The impact of breast cancer and treatment on cognition

Melissa SiscoMay 20, 2011

THE IMPACT OF BREAST CANCER AND

TREATMENT ON COGNITION

OVERVIEW OF BREAST CANCER DETECTION SYMPTOMS PROGNOSIS

CASE PRESENTATION DEMENTIA V. CANCER

RECOMMENDATIONS FOR CANCER CLIENTS MEDICAL ALTERNATIVE COGNITIVE BEHAVIORAL PSYCHOSOCIAL

AGENDA

Most common cancer among women 1 in 800 US women are diagnosed annually 19% die of breast cancer (CDC, 2010)

90.4% white; 77.0% black survived (SEER, 2008) 12% of women dx during lifetime (BCS, 2011) Median age of dx=61, median age at mortality=68

Risk Being female, 55+, Personal or family hx of breast cancer, Inherited genetic mutations (BRCA1 and BRCA2) Chest exposure to radiation, obesity, Menarche<12, menopause>55, first child past 35, Postmenopausal

hormone therapy, Drinking excessively (Mayo Clinic, 2010)

Free screening for low-SES women 40-64 saved 0.06 life years v. no program & 0.26 life years compared to no screening Per invasive, screen-detected breast cancer, 0.71 life years saved v. no program

(n=1.8 million from 1991-2006) (Hoerger et al, 2011) 1998 to 2006, incidence and mortality decreased 2% (Edwards et al,

2010)

FACTS ABOUT BREAST CANCER

US WOMEN 40+ SCREENED IN PAST 2 YEARS (HYATTSVILLE, 2010)

Breast Self Examination(BSE) has been shown to be ineffective, awareness of changes is more important

Mammograms 10% of cancer is missed

Some estimates have read as high as 30% 15% of abnormalities are a false positive

1/3 screened get a false-positive in a 10-yr time (n=9762) (Elmore et al, 1998)

3D Mammography reduces false positives by 49% (n=1093) (BCS, 2011) U.S. Preventative Services Task Force reversed the suggestion of

annual mammography for women over 40 in 2009. Additional Examinations

Ultrasound- Exploration of felt or seen masses Ductograms- Evaluation of bloody nipple discharge MRI- determination of surgical approach of resection

DETECTION

Is it cancer? Not al l abnormal cel ls or lumps are. Biopsy the tissue or the removed tumor

Size and origin point: Ducts, lobules, or connective tissue How bad is it?

Stage 0- Noninvasive (In situ) Cancer Most common- ductal carcinoma in situ (DCIS) in lining of milk ducts

Stage I-IV- Invasive (infiltrating) Cancer- outside of ducts or lobule What are the treatment options?

Resection (lumpectomy, mastectomy, lymph node dissection) Radiation Chemotherapy Hormone Therapy Immunotherapy & Stem Cell Transplant

Are there other drugs that are used? Trastuzumab (Herceptin) reduces human growth factor receptor 2 (HER2)

that cause breast cancer. Lapatinib (Tykerb) targets the HER2 protein and is approved for use in

advanced metastatic breast cancer. Lapatinib is reserved for women who have already tried trastuzumab and their cancer has progressed.

Bevacizumab (Avastin) stops the signals cancer cells use to attract new blood vessels; associated with kidney and cardio-vascular failure.

BREAST CANCER 101

Determined by area of mets (e.g. lesions in brain)Difficult to tease apart cancer, distress, fatigue, and

treatment effectsNo studies were found that look at the neuropsychological

performance of women prior to treatment of breast cancerCommon complaints according to the American Cancer

Society: swelling of all or part of the breast skin irritation or dimpling breast pain nipple pain or the nipple turning inward redness, scaliness, or thickening of the skin a nipple discharge other than breast milk a lump in the underarm area

BREAST CANCER’S COGNITIVE SYMPTOMS

What is the cause of the problem?

CASE PRESENTION

54-year-old, Caucasian female homemaker & socialite 12 years of education

She was an avid reader and average student Trauma Hx:

No history of TBI or stroke Age 3, she cut her wrist on a milk bottle requiring stitches Age 11, she rolled out of a car when the door swung open No history of sexual, physical, and emotional abuse

Medical Hx: Medically-controlled hypertension & menopause Cyst in right maxillary sinus Breast Cancer (2008) Chemotherapy and Radiation (2009)

Psych Hx: None, aunt suspected to have dementia at age 60 Drinks social ly- chemically sensit ive; she generally takes a quarter of

recommended medication doses and her family often jokes that she ‘gets tipsy even thinking about a glass of wine’

BACKGROUND

Concentration and Attention: conversations & multi-tasking

Memory: Forgetting important dates and current tasks

Word Finding difficulties: Cues are ineffective in increasing articulation.

