Table of contents
- 1. Introduction
- 2. Risk Factors:
- 3. Genetics:
- 4. Risk Reduction
- 4.1. Chemoprevention
- 4.2. Prophylactic Surgery
- 5. Staging
- 6. DCIS
- 7. Invasive Breast Ca
- 7.1. Staging
- 7.2. Management
- 8. Adjuvant Therapy
- 8.1. Endocrine Therapy
- 8.2. Adjuvant Chemotherapy
- 9. Metastatic Breast Ca
- 9.1. Therapy
- 9.2. Metastatic Bone Disease
- 10. Follow-Up
- 11. Treatment S/E
.
Source: MKSAP 16
Introduction
- Apart from skin cancer, breast cancer is the most common malignancy among women in US
- 207,090 women in 2010
- 2nd leading cause of cancer-related mortality among women.
- Sites of metastasis:
- Bone (most common)
Risk Factors:
- Older Age, Female sex
- Family history of breast Ca. (Esp of BRCA mutations)
- Higher Estrogen Exposure:
- Nulliparity
- First childbirth > 30yo
- Early Menarche
- Late menopause
- Overweight (post-menopausal)
- Lack of physical activity
- Heavy Alcohol
Genetics:
- BRCA1 BRCA2, p53 mutations.
- 5-10% of women with breast cancer have one of these.
- Ashkenazi Jewish: have high risk of having these.
- Consider doing it in Ashkenazi Jews, esp if family history if breast/ovarian cancer.
- Testing indications are controversial:
- BRCA/p53 testing is controversial, and generally only indicated after a discussion with patient around implications, and done only if likely to be positive: typically strong family history or younger age (<40yo) are indications. (controversial)
- Difficult decision: to test or not. Involve genetics counsellor.
-
USPSTF Guideline - Recommended BRCA1/BRCA2 Gene Mutation Testing Criteria in Women of Non-Ashkenazi Jewish Descent Two first-degree relatives with breast cancer, one at age ≤50yo
A combination of three or more first- or second-degree relatives with breast cancer
A combination of both breast and ovarian cancer among first- or second-degree relatives
A first-degree relative with bilateral breast cancer
A combination of two or more first- or second-degree relatives with ovarian cancer
A first- or second-degree relative with both breast and ovarian cancer
A male relative with breast cancer
Risk Reduction
Chemoprevention
- National Surgical Adjuvant Breast and Bowel Project–Protocol P-1 (NSABP P-1 Trial)
- Randomized pre- and post-menopausal women with increased lifetime risk of breast ca to tamoxifen (20mg/d x5y or placebo).
- Risk determined with Gail Model Score.
- Tamoxifen could reduce risk of breast cancer by 50%.
- placebo: 6% risk of breast ca over that time
- tamoxifen: 3% (ARR: 3%)
- Tamoxifen increases risk of endometrial cancer, but reduces risk of breast cancer. (safer if hysterectomy)
- Increases risk of thromboembolism, cataracts, hot flashes.
- NSABP P-2 Trial
- Used a different SERM (Raloxifene) instead of Tamoxifen.
- SERM: (Differential Estrogen Effects by organ system)
- Raloxifene vs. Tamoxifen
- Breast: Both anti-estrogens
- In uterus Tamoxifen is a pro-estrogen (raises risk of uterine cancer), but raloxifene is not.
- Vascular: Both pro-estrogen in the vascular tree (high thromboembolic risk, but tamoxifen is higher)
- Eyes: Raloxifene has less eye effects (lower risk of cataracts)
- Tested both in women without hx of breast cancer (but at a high risk)
- Found: equivalent efficacy in prevention of breast ca (raloxifene, tamoxifen)
- Bottom line:
- Both tamoxifen and raloxifine reduce the incidence of hormone receptor positive breast ca by about 50%.
- Raloxifene is less effective than tamoxifen in reducing the incidence of non-invasive breast ca.
- Do not translate to a survival advantage.
