Primary Care of the Breast Cancer Survivor. Case Presentation. Case Presentation (cont) Case Presentation (cont) Breast Cancer

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2 Primary Care of the Breast Cancer Survivor Janet P. Pregler, MD Professor of Clinical Medicine Director, Iris Cantor UCLA Women s Health Center Case Presentation B.C. is a 58 year-old African American woman who presents for initial history and physical examination, having recently moved to Southern California from Illinois. She reports she was treated for a right breast cancer detected by mammography 5 y ago. She underwent a lumpectomy with sentinel node evaluation, which was negative. She had postoperative radiation. She was initially treated with an aromatase inhibitor, but stopped because of joint aches. She currently has complaints of hot flashes, irritability, diffuse muscle aches, and vaginal dryness Case Presentation (cont) Allergies: none Medications: tamoxifen Previous medical history/social history: as above, and s/p hysterectomy for uterine fibroids at age 37, ovaries intact Family history: father had myocardial infarction (MI) at age 62, mother died of CVA at age 8 Social history: no tobacco, alcohol, drugs Case Presentation (cont) Review of symptoms: As above The patient asks: My oncologist said I would stop tamoxifen after 5 years. Should I stop now? Do I need any other tests or treatments? Do I need a test for the breast cancer gene? Should I have an MRI of the breast with my yearly mammogram? Is there any treatment available for my hot flashes? I saw an ad for a pill for vaginal dryness, should I take it? Breast Cancer 5-year Survival after Breast Cancer Diagnosis in White vs. Black Medicare Beneficiaries Silber JAMA 213 Are African American Women at Special Risk after Breast Cancer Diagnosis? 8.% 7.% 6.% 5.% 4.% 3.% 2.% 1.%.% White Black Statistically significant difference, median survival 34 months less for demographics-matched black compared to white patients

3 Analysis of Disparities in Breast Cancer Survival Between Black and White Medicare Beneficiaries After adjusting for socioeconomic status, the hazard ratio for breast cancer mortality was no longer significant Black women waited longer for treatment, and were more likely to receive no treatment or no treatment except breast-conserving surgery. Analysis found they had less frequent mammograms, and less evidence of receiving continuity primary care Most of the difference in 5-year survival was attributed to differences in breast cancer presentation and co-morbidities Black women were diagnosed with more advanced stage disease with more adverse biological features Black women had more comorbid conditions and poorer health Potentially important data elements, including use of endocrine therapies, and characteristics to identify triple negative tumors were not available Silber JAMA 213 Adjuvant Therapy Update Aromatase Inhibitors and Tamoxifen Androstenedione Testosterone Peripheral tissues: subcutaneous fat, liver, muscle, brain Aromatase Breast carcinoma tissue Estrone Estradiol Effect of Switching from Tamoxifen to Exemestane on Disease-Free Survival -5-1 % Change Relative Risk Reduction -32 Absolute Risk Reduction -4.7 Local or metastatic recurrence, contralateral breast cancer, death % Change Adapted from: Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 23; 348: [Evidence Level C] Coombes RC, Hall E, Gibson LJ, et al. NEJM 24; 35: 181. Aromatase Inhibitors for Breast Cancer: Take Home Message Background: Adjuvant Treatment of Breast Cancer with Tamoxifen Aromatase inhibitors increase the risk of osteoporosis and osteoporotic fracture Baseline bone density testing should be performed on women starting aromatase inhibitor treatment Bisphosphonates are the preferred treatment for osteoporosis in breast cancer survivors Tamoxifen is a selective estrogen receptor modulator that decreases recurrence and increases survival in women with estrogen receptor positive tumors Based on data from previous trials, 5 years of treatment has been standard The American Society of Clinical Oncology recommends adjuvant treatment with tamoxifen for premenopausal women with estrogen receptor positive tumors, and postmenopausal women with estrogen receptor positive tumors who are unable to tolerate aromatase inhibitors Recognized significant risks are increased incidence of pulmonary embolism and endometrial cancer Barstein J Clin Oncol 21

4 ATLAS: Effect of Continuing Adjuvant Tamoxifen for 1 years Davies Lancet 213 Implications: Two Large Trials Reported in 213 Showed Benefit for Continuing Adjuvant Tamoxifen for 1 Years # pts Tamoxifen x 5 yrs Tamoxifen x 1 yrs Continuing tamoxifen for 1 years should be considered for women who have completed 5 years of adjuvant therapy for breast cancer Aromatase inhibitors, with or without sequential tamoxifen, remain the preferred adjuvant treatment for postmenopausal women Many women who begin adjuvant tamoxifen prior to menopause will become menopausal over the course of the first five years of treatment. The optimal approach to such women is not clear. Continued care or reconsultation with an oncologist is recommended. 1 Recurrence Breast Cancer Mortality Overall Mortality Statistically significant difference N= 6846 Internists should remain alert for signs and symptoms of uterine cancer (vaginal bleeding) and venous thromboembolism in women taking tamoxifen Barstein J Clin Oncol 21 Primary Care of the Breast Cancer Survivor Evidence-Based Guidelines From the American Society of Clinical Oncology (ASCO) American Cancer Society / American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline History and physical examination every 3 6 mo for 3 y, then every 6 12 mo for 2 y, then annually Yearly mammography of the contralateral breast Mammography of the affected breast, if treated with breastconserving surgery, 6 mo after completion of radiation therapy, then annually DEXA scan every 2 years if on aromatase inhibitor, premenopausal on therapy associated with premature menopause, or other usual indication Instruct women taking tamoxifen to report vaginal bleeding, annual gynecological assessment Consideration of BRCA testing/genetic counseling Source: Runowicz, et al. CA Cancer J Clin 215, cacancerjournal.com American Cancer Society / American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline: Patient Counseling/Monitoring American Society of Clinical Oncology Guidelines 212: Who to refer for testing Signs and symptoms of recurrence Adherence to adjuvant endocrine therapies Evaluation and management of Lymphedema: Consider targeted PT/OT/Lymphedema specialist Cardiotoxicity: Monitor for CHF symptoms, standard risk reduction strategies for CAD Cognitive impairment Depression/anxiety Post-treatment pain: Physical activity, physical therapy, for neuropathy, consider duloxetine, TCAs and anticonvulsants not consistent effective in RCTs Infertility: Immediate referral Sexual health/menopause symptoms For breast cancer survivors: Known Ashkenazi Jewish heritage Personal history of ovarian cancer, or in any first or second degree relative Any first degree relative with breast cancer before the age of 5 years, or 2 or more first or second degree relatives diagnosed with breast cancer at any age Personal or family history of bilateral breast cancer Family history of male breast cancer Source: Runowicz, et al. CA Cancer J Clin 215, cacancerjournal.com

5 Care for Women with BRCA1/BRCA2 ACS Guidelines: Enhanced Screening for Women at High Risk for Breast Cancer Prophylactic bilateral salpingo-oophorectomy to prevent ovarian and breast cancer Screening MRIrecommended by the American Cancer Society, WITH screening mammography Prophylactic mastectomy? SERMs for women with BRCA2 Recommended for enhanced screening: BRCA 1 or 2 mutation, or first degree relative with BRCA 1or 2 mutation and not tested Lifetime risk of breast cancer 2% or greater Radiation to the chest between the ages of 1-3 years Some very rare genetic syndromes Definition of enhanced screening: Annual screening MRI as adjunct to mammography and clinical breast examination Insufficient evidence for or against addition of screening ultrasound Saslow D. CA Cancer J Clin 27, 57:75., image courtesy of Lawrence Bassett, M.D. ACS Guidelines: Enhanced Screening for Women at High Risk for Breast Cancer Treatment of Menopausal Symptoms and Breast Cancer For women who do not meet criteria listed above for enhanced screening, ACS makes the following statements: Recommended against annual screening MRI: Lifetime risk of breast cancer < 15% Insufficient evidence for or against annual screening MRI: Lifetime risk of breast cancer 15-2% Personal history of breast cancer, DCIS, LCIS, ADH, ALH Dense breast tissue HABITS (hormonal replacement therapy after breast cancer- is it safe?)- Breast Cancer Survivors with Menopausal Symptoms Factors Associated with Successful Discontinuation of Hormone Therapy Newton J Women s Health Hormone therapynon-hormonal symptomatic therapy Breast cancer events RH= 3.3, CI Trial stopped early by DSMB Survey of 1,358 women on HT at Group Health, Washington State, Harvard Vanguard Medical Associates in Massachusetts, 82 attempted discontinuation, mean age 57 years, 91% white Factors associated with successful discontinuation: Doctor s advice OR 2.62 Lack of symptom improvement with HT OR 4.21 Vaginal bleeding OR 5.96 Learning to cope with symptoms OR 3.36 Factors associated with unsuccessful discontinuation: Trouble sleeping OR.4 Mood swings/depression OR.63 Adapted from Holmberg L. Lancet 24; 363:453 Tapering did not affect discontinuation rates

6 Newly Approved Treatments for Menopausal Symptoms NOT Recommended for Breast Cancer Survivors per FDA 6 s of ly Cognitive Behavioral Therapy Improves Quality of Life for Breast Cancer Survivors with Hot Flashes and Night Sweats Conjugated equine estrogens.45 mg/bazedoxifene 2 mg(duavee ) Estrogen with new SERM, approved by FDA in 213 for treatment of vasomotor symptoms and prevention of osteoporosis in women with a uterus FDA recommendation: Do not use if breast or other estrogen-dependent cancer; breast cancer effects unknown (62 pts studied for 2 years) Ospemiphene 6 mg (Osphena ) SERM approved in 213 by the FDA for treatment of moderate to severe dyspareunia FDA recommendation: Do not use if breast or other estrogen-dependent cancer; breast cancer effects unknown, only 49 patients studied for 12 or more months Boxed warning: risk of endometrial cancer, stroke, DVT FDA 213 Hot Flush Rating Scale Baseline 9 weeks 26 weeks Statistically better mood, sleep, quality of life. No significant difference in hot flash frequency Mann Lancet Oncol 212: 13:39 Usual Care CBT Nonhormonal Pharmaceuticals for Hot Flashes More Effective Than Placebo in Randomized, Controlled Trials: Lowest Effective Dose, non-fda Approved Use Unless Noted Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial Freeman JAMA 211 Venlafaxine XR 75 mg/d (37.5 mg/d also effective) Desvenlafaxine 1 mg/d Paroxetine CR 12.5 mg/d; Paroxetine 1 mg/d; Paroxetine 7.5 mg/ day (FDA approved 213, Brisdelle (R) ) Fluoxetine 2 mg/d Sertraline 5 mg/d Citalopram 2 mg/d Escitalopram 1-2 mg/d Note: There is evidence that SSRIs (paroxetine) may interfere with tamoxifen metabolism, rendering it less effective. Gabapentin 3 mg tid (up to 27 mg/d may increase relief) Pregabalin 75 mg bid Clonidine.1 mg/d Loprinzi Lancet. Guttuso Obstet Gynecol. Loprinzi J Clin Oncol. Stearns JAMA. Kimmick The Breast Journal 26 Pandya Ann Intern Med. Sterns J Clin Oncol 25 Gordon Menopause 26, Speroff Obstet Gynecol 28; Kalay Menopause 27; Freeman JAMA 211; Kelly BMJ 21; FDA 213 Statistically fewer hot flashes than placebo Treatment of Vaginal Atrophy: ACOG Committee Opinion Treatment of Severe Dyspareunia in Breast Cancer Survivors: New Research Goetsch, et al. J Clin Oncol 215 Lubricants- Preferred Eg, KY Jelly, Astroglide, etc, as needed or on a regular basis Replens on a regular basis Local hormone therapies- more effective Per ACOG 216: Data do not show an increased risk of (breast) cancer recurrence Estring insert one q 12 weeks Vagifem 1 ug nightly x 14 d then biw Low dose topical estrogen Cochrane review found? more risk of endometrial hyperplasia, Premarin vaginal cream.5 gm biw studied for one year Per ACOG 214: Progestins not required with local vaginal therapies Avoid systemic therapies, ospemiphene Cochrane Database Syst Rev. 26, 21; FDA 213; ACOG Committee Opinion Summary # ; ACOG Committee Opinion # Women randomized to a compress of 4% aqueous lidocaine to the vulvar vestibule for three minutes just before vaginal penetration or placebo (both groups were given a silicone lubricant to use immediately before vaginal penetration) Women in the lidocaine arm had statistically less pain (median pain score of 1. compared to 5.3 for placebo on a 1 point scale) After open label follow up, 9% reported comfortable penetration, sexual distress scores reduced from a median of 3.5 pre-study to 14 post study, a statistically significant decrease. Of 2 women who were abstaining from intercourse before the study, 17 resumed comfortable penetrative intercourse. No partner side effects were noted At six month follow up, 95% were still using lidocaine, none had been able to discontinue and have acceptable intercourse

7 Common Complementary Treatments for Vasomotor Symptoms Studied in at Least One Randomized, Controlled Trial Treatment of vasomotor symptoms with black cohosh, multibotanicals, soy, hormone therapy, or placebo: Selected results at 3 months compared to baseline 7 Soy Vitamin E Black Cohosh Oil of Primrose Yam Progesterone Dong Quai Red Clover Ginseng Acupuncture Baseline Placebo Black cohosh Estrogen # hot flashes Statistically significantly lower than placebo Adapted from Newton KM, Ann Intern Med 26: 145:869 Complementary Treatments for Vasomotor Symptoms Efficacy is similar to placebo Placebo benefit is about 25%-5% reduction in vasomotor symptoms Back to the Future : Anxiolytics for Hot Flash Related Sleep Disturbance % indicating better sleep Zolpidem 1 mg qhs Placebo p <.1 for each week, improvement in sleep-related daytime functioning p<.5 for zolpidem group Adapted from Dorsey CM, Clin Ther 24 An Intensive Behavioral Weight Loss Intervention and Hot Flushes in Women Haung Arch Intern Med 21; 17:161 Conclusions Reductions in weight (OR 1.32, 95% CI per 5 kg decrease), BMI (OR 1.17, 95% CI per 1 point decrease), and abdominal circumference (OR 1.32, 95% CI per 5 cm decrease) were associated with a 1 point improvement in a five point self-reported hot flush scale. Changes in physical activity, calorie intake, blood pressure, and physical and mental functioning were not associated with a change in hot flush symptoms African American women have shorter median survival after breast cancer diagnosis Breast cancer survivors should be followed for local recurrence, which is potentially curable All Ashkenazi Jewish breast cancer survivors, as well as others who fit criteria for testing, should be considered for genetic counseling For most breast cancer survivors, screening MRI and ultrasound are currently NOT recommended. SRIs and gabapentin may offer significant relief from vasomotor symptoms Cognitive behavioral therapy for hot flash symptoms improves quality of life When vaginal lubricants fail to adequately treat dyspareunia, topical estrogen may be considered Topical lidocaine may improve dyspareunia and therefore sexual function for some women