Breast

							BREAST CANCER


한림대 강동성심병원 혈액종양내과
       이정애
EPIDEMIOLOGY
• Risk factors
     increasing age: rate slows after menopause
     early menarche, late menopause , nulliparity
     atypical lobular or ductal hyperplasia(benign breast disease)
     early exposure to ionizing radiation
     long-term postmenopausal estrogen-replacement therapy
     alcohol consumption
     family history of breast ca.( most important )
           - 5 to 10% occur in high-risk families
           - familial breast ca. syndrome : breast-ovarian cancer synd
                            Li-Fraumeni synd
                           Cowden's ds
BIOLOGY
 Genetic abnormalities
    (1) familial breast ca
      BRCA1 and BRCA2 germ line mutation
       . 50 to 85 % lifetime risk breast ca, ovarian ca, or both
       . genetic screening and counseling programs are ongoing


   (2) sporadic breast ca
       p53, bcl-2, c-myc, c-myb gene abnormality
       HER-2/neu
DIAGNOSTIC APPROACHES
• Screening by mammography and physical examination
   - early diagnosis
       25 to 30 % decrease in mortality over age of 50 yrs
          & probably in btw age of 40-50 yrs
• American Cancer Society, the National Cancer Institute recommend
    1) annual mammography for > 40 yrs
   2) high-risk families, with BRCA1 or BRCA2 mutant
        : at 25 yrs of age
         or 5 yrs earlier than earliest age at which breast ca diagnosed
             in family member
• Standard method for confirming diagnosis
     fine-needle aspiration or core needle biopsy
THERAPY

1. Primary Breast Cancer

• Local disease without distant spread
   curable with local or regional treatment alone

  but, most pts have subclinical metastasis
   distant metastasis ultimately develop
1) Local and Regional Treatment

  early breast cancer
    lumpectomy
    (wide excision of tumor with preservation of breast)
      with radiotherapy
2) Axillary Lymph-Node Dissection

• standard for invasive or large non-invasive tumors (>2.5 cm)
• Prognosis information
  - recurrence is higher for histologically positive axillary LNs
• responsible for morbidity associated with surgery
• alternative method
    : Sentinel-lymph-node mapping
3) Postop. Adjuvant Therapy
 (1) Chemotherapy
 (2) Hormone therapy
 (3) Radiotherapy

 • Prognostic factors
   Gold Standard
       Axillary lymph node status
       Tumor size
       Histologic subtype, Histologic or nuclear grade
       ER and PgR status
   Potential
       proliferation marker (S-phase fraction, Ki67, TLI )
       c-erbB-2(HER-2/neu)
• Axillary LN status and recurrence rate
          Positive nodes(No.)    10 year recurrence rate(%)
               0                          20
               1-3                        47
               4-6                        59
               7-12                       69
               >13                        87



• Hormone receptor and response to endocrine therapy
               Receptor status     Response rate(%)
               ER -, PR -                10
               ER -, PR +                33
               ER +, PR -                34
               ER +, PR +                74
• Risk categories for pts with node-negative breast ca.


   Factors              Low                Intermediate          High
                (has all listed factors)                  (at least one factor)
   Tumor size          < 1cm                  1-2 cm             > 2 cm
   ER and PgR            +                     -                  -
   Grade               Grade I              Grade 1-2         Grade 2-3
   Age                 > 35 yrs                                 < 35 yrs
(1) Adjuvant Systemic Chemotherapy

• combination chemotherapy
    - more effective than single-drug treatment
    - effects : marked in < 60 yrs ( esp. premenopausal )
    - reduce annual risk of death by 20%

• duration of chemotherapy
  - usually used combination regimens
     : FAC, FEC, CMF ( 6 cycles )
       AC ( 4 cycles )
(2) Adjuvant Hormone Therapy

• Tamoxifen
  - breast ca. is estrogen-dependent
  - antiestrogenic activity mediated by competitive inhibition
      of estrogen binding to estrogen receptors
  - inhibits expression of estrogen-regulated genes including
      growth factors and angiogenic factors secreted by tumor

• reduce recur & death in all age group
  - when to estrogen-receptor-positive tumor
  - when for about 5 yrs, rather than 1 to 3 yrs
     ( for more than 5 yrs is no more effective than for 5 yrs )
     Adjuvant therapy for node-negative breast ca.
           (1998 International Consensus)


Pt group                         Low risk      Intermediate risk   High risk

Premenopausal, ER or PgR +      None or TMF       TMF + CTX        CTX + TMF
                ER and PgR -    NA                NA               CTX
Postmenopausal, ER or PgR +     None or TMF       TMF + CTX        TMF + CTX
                ER and PgR -    NA                 NA              CTX
Elderly                         None or TMF       TMF               TMF

•   ER: estrogen receptor, PgR: progesteron receptor
•   TMF : tamoxifen, CTX : chemotherapy, NA : not applicapable
   Adjuvant therapy for node-positive breast ca.
        (1998 InternationalConsensus)

   Pt group                                  Minimal/low risk
Premenopausal, ER or PgR +                      CTX + TMF
                  ER and PgR -                 CTX
Postmenopausal, ER or PgR +                     TMF + CTX
                   ER and PgR -                 CTX
Elderly                                         TMF
 ER: estrogen receptor, PgR: progesteron receptor
  TMF : tamoxifen, CTX : chemotherapy
(3) Adjuvant Radiotherapy (RT)


   Postmastectomy RT
    - reduces local recur by 50-75%
      but this reduction was not accompanied by increased survival

   so, postop. RT indication
       only for high risk local recur. pts
       - large tumors > 5 cm
       - invading the skin of the breast or chest wall
       - many (> 4 ) positive axillary LNs
Radiotherapy in high risk premenopausal pt.s
4) Preoperative Chemotherapy

  -   large operable tumor
  -   90% of tumor decrease in size by more than 50%
  -   lumpectomy possible
  -   survival benefit : no apparent advantage
                         as compared with postop. chemotherapy


5) Dose-Intensive and High-Dose Chemotherapy Regimens

  - ongoing randomized trial should help to determine the efficacy
2. Locally Advanced and Inflammatory Breast Ca.

1) Stage III breast ca.
     tumor > 5 cm in diameter
     any size with invasion of skin of breast or chest wall
     any tumors with fixed or matted axillary LNs

2) Inflammatory breast ca.
   - should treat with preoperative chemotherapy or hormonal therapy
   - excellent local control achieved in 80 to 90% of pts
      and 30% pts remain free of cancer after 10 yrs
3. Metastatic Breast Cancer

• clinical course is variable
   - large variation in growth rate and responsiveness
       to systemic therapy

• main goals of treatment
   - optimal palliation and prolongation of life

• therapeutic strategy on basis of
     age, disease-free interval, hormone-receptor status,
      and extent of disease
                                                           Metastatic Breast Cancer
1) Hormonal intervention
   - 20 to 35% response to initial hormonal therapy
   - 10 to 20% to second-line
   - 15 to 30% to another

  • Hormonal Therapies for Metastatic Breast Ca.

  Order of Tx.            Premenopausal                   Postmenopausal

  First line      Antiestrogens or ovarian ablation       Antiestrogens
                    (chemical, surgical or postRT)
  Second line     Ovarian ablation after antiestrogens    Aromatase inhibitors*
                  ; antiestrgens after ovarian ablation
  Third Liline     Progestins                              Progestins
  Forth line       Androgens                               Androgens or estrogens


  * Aromatase inhibitor: Formestane, Anastrozole(Arimidex), Letrozole(Femara)
                                             Metastatic Breast Cancer

2) Chemotherapy
 - refractory to hormonal therapy
      40 to 60% response to CMF
 - anthracycline-containing combination superior to CMF
      50 to 80% response to FAC
 - new drugs
    vinorelbine( third-generation vinca alkaloid )
    taxanes (paclitaxel and docetaxel)
 * Combinations of taxanes and anthracyclines
        responses in 40 to 94%
        complete remissions in 12 to 41%
                                              Metastatic Breast Cancer




•   Bone
    - most common site of metastasis
       cause of substantial morbidity, complication

    * Bisphosphonate (pamidronate and clodronate)
        add to chemotherapy or homonal therapy

     - reduce pain and complication
     - prolong survival free of bone-related event
                                                  Metastatic Breast Cancer

3) High-Dose Chemotherapy

I. single cycle of high-dose combination of cytotoxic drug
   (usually alkylating agent)
    bone marrow damage is earliest limiting toxic effect
   - eliminated by reinfusing autologous hematopoietic stem cell

II. 2 to 4 cycles of cytotoxic-drug combination
     at dose higher than usual but not ablate bone marrow

    higher complete remission (40 to 60%)
      15 to 25% free of cancer for 3 to 5 yrs
CHEMOPREVENTION

   • administration of adj. tamoxifen for 5yrs after primary Tx.
      - reduce incidence of contralat. breast ca. by 47%
      - endometrial ca. in twice
      - increase in thromboembolic event
          occured predominantly in older than 50 yrs

         * overall beneficial effect of tamoxifen
               outweighed adverse effect
NOVEL THERAPIES
 • HER-2/neu oncogene overexpressed in 20 to 30%
    - more aggressive
    - more resistant to chemotherapy

 • 13% of metastatic breast ca with HER-2/neu
   - response to monoclonal antibody against
       extracellular domain of HER-2/neu oncoprotein

 • chemotherapy combined with anti HER-2/neu antibody
    - increase response rate & prolongation of survival