1. BREAST CANCER FOR THE INTERNIST
Rajiv Doddamani
PGY – 3, Internal Medicine
St. Joseph Mercy Ann Arbor

2. Learning objectives Explain the principles of breast cancer screenings
Know when to refer a patient for genetic testing and to a high risk clinic
Describe the goals of chemo-prevention
Be aware of the modalities of local treatment of breast cancer
Know the options of adjuvant systemic therapy and generally when they are used
Understand in general the sequence of therapy for metastatic disease
Be familiar with the principles of survivorship
Why these three are important?
After finishing treatment years out, they are released from oncology and then PCP follows that

3. Overview of breast cancer in the US

5. Screening
Test to detect early stage or pre-cancer lesions in an asymptomatic individual
Test should result in improved disease specific survival
Good example is cervical cancer screening
Screening tests – They are example of secondary prevention
You can ask if a screening test should be more sensitive or specific

6. Screening – Why do we use mammograms for screening?

7. Screening Prevention group Age 40-44 Age 45-54 >55
American Cancer Society
Individualized decision
Annual
Switch to every 2 years or continue annually
ACOG
USPSTF
(Grade C)
Every 2 years (50-74)
(Grade B)
ACR
Different societies have varying recommendations
Why the variations? – Over-diagnosis vs fear of missing any cancer
Why 2 years in age >55 or approximately around the time of menopause – Mammograms will catch indolent breast cancers. Usually after that age, it is much more likely to have HR positive indolent (slow growing) breast cancer than young women. So you don’t one every year. If you have an indolent breast cancer, it is not going to grow rapidly in 2 years to a point where it would cause too much morbidity

8. Screening tools - Mammogram
Single most effective technique to detect breast cancer before it becomes palpable
Overall sensitivity is about 85%
Principle - Low dose X-rays of breast tissue
Diagnostic vs Screening – Primary difference is based on the reason for the exam
Diagnostic mammogram may include additional images
BI – RADS (Breast Imaging Reporting and Data System)

10. Screening
We do not do ultrasounds alone – Very sensitive, not specific
For women with very dense breasts, ABVS (automated breast volume scanner) may be helpful. If you are not sure, contact one of the breast imaging radiologists to discuss if this could help your patient
Scenario: A 38 year-old woman who felt a mass on self-breast exam. A diagnostic mammogram revealed no evidence of disease
Next step: USG guided-biopsy
Mammograms – Very painful
USG – Not specific
ABVS – Automated USG, radiologist reads it

11. High risk populations Known BRCA mutations
Multiple family members with breast and/or ovarian cancer or a male relative with breast cancer
Benign high risk breast lesions - Atypical hyperplasia or LCIS (lobular carcinoma in-situ)
Clinical risk factors
Multiple breast biopsies
Several risk assessment models (Gail, Claus etc)
If they have a known BRCA mutation or >20% lifetime risk based on one of those models, she qualifies for annual breast MRI in conjunction with annual mammogram
No evidence for breast MRI or ultrasound alone
MRI + Mammogram – Will increase sensitivity and specificity
Age, family – Consider various factors and give probability of cancer incidence

12. MKSAP – Question 113
A 34-year-old woman is evaluated for a 4-week history of tenderness in her left lower breast. Her paternal grandmother died of ovarian cancer at age 54 years. There is no family history of breast cancer. She has a 2-cm palpable left lower outer breast mass on exam. The remainder of the examination is unremarkable.
Results of complete blood count and serum chemistry panel are normal. A mammogram shows increased density and calcifications at the site of the palpable mass. Ultrasound examination reveals a 1.9-cm hypoechoic mass. Ultrasound-guided needle biopsy specimens show a high-grade invasive ductal carcinoma, estrogen receptor–negative, progesterone receptor–negative, and negative for HER2 amplification.
Which of the following is the most appropriate initial management?
A Bilateral mastectomy
B BRCA1/2 testing
C Left mastectomy
D Lumpectomy with sentinel lymph node biopsy

13. Who should be tested for BRCA mutations?
Highlights from NCCN guidelines
Family history of known deleterious BRCA 1/2 mutation
Personal history of breast cancer at any age with multiple family members with breast and/or ovarian cancer
Ashkenazi Jewish descent
Young age at diagnosis (<45 years)
Triple negative cancer diagnosed before age <60
Personal history of epithelial ovarian cancer
Men with breast cancer diagnosed at any age
NCCN guidelines have more info

14. Management of high risk patients
BRCA 1 or 2 mutations – Aggressive screening program with annual breast MRI and annual mammogram starting at age 25 OR prophylactic bilateral mastectomy which reduces risk by 90%
Chemoprevention – Use of SERM or aromatase inhibitor to reduce risk of getting breast cancer in patients that are at high risk due to history of AH, LCIS or based on risk model
5 years of therapy
Prevents HR+ breast cancer ( risk by about 50%) and not HR- cancer
No known survival benefit; just reduces the incidence
Tamoxifen, raloxifen or aromatase inhibitors can be used
Ask about HR status
Definition of chemoprevention
Gail model – (Women > 35 yrs with a 5 year breast cancer risk of 1.7%)

15. Flowchart of a patient’s care
Most women present first to radiology for a screening mammogram or to their PCP with a breast finding (lump, discharge, skin change like nipple retraction etc.)
If you have a patient with a breast finding, you must get a diagnostic mammogram, ultrasound and biopsy (if palpable lesion)
From radiology, the patient will usually a surgeon if the biopsy is proven cancer
Surgeon will discuss surgical options
If the surgeon wants to have the patient considered for pre-operative systemic treatment, the patient will be sent to medical oncology
Radiation oncology usually joins the party after surgery. Not all patients get radiation
Multidisciplinary approach for localized (breast) or locally advanced (breast + LNs)
Backbone is surgery
Chemo + RT  To reduce the risk of recurrence

16. Principles of management
Multidisciplinary approach
Surgery is cornerstone
Chemo and RT – To lower risk of relapse
Most important slide

17. Staging

18. Principles of surgery For stages I-III (curative intent)
Crucial role in local control of disease and accurate staging
Breast conservation therapy (BCT) – Lumpectomy (tumor and surrounding tissue removed) plus whole breast radiation therapy
Mastectomy – All breast tissue removed
Sentinel lymph node biopsy is standard unless there is clinically or radiologically (USG) detectable nodal metastasis
Survival is the same with BCT and mastectomy
No survival benefit to prophylactic contralateral mastectomy
SNL – Done during surgery
Once one side breast cancer is managed, is there any role for contralateral mastectomy - NO

19. Principles of radiation therapy
Why? When? Where?
Helps to achieve goal of local control of the disease (reduces locoregional recurrence by 50%)
Axillary radiation
Regional node irradiation
Post mastectomy radiation therapy
Small benefit in survival
Elderly women may be spared
Why – To prevent local relapse
When – After surgery
Where – Mastectomy site + or – locoregional areas

20. Role of systemic therapy
For loco-regional disease, systemic therapy is given in addition (adjuvant or neo-adjuvant) to surgery with a curative intent
For metastatic disease, systemic therapy is mainstay of therapy with a palliative intent
Prolong life expectancy
Improve symptoms
Prevent symptoms from cancer (in asymptomatic individuals)
Immunotherapy – In trials for breast cancer
Targeted therapy – Anti HER2 therapy, CDK 4/6 inhibitors, P13K inhibitors
Endocrine therapy – Tamoxifen, aromatase inhibitors and fulvestrant
Chemotherapy (Neo-adjuvant, adjuvant and palliative)

21. Indications for HER2 therapy
HER – Human epidermal receptor
HER2 overexpression (IHC) or amplification (genetic) is a predictive marker for response to therapy
Prognostic when used in conjunction with ER and PR status
Can be used in neoadjuvant, adjuvant or palliative settings
Trastuzumab (Herceptin) and pertuzumab (Perjeta) and monoclonal antibodies (IV)
Lapatinib is a small molecule inhibitor (oral)
Overexpression of HER2 – Poor prognostic factor
MAB – Bind to extracellular domains
IBs – Smaller molecules that bind to the internal domains eg: tyrosine kinase domain

22. MKSAP - 148
A 43-year-old woman undergoes follow-up evaluation following a recent diagnosis of estrogen receptor– positive, progesterone receptor–positive, HER2-negative, grade 2 invasive ductal carcinoma of the left breast. The patient was treated with surgery, adjuvant chemotherapy, and radiation therapy. This is her first postradiation visit. She currently takes no medications. She is premenopausal.
On physical examination, vital signs are normal. Well-healed incisions of the left breast and left axilla are present. There is no lymphadenopathy and no right breast masses. The remainder of the examination is unremarkable.
Results of a complete blood count and serum chemistry panel are normal.
Which of the following is the most appropriate therapy?
A Exemestane alone
B Tamoxifen alone
C Maintenance chemotherapy with oral capecitabine
D No additional adjuvant therapy

23. Endocrine therapy
Tamoxifen – SERM which blocks ER receptor in breast tissue
Aromatase inhibitors (AIs) – Inhibit aromatase which is needed to convert androgen to estrogen; thus depletes the body of systemic estrogen
Fulvestrant – SERD (selective estrogen receptor down-regulator)
Tamoxifen – Can be used in pre or post-menopausal women, adjuvant setting (5 years) and palliative (continue as long as it works)
Should not take certain SSRIs (fluoxetine) – Interfere with tamoxifen metabolism and reduce its effectiveness
AI – Only for use in post-menopausal women
Fulvestrant – Approved for post menopausal women
Tamoxifen – ER blocker in breast, ER agonist in bone, uterus and CVS tissue. Risk of DVT and endometrial cancer

24. Cytotoxic chemotherapy
Adjuvant and neoadjuvant - Combination
Taxanes
Doxorubicin
Cyclophosphamide
Palliative
Single agent sequential chemo

25. Genomic assays Oncotype DxTM and MammaprintTM
Uses a panel of genes associated with breast cancer tumor behavior to test a patient’s tumor and come up with a risk of recurrence and a benefit to chemotherapy
Spares some patients from getting adjuvant chemotherapy

26. Common toxicities Doxorubicin – Cardiomyopathy
Tamoxifen – Hot flashes, DVT and endometrial carcinoma (post-menopausal women)
AIs – Joint aches, loss of bone density, fatigue, vaginal dryness
Trastuzumab – Generally well tolerated, cardiomyopathy in a small number of patients (reversible on cessation of therapy)
Pertuzumab - Diarrhea
AIs – check DEXA bone scan every 2 years

27. Survivorship
An increasing proportion of cancer patients survive their cancer
Have specific risks related to previous treatments and risks related to other types of cancer as well as unique financial and psychosocial issues
Survivorship care plan is now mandated by the Commission on Cancer

28. MKSAP 126
A 44-year-old woman undergoes follow-up evaluation. Stage I cancer of the left breast was diagnosed 3 years ago (1.4-cm, grade 2 invasive ductal carcinoma, estrogen receptor positive, progesterone receptor positive, HER2 negative, 0/2 positive sentinel lymph nodes, and a low score on 21-gene recurrence score testing). BRCA1/2 testing results were negative. She underwent breast-conserving surgery and radiation therapy and then started tamoxifen. The patient is concerned about her risk of recurrence. Menses are irregular. She has occasional hot flushes and night sweats on tamoxifen but otherwise feels well. There is no family history of breast or ovarian cancer.
On physical examination, vital signs are normal. BMI has remained stable at Well-healed left breast and left axilla incisions are present. There are no breast masses or lymphadenopathy. The remainder of the examination is unremarkable.
Results of a bilateral mammogram obtained 1 month ago were normal.
Which of the following is the most appropriate next step in the management of this patient?
A Bilateral breast MRI
B Complete blood count, liver chemistry studies, and CEA and CA 15-3 measurement
C CT of the chest, abdomen, and pelvis and bone scan
D No diagnostic studies at this time

29. Survivorship Body image issues – Hair, breasts, skin
Mental health – Depression, anxiety related to risk of recurrence, sleep disturbance
Sexual health/function – Loss of interest, loss of libido
Long term SEs from chemotherapy – Neuropathy, cardiomyopathy
Long term SEs from XRT and surgery - Chronic pain, risk of second tumors
Endocrine therapy – Joint pain, weight gain
Preventative care – Immunizations, physical activity, prevention of 2nd primary cancers, bone density

30. Survivorship
Breast exam every 6-12 months and annual breast cancer screening (until life expectancy less than 5 years)
Breast exam – inspection, palpation, nipple examination and regional node exam
Doxorubicin toxicity – Echo q5yrs after chemo
PT/OT for neuropathy
Utilize psychiatry/psychology for mental health issues
Encourage breast cancer support groups for struggling patients
Smoking cessation, limit alcohol intake

31. References
NCCN
UpToDate
MKSAP
ASCO
ESMO