Prophylactic Surgery
- Typically considered for very high-risk groups:
- BRCA1 mutation has lifetime breast ca risk 50-60%
- Prophylactic Surgeries:
- Bilateral Mastectomy: 90% decrease in risk of breast cancer
- Salpingo-oophorectomy:
- 95% decrease in risk of ovarian cancer
- 50% decrease in risk of breast cancer
- Requires extensive discussion with patient.
Staging
- Stage 0 -> DCIS
- Stage I --> ≤2cm
- Stage II --> <5cm, (+/- ipsilateral mobile nodes)
- Stage III --> Any size, fixed nodes, or extra-axillary
- Stage IV --> Metastasis
DCIS
- Stage 0 ductal carcinoma in situ (DCIS)
- 50,000 cases in US/year
- Does not present with palpable mass, but found on mammogram (calcifications)
- Risk: Can break through walls of duct and become invasive
- Treatment:
- Two options:
- "Breast-conserving" treatment
- Lumpectomy + Radiation Therapy.
- Usually no LN assessment, but if invasive on pathology, must go back and take LNs.
- Mastectomy
- Usually includes a sentinal lymph node biopsy
(done b/c already have access to LN's anyway)
- Usually includes a sentinal lymph node biopsy
- Other Therapies:
- Tamoxifen:
- New: All DCIS now tested for estrogen receptor, and if positive, women can decide to use tamoxifen to decrease their risk even more.
- Aromatase Inhibitors
-
NSABP B-35: Anastrozole
-
- Tamoxifen:
Invasive Breast Ca
- Thought to have broken through the walls of the duct
- Staged 1-4 (Stage 0 is DCIS)
Staging
- Goal: Evaluate tumor size, node involvement, distal spread.
- Staging with Bone Scan and CT Scan:
- Inicated only in: large tumors, palpable lymph nodes, and obvious locally advanced or inflammatory breast ca.
- I.e. if small nodule on screening, and Stage 1 node-negative... generally does not need staging.
Management
- Moved away from more radical, deforming surgeries (more conservative surgeries equivalent)
- Previously: radical mastectomy (all breast tissue + ipsilateral axillary LNs) was standard
- TWO new Options:
- Mastectomy + Sentinel LN evaluation
- Additional radiation: (for possible chest wall involvement)
- ONLY IF: positive margins, inflammatory tissue, >5cm tumors, ≥4 + LNs (2-3 + LN's --> controversial)
- (in this group, radiation can improve survival) [2-3 + LN's --> controversial]
- Additional radiation: (for possible chest wall involvement)
- Lumpectomy + Sentinel LN evaluation + Whole-Breast radiation
- Aka "Breast Conserving"
- Less suitable if
- >5cm (or small tumors on small breast
- Nipple / Areola involvement
- Multicentric tumors
- Scleroderma, SLE, or previous irradiation.
- Sentinel LN Evaluation:
- Replaced axillary LN dissection as standard of care. (avoid lymphedema, etc..)
- Sentinel LN negative: 5-10% chance of other axillary LN involvement.
- If POSITIVE --> Ipsilateral LN dissection
Adjuvant Therapy
Endocrine Therapy
- Presence of hormone receptors = cell dependent on estrogen for growth.
- Anti-estrogens are lethal to these cells.
- Reduces risk of cancer recurrence by 50%
- Magnitude of effect proportional to degree of expression
- Indicated for all patients who are Estrogen or Progesterone positive.
- Premenopausal Women:
- Estrogen produced by ovaries.
- Tamoxifen x 5-10 year course--> blocks effect on cellular receptors.
- Ovarian ablation if tamoxifen is contraindicated!
- (Aromatase inhibitors contra-indicated, but recently looked at for women with ovarian ablation and GnRH agonists + tamoxifen or aromatase inh... research ongoing)
- Post-menopausal Women:
- Estrogen made in fat, muscles through aromatase enzymes (not ovaries).
- Need 5-year course of hormonal therapy.
- Usually 5 years of aromatase inhibitor (shown better than tamoxifen in large clinical trials)
- 5 years of aromatase inhibitor or for an additional 5 years after tamoxifen therapy.
- Patients initial tx with tamoxifen, aromatase inhibitor can be started following 2-3y of tamoxifen use. (to complete 5 years of hormonal therapy).
- Men --> use tamoxifen
- NOTE:
- Tamoxifen S/E:
- Eyes: Cataracts
- Vessels: Thromboembolism, hot flashes
- Uterine: Endometrial cancer
- Aromatase S/E:
- No increased VTE risk.
- No increased endometrial cancer risk.
- Larger loss of bone mineral density/fractures.
- Use bisphosphonates.
- MSK/arthralgia syndrome --> symmetric pain and joint stiffness. (discontinue to resolve).
- Tamoxifen S/E:
Adjuvant Chemotherapy
- HER2/neu patients have poorer prognosis, but derive a greater benefit from chemo.
- Typically needs 3-6mo of treatment with 2-3 agents.
- Others:
- Cyclophosphamide
- Anthracyclines (doxorubicin, or epirubicin)
- Methotrexate
- 5-FU
- Taxanes (docetaxel, paclitaxel)
- S/E:
- Nausea, vomiting, alopecia, peripheral neuropathy (taxanes), fluid retention, allergic reactions, BM suppression,
- Risk of leukemia, MDS, and anthracycline-induced cardiotoxicity.
- Trastuzumab --> monoclonal antibody targeting HER2 receptor fo those that express HER2/neu.
- Women <50yo with LN+ disease --> can benefit
- Give x1 year with or after chemo --> reduces recurrence by 50%.
- 4 large RCTs show benefit.
- Must get LVEF measurements baseline + q3mo with treatment.
- S/E: impair systolic ventricular function, heart failure.
- Cardiotoxicity risk factors: Age >50yo, HTN, previous or concurrent anthracyclines.
- Cardiotoxicity usually reversible (unlike anthracyclines).
Metastatic Breast Ca
Therapy
- Generally incurable, median survival 2 years. (but improving)
- Must establish treatment (toxicity) goals, and discuss advanced directive.
- Workup:
- Critical to establish hormone status of the tumor.
- HER2/neu, ER
- Often need biopsy of recurrence to confirm (may not be same as primary).
- Critical to establish hormone status of the tumor.
- Management principles:
- NO surgery or radiation to primary site unless symptoms.
- Surgical resections of metastasis in breast cancer = NO survival benefit (unlikel colon ca).
- Systemic therapy is cornerstone or tx!
- Hormonal
- If Premenopausal:
- Tamoxifen
- Ovarian ablation (especially if tamoxifen not used due to thrombosis etc.)
- If Postmenopausal:
- Aromatase Inhibitor
- If Still progressing, 2nd line:
- Exemestane (Aromatase inh.)
- Fulvestrant (Estorgen receptor down-regulator)
- If Premenopausal:
- Trastuzumab: if HER2/neu+
- Effective as single agent or combination with endocrine therapy.
- Lapatinib can be added if still progressing (Oral HER1/HER2 tyrosine kinase inhibitor)
- S/E: dermatitis, diarrhea, and rarely cardio/hepatotoxicity.
- Single-Agent Chemothreapy:
- For: Triple-negative or refractory to endocrine therapy
- Adding other agents = more toxicity, unchanged survival.
Metastatic Bone Disease
- IV bisphosphonate (pamidronate or zoledronic acid) or a receptor activator of NF kappa B inhibitor)
- Decreases pain, fractures, and need for radiation therapy.
- Adjust for renal failure.
- Dental evaluation before + during treatment to prevent osteonecrosis of jaw.
- (if develops osteonecrosis of jaw: do not resume bisphosphonates)
Follow-Up
(ASCO guidelines)
- Regular Breast Exams (from q3-6mo to q1y)
- Do own breast exam
- Mammogram q1y
- (No role for MRI unless high risk (BRCA, etc..)).
- (No role to follow tumor markers)
Treatment S/E
- Low estrogen states (weight loss, decr. libido, osteoporisis, etc..)
- Can use topical estrogen (not studied if goes systemic)
- Can (in very rare cases) use systemic estrogen (esp if no recurrence in pregnancy - high est state).
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