Breast Cancer

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    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:
    1. "Breast-conserving" treatment
    • Lumpectomy + Radiation Therapy.
    • Usually no LN assessment, but if invasive on pathology, must go back and take LNs.
    1. Mastectomy
      • Usually includes a sentinal lymph node biopsy
        (done b/c already have access to LN's anyway)
    • 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

                  

    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:
       
    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

     

    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).

     

    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). 
    • 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)

     

    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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