Fatigue: Mental and physical dullness after 3:00 pm Affective Expressiveness: My forehead feels ‘heavy

as if it were retaining water’ and that she is less capable of making facial expressions and her husband complained that she ‘looked at him differently.’ 

Marital Conflict: Mr. Doe is domineering. When he becomes upset with her, she ‘freeze[s] like a deer in headlights’

PRIMARY COMPLAINTS

Presentation: On-time, escorted by a close friend Well-groomed and cooperative yet initially slightly anxious Client drank several caffeinated beverages during the day

Speech: Normal prosody/volume; word finding trouble She communicated through gestures She used semantically similar words- ‘raid’ for ‘mace’

Vigilance: Cues/instruction repetit ion to stay on task Insight: Painfully aware of her cognitive challenges Thought process: Linear, slowed, i l logical at times

It took over 40 seconds for each of the 128 WCST cards On WCST, she attempted to add the numbers of the diagonal piles

BEHAVIORAL OBSERVATIONS

Fall 08 The basement flooded and Mrs. Doe froze; she did not know how to respond. She was otherwise intact.

Feb 09 Stage 1, Grade 3 Breast Cancer dx Memory becomes impaired and thoughts are slowed Taxotere/Cytoxan Chemotherapy from February to August 2009 Bilateral Mastectomy w/ complication of anesthesia 5-6 hour recovery

March 09 Tamoxifen administered to suppress effects of Estrogen ‘It hit me bad.. I couldn’t walk across the street and remember what happened

from one side to the next… removed when people were talking… like nobody [was] in there.’ Mrs. Doe

November 09 Forgets not cooking, looking in spare rooms for the turkey to cook at her friends home. Breaks down emotionally

December 09 Uncharacterist ical ly forgets to buy family presents March 10 Goes for aspirin for headache while vacationing in Paris,

cannot find room for 3 hours. Forgets the name of the Eiffel tower April 10 Neuropsychological Evaluation #1; she feels she was stressed

and the results are not accurate October 10: Symptoms persist, current evaluation

*2006 2010 Imaging- Mild diffuse volume loss & small vessel ischemic changes.

TIMELINE

RBANS DELAY & COPY

BVMT-RT3

DC after 5 minutes

TRAILS B

*Discontinued after 5 minutes

MRS. DOE’S RESULTS

WHAT IS OUR DIFFERENTIAL RULE OUT OF DIAGNOSIS?

Fall 08 The basement flooded and Mrs. Doe froze; she did not know how to respond. She was otherwise intact.

Feb 09 Stage 1, Grade 3 Breast Cancer dx Memory becomes impaired and thoughts are slowed Taxotere/Cytoxan Chemotherapy from February to August 2009 Bilateral Mastectomy w/ complication of anesthesia 5-6 hour recovery

March 09 Tamoxifen administered to suppress effects of Estrogen ‘It hit me bad.. I couldn’t walk across the street and remember what happened

from one side to the next… removed when people were talking… like nobody [was] in there.’ Mrs. Doe

November 09 Forgets not cooking, looking in spare rooms for the turkey to cook at her friends home. Breaks down emotionally

December 09 Uncharacterist ical ly forgets to buy family presents March 10 Goes for aspirin for headache while vacationing in Paris,

cannot find room for 3 hours. Forgets the name of the Eiffel tower April 10 Neuropsychological Evaluation #1; she feels she was stressed

and the results are not accurate October 10: Symptoms persist, current evaluation

*2006 2010 Imaging- Mild diffuse volume loss & small vessel ischemic changes.

TIMELINE

The Cell CycleG0 phase (resting stage): The cell

has not yet started to divide; a few hours to a few years.

G1 phase: The cell grows and produces more proteins; about 18 to 30 hours.

S phase: DNA are copied to the new cell; 18 to 20 hours.

G2 phase: The DNA is checked and cell readies to split; 2 to 10 hours.

M phase (mitosis): A cell splits; 0.5-1 hrs

CHEMOTHERAPY

*Chemotherapy attacks cells in M or S only; but can’t differentiate healthy from abnormal cells. Other forms are used to kill dormant cells when they are cycle-nonspecific.

Damage to neurons or altered neurotransmitter metabolism Frontal cortex and integrity of white matter

Damage to DNA and inability to rebuild the system Cell death and slowing of cell division in

subventricular zone Worse if predisposed- E4 allele of

apolipoprotein E Disregulation of the immune system Release of cytokines (IL-6)

Cytokinesis is the last phase of a cell having a protein form around the nucleus of a replicated cell.

Reduction of estrogen & progesterone Blood clotting in small central nervous

system Wong, 2011

MECHANISM OF CHEMOTHERAPY DAMAGE

Acute encephalopathy Confusional state, insomnia, and often agitation, which is

commonly believed to resolve off treatmentChronic encephalopathy

Cognitive dysfunction consistent with a ‘subcortical dementia’, incontinence, and gait disturbance

Stroke-like episodes Transient motor impairments

Cerebellar syndrome Ataxia to a pancerebellar syndrome

Peripheral neuropathies

(Wefel et al, 2004)

CHEMOTHERAPY RELATED SIDE EFFECTS

Memory and concentration problems associated with chemotherapy: Being unusually disorganized Confusion Difficulty with concentration, attention, and ‘multi-tasking’ Difficulty finding the right word Difficulty learning Fatigue Short-term & Long-term memory problems Mental slowing

Risks: Brain cancer Chemotherapy given directly to the central nervous system Chemotherapy combined with whole-brain radiation Higher doses of chemotherapy or radiation Radiation therapy to the brain Younger age at time of cancer diagnosis and treatment

Symptoms typically subside within 2 yrs of treatment (Mayo Clinic, 2011)

“CHEMO BRAIN”

15 to 70% of persons who undergo chemotherapy experience learning and memory deficits that generally persist after treatment (Meyers, 2008)

Of individuals with breast cancer treated with chemotherapy, 61% experience cognitive symptoms that remain post-treatment one-year after baseline. The most common impairments were learning, memory, executive function, and processing speed deficits (Wefel et al, 2010)

When combined with chemotherapy or taken alone, Tamoxifen exacerbates memory deficits (Bender et al, 2006; Paganini-Hil l , & Clark, 2000) Some persons are more prone to these deleterious side effects of the drug

due to metabolic variation (Wilkinson, 2005)

Tamoxifen is the only hormonal therapy approved for breast cancer prevention (prophylaxis). Cognitive side effects are not often included in information on cancer websites.

MRS. DOE’S SITUATION

1. Tamoxifen w/o chemo causes objective verbal memory loss and executive dysfunction.80 tamoxifen users v. 99 exemestane

postmenopausal women with breast cancer were assessed prior to (T1) and 1-year into treatment (T2); none had chemotherapy. NS changes from exemestane users on any cognitive

domain Tamoxifen users were worse than healthy controls on

verbal memory (Cohen's d = .43) and executive functioning (Cohen's d = .40), and worse than exemestane users on information processing speed (Cohen's d = .36)

NS of 3 groups of visual memory, working memory, verbal fluency, reaction speed, and motor speed (Shilder et al, 2010)

TAMOXIFEN STUDIES

1. Tamoxifen w/o chemo causes objective verbal memory loss and executive dysfunction.94 breast cancer patients were

randomized into trials of anastrozole, tamoxofin, or both (n=35 controls): Treatment clients were impaired on

a processing speed task (p =0.032) and immediate verbal memory (p =0.026) after controlling for the use of hormone replacement therapy.

Performance was not related to length of treatment or measures of psychological morbidity (Jenkins et al, 2004).

TAMOXIFEN STUDIES

Schiller et al, 2010TAMOXIFEN STUDIES

1. Tamoxifen w/o chemo causes objective verbal memory loss and executive dysfunction.PET scan (controls v. breast cancer survivors w/

chemo 5-10 years ago) cerebral blood flow during memory and control tasks.

Chemos had less blood flow in the frontal cortex, cerebellum, and basal ganglia. The inferior frontal gyrus was most impacted.

Metabolism of the basal ganglia was significantly decreased in tamoxifen + chemotherapy over chemotherapy or controls (Silverman et al, 2007)

TAMOXIFEN STUDIES

Jenkins et al, 2004anastrozole, tamoxifen (n=94), control (n=35)

Regional cerebral glucose metabolism in dorsal lateral frontal cortex (DLF) and orbital cortex (ORB) of breast cancer female clients taking estrogen (ERT+, n=15), not taking estrogen (ERT−, n=15), and tamoxifen for breast cancer (TAM, n=10, 50% had radiation). None had chemo.

TAM lower metabolic ratios for rORBF and lORBF than the ERT+ (0.06) (Eberling et al, 2004)

Mean normalized hippocampal volumes. * TAM < ERT+, P = 0.05. (Eberling et al, 2004)

PET SPM maps- Shaded areas indicate areas of significant (p < 0.01) differences.

*ERT+ > TAM: left superior and middle frontal gyrus, right middle and medial frontal gyrus, right medial frontal gyrus.

*ERT− > TAM: left and right superior and medial frontal gyrus, left postcentral gyrus

(Eberling et al, 2004)

2. Tamoxifen w/o chemo causes subjective impairment.

120 breast cancer clients with chemo w/ or w/o 6 months of hormone therapy of different sorts (healthy control=208). Chemo or tamoxifen increased encephalopathy 3x (Debess, 2010) 3. Tamoxifen does not increase remission.

10 yrs post-tx (98.7% survival rate), 282 breast cancer survivors w/ chemo and tamoxifen (Wood, 2002).

TAMOXIFEN STUDIES

Tamoxifen Usefulness: Of 1385 elderly women in assisted living

(1/4 on Tamoxifen), less Alzheimer's disease documented, more independent in bed mobility, eating, toileting (in each case P < 0.0001), personal hygiene (P = 0.0155), dressing (P = 0.0015), transferring (P = 0.0006), locomotion (P = 0.0016), and cognitive skills for daily decision-making (P < 0.0001). They were 42% more likely to be depressed (P < 0.0001). *Not randomized treatment (Breur, 2000) 

Hormone Replacement Helps 1-yr post tx, 50 breast cancer women on

Tamoxifen (randomly assigned estradiol or progestogen). Hormones increased global quality of life (p<0.01) (Fahleen et al, 2011).

MEDICAL USE?

Above average pre-morbid cognitive abilityLanguage abilities remain intact. Word-

finding difficulty cannot be attributed to general naming or language ability rather due to deficits in concentration and shifting attention.

Cognitive impairment in all other domains Largest deficits: Learning, retention, attention,

processing speed Not due to low mood, lack of effort, fatigue, or

mild cardiovascular changes. After careful review of client’s history and

speaking with collateral sources of information, it appears that the deficits originated during chemotherapy and were substantially worsened by Tamoxifen.

MRS. DOE’S CASE SUMMARY

In 2010, there were more than 2.5 mil l ion breast cancer survivors  in the U.S (Breast Cancer Society, 2011)

Subjective cognitive complaints (n=24 studies) There was not significant consistent differences in subjective cognitive complaints

amongst treatment groups or cancer without treatment Subjective cognitive complaints were not related to objective measures of cognitive

dysfunction E.g. Many with complaints score average on memory tests (Mayo Clinic, 2011)

Subjective cognitive complaints were related to: psychological distress, fatigue, and health status (Pullens et al, 2010)

Objective cognitive dysfunction (n=30 studies) Verbal memory and executive function (Cohen’s d=0.9, large effect) Motor function (Cohen’s d=0.5, moderate effect) Attention, processing speed, and visuospatial also declined but not significantly and

consistently across regimens (Anderson-Hanley et al, 2003)

Chemotherapy as a Toxic Agent is a Controversial Topic Per breast cancer, 6 of 8 studies showed substantial cognitive decline. Little is

known of differences in treatment regimens, baseline function, neurogenic factors, and cancer severity (Morse et al, 2003)

META-ANALYSES

WHEN AND WHAT SHOULD A BREAST

CANCER PATIENT BE TOLD OF THE

POTENTIAL SIDE EFFECTS OF

TREATMENT?

Reduce peripheral illnesses associated with cancer treatment: anemia, depression, anxiety, insomnia, infection, early menopause Keep a journal of symptoms and how they are affecting life

Medication Methylphenidate (Concerta, Ritalin, others), a drug approved for

attention-deficit/hyperactivity disorder (ADHD) Donepezil (Aricept), a drug used in people with Alzheimer's

disease Modafinil (Provigil), a drug used in people with certain sleep

disordersAcupunctureSupplements- Gingko & Vitamin E

Consult with doctor- these often interfere with chemotherapy and blood thinning medications

MEDICAL TREATMENTS

Cognitive Rehabil itation Repetitive mental tasks Identifying compromising times (hungry, tired, emotional) Master new hobbies Coping strategies

Notes, outlines, use a recorder for important meetings, write down important questions to ask doctors, keep a written summary of personal information including medications, treatment regimen, personal history, medical history

Stress-relief techniques Muscle relaxation, visualization Cognitive reframe: Recognize that memory problems happen to everyone

Use a daily schedule book with a to-do l ist Write down distracting thoughts in schedule as they arise Write down appointments and priorities in the schedule book

Live a health l i fe with regular meals and exercise When taking part in a task, reduce distractions, take breaks

Try to do tasks in the ‘high part’ of the day Social Support

Be honest about your symptoms with loved ones Give loved ones a way to support you

COGNITIVE-BEHAVIORAL TREATMENTS

 Cancer caregiver average age = late 50s to early 60s

Younger caregivers have lower sense of wellbeing 35% of caregivers reported positive emotionality that

surpassed the normAmount of social support, familial cohesiveness, and

strong faith lessened the emotional distress of care giving for a loved one with cancer or dementia

(Rabins et al, 1990; Clip & George, 1993)

CAREGIVER CONSIDERATIONS

THANK YOU FOR

YOUR TIME AND

ATTENTION

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SELECTED REFERENCES

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SELECTED REFERENCES (CONT’D)

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Wood, WC et al (2002). Can we select which patients with small breast cancers should receive adjuvant chemotherapy? Annals Of Surgery, 235(6), 859-862.

SELECTED REFERENCES (CONT’D)