observational Assessment

Randomized Controlled

Trials

Community-Participatory

PREDICTORS Person Factors

Socio-cultural Factors

QOL OUTCOMES Behavioral

Psychological Physical

MEDIATORS Behavioral Processes Biological Processes

Family effects across continuum

Cancer detection

Cancer treatment

Persisting symptoms

and late effects

Longer-term Survivorship

Behavioral and psychological interventions for physical, social

and psychological adaptation

Behavioral interventions for symptom mgmt, late effects and optimizing

survivorship

Community Translation of intervention for minority

populations

Cancer prevention

Early survivor-

ship

Behavioral Intervention for risk reduction & screening behavior

Biobehavioral Intervention Research Goals: Behaviorally Intervening Across

the Cancer Continuum

Cognitive Behavioral Stress Management and

Breast Cancer Research at UM (1992-2013)

Post-

Adj

Stage I-IIla

BRCA

Pre-

Adj

Stage I-II

Stage I-IIIa

Dismantle

CBSM

Abbrev

CBSM

E.g., Stress Management for

Women with Breast Cancer

• Rationale

– Breast Cancer (BCa) is a stressor

– Challenges of surgery and adjuvant tx

– Patient assets can facilitate adjustment

– CBSM can fortify these assets in

women with BCa

– Improving Psychosocial Adaptation

may Affect Physiological Adaptation

1980s 1990s 2000-

Study 1: Psychosocial processes in adaptation

to breast cancer treatment over 1st year

His

tory

of

BREAST C

AN

CER R

ESEARCH

Why Stress Management for

Women with BRCA?

• What are the challenges?

– Life goals are threatened

– Self-image is questioned

– Physical side-effects of adjuvant tx compromise QOL

Spencer et al. (1998) Health Psychology

Stress Management for

Women with BRCA

• What are the challenges?

– Life goals are threatened



• What characteristics relate to better/worse

adjustment after treatment?

Pre-surgical Accept & optimism

Post-surgical distress

3-mo. denial & disengagement

6-mo. distress

–

+

+

Social Support and

Distress

• Greater social support pre and post-surgery predicts less distress in months after

• Spousal support just after surgery is important

• But support from other women is also important in the months that follow

(Alferi et al., 2001; Petronis et al., 2002)

Stress Management for Women with BCa

QUESTIONS AND OBSERVATIONS

• What are the challenges of BCa? – Life goals are threatened



• What characteristics relate to better/worse

Adaptation and Health outcomes after treatment? – Optimism

– Adaptive coping

– Social support

• Can these assets be built by intervention?

• Cognitive Behavioral Stress Management (CBSM)

CHALLENGES: Petronis et al., 2002; Spencer et al., 1999. ADAPTATION: Alferi et al., 2001; Carver et al., 1993; Stanton et al., 1993 HEALTH: Levy et al., 1991; Watson et al., 1999; Fawzy et al., 1993; Cutrona et al.; Lutgendorf & Antoni, 2007

C

B

S

M

Awareness

Cognitive

Appraisals

Emot Processing

Relaxation

Arousal

Social Support

Physical

Health

QOL

Normalize

endocrine and

immune

regulation

+ Health Beh.

Negative Adapt

Positive Adapt

Physical Funct

Theoretical Model for

CBSM during CA Tx

Antoni (2003). Stress Management for Women with Breast Cancer.

American Psychological Association.

CBSM: Aims, strategies,

techniques Aims Strategies Techniques

Increase awareness of

stress response

Provider information (i.e.,

stress response); provide

in-session experiences

Didactic and written

information, self-monitoring

exercises

Teach anxiety

reduction skills

Provide relaxation training PMR, guided imagery,

autogenics, deep breathing

exercises

Modify cognitive

appraisals

Teach CBSM techniques Cognitive restructuring,

rational thought replacement

Build coping skills and

increase emotional

expressiveness

Provide cognitive,

behavioral, and

interpersonal skills training;

facilitate disclosures

Coping skills training,

assertion training, anger

management

Reduce social isolation Build social support

network

Group support, raising

awareness of social network



CBSM Intervention:

Relaxation Component

• Progressive muscle relaxation

• Guided imagery

• Autogenic training

• Meditation

• Breathing exercises

Components of CBSM: CBT

• AWARENESS

– Physical

– Emotional

– Cognitive

– Social

• COPING RESPONSES

– Coping repertoire

• (direct, indirect)

– Coping Appraisals

– Coping execution

steps

• APPRAISALS

– Automatic thoughts

– Refuting and replacing

– P-E transactions

• USE OF COPING RESOURCES

– Social support sources

– Social support seeking

Anger

Management

Social

Support Assertiveness

Stress Response

Cognitive Restructuring

(challenging thoughts)

YES

NO Automatic Thought

Cognitive

Emotion Focused

Softening

(If still distressed)

Coping Social Physical Behavioral Emotional

Distorted?

Problem Focused

Uncontrollable Controllable

•Reframing

•Venting

•Making behavioral changes

•Practicing relaxation

•Making decision

•Seeking information

•Seeking advice

•Setting goals

Stressful Event

Antoni, 2003

C

B

S

M

Awareness

Cognitive

Appraisals

Emot Processing

Relaxation

Arousal

Social Support

Physical

Health

QOL

Normalize

endocrine and

immune

regulation

+ Health Beh.

Negative Adapt

Positive Adapt

Physical Funct

Theoretical Model for

CBSM during CA Tx



Assessment Time Points

T1

surgery

T4

One year post surgery

T3 T2

2-8 wks

post

B SMART-10 wks.

3 months

post

6 months post

Week Relaxation Stress Management

1 PMR 7 Stress & Awareness

2 PMR 4/D.B. Stress & Awareness/Stress Appraisals

3 D.B./PMR Disease-Specific, Automatic Thoughts

4 Autogenics Auto. Thghts, Distortions, Thght Rep.

5 D.B./Visualiz. Cognitive Restructuring

6 Sunlight Med. Effective Coping I

7 Color Meditation Effective Coping II

8 Meditation Social Support

9 Mindfulness Anger Management

10 Part. Choice Assertion Training & Program Review

Topics of CBSM

(Antoni et al., 2003, 2007; Penedo et al., 2008)

Control Condition

• Std Care Plus Half-day Psychoeducational Seminar

– Groups of 4 – 6 women

– Health Educational on BCa

– Outlined Stress Management Techniques

– Akin to Self-Help Seminar

403 screened for eligibility

204 excluded

55 ineligible

149 declined participation

or failed to appear for T1

199 randomized

107 assigned to control

92 assigned to intervention

85 assessed at T2 (6 mo) 74 assessed at T2 (6 mo)

83 assessed at T3 (12 mo)


Second NCI Trial: CONSORT DIAGRAM

Negative Affect (ABS)Negative Affect (ABS)

ControlControl

ExptlExptl

2.22.2

2.02.0

1.81.8

1.61.6

Time 1Time 1 Time 2Time 2 Time 3Time 3

Rated Anxiety (Hamilton)Rated Anxiety (Hamilton)

ControlControl

ExptlExptl

8.58.5

8.08.0

7.57.5

6.56.5


7.07.0

6.06.0

5.55.5

Social Disruption (SIP z scores)Social Disruption (SIP z scores)

ControlControl

ExptlExptl

0.20.2

0.00.0

--0.10.1


0.10.1

--0.20.2

Thought Intrusion (IES)Thought Intrusion (IES)Thought Intrusion (IES)

ControlControlControl

ExptlExptlExptl

2.62.62.6

2.22.22.2

1.81.81.8

1.41.41.4

Time 1Time 1Time 1 Time 2Time 2Time 2 Time 3Time 3Time 3 Antoni et al. (2006). Amer J Psychiatry

CBSM Reduced

Sleep and Fatigue-

related Disruption

Antoni et al. (2006). JCCP

Intervention Effect on Benefit Finding and

Other Positive Adaptation Indicators

How Did CBSM Work?

• Which elements of CBSM were accounting for these effects?

• Measure of Current Status (MOCS, Carver 2004)

– Separate scales for different perceived SM skills

• Relaxation and imagery skills

• Coping and CBT skills

• Ability to use cog restructuring skills

• Ability to act assertively and express needs

– Scales for non-specific effects of group tx

• Cognitive-Affective Processing:

– Emotion Approach Coping (EAC, Stanton 1998)

Latent Growth Modeling

How Did CBSM Work?

• Which elements of CBSM were accounting for these effects?

• Measure of Current Status (MOCS, Carver 2004)

– Separate scales for different perceived SM skills

• Relaxation and imagery skills ( p < .01)

• Coping and CBT skills (p < .05)

• Ability to use cog restructuring skills (p < .05)

• Ability to act assertively and express needs (NS)

– Scales for non-specific effects of group tx (NS)

• Emotion Approach Coping (EAC, Stanton 1998) (p < .01)

Relaxation Confidence (MOCS)

Control

Exptl 3.2

2.8

2.4

2.0

Time 1 Time 2 Time 3

Antoni et al. (2006). J. Consult Clin Psychol, 74, 1143-52.

CBSM Effects on Emotional

Processing

As s es s m en t Tim e Po in t

4321

Mea

n E

mot

iona

l E

xpre

ssio

n S

core

. 3

. 2

. 1

- . 0

- . 1

- . 2

- . 3

condit ion

co nt r o l

ex pt l

CBSM Effects on slope (z) with mediation by MOCS Relax

(MOCS-R) and Emotional Processing (EAC)

Effect of CBSM w/o Relax w/o Relax & Emot Processing

Positive Adaptation Positive States of Mind (PSOM) 3.17* -0.57 -0.27

ABS Positive Emotions 2.19* -0.82 -0.01

Benefit Finding (17 item) 3.31* -0.61 -0.20

Positive Lifestyle Change 2.64* -0.28 0.20

FACT Emotional Wellbeing 2.96* -0.37 0.32

Negative Adaptation Interviewer-rated Anxiety -2.71* 0.28 -0.23

Interviewer-rated Depression -2.48* 0.46 0.15

IES Intrusive Thoughts -3.64* -1.19 0.04

ABS Emotional Distress -2.48* 0.63 0.13

ABS Depression -2.55* 0.33 0.58

Disrupt. Recreation & Pastimes -2.86* -0.29 -0.45

Disrupt. Social Interaction -2.52* 1.01 -0.48

Up to this point we learned……

• CBSM had beneficial effects on negative and positive adaptation

• Appears to work by instilling confidence in using relaxation skills and facilitating emotional processing

• Supports the CBSM skills + cog/aff processing as important

• But did CBSM affect physiological adaptation?

1980s 1990s 2000s

Study 1: Psychosocial processes in adaptation

to breast cancer treatment

His

tory

of

BREAST C

AN

CER R

ESEARCH

Study 2: CBSM Effects on Psy Adaptation to

Breast cancer treatment: Main Effects and Mediators

Study 3: CBSM Effects on Psy and Physiol

Adaptation to breast cancer treatment

•Cortisol reduction

•Increased cellular immune function

Autonomic nervous system

•NE

•Epinephrine

•Other neuropeptides

Adrenal

Gland

DNA Repair

Proliferation

Migration & invasion

Proteases (MMPs)

Angiogenesis / Pro-angiogenic cytokines (VEGF, IL-6)

ACTH

Cortisol NE/Epi

CRF / Locus Coeruleus

Cancer cells

Immune cells (will need to

show different types of cells –

NK, T, Macroph, etc.)

Dopamine

Endothelial cells

(or a blood vessel)

Oxytocin

Oncogenic viruses

Oncogene transcription

Viral replication

Host cell cycling

Immune response

Activity

Optimism

Perceived Stress

Depression

Social Isolation

Negative Life Events

Environmental stressors (SES)

External Events Psychological Reactions

Neuroendocrine Activity

Peripheral Tissue

Antoni, Lutgendorf, Cole, Sephton, Dhabar, McDonald, Stefanek & Sood (2006). Nature Reviews Cancer, 6, 240-248.


•NE

•Epinephrine


Adrenal

Gland

DNA Repair

Proliferation


Proteases (MMPs)


ACTH

Cortisol NE/Epi

CRF / Locus Coerules

Cancer cells




Dopamine

Endothelial cells

(or a blood vessel)

Oxytocin

Oncogenic viruses


Viral replication

Host cell cycling

Immune response

Activity

Optimism

Perceived Stress

Depression

Social Isolation





Peripheral Tissue


Elements of CBSM and Putative

Effects on Physiology • Relaxation

– PMR, Imagery, Mindfulness, Breathing

– Decreases tension and anxiety and SNS activation

– SNS-immune communications: NE is ligand for immune cells b-adrenoreceptors down-reg of cellular immune function

• Cognitive Restructuring and Coping Effectiveness Training

– Raise awareness of stress cues

– Change negative/inaccurate stressor appraisals

– Increase pos reframing and acceptance coping

– CBT decreases depression and anxiety which also relate to immune function via HPA and cortisol dysregulation

• Interpersonal Skills Training/Supportive Group

– Assertiveness and anger mgmt to attract /maintain social support

– Group format models seeking and receiving support

– Social support may buffer stress effects on neuroimmune processes

Surgery

T1 T2 T3

CBSM starts

3 mo 9 mo

Adjuvant

therapy

starts

CBSM ends

T4 15 mo

2-8 w.

•Blood*

•Psychological

assessment

•Blood*

•Psychological

assessment

•Blood*

•Psychological

assessment

•Blood*

•Psychological

assessment

3 mo

0

Detailed Design: Blood Draws

Adjuvant

therapy

ends

Effects of CBSM on Relaxation

and Cortisol

MEDIATION: Did early gains (0 – 6 months) in CBSM

skill components relate to cortisol changes @ 6 – 12

months?

• Relaxation and CBT skills

mediate CBSM effects on cort

Phillips, Antoni et al.

(2011, Cog Ther Res)

Does CBSM also affect cellular

immunity in Women with

BCa? •Prior work had shown Psy Intervention effects on

lymphocyte proliferation in women with BCa

•Other work showed effects of Psy Intervention on NKCC in

patients with MM

•Patients with lower T lymphocyte counts and T-cell

responsivity to mitogen prior to surgery higher risk for

recurrent disease

(Andersen et al., 2004 Fawzy et al., 1990)

Immunologic Protocol Blood

5 – 6pm

PBMCs

Ficoll

Anti-CD3 stimulation

IL-2 (1000 U/ml) or IFNg (250 U/mL) Stimulation Cell phenotyping:

CD3,CD4,CD8,CD19,CD56

48 hrs

48 hrs 4 hr 51Cr assay:

LPR-tritiated thymidine

TH1: TH2:

IFNg IL4

IL2 IL5

IL12 IL10

TNFa

ELISAs:

NK/LAK activity

(K562)

Analyzed by % specific lysis at 50:1, 25:1, 12:1,6:1, 3:1, and 1:1 effector to target ratios.

LAK activity

(Daudi)

-4000

-2000

0

2000

4000

6000

8000

Comparison

Group

CBSM

Group

Pro

lifera

tion (

CP

M)

P < .05

Change in Lymphocyte Proliferative

Response 3 Months Post-CBSM

McGregor et al. (2004) J. Psychosomatic Res, 56, 1 – 8

Change in Proliferation T1-T3

6000040000200000-20000-40000

Ch

an

ge

in B

en

efit

Fin

din

g T

1-T

2

2.5

2.0

1.5

1.0

.5

0.0

-.5

-1.0

-1.5

CBSM

Control

Scatterplot showing correlation between change in proliferative

response to anti-CD3 (counts per minute, CPM) from entry (T1) to 3

month follow-up (T3) and change in benefit finding over the 10-

week CBSM period (T1 – T2) among breast cancer patients assigned

to the CBSM vs. control (McGregor, Antoni et al., 2004, J.Psychsom Res,

56, 1 - 8)

Immunologic Protocol Blood

PBMCs

Ficoll

Anti-CD3 stimulation

IL-2 (1000 U/ml) or IFNg (250 U/mL) Stimulation Cell phenotyping:

CD3,CD4,CD8,CD19,CD56

48 hrs

48 hrs 4 hr 51Cr assay:

Supernatant harvest

TH1: TH2:

IFNg IL4

IL2 IL5

IL12 IL10

TNFa

ELISAs:

NK/LAK activity

(K562)

Analyzed by % specific lysis at 50:1, 25:1, 12:1,6:1, 3:1, and 1:1 effector to target ratios.

LAK activity

(Daudi)

T helper 1 profile in CBSM intervention and

control group

IFN-g IL-2

IL-12 TNFa

*

IFNg

Time

T1 T2 T3

IFN

g (p

g/m

l)

0

2000

4000

6000

8000

IL-2

Time

T1 T2 T3

IL-2

(pg/m

l)

0

5

10

15

20

25

IL-12

Time

T1 T2 T3

IL-1

2 (p

g/m

l)

0

100

200

300

400

500

600

700

Col 12

Col 14

TNFa

Time

T1 T2 T3

TN

Fa

(p

g/m

l)

0

2000

4000

6000

8000

10000

12000

14000

Intervention

Control

* n=16

n=16 n=15

n=14

n=14

n=12

n=19

n=17

n=16

n=14 n=14 n=12

n=16

n=16 n=15 n=14

n=14

n=12

n=16

n=16

n=15

n=14

n=14

n=12

Time

T1 T2 T3

IFN

g (p

g/m

l)

0

2000

4000

6000

8000

IFN g Intervention

Control

Changes in Positive Psy Adaptation (slope) and

Changes in Th1 Cytokine Production (slope)

Measure1 g-IFN IL-2

ABS-Pos Affect .59** --

BF-Spiritual .46* .82**

BF-Lifestyle .71** --

**p < .01 *p < .05

1all measures slope of chg over 3, 6, 12, and 18 months post-surg

ABS: Affect Balance Scale

BF: Benefit Finding

CBSM Intervention after

Surgery for Breast Cancer: Psychological adaptation:

•increased benefit finding and optimism

•decreased anxiety, depression, soc disruption, fatigue, sleep disruption

•increased perceived relaxation skills, CBT and emotion processing important

Physiological adaptation:

•decreases in PM cortisol levels

•increased LPR to anti-CD3 challenge

•increased g-IFN and IL-2 and Th1/Th2 ratio production during LPR

Pattern of effects suggest a faster recovery after adjuvant therapy in CBSM pts vs controls

Antoni et al (2001) Health Psychology, 20, 20-32;

Cruess, Antoni et al (2000) Psychosomatic Medicine, 61, 94.

McGregor et al., (2004) J. Psychosom Res, 56, 1 – 8;

Antoni et al. (2006) Amer J. Psychiatry

Antoni et al., (2006) JCCP; Phillips et al. (2008) Psychosom Med;

Antoni et al. (2009) Brain Beh Imm


•NE

•Epinephrine


Adrenal

Gland

DNA Repair

Proliferation


Proteases (MMPs)


Inflammation (NFkB)

ACTH

Cortisol NE/Epi

CRF / Locus Coeruleus

Cancer cells




Dopamine

Endothelial cells

(or a blood vessel)

Oxytocin

Oncogenic viruses


Viral replication

Host cell cycling

Immune response

IFN Activation

Optimism

Perceived Stress

Depression

Social Isolation





Peripheral Tissue


• Individual Differences in Psy

Factors (cognitive,

behavioral, and social) may

contribute to stress

adaptation, and

neuroendocrine changes

during the cancer

experience

• These adaptations may be

transduced by

neuroendocrines into

transcriptional (gene

expression) changes in

disease tissue (e.g., tumor)

and circulating immune cells

• Implication: If so, can we

facilitate adaptation early in

the disease process via psy

intervention to influence

circulating immune cells and

ultimately clinical disease

course? e.g., Inflammation

Stress, Adaptation and Cancer Lutgendorf, Sood & Antoni, J. Clin Onc, 2010

Slavich & Cole Clin Psy Sci 2013

Biobehavioral Pathways Associated with Stress

and Cancer Pathogenesis (Miller & Cole, 2009 Ann Rev Psychol.)

CREB/ATF

GR

NFkB/ IL-1

STRESS •Chronic stress •Depression •Social Adversity

CANCER PATHOGENESIS •Apoptosis/Anoikis •Angiogenesis •Growth & Metastasis

BIOBEHAVIORAL MEDIATORS

•SNS Activation

•HPA dysregulation

•Inflammation

•Cellular Immune Suppression Type I IFN

Slavich & Cole Clin Psy Sci 2013

Chronic Stress/Adversity and

Negative Affect

Inflammation: e.g., NFkB response

elements in promoters of downstream

transcription

Cytokines (IL1A, IL1B, IL1RA, IL6, TNF)

Chemokines (CCLs, CXCLs)

Oxidative stress (Superoxide dismutase, SODs)

Prostaglandin signaling (cyclooxygenase: CoX 2)

Pro-Inflammatory Cytokines and their Sequelae

IL-1-a, IL1-b, IL-6, TNF-a, IL-8, PGs

CRF

Upstream DNA

Transcriptional

Control Pathway

Downstream

Gene Expr for

translation of

RNA

Protein

Synthesis

Stress and Inflammatory Gene Expression in cells making inflammatory proteins

Neuroendocrine regulation:

SNS, HPA

Study Aims

• Aim 1: Determine whether individual differences in

psychological adaptation relate to differences in

leukocyte gene expression among women early in

their treatment for primary (non-metastatic) breast

cancer.

• Aim 2: Test whether a psychological intervention

(CBSM) designed to facilitate adaptation is

associated with changes in leukocyte gene

expression over time

Study Sample and Measures

• Sample: 79 Women undergoing surgery for non-metastatic BCa in prior 2

– 10 wks and not yet started adjuvant therapy

• Psychological Adaptation

– Positive Affect/Negative Affect Balance (Affect Balance Scale, ABS, Derogatis, 1975)

• Other Psy Factors

– Perceived stress management skill efficacy

– Personal growth (benefit finding scale: BFS)

– Fatigue (FSI) and Sleep quality (PSQI)

– QoL/Well-Being (FACT)

• Transcriptional Indicators

– miRNA expression: pro-inflam cytokines, chemokines and tumor promoting transcripts

– Gene Library convergence: pro-inflammatory and wound healing pathways

– Bioinformatically inferred upstream transcripts: NFkB, GATA, STAT, GR

• Criteria for differential expression

– 50% up- or down-regulation (< 5% false discovery rate)

– Traditional p-value

• Covariates

– Sociodemographic (age, race, SES)

– Biomedical (disease stage, ER/PR/HER1Neu, surgery type, days since surg, meds)

Hypotheses

• Hyp 1: Greater Levels of Adaptation (Positive: Negative affective

state = ABS composite score) will relate to a better leukocyte

transcriptional profile

– Less Pro-Inflammatory Signaling (cytokines, chemokines, Cox2/PG, oxidat stress)

– Less Pro-Metastatic Signaling (enzymes for tissue invasion, remodeling and

epithelial-mesenchymal transition [EMT])

• Hyp 2: CBSM will facilitate adaptation and improve leukocyte

transcriptional profile

– Increased Positive Affect

– Decreased Negative Affect

– Increased Affect Balance (Positive – Negative Afect)

– Less Pro-Inflammatory Signaling

– Less Pro-Metastatic Signaling

– Greater Glucocorticoid Receptor Sensitivity

Study Analyses

• Hyp 1: Genomic-Affect Association: Relationships between

baseline affective state (ABS composite score) and expression of

each analyzed transcript were assessed by multiple regression

– controlling for age, race (white vs. non-), and tumor stage, estrogen receptor

(ER)-, and progesterone receptor (PR) status. Genes showing > 50% differential

expression for each 1SD diff in ABS composite scores were identified as

differentially expressed

• Hyp 2: Effects of CBSM on expression of each analyzed transcript

were assessed in a 2 (Group: CBSM vs. Control) x 3 (Time: baseline,

6-, and 12-month follow-up) mixed model factorial design

– controlling for individual differences in age, race, tumor stage, ER status, PR

status, treatment with chemotherapy, and treatment with radiation.

– All analyses were conducted on an intent-to-treat basis with parameters estimated

in the context of mixed effect linear models including all cases


204 excluded

55 ineligible



199 randomized


107 treated as assigned

34 provide T1 PBMC samples




CONSORT DIAGRAM

Affect Balance Scale

Transcriptional Indicators Focus on Pro-inflammatory and Pro-Metastatic Signaling

in Circulating PBMCs

• miRNA expression: pro-inflam cytokine, chemokines and tumor

promoting transcripts

• Gene Library convergence: functional significance of genes identified:

pro-inflammatory and wound healing pathways

• Bioinformatically-inferred upstream transcripts controlling gene

expression: NFkB, STAT, GATA

• Bioinformatically-inferred cell populations involved within the PBMC

compartment

Genomic Studies: Microarray Analysis

• PBMCs analyzed with Illumina Human HT-12 v3 Expression BeadChips

• Expression of 27,455 human genes derived from low-level fluorescence

intensity values & quantile normalized w/ Illumina Genome Studio software

• Functional characteristics-GOstat Gene Ontology, GeneCards, EntrezGene

• Activity of specific transcription control pathways* assessed by TELiS

bioinformatic analysis of transcription factor-binding motif (TFBM)

distributions in the promoters of differentially expressed genes:

NF-kB, STAT, GATA, IFN, GR

*transcripts identified as differentially expressed by microarray analysis were re-verified using quantitative RT-PCR with TaqMan

gene expression assays (Applied Biosystems Inc), a one-step enzyme system (Quantitect RT-PCR; Qiagen), and manufacturer’s

specified thermal cycling protocol on a iCycler real-time PCR instrument (BioRad Inc.). Data were analyzed by standard

threshold cycle analysis after normalization to parallel-assayed ACTB mRNA concentrations

Aim 1 Study Analyses

• Genomic-Affect Association: Relationships between baseline

affective state (ABS composite score) and expression of each

analyzed transcript were assessed by multiple regression

– controlling for age, race (white vs. non-), and tumor stage, estrogen receptor

(ER)-, and progesterone receptor (PR) status. Genes showing > 50% differential

expression per 1 SD diff in ABS affect balance composite scores were identified

as differentially expressed

RESULTS:

Affect and Gene Expression • 201 named human genes showed > 50% difference in expression

across the range of ABS composite scores at study entry (2 – 8

wks post-surgery)

• 177 genes were up-regulated in association with affect ratio

reflecting more negative affect, including genes encoding:

– pro-inflammatory cytokines (IL1A, IL1B, IL6, TNF)

– prostaglandin-synthesis enzyme COX2 (PTGS2)

– the oxidative stress response (SOD2)

– inflammatory chemokines and related receptors (CCL3, CCL3L1, CCL4L2,

CCL7, CCL20, CXCL9, CXCL10, CXCR6, CXCR7)

– tissue remodeling and epithelial-mesenchymal transition (LMNA, MMP9)

• Bioinformatic Analysis

GOstat Gene Ontology Analyses (p’s < .0001) for pro-inflammatory and wound-

healing signaling

Upstream Signaling Implicated: NFkB

Inferred Cell Populations: Myeloid

Antoni, Lutgendorf, Blomberg et

al….Cole (2012) Biol Psychiatry

controlling for age, race

(white vs. non-), and tumor

stage, estrogen receptor

(ER)-, and progesterone

receptor (PR) status.

Comparing Mood X Leukocyte Gene Expression

Associations in Different Cancer Populations

Antoni et al. (2012) Biol. Psychiatry

Breast Cancer (N = 79)

Lower PA/Greater NA associated w/ 50% diff in exp of 201 genes:

•Pro-Inflammatory Signaling: –Cytokines [IL1A,IL1B,TNF,IL6,IL1RN]

–Chemokines [CCL2, CCL3, CCL3L1, CCL4L2, CCL7, CCL20, CACL9, CXCL10, CXCR6, CXCR7]

–Oxidative Stress [SOD2]

–COX 2 [COX2/PTGS2]

•Pro-Metastatic Signaling (PBMCs): –MMP9, LMNA

•Gene Ontology Analyses: –Transcripts converging on pro-inflammatory signaling (p < .0001)

•Inferred* Upstream Signaling –NFkB

•Implicated* PBMC Population –Myeloid * Based on TeLiS Bioinformatic Program

Cohen et al. (2012) PLoS One

Metastatic RCC (N = 30)

Depression associated w/ 50% diff in

exp of 177 genes:

•Pro-Inflammatory Signaling: –Cytokines [IL1A,IL1B,TNF,IL6,IL1RN]

–Chemokines [CCL2, CCL3, CCL3L1, CCL4L2,

CCL7, CCL8, CCL20, CCR7, CXCL1, CXCL16]

–Oxidative Stress [SOD2]

–COX 2 [COX2/PTGS2]

•Pro-Metastatic Signaling (tumor) –MMP9, MMP2

•Gene Ontology Analyses: –Transcripts converging on pro-inflammatory signaling (p < .0001)

•Inferred* Upstream Signaling –NFkB

•Implicated* PBMC Population –Myeloid (greater TAMs in depressed)

Study Aims

• Aim 1: Determine whether individual differences in

psychological adaptation relate to differences in

leukocyte gene expression among women early in

their treatment for primary (non-metastatic) breast

cancer.

• Aim 2: Test whether a psychosocial intervention

(CBSM) designed to facilitate adaptation is

associated with changes in leukocyte gene

expression over time

Effects of Intervention Targeting Adaptation: Cognitive

Behavioral Stress Management (CBSM)


204 excluded

55 ineligible



199 randomized















34 analyzed for gene expression

18 T1 & T2 PBMC samples


45 analyzed for gene expression



CONSORT DIAGRAM

No Between-Group Differences

• Surgery

• Adjuvant type (chemo, radiation)

• Time since surgery

• Endocrine therapy

• Demographics

Study Analyses

• Effects of CBSM on psychological adaptation were first assessed in

the subsample with gene expression data in a 2 (Group: CBSM vs.

Control) x 3 (Time: baseline, 6-, and 12-month follow-up) factorial

design

• Effects of CBSM on expression of each analyzed transcript were

assessed in a 2 (Group: CBSM vs. Control) x 3 (Time: baseline, 6-,

and 12-month follow-up) factorial design





Did CBSM Facilitate Psy Adaptation?

• ABS Affect Balance Score (Group x Time effect, p = .0042), with:

• CBSM-treated group showing: (linear time trend over 12 months)

– increased positive affect: +6.8 ± 2.36, p = .0055

– decreased negative affect: -8.22 ± 2.08, p = .0003

– Increased composite affect balance scores: +17.54 ± 4.12, p < .0001

• Control group showed

– negligible change over time on each dimension:

– positive affect: -0.16 ± 1.94, p = .936

– negative affect: -4.64 ± 3.94, p = .245

– overall affect balance: 1.00 ± 3.62, p = .784.

CBSM Effects on Adaptation and Other

Psychological Variables

Other Significant Psy Effects in the

Genomic Subsample at 12 mo

• Negative Mood

– ABS Anx p < .005

– ABS Dep p < .08

• Positive Mood

– ABS Happy p < .05

– ABS Vigor p < .002

• QoL/Well-Being

– FACT Physical WB p < .001

– FACT BCa Specific p < .03

– FACT General WB p < .001

• Social Disruption

– SIP Social Interact p < .02

– SIP Recreat/Pastimes p < .001

• Fatigue

– FSI-Intensity p < .001

– FSI-Disruption p < .001

CBSM Effects on Perceived Stress Management

Skills at 6 months in this Subgroup

MOCS Scale F p

Tension Awareness 19.65 < .001

Relaxation 11.67 < .003

Assertiveness 6.53 < .02

Coping 8.08 < .01

Study Analyses

• Effects of CBSM on psychological adaptation were first assessed in

the subsample with gene expression data in a factorial design

• Effects of CBSM on expression of each analyzed transcript were

assessed in a 2 (Group: CBSM vs. Control) x 3 (Time: baseline, 6-,

and 12-month follow-up) factorial design





CBSM Control

Baseline

Figure 1

Antoni, Lutgendorf, Blomberg et al. ….Cole (2012) Biol Psychiatry

IFN

Imm Act

GCS Sens

CREB/PKA

NFkB

Inflammation

MMP9

27

3 g

enes

33

6 g

enes

Relative Expression

High

Intermediate

Low

CBSM Control CBSM Control

Baseline Month 6

Figure 1

27

3 u

preg

ulated

3

36

do

wn

regu

lated

Antoni, Lutgendorf, Blomberg et al….Cole (2012) Biol Psychiatry

IFN

Imm Activ

GCS Sensitiv

CREB/PKA

NFkB

Inflammation

MMP9

CBSM Control CBSM Control CBSM Control

Baseline Month 6 Month 12

Figure 1

27

3 u

preg

ulated

3

36

do

wn

regu

lated

IFN

Imm Activ

GCS Sensitiv

CREB/PKA

NFkB

Inflammation

MMP9

Antoni, Lutgendorf, Blomberg et al (2012) Biological Psychiatry

2 X 3 RANOVAs: Effects of CBSM on

Reversing Stress-Related Genomic Expression

• 62 transcripts showed significantly greater down-regulation in CBSM-

treated patients relative to controls, including genes encoding:

– pro-inflammatory cytokines (IL1A, IL1B, IL6)

– the prostaglandin-synthesis enzyme COX2 (PTGS2)

– inflammatory chemokines and their receptors (CCL2, CCL3, CCL3L1,

CCL3L3, CCL4L1, CCL4L2, CCL7, CXCL1, CXCL2, CXCR7),

– mediators of tissue remodeling and epithelial-mesenchymal transition (G0S2,

LMNA, MMP9, OSM).

GOstat Gene Ontology analyses (p’s < .0001)

• 29 genes showed significantly greater up-regulation in CBSM-treated

patients vs. controls, including genes involved in:

– Type I interferon response (IFIT1, IFIT2, IFIT3, IFI44, IFI44L, ISG15, MX2,

OAS2, OAS3),

– Type II interferon signaling (IFN-g), and interferon signal transduction (STAT1,

STAT2).


Antoni, Lutgendorf, Blomberg et al…..Cole (2012) Biological Psychiatry



(N = 79)

• INFLAMMATION: 62 transcripts showed significantly greater down-

regulation in CBSM-treated patients relative to controls, including

genes encoding:






LMNA, MMP9, OSM).

• ANTI-VIRAL IMMUNITY: 29 genes showed significantly greater up-

regulation over time in CBSM-treated patients vs. controls, including

transcripts involved in:

– Type I interferon response (IFIT1, IFIT2, IFIT3, IFI44, IFI44L, ISG15, MX2,

OAS2, OAS3),

– Type II interferon signaling (IFN-g), and interferon signal transduction (STAT1,

STAT2).


2 X 3 Mixed Model Effects of CBSM on Negative

Mood-Related Genomic Expression (Highlighted changes in those genes associated with baseline Negative Affect)

• 62 transcripts showed significantly greater down-regulation in CBSM-

treated patients relative to controls (> 50% differential chg), including

genes encoding:






LMNA, MMP9, OSM).


Thirty-one (50%) of the total 62 CBSM-downregulated transcripts also

appeared on the list of genes upregulated in association with negative

affect at baseline (greater than the <1% overlap expected by chance;

binomial p < .0001).

pro-inflammatory transcriptional activation effects hold in ancillary analyses that controlled for additional

treatment-related variables: chemotherapy or radiation (within 3 weeks before each study visit), primary

surgery type (lumpectomy, mastectomy, or bilateral mastectomy), and use of pain medications, anxiolytics, or

antidepressants (downregulation of pro-inflammatory genes, GO:0006954; GO:0009611; both p < .0001;


Fold Difference in Average Gene Expression Change at 6 –

12 mo f/u in CBSM vs Ctrls estimated by mixed effect repeated measures ANCOVA controlling for age, ethnicity, tumor grade,

disease stage, tumor ER and PR status, use of radiation therapy and chemotherapy



• INFLAMMATION: 62 transcripts showed significantly greater down-

regulation in CBSM-treated patients relative to controls, including genes

encoding:

– pro-inflammatory cytokines (IL1A, IL1B, IL6)


– inflammatory chemokines and their receptors (CCL2, CCL3, CCL3L1, CCL3L3,

CCL4L1, CCL4L2, CCL7, CXCL1, CXCL2, CXCR7),

– mediators of tissue remodeling and epithelial-mesenchymal transition (G0S2, LMNA,

MMP9, OSM).

• ANTI-VIRAL IMMUNITY: 29 genes showed greater up-regulation over

time in CBSM-treated patients vs. controls, including transcripts involved

in:

– Type I interferon response (IFIT1, IFIT2, IFIT3, IFI44, IFI44L, ISG15, MX2, OAS2,

OAS3),

– Type II interferon signaling (IFN-g), and signal transduction (STAT1, STAT2).

– These mirror prior CBSM effects on IFN-g production in women with BCA

Antoni, Lutgendorf, Blomberg et al…..Cole (2012) Biological Psychiatry; Antoni et al (2009), BBI

Fold Difference in Average Gene Expression Change at 6 –

12 mo f/u in CBSM vs Ctrls estimated by mixed effect repeated measures ANCOVA controlling for age, ethnicity, tumor grade,

disease stage, tumor ER and PR status, use of radiation therapy and chemotherapy

Antoni, Lutgendorf, Blomberg et al…..Cole (2012)

Genomic Studies: Microarray Analysis Pre-Post

• PBMCs analyzed with Illumina Human HT-12 v3 Expression BeadChips

• Expression of 27,455 human genes derived from low-level fluorescence

intensity values & quantile normalized w/ Illumina Genome Studio software

• Genes > 50% difference in average expression in CBSM vs control

identified as differentially expressed (False Discovery Rate ≤ 5%)

• Functional characteristics-GOstat Gene Ontology, GeneCards, EntrezGene

• Activity of specific transcription control pathways* assessed by TELiS

bioinformatic analysis of transcription factor-binding motif (TFBM)

distributions in the promoters of differentially expressed genes:

NF-kB, STAT1, GATA, GC Receptor (GR)

• Transcript origin analysis was employed to identify the specific leukocyte subsets

predominately mediating CBSM effects on the overall PBMC pool transcriptome.

*transcripts identified as differentially expressed by microarray analysis were re-verified using quantitative RT-PCR with TaqMan

gene expression assays (Applied Biosystems Inc), a one-step enzyme system (Quantitect RT-PCR; Qiagen), and manufacturer’s

specified thermal cycling protocol on a iCycler real-time PCR instrument (BioRad Inc.). Data were analyzed by standard

threshold cycle analysis after normalization to parallel-assayed ACTB mRNA concentrations

Chronic Stress/Adversity and

Negative Affect

Inflammation: e.g., NFkB

response elements in promoters

of downstream transcription

Cytokines (IL1A, IL1B, IL1RA, IL6, TNF)

Chemokines (CCLs, CXCLs)

Oxidative stress (Superoxide dismutase, SODs)

Prostaglandin signaling (cyclooxygenase: CoX 2)

Pro-Inflammatory Cytokines and their Sequelae

IL-1-a, IL1-b, IL-6, TNF-a, IL-8

CRF

Upstream

Transcriptional

Control Pathway

Downstream

Gene

Expression

Protein

Synthesis

Stress and Inflammatory Gene Expression

Neuroendocrine regulation:

SNS, HPA

Fold Difference in TFBM Expression over 6 – 12mo

(log CBSM vs Control)

Interferon

Imm Act

GCS Sens

NFkB

Inflammation

Antoni, Lutgendorf, Blomberg et al…..Cole, Biological Psychiatry (2012)

Stress-related Neuroendocrines can modulate cell-

signaling and inflammatory protein synthesis

Cells Involved in Up-Regulation and Down-

Regulated Genes?

Transcript Origin Analysis was

employed to identify the specific

leukocyte subsets predominately

mediating CBSM effects on the

overall PBMC pool transcriptome.

Antoni, Lutgendorf, Blomberg et

al…..Cole (2012) Biological Psychiatry

CBSM Effects on CREB/ATF (SNS) BL 12mo

and GCS gene expression Ctrl CBSM Ctrl CBSM

suggest impact on on stress pathways

IFN

Imm Act

GCS Sens

Antoni, Lutgendorf, Blomberg et al….Cole

(2012) Biol Psychiatry

CREB/PKA

NFkB

Inflammation

MMP9

CBSM Effects on NFkB and IFN

expression suggest decreased

inflammation and increased Type I

IFN signaling

Transcription Factor Binding Motifs (TFBMs) *Ratio CBSM: Ctrl

Antoni, Lutgendorf, Blomberg…..Cole (2012) Biol Psychiatry, 71, 366-72

Antoni (2013). Brain, Behavior and Immunity, 30, S88 – S98.

Matrix Metalloproteases (MMPs)

Secreted into the extracellular

matrix (ECM) by stromal

leukocytes such as macrophages

Capable of degrading many

kinds of ECM protein and

facilitating invasion and

migration.

One of the most studied in

metastasis and angiogenesis

MMP-2 and MMP-9 promote

angiogenesis and invasion and

are associated with shorter

disease free survival (Kamat et

al, 2006).

Conclusions

• Psychological processes (adaptation and stress mgmt

interventions) – may be associated with biological indicators that

– may predict breast cancer disease activity and clinical outcomes

• That is a lot of “Maybes”

• Is it: – Psy Biological Disease Outcome..”my stress makes me inflamed & sicker”

– Disease Biological Psy…”I am stressed and inflamed as my disease worsens”

– Biological Psy and Disease Outcome…”my treatments make me stressed and

inflamed so I skip them and get sicker”

– None of the above? All of the above?.....”these are all random happenstances”

• Limits – Microarray analyses need confirmation by protein tests

– Our understanding of biology of breast cancer is still evolving

– Our findings can be over-interpreted so caution is in order in our claims

Examining Leukocyte Transcription

Provides BIG data • Does Facilitating Adaptation relate to gene expression in

PBMCs for:

– Inflammation? (NFkB, STAT cytokine/chemokine/PGs)

– HPA regulation? (GR) affects anti-inflammatory control

– Disease progression promoters? MMP-9, LMNA, G0S2

– Myeloid cells (monocytes and DCs) likely mediators

• $$$ Questions: Are these differences in expression tied to:

– QOL and symptom management?

– Faster recovery from surgery or adjuvant therapy?

– Ability to tolerate larger dosage of adjuvant tx?

– Success of cancer treatments vs resistance?

– Clinical disease outcomes (recurrence, mortality)?

Lutgendorf, Sood & Antoni, J. Clin Onc, 2010

Tracking Gene Gangs in the Hood………

Tracking patterns of gene

expression changes in

cells in the

“neighborhood of tumors”

may give us a window

into how stress affects

body’s ability to stay

healthy, less inflamed

and better defended

If so then we can observe

how stress management

affects these processes

as well over the long

term!

Parallel Adaptation: Cognitive-

Behavioral Stress Management and

Breast Cancer • Psychological Adaptation

– Less social disruption

– Less interviewer-rated anxiety symptoms

– Less cancer-specific anxiety

– Greater emotional well-being

– Greater positive states of mind

– More benefit finding

– Positive lifestyle changes

– Positive affect

(Antoni et al., 2006a; Antoni et al., 2006b, Antoni et al., 2009; Antoni et al., 2012; Phillips et al., 2008)

• Physiological Adaptation

– Lower PM serum cortisol

– Greater Th1 cytokines (IL-2, IFN-y)

production from stimulated cells

– Up-regulation of type I IFN

response genes

– Down-regulation of pro-

inflammatory encoding genes

– Down-regulation of genes encoding

for metastases

– Up-regulation of glucocorticoid

receptor expression

?

Immune Findings Mirror Other Recent Work Using

Psychosocial Interventions In Bca Women Post-Surgery

• 16-wk + Monthly Booster CBT + Lifestyle Change

(Andersen et al. 2004, 2007)

• 8-wk Mindfulness Based Stress Mgmt

(Witek-Janusek….. Mathews, 2008)

• 8-wk CBT

(Savard, Simard, Ivers, & Morin, 2005)

Coping?

• Reframing

• Acceptance

Social Support?

Decreased Vigilance

Decreased Arousal

• Relax confidence

• Tension Awareness

Positive Attitude:

• Optimism

• Self-efficacy

Emotional

Openness,

Awareness

and

Expression

Pos. Adaptation

Neg. Adaptation

CBSM and Adaptation During

Breast Cancer Treatment

Physiological Effects?

Health Effects?

Model for Psychosocial Intervention Effects on

Psychological Adaptation, Biobehavioral Processes and

Cancer Pathogenesis and Clinical Outcomes

CREB/ATF

GR resistance

NFkB/ IL-1

PSYCHOLOGICAL ADAPTATION

•Chronic distress •Negative affect •Social Adversity

CANCER PATHOGENESIS •Apoptosis/Anoikis •Angiogenesis •Growth & Metastasis

BIOBEHAVIORAL PROCESSES

•SNS Activation

•HPA dysregulation

•Inflammation

•Cellular Immune Suppression

Type I IFN

PSY INTERVENTION •Cognitive

•Appraisals •Coping

•Behavioral •Relaxation •Health behaviors

•Interpersonal •Assertiveness •Anger Mgmt •Social Support

CLINICAL OUTCOMES

•Recurrence •Mortality •Co-Morbidity

Antoni (2013). Brain, Behavior and Immunity.

Model’s Implications in Breast

Cancer

• Individual Differences in Psy Factors may contribute to

stress adaptation during the cancer experience

• Adaptation may accompany neuroendocrine changes

• Neuroendocrine changes transcriptional changes in

circulating immune (stromal) cells that could interact with

tumor to promote disease progression

• Implication: If so, can we facilitate adaptation early in the

disease process via psychosocial intervention to influence

circulating immune cells and ultimately clinical disease

course?

Gaps Remaining

• Integrating Changes in Psychological and

Physiological Adaptation with Longer-Term

Clinical Outcomes

• Identifying Intervention Moderators?

• Best Timing for Delivering CBSM in the

context of care?

