The impact of breast cancer and treatment on cognition

1. The impact of breast cancer and treatment on cognition Melissa Sisco May 20, 2011

2. Agenda • OVERVIEW OF BREAST CANCER • DETECTION • SYMPTOMS • PROGNOSIS • CASE PRESENTATION • DEMENTIA V. CANCER • RECOMMENDATIONS FOR CANCER CLIENTS • MEDICAL • ALTERNATIVE • COGNITIVE BEHAVIORAL • PSYCHOSOCIAL

3. Facts about breast cancer • 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 hxof 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)

4. US WOMEN 40+ screened in past 2 years (HyattsvilLe, 2010)

5. Detection • 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

6. Breast cancer 101 • Is it cancer? Not all abnormal cells 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.

8. Breast Cancer’s Cognitive Symptoms • Determined by area of mets (e.g. lesions in brain) • Difficult to tease apart cancer, distress, fatigue, and treatment effects • No studies were found that look at the neuropsychological performance of women prior to treatment of breast cancer • Common 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

9. Case Presention What is the cause of the problem?

10. Background • 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 socially- chemically sensitive; 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’

11. Primary Complaints • 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’

12. Behavioral Observations • 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 repetition to stay on task • Insight: Painfully aware of her cognitive challenges • Thought process: Linear, slowed, illogical 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

13. Timeline • 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 09Tamoxifen 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 Uncharacteristically 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.

14. RBANS Delay & Copy

15. BVMT-R T3

16. Trails B • DC after 5 minutes *Discontinued after 5 minutes

17. MRs. DOE’S RESULTS

19. What is our differential rule out of diagnosis?

20. Timeline • 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 09Tamoxifen 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 Uncharacteristically 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.

21. ChemotherapY The Cell Cycle • G0 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 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.

22. Mechanism of chemotherapy damage • 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 subventricularzone • Worse if predisposed- E4 allele of apolipoproteinE • 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

23. CHEMOTHERAPY RELATED SIDE EFFECTS • Acute encephalopathy • Confusionalstate, insomnia, and often agitation, which is commonly believed to resolve off treatment • Chronic encephalopathy • Cognitive dysfunction consistent with a ‘subcortical dementia’, incontinence, and gait disturbance • Stroke-like episodes • Transient motor impairments • Cerebellar syndrome • Ataxia to a pancerebellarsyndrome • Peripheral neuropathies (Wefel et al, 2004)

24. “Chemo brain” • 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)

25. Mrs. Doe’s Situation • 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-Hill, & 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.

26. Tamoxifen Studies 1. Tamoxifenw/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 exemestaneusers on any cognitive domain • Tamoxifenusers 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)

27. 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).

28. TAMOXIFEN STUDIES Schiller et al, 2010

29. Tamoxifen 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. • Chemoshad 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)

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

31. 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 tamoxifenfor 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)

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

33. 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 postcentralgyrus (Eberling et al, 2004)

34. Tamoxifen Studies 2. Tamoxifenw/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).

35. Medical use? • TamoxifenUsefulness: • 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).

36. Mrs. Doe’s Case Summary • Above average pre-morbid cognitive ability • Language 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.

37. Meta-Analyses • In 2010, there were more than 2.5 million 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)

38. When and what should a breast cancer patient be told of the potential side effects of Treatment?

39. Medical Treatments • 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 disorders • Acupuncture • Supplements- Gingko & Vitamin E • Consult with doctor- these often interfere with chemotherapy and blood thinning medications

40. Cognitive-behavioral treatments • Cognitive Rehabilitation • 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 list • Write down distracting thoughts in schedule as they arise • Write down appointments and priorities in the schedule book • Live a health life 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

41. CAREGIVER CONSIDERATIONS • 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 norm • Amount 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)

42. Thank you for your time and attention

43. Selected References • Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, & CompasBE (2003). Neuropsychological effects of treatments for adults with cancer: a meta- analysis and review of the literature. Journal of the International Neuropsychological Society, 9, 967–982. • Breur, B., & Anderson, R. (2000). The relationship of Tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents. Women & Health, 31(1), 71-85. • CDC (2010). U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2007 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2010. Available at: http://www.cdc.gov/uscs. • Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, Jemal A, Schymura MJ, Lansdorp-Vogelaar I, Seeff LC, van Ballegooijen M, Goede SL, & Ries LA (2010). Annual report to the nation on the status of cancer, 1975-2006 featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer, 116(3), 544-573. • Elmore, J.G., Barton, MB, Moceri, VM, Polk, S, Arena, PJ, & Fletcher, SW (1998). Ten-year risk of false positive screening mammograms and clinical breast examinations. New England Journal of Medicine, 338(16), 1089-1096. • Debess, J et al (2010). Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study. Breast Cancer Research & Treatment, 121(1), 91-100. • Eberling, JL et al (2004). Estrogen- and tamoxifen-associated effects on brain structure and function. NeuroImage, 21(1), 364-371.  

44. SELECTED References (ConT’D) • Fahleen, M et al (2011). Health-related quality of life during hormone therapy after breast cancer: a randomized trial. Climacteric, 14(1), 164-170. • Hoerger, T.J., Ekwueme, D.U., Miller, J.W., Uzunangelov, V., Hall, I.J., Segel, J., Royalty, J., Gardner, J.G., Smith, J.L, and Li, C (2011). Estimated effects of the National breast cancer and cervical cancer early detection program on breast cancer mortality. American Journal of Preventative Medicine, 40(4), 397-404. • Jenkins, V et al, (2004). Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psycho-Oncology, 13(1), 61-66. • HowladerN, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. • Hyattsville, M.D. (2010). Health, United States, 2009: Special Feature on Medical Technology. National Center for Health Statistics. • Morse, R., Rodgers, J., Verrill, M., Kendell, K. (2003). Neuropsychological functioning following systemic treatment in women treated for breast cancer: A review. European Journal of Cancer, 39(16), 2288-2297. • Pullens, M. J., De Vries, J. and Roukema, J. A. (2010), Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psycho-Oncology, 19: 1127–1138.

45. SELECTED References (ConT’D) • Rabins, PV, Fitting, MD., Eastham, J, & Fetting, J (1990). Cariing for the chronically ill. Psychomatics, 31(3), 331-336. • Shilder, CM et al (2010). Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. Journal of Clinical Oncology, 28(8), 1294-1300. • Silverman, DHS et al (2007). Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated beast cancer survivors 5-10 years after. Breast Cancer Research & Treatment, 103(3), 303-311. • Wefel, J.S., Kayl, A.E., & Meyer, C.A. (2004). Neuropsychological dysfunction associated with cancer and cancer therapies: A conceptual review of an emerging target. British Journal of Cancer, 90, 1691-1696. • Wong, S.F. (2011). Cognitive Impairment in Cancer Patients. Retreived on May 14th, 2011 from www.swog.org/Visitors/Download/Meetings/Lecture.pdf. • 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.