Breast Cancer

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

• 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:
   

1. 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]
        
2. 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

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).

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).

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). 
• 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)
  • 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)