• Briefer Forms Effective?

• What are essential ingredients?

• Alternative Methods Effective for

Delivering to Underserved Populations?

Long-Term Study: Aim 1

• Examine whether women with breast

cancer assigned to the 10-week CBSM

group differ from those in the 1-day

psycho-educational control group on

psychological status at 5year follow-up:

– Depression

– Vigor and fatigue

– Social disruption

CBSM and depression: long-term

(Stagl et al., 2013, SBM)

0 2 4 6 8 10 12

CBSM

Control

9.53

11.7

Differences in Depression on CES-D in 5-year follow up of

Breast Cancer Survivors

*

CBSM Effects over 5 years: Energy

ABS-VIGOR F(3,107) = 3.81, p = .012 FSI- INTERFERENCE F(3,99)=2.81, p=.047.

T1: Baseline T2: 6 mo T3: 12 mo T4: 5 yrs

SIP-RECREATIONS /PASTIMES F(3,105) = 3.14, p = .030

CBSM Effects over 5 years:

Social Disruption

T1: Baseline T2: 6 mo T3: 12 mo T4: 5 yrs

12 Month Pre-post CBSM Chg Predicts 5yr Status

• Greater 12mo change 5yr Outcome

– ABS-NA, ABS-PA, FSI-fatigue, FACT, PM cort, IFN-g - CES-D ABS Depression

– ABS-NA, BS-PA, FACT, leukocyte pro-inflamm gene express1 - FSI-fatigue

– ABS-NA, ABS-PA, PSQI, leukocyte pro- inflamm/pro-met2 - ABS-Vigor

– ABS-NA, ABS-PA - ABS-PA

1greater 12-mo reductions in pro-inflammatory [cytokine and chemokine) leukocyte gene expression

(e.g., TNF-a, IL-1b) predicted greater 5-yr ABS vigor (b = -.35) and ABS affect balance (b = -

.44), and less FSI fatigue disruption (b = .40).

2greater 12-mo reductions in MMP-9 and LMNA gene expression related to greater 5-yr ABS-Vigor

and greater emotional well-being (b = -.41 to -.65).

Findings held controlling for covariates (e.g., sociodemographic, adjuvant treatment).

Long-Term Study: Aim 2

• Examine whether women with breast cancer assigned to the 10-week CBSM group differ from those in the 1-day psycho-educational control group on clinical disease endpoints at 8-15 year follow-up:

– disease free interval

– breast cancer specific mortality

– all-cause mortality

Methods

Sample:

• 240 women post-surgery for non-metastatic stage 0-IIIb breast cancer accrued between 1998-2005.

• Randomized to 10-week group based Cognitive-Behavioral Stress Management Intervention (CBSM) or a 1-day Psycho-educational Control Seminar (PE)

• CBSM =120; PE = 120

• Currently 8-15 years post study enrollment

• Tumor Registry link and Chart Reviews ongoing

Gaps Remaining


Physiological Adaptation with Clinical

Outcomes



context of care?





Identifying Intervention Moderators?

• Consider CBSM effects in context of:

– Person (ethnicity, SES, age, personality, social

context)

– Treatment (surg type and adjuvant)

– Disease (e.g., use Tissue Bank to measure

genomic, hormonal and immune markers)

• Clinicopathological: tumor sz, nodal status, grade, LVI tumor

lymphatic vessels and ER/PR status

• Tissue-derived: p27, pai-1, VEGF, IGF-1

DX Surgery

Specimen Repository

Core

•Tissue

•Blood

•History

Informed

consent

experimental control

(2-8 weeks) Group start T1 Randomize

Study Timeline Prior to the

Start of Intervention

prog. markers cells serum clinico-path.

Gaps Remaining



Outcomes



context of care?





Does Timing Within Treatment

Matter?

Can Stress Management Intervention Facilitate

Positive Adjustment after Adjuvant Therapy

for Breast Cancer has ended?

NCI grant P50CA84944. M. Antoni, P.I.

Examining the effects of CBSM at 3 - 24

months after adjuvant therapy has been

completed

Assessment Time Points

T1

surgery

T4

1 -2 year post surgery

T3 T2

2-8 wks

post

B SMART-10 wks.

3 months

post

6 months post

Testing Timing: Can Stress Management

Intervention Facilitate Positive Adjustment 3 – 24

months after Adjuvant Therapy for Breast Cancer

has ended?

Outcomes Grp X Time

PSYCHOSOCIAL

Increased Benefit Finding p = .046 Increased Post traumatic Growth (PTGI) p = .006 Increased Spirituality p = .020

Increased FACT-B p = .080

PHYSIOLOGICAL

Decreased Urinary Free Cortisol p = .048 Increased NKCC p = .031

Intervention Components

CBSM-specific

Relaxation confidence p = .001

Tension awareness p = .057

Non-CBSM –specific

Connection w/other CA pts p = .027

NCI CA84944-P50 M. Antoni, P.I.

Effects of CBSM in BRCA: Is timing important?

Physiol Post-surg (101) Post-surg (199) Post-Adj (126)

Cortisol Y Y Y

NK/LAK Y Y

LPR Y

TH1 cyto Y

Psych

Neg Mood Y Y

Pos Mood/BF Y Y Y

Fatigue Y

QOL/sleep Y Y Antoni et al. 2001 Antoni et al. 2006 a,b;

2009; Phillips et al.,

2008

Ironson et al., 2004

Gaps Remaining



Outcomes



context of care?





Other Ongoing Work In CBSM

• Can CBSM be delivered effectively:

– In abbreviated components?

– In the community?

– In different languages?

– Over the telephonevideophoneTablet/Web

Dismantling CBSM into its Active

Components

• Observations of Prior CBSM groups

– Attendance: effects for [5] = [10] > [1 – 2] sessions

– Mediators: Relaxation Confidence, Cognitive appraisal skills and

Emotional Expression

• Ongoing NCI Trial (2R01 CA064710 Antoni, PI) “Dismantling Study”

– 5wk CBT only (group)

– 5wk Relaxation Training only (group)

– 5wk Health Education (attention) only (group)

5-Week Intervention

W

k

RT

1 PMR-7

2 PMR-4, Beach Scene Imagery

3 Passive PMR, Special Place

Imagery

4 Light Imagery

5 Meditation

Streamlined Interventions

5-Week Intervention

Wk CBT

1 Stress Symptoms & Appraisals

2 Distortions & Reappraisals

3 Coping, Acceptance/Softening

4 Social Support & Anger

Management

5 Assertiveness & Review

5-Week Control Group

EE

Info about BCa, treatment, side effect management, healthy lifestyle, & Q.O.L.

5wk RT vs 5wk CBT vs 5wk Educ

grp grp grp

• Psychosocial adaptation (BF, FACT-B, PSS, FSI, PSQI)

• HPA axis regulation (sal cortisol output & regulation)

• Th1/Th2 cytokine production (anti-CD3 stim for IFN-g/IL-4)

• Pro-inflammatory cytokines (IL-1, TNF-a and IL-6)

• Health behaviors (exercise)

• Intervention processes (CBT-specific and non-specific)

(2R01 CA064710-10A1)

Specificity of Effects after 5-wk Training

Period

RT CB EE Target: Tension/Arousal Cognitive/Affective Health Information

Effects:

• Anxiety Depression/Neg Affect None

ABS Anx -ABS Dep None

Relaxation Efficacy -FACT Emot Well-being None

• Recreations Pastimes (SIP) Intrusive Thoughts (IES) None

-Hobbies/Social Activities -Cancer-related thts

• Positive Mood Positive Mood None

– Happiness -Happiness

– Joy -Joy

– Affection -Affection

Significant Psy Effects for 5wk RT/CB vs

EE at 12 mo

RT/CB* EE

• Negative Mood

– ABS Dep F = 7.81, p < .01 N.S

• Positive Mood

– ABS Balance (PA-NA) F = 8.71, p < .01 N.S

– ABS Vigor F = 3.74, p < .05 N.S

• Benefit Finding F = 14.7, p < .01 N.S

• SIP Social Disruption F = 18.7, p < .01 N.S

• Serum PM cortisol F = 9.21, p < .01 N.S

• IFN-g production F = 4.6, p < .05 N.S

• IL-4 production F = 3.4, p < .05 N.S

*no diffs in RT vs CB so we combined active conditions (RT/CB)

Significant Psy Effects for 5wk RT/CB vs

5wk EE vs 10wk CBSM @ 12 mo

5wks 10wks

RT/CB EE CBSM

• Negative Mood

– ABS Dep ** N.S ***

• Positive Mood

– ABS Balance ** N.S ***

– ABS Vigor * N.S ***

• Benefit Finding ** N.S ***

• SIP Soc Disruption ** N.S ***

• Serum PM cortisol ** N.S **

• IFN-g production * N.S **

Combined active 5wk conditions (RT/CB), 5wk Enhanced Health Education (EE), 10wk Cognitive

Behavioral Stress Management (CBSM). ***p < .001 **p < .01 *p < .05 on RANOVAs

Delivering CBSM in the Community: Project CARE (Lechner, P.I., Antoni, co-PI, Kobetz, co-PI) NCI R01CA131451

• Minority Breast Cancer Patients underserved and understudied

• Partnered with Community Organizations in Overtown and other Miami regions of minority and underserved populations

• Formative research to tailor CBSM-based intervention

• Community-Based Participatory Research methods used to train assessors to collect physiologic and psychosocial measures in home

• CBSM groups conducted in community (church & community centers)

• Pre-post-F/U of psychosocial, physiological and symptom cluster outcomes – PSS, Mood, QOL

– Fatigue, sleep, symptoms

– Salivary cortisol, HRV

Can You Hear Me Now?: Can CBSM groups be Delivered Over

the Phone?

• Patients with advanced disease not able to attend groups

• Some patients have transportation issues

• Some prefer to maintain anonymity

• Worked with Psychiatry and Engineering to develop Telecare-based technology with conference calling to allow access to CBSM via phone: “TELEPHONE GROUPS”

E.g., Patients Participate in “Tele-Groups” at Home

• 10 one-hour modules delivered in conference call on CTIS or cell phone

• Each module contains relaxation and cognitive-behavioral stress reduction (CBT) components

• System provides menus for review of 10 CBT modules during and after session

• Menu also allows user to play back audio of relaxation exercises

• The system collects real-time usage data on a per call basis to measure “dose” received

• Other Menu buttons: – Calling group leader or members – Contacting PCa support organizations

Communication Technology On

the Horizon

• Using Videophone Technology/Internet to deliver

CBSM in group-based form at home to patients (and

partners) who cannot attend clinic-based groups due

to advanced disease, mobility issues/personal

preference:

– Chronic Fatigue Syndrome

1R01NS072599-01

-Advanced Prostate Cancer

NCI R01

ANSWER CALL Press this button to answer an incoming call or to end video.

FULL SCREEN Press this button to expand the video to full screen.

GO BACK Press this button to return to the previous screen.

HELP Press this button to bring up the help menu with topics you can view.

NO MIC Press this button to turn off the microphone. Others will not hear you.

NO VIDEO Press this button to turn off the video camera. Others will not see you.

SEE YOURSELF Press this button to view yourself on screen and adjust the image.

SERVICES Press this button to bring up the system menu with topics you can view.

VOLUME Press this button to adjust the volume. Clicking on the plus side of the

button increases the volume. Clicking on the minus side decreases it.

CBSM Videophone

Programming

• CBSM Modules 1 – 10 Video Reviews

• Relaxation and Interpersonal Skills

Video Enactments

• Expert Videos

• Daily Stress Ratings Prompting

• System captures usage (adherence and

dosage data)

• Prototype for Web-Based (SKYPE)

• Transitioning from Videophone to Tablet

Demonstration Videos

Assertiveness

Deep Breathing Special Place

Imagery

Progressive Muscle

Relaxation

Mindfulness

Meditation

Ongoing and Future Work In CBSM

• Can CBSM be delivered effectively:

– In abbreviated components?

– In the community?

– In different languages?

– Over the telephonevideophoneTablet/Web

Stress Management Studies at UM (1986-

2013)

HIV

MSM Hetero

Men

Inner-City

Women

Asymp

Dx Notif

Symp

Pre-HAART

HAART

Asymp. HIV+

AIDS

HAART

Eng

Lang

Spa

Lang

Spa

Lang

Eng

Lang

HPV +

SIL

Post-

Adj

Stage I-IIla

BRCA

Pre-

Adj

Stage I-II

Stage I-IIIa

Dismantle

CBSM

Abbrev

CBSM

PRCA

Post

Surg

Post

Radiation

Advanced

Disease

Eng

Lang

Spa

Lang

Eng

Lang

Spa

Lang

Eng

Lang

CFS

SMART

ENERGY

TELE

CBSM

TELE-

CBSM Community-based

CBSM

1970s/80s 1990s 2000s 2010s

Phase 1: Stress/Stress Management Effects on

QoL in Cancer Patients

His

tory

of

Bio

beh

avio

ral

Res

earc

h

Phase 2: Stress/Stress Mgmt Effects

on “Adaptation” to Medical Treatment

Phase 3: Stress/Stress Mgmt

Effects on Neuroimmune

Indicators of Unknown Duration

Phase 4: Stress/Stress

Mgmt Effects on Molecular

Interactions/ Processes

Controlling Cell Function

Over Longer Periods?

Developing and Testing Psychosocial Interventions in

Clinical Disease: “Drilling Down and Reaching Out”

• Combining “Mechanism Research” with “Clinical Efficacy Research” is Efficient Science

• Using microarray and bioinformatics technology we now see that Stress Management may produce molecular “footprints” in leukocytes pursuant to changes in neuroendocrine regulation over sustained periods

• These changes portend improved ability to respond to stress and optimize quality of life across the cancer continuum over the long term

• Using Community-based Approaches and Telecommunication Technology Reaches Populations Most in Need

Acknowledgments NCI

R01 CA64710

NCI R01CA131451

P50CA84944

Sylvester Cancer Center

• Robert Derhagopian, MD

• Frederick L. Moffat, MD

• Tammy Enos Sifre, PhD

• Kristin Kilbourn, PhD

• Susan Alferi Fox, PhD

• Patti Arena, PhD

• Jessica Lehman, PhD

• Amy Boyers, PhD

• Jennifer Culver, PhD

• Susan Yount, PhD

• Suzanne Harris, PhD

• Dean Cruess, PhD.

• Stefan Gluck, MD, Ph.D.

• Bonnie McGregor, PhD

• Alicia Price, PhD

• Vida Petronis, PhD

• Roselyn Smith-Gonas, PhD

• Kurrie Wells, MS

• Cassy Vaughn, MS

• Kenya Urcuyo, MS

• Sophie Guellati, PhD

• Sarah Wimberly, Ph.D.

• Aisha Kazi, Ph.D.

• Kristin Phillips, Ph.D.

• Janny Rodriguez, MEd

• Nicole Whitehead, Ph.D.

• Jarrard Goodwin, M.D.

• Bonnie B. Blomberg, Ph.D., Microbiology/Immunology, University of Miami School of Medicine, Miami

• Suzanne Lechner, Ph.D., Psychiatry, University of Miami School of Medicine, Miami

• Charles S. Carver, Ph.D., Psychology, University of Miami, Coral Gables

• Susan Lutgendorf, PhD, Psychology, University of Iowa, Iowa City, IA

• Steven W. Cole, PhD, Medicine, UCLA, Los Angeles, California

the effects of stress management on adaptation and

Documents