Breast Cancer Review 2/3/2018 Mahmoud Charif M.D. Associate Professor of Medicine Division of Hematology & Oncology University of Cincinnati College of Medicine

Outline Pathology Incidence Risk factors Prevention Screening Treatment Localized disease Advanced/metastatic disease

Breast Cancer Pathology Invasive (infiltrating): Ductal: Most common 70+% Lobular Noninvasive, ductal carcinoma in situ (DCIS): No findings on exam Microcalcifications on mammogram Risk of local recurrence, no metastatic potential Aim of treatment: local recurrence prevention, risk reduction

Breast Cancer Burden Most common cancer in the world Leading cause of death in women globally Most common cancer in women in the US: 250,000/year Second leading cause of cancer death in women in the US: 40,000 1 in 8 women will be affected in their lifetime Since 1999 incidence has decreased by approximately 2% per year: Decrease in estrogen use Leveling off mammography effect J Natl Cancer Inst. 2011;103(9):714. CA: A Cancer Journal for Clinicians, 65: 87–108 CA: A Cancer Journal for Clinicians, 67: 7–30

Breast Cancer Screening Screening mammogram: Only routine screening modality ACS: 40-44: ?annual by choice, 45-54 annually, >55: biennial USPTF: every other year age 50-74 Older woman may be screened if life expectancy >10 years No proven benefit to clinical or self breast examination Breast MRI: For patients with lifetime risk >20% Ultrasound: adjunct to mammogram only

Screening Mammogram 15-20% reduction in breast cancer mortality Sensitivity and specificity: 90+ % 1 life saved per 2000 screened for 10 years starting age 40 5 lives saved per 1000 screened for 10 years starting age 50 Overdiagnosis: Up to 1 in 3 breast cancers False positive: 50% of women screened for 10 years will have a false positive result 10% recall rate. Cancer in 5% of recalled Lancet 368 (9552): 2053-60, 2006. Ann Intern Med. 2009;151(10):727. Lancet 2012 Nov 17;380(9855):1778-86. Ann Intern Med. 2011 Oct 18;155(8):481-92. N Engl J Med. 2012 Nov 22;367(21):1998-2005.

Screening Mammogram More than 90% of breast cancers diagnosed by mammogram Palpable mass should be investigated even if negative mammogram Abnormal exam should trigger DIAGNOSTIC mammogram ( includes additional views)

Breast Cancer Risk Factors Female gender BRCA: X 7 (about 5% of breast cancers) Proliferative breast disease : LCIS, ALH, ADH: X 2-4 Age: (continuous risk) Personal history of breast cancer X 2+ Family history (first degree): X 2-3 Breast density on mammogram X >2+ Early menarche <12 Late menopause >55 Age at first birth >30: X 2-3 Race: White > Black (higher mortality in blacks) Postmenopausal obesity Postmenopausal hormonal therapy Alcohol Protective factors Birth to age 49 – 1.9 (1 in 53 women) ●Age 50 to 69 – 2.3 (1 in 44 women) ●Age 60 to 69 – 3.5 (1 in 29 women) ●Age 70 and older – 6.8 (1 in 15 women) ●Birth to death – 12.4 (1 in 8 women) Oophorectomy Breast feeding Parity Exercise Aspirin N Engl J Med. 2016;375(8):794. CA Cancer J Clin. 2017;67(1):7. Cancer Epidemiol Biomarkers Prev. 2004;13(12):2090.

Risk Reduction Bilateral mastectomy: Endocrine blockade therapy: Most effective, only recommended in high risk ie. BRCA patients Endocrine blockade therapy: Age greater than 35 and: LCIS or Atypical hyperplasia or Gail model 5 year risk of 1.7% or more NCCN Guidelines 

Risk Reduction: Tamoxifen/raloxifene Tamoxifen/Placebo Tamoxifen/Raloxifene Risk reduction 50% Similar Cancer reduction 7 cancers per 1000 women over 5 years Fractures 3 fractures per 1000 women Survival No benefit Endometrial cancer 4 in 1000 none Stroke 1 in 2000 less Pulmonary embolus 1 in 3000 Cataract Ann Intern Med. 2013;158(8):604-614.

Risk Reduction: Aromatase Inhibitors Anastrozole/exemestane Postmenopausal women only Invasive cancer 5-8 less cancers in 1000 50-65% reduction Increased: Bone loss: Fractures: 9% vs. 8% Bone pain Vaginal dryness Hypertension Vasomotor symptoms N Engl J Med. 2011;364(25):2381. Lancet. 2014;383(9922):1041.

Locoregional treatment Aim of treatment is locoregional control Early-stage: Less than 5 cm Clinically node-negative Mastectomy alone or lumpectomy followed by radiation Similar local control and long-term survival Radiation reduces local recurrence following lumpectomy Sentinel lymph node biopsy replaced routine axillary dissection Reduced risk of lymphedema with SLN biopsy Lancet Oncol. 2016;17(8):1158. J Clin Oncol 31, 2013 (suppl; abstr 1000)

Adjuvant Systemic Therapy Aim of any systemic therapy is to reduce the risk of systemic recurrence and death Eradicates micrometastatic disease present at diagnosis Risk of systemic recurrence: Lymph node status and number of involved nodes Tumor size Tumor biology: Hormone negative: high risk of recurrence HER-2 positive, high risk for systemic recurrence BUT treatment is very effective Hormone positive: lower recurrence risk but can recur late

Neoadjuvant Therapy: Locally Advanced Large tumors Clinically positive lymph nodes Tumor downstaging to enable surgical resection or breast conservation (lumpectomy) Achievement of pathologic complete response (no tumor at surgery) is associated with improved prognosis

Choice of Adjuvant Systemic Therapy Nearly all hormone receptor positive tumors require endocrine therapy Nearly all hormone receptor-negative tumors require chemotherapy Nearly all HER-2 positive cancers require chemotherapy and anti-HER-2 therapy High-risk hormone positive tumors require chemotherapy: Advanced stage High recurrence risk on genomic testing Prognostic Predictive NSABP B-14

Adjuvant Endocrine Therapy Tamoxifen X 5 years: Reduction in the risk of recurrence at 15 years Reduction in the risk of breast cancer death at 15 years Caution with CYP2D6 inhibitors (SSRIs) venlafaxine OK Aromatase inhibitors for 5 years (postmenopausal only): Further 20+% reduction in the risk of recurrence compared to tamoxifen No benefit in hormone receptor negative disease J Clin Oncol. 2010;28(21):3411. The Lancet Oncology December 2010 2011 Early Breast Cancer Trialists Collaborative Group (EBCTCG)

Adjuvant Chemotherapy Generally for high risk disease: Triple negative HER-2 positive High risk hormone positive Anthracycline based chemotherapy standard treatment Taxanes added about 10% recurrence risk reduction Taxanes without anthracyclines option for low risk or anthracycline contraindication Duration: 12-24 weeks The Lancet 2012 379, 432-444 Jones, S. et al. J Clin Oncol; 2009 Bonadonna G et al. N Engl J Med 1976;294:405-410.

Chemotherapy long-term toxicities Anthracyclines: Irreversible cardiomyopathy, ~ 1% Acute or delayed Leukemia ~ 1% Taxanes: Peripheral neuropathy Lancet. 2012;379(9814):432.

HER-2 Positive Breast Cancer High recurrence risk Adjuvant chemotherapy with trastuzumab (Herceptin) Trastuzumab can cause reversible cardiomyopathy Reduction in recurrence and death compared to chemotherapy alone J Clin Oncol. 2014;32(33):3744.

Metastatic Breast Cancer Goals of therapy: Disease control Palliation of symptoms Prolongation of life Generally not curable Endocrine therapy preferable for hormone-positive disease Tamoxifen, Aromatase inhibitors, Fulvestrant Single agent chemotherapy preferable to combination chemotherapy

Metastatic Breast Cancer Biologic Therapy Anti-HER-2 therapy always in HER-2 positive disease Trastuzumab, pertuzumab Lapatinib: Oral tyrosine kinase inhibitor against HER-2 Targeting hormone resistance: Endocrine therapy plus: MTOR inhibitors CDK inhibitors Bone directed therapy: Bisphosphonates, denosumab, reduces bone events N Engl J Med. 2015;372(8):724.  N Engl J Med. 2012;367(19):1783.  N Engl J Med. 2012;366(6):520. N Engl J Med. 2016;375(20):1925.

Annual mammogram, tamoxifen for 5 years Question 1 38-year-old healthy woman presents for consultation regarding her risk of developing breast cancer, her paternal cousin was diagnosed with breast cancer at age 45 recently. She has no other family history of breast or ovarian cancer. She does not exercise regularly. She recently started drinking 2 glasses of wine every night for her heart health. She has 3 children whom she breast fed for 6 months each. She has never had a breast biopsy. She started menstruating at age 14. Her breast examination is normal. What do you recommend for breast cancer risk reduction: Annual mammogram, tamoxifen for 5 years Anastrozole for 5 years, mammogram every 1-2 years after age 40 Raloxifene for 5 years Reduce alcohol intake, exercise 30 minutes 5 times per week, mammogram every 1-2 years after age 40 Bilateral mastectomy

Answer 1 D Routine mammography is not indicated before the age of 40 Aromatase inhibitors and raloxifene are not indicated in premenopausal women Her risk is not high enough for chemoprevention with tamoxifen Alcohol reduction and exercise can reduce the risk

Discuss discontinuing estrogen replacement therapy Question 2 60-year-old female presents to discuss reducing her risk of developing breast cancer. She is in good health. She started menstruating when she was 11 years old and underwent menopause at 55 and she has been on estrogen replacement therapy since then. Her mother died of breast cancer at age 70 and her sister was recently diagnosed with breast cancer. 5 years ago she had a breast biopsy for a mammographic abnormality which was benign. She had no children. You would recommend which of the following Discuss discontinuing estrogen replacement therapy Discuss therapy with raloxifene Discuss therapy with tamoxifen Discuss therapy with an aromatase inhibitor All of the above

Answer 2 E This patient has multiple risk factors for breast cancer including family history, early menarche, late menopause, history of breast biopsy, nulliparity and estrogen replacement therapy. She would benefit from risk reduction endocrine therapy. Tamoxifen, raloxifene and aromatase inhibitors have been shown to reduce the risk.

Mastectomy, axillary dissection, tamoxifen Question 3 45-year-old lady found to have a 6 mm nodule in the LEFT breast on mammogram. She has no palpable axillary nodes. Biopsy revealed grade 1 invasive ductal carcinoma, estrogen receptor positive, and HER-2 negative. What is the most optimal management: Mastectomy, axillary dissection, tamoxifen Lumpectomy, sentinel lymph node biopsy, radiation, tamoxifen Chemotherapy, lumpectomy, sentinel lymph node biopsy, radiation, tamoxifen Lumpectomy, sentinel lymph node biopsy, aromatase inhibitor Lumpectomy only

Answer 3 B Breast conserving surgery is appropriate in this small tumor, sentinel lymph node biopsy is the standard of care. While chemotherapy may be considered in some early stage high-risk tumors, this is clearly low-risk tumor, and neoadjuvant chemotherapy is not standard. Aromatase inhibitors have no role in the management of a premenopausal woman

Chemotherapy, surgery, aromatase inhibitor Question 4 62-year-old woman presents with a painful 7 cm mass in the LEFT breast with several enlargement matted axillary lymph nodes. Biopsy revealed grade 3 invasive ductal carcinoma, hormone receptor positive, HER-2 positive. CT scan of the chest, abdomen and pelvis and a bone scan showed no evidence of metastases. What is the most optimal treatment: Chemotherapy, surgery, aromatase inhibitor Surgery, chemotherapy, aromatase inhibitor Chemotherapy + trastuzumab, surgery, aromatase inhibitor Chemotherapy + trastuzumab, surgery Surgery followed by adjuvant tamoxifen

Answer 4 C HER-2 positive breast cancer, chemotherapy and anti-HER-2 therapy are standard and are associated with survival benefit. In locally advanced disease neoadjuvant chemotherapy is generally indicated. Adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen is standard in hormone receptor positive cancer