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A. Therapy Overview [1,2,28] navigator

  1. Multimodal therapy is recommended for all but earliest stage breast Ca
  2. Surgery - breast preserving surgery versus mastectomy
  3. Radiation Therapy
  4. Adjuvant or Systemic Chemotherapy (chemo)
  5. Hormonal Ablation Therapy
    1. For reducing recurrence in early stage disease
    2. For combination therpay of metastatic disease
    3. For chemoprevention in (high risk) women
  6. Biotherapeutics for diagnosis and treatment
    1. Anti-HER2/neu antibodies (prognostic, therapeutic; see below)
    2. Several vaccines for treatment of breast cancer (Ca) are under development
  7. Control of Specific Complications
    1. Brain metastases
    2. Lung carcinomatosis
    3. Pleural effusion
    4. Bone metastases
  8. Psychosocial Support [3]
    1. Earlier studies suggested benefit on mortality in metastatic Breast Ca
    2. Supportive-expressive group therapy does not prolong survival in metastatic Breast Ca
    3. Supportive-expressive group therapy improves move and perception of pain
    4. Particularly effective on quality of life measures in women who are initially very distressed
  9. Alternative Medicine
    1. Commonly used (~30%) after surgery for stage I/II breast Ca
    2. Alternative medicine use was highest in women with higher education and income
    3. Use of alternative medicine after surgery associated with increased depression, fear of recurrence, lower scores for mental health and sexual satisfaction, more symptoms
    4. Use of alternative medicine appears to be a marker for greater psychosocial distress and worse quality of life
  10. Physical activity after initial therapy appears to reduce risk of breast ca specific death [5]
  11. Treatment of Stage IV disease remains poor, with ~5% long term survival

B. Surgical Therapynavigator

  1. Originally, total radical mastectomy was the major treatment for Stages I, II and III
  2. Goals have been to provide equivalent or better control of disease with better cosmesis
  3. Lumpectomy with Radiation Therapy
    1. Appears to be as good as mastectomy for early disease
    2. Lumpectomy alone has same morality rate as lumpectomy + radiation at 10 years
    3. Concern that radiation confers a small increase in Ca mortality in >60 year olds
    4. Radiation to control local nodal and total ipsilateral breast recurrence
    5. Good cosmesis, requires careful follow-up screening
    6. Unclear if all patients with early stage breast Ca will benefit from radiation
    7. Axillary lymph node (LN) dissection is usually carried out for staging
  4. Axillary Node Dissection (AND)
    1. AND allows staging of tumor only
    2. AND provides no therapeutic benefit
    3. Sampling without full dissection can be helpful in staging with less morbidity
    4. For women with small tumors and negative margins, <5% have positive LN
    5. May provide up to 5% improvement in survival [30]
  5. Simple Mastectomy with Axillary Node Dissection
    1. Does not involve the pectoralis muscles
    2. Prevention of local recurrence
    3. Radiation now recommended for Intraductal breast Ca as adjuvant therapy
    4. Simple mastectomy for confined masses is probably as effective as more extensive surgery
  6. Radical Mastectomy
    1. Halsted Procedure: Complete removal of breast and underlying pectoralis muscles
    2. High rate of morbidity post-procedure due to edema
    3. Long term followup shows similar results for mastectomy and breast conserving therapy (quandrantectomy or lumpectomy + radiation) for tumors <2cm diameter [74,75]
    4. Radical mastectomy is no longer recommended
  7. Mastectomy for prophylaxis in very high risk women reduces breast Ca >90% [37]
  8. Treatment of DCIS
    1. Lumpectomy (± radiation treatment) is now standard treatment
    2. Radiation reduced both recurrent DCIS and invasive ca 35-40% in ipsilateral breast [48]
    3. For margin width >10mm at surgery, radiation did not reduce recurrence risk [49]
    4. For margin width <1mm, radiation reduced local recurrence by ~50% over 8 years [49]
    5. Mastectomies is not necessary for treatment unless margin contains DCIS cells
    6. Axillary lymph node dissection is not required (only ~1% would be positive)

C. Radiotherapy navigator

  1. Radiation Therapy [80]
    1. Reduces risk of local recurrence by ~70% [55]
    2. Associated with 5% overall mortality reduction [80]
    3. Data support use in all intraductal carcinoma
    4. Also recommended for ductal carcinoma in situ (DCIS) with high risk for recurrence
    5. All tumors >5cm or with 4 or more lymph nodes involved should receive radiation
  2. With surgery, survival and local recurrance rates similar to total mastectomy
  3. Radiation Treatