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

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

3. 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

4. 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

5. Breast Cancer Screening
Screening mammogram: Only routine screening modality
ACS: 40-44: ?annual by choice, 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

6. 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): , 2006.
Ann Intern Med. 2009;151(10):727.
Lancet 2012 Nov 17;380(9855):
Ann Intern Med Oct 18;155(8):
N Engl J Med Nov 22;367(21):

7. 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)

8. 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.

9. 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 

10. 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):

11. Risk Reduction: Aromatase Inhibitors
Anastrozole/exemestane
Postmenopausal women only
Invasive cancer
5-8 less cancers in % 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.

12. 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)

13. 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

14. 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

15. 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

16. 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)

17. 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: weeks
The Lancet  ,
Jones, S. et al. J Clin Oncol; 2009
Bonadonna G et al. N Engl J Med 1976;294:

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

19. 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.

20. 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

21. 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.

22. 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

23. 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

24. 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

25. 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.

26. 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

27. 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

28. 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

29. 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