PHRM 542 Breast Cancer Risk Factors, Screening, and Prevention

What are familial/genetic risk factors for developing breast cancer?

Hereditary = 5-10% of all cases

BRCA1/2 (tumor suppressor gene)

CDH1, PALB2, PTEN, TP53

What are examples of progression genes in breast cancer?

HER2

ER/PR = HR positive

Stage a tumor based on size

T1 = 2 cm (20 mm) or less

T2 = 2.1 cm to 5 cm

T3 = more than 5 cm

T4 = any size that has invaded nearby structures

Describe an N0 tumor

No cancer in the regional lymph nodes

Isolated tumor cells may be present

These are malignant cell clusters no larger than 0.2 mm

Describe an N1mi tumor

Micrometastases are found in lymph modes

Describe an N1, N2, and N3 tumor

Regional lymph node metastases are found

The higher the number, the more lymph nodes that have metastases

Describe stage 0 breast cancer

Ductal carcinoma in situ; noninvasive

No lymph node invasion

No metastases (M0)

Describe stage I breast cancer

Small (≤ 2 cm); confined to the breast

No or limited lymph node invasion (1-3 nodes)

No metastases (M0)

Describe stage II breast cancer

Medium (2-5 cm) or multiple tumors

Lymph node invasion (up to 9 nodes)

No metastases (M0)

Describe stage III breast cancer

Large (> 5 cm) tumor

Extensive lymph node invasion (10+ nodes)

No metastases (M0)

Describe stage IV breast cancer

Any size tumor with any lymph node invasion

Metastatic (M1)

What are risk factors for developing breast cancer?

1. Family history

2. Increasing age

3. Lifestyle factors

4. Reproductive history + endogenous estrogen exposure

5. History of lobular carcinoma in situ

6. Mammographic breast density

7. Prior thoracic radiation < 30 yrs of age

8. Lifestyle

What can decrease the risk of breast cancer?

Menopause before age 45 years

Breast feeding

Healthy lifestyle = exercise and weight control

When are breast cancer risk reducing agents used?

In patients with increased risk of developing breast cancer

What are examples of risk reducing surgery for breast cancer?

Mastectomy

Bilateral salpingo-oophorectomy

What is the Gail model used for?

Mathematical model to determine RR of developing breast cancer compared to an age matched control at 5 years and during life time

Considers age ≥ 35, age at menarche, # of 1st degree relatives with invasive breast cancer, nulliparty, # of previous benign breast biopsies

What is the BRCAPro model used for?

Computer program for calculating an individuals probability of carrying a deleterious mutation of BRCA1, BRCA2, neither or both

What is the CanRisk tool used for?

Models the risk of breast and ovarian cancer on family history and genotypes for variants in BRCA1 and BRCA2

Incorporates variants in other genes, lifestyle, hormonal and clinical features, breast density

What screening tests are recommended for patients at average risk of breast cancer?

Breast Self-Examination (BSE)

Clinical Breast Examination (CBE)

Mammography

What screening tests are recommended for patients at high risk of breast cancer?

Breast Self-Examination (BSE)

Clinical Breast Examination (CBE)

Mammography

Breast MRI

What can be used for breast cancer primary prevention (risk reduction)?

Prophylactic mastectomy

Bilateral oophorectomy

Medications

What medications can be used for breast cancer risk reduction?

Tamoxifen

Aromatase inhibitors

Describe the dosing and duration of tamoxifen for breast cancer risk reduction

20 mg PO daily for 5 years

What population can tamoxifen be used in?

Pre and post menopause

What are notable ADEs of tamoxifen?

Increased endometrial cancer (post menopause)

Increased thromboembolic events (≥ 50)

Hot flashes

Osteopenia

Cataracts

What patients did not have a reduction in breast cancer with tamoxifen use?

Women with BRCA1 mutations

Describe the dosing and duration of raloxifene for breast cancer risk reduction

60 mg PO daily for 5 years

What are notable ADEs of raloxifene?

Hot flashes

Osteopenia

Cataracts

VTE

Describe monitoring for tamoxifen and raloxifene

Annual eye exam

BMD

Annual gynecologic exam

Describe the dosing and duration of exemestane for breast cancer risk reduction

25 mg PO daily for 5 years

Describe the dosing and duration of anastrozole for breast cancer risk reduction

1 mg PO daily for 5 years

What population can raloxifene and aromatase inhibitors be used in?

Post menopause

What monitoring should be done for aromatase inhibitors?

BMD

Lipid panel

In what patients should breast cancer risk reduction be considered?

Age ≥ 35 with ≥ 1 of the following:

-atypical hyperplasia

-age 35-59 years and estimated 5-year risk ≥ 3% by BRCAT or ≥ 5% by IBIS tool

What agent can be used in premenopausal patients for breast cancer risk reduction?

Tamoxifen 20 mg/day

What agent can be used in postmenopausal patients for breast cancer risk reduction?

Anastrozole 1 mg/day

Exemestane 25 mg/day

Raloxifene 60 mg/day

Tamoxifen 20 mg/day

When are raloxifene and tamoxifen contraindicated and why?

Contraindicated in patients with a HX of VTE, PE, stroke, TIA, or clotting disorder due to an increased risk of VTE

What assessment should be performed at baseline prior to starting breast cancer risk reduction therapy and why?

Baseline gynecologic assessment (for intact uterus) to ensure no abnormal bleeding

When should raloxifene be used over aromatase inhibitors?

In postmenopausal women with low bone density

If using an AI, use bone protective agents

What is a relative contraindication to aromatase inhibitors?

History of osteoporosis and bone loss

What agents can be used for hot flashes as a result of breast cancer risk reduction therapy?

Gabapentin, venlafaxine, sertraline, citalopram

Clonidine oral and transdermal, vitamin E

What non-pharm options can be used for hot flashes as a result of breast cancer risk reduction therapy?

Relaxation training, acupuncture, avoidance of caffeine and alcohol, exercise

What is the MOA of tamoxifen?

SERM = blocks the effect of estrogen at the cellular level

What are estrogenic activities of tamoxifen?

Bones, lipids, endometrium

What are antiestrogenic activities of tamoxifen?

Breast and vaginal mucosa

What CYP enzymes mediate tamoxifen's activation to active metabolites?

CYP2D6, CYP2C19, and CYP3A4

When should tamoxifen be used with caution?

CYP2D6 and CYP3A4 inhibitors

What drugs are aromatase inhibitors?

Anastrozole

Letrozole

Exemestane

What is the dose of anastrozole?

1 mg daily

What is the dose of letrozole?

2.5 mg daily

What is the dose of exemestane?

25 mg daily

What is exemestane metabolized by?

CYP3A4

What are notable DDIs with exemestane?

Rifampin, phenytoin, carbamazepine, St. John's wort all decrease exemestane concentration

What is a notable ADE associated with aromatase inhibitors that leads to discontinuation?

Myalgias/arthralgia

Often does not respond to NSAIDs or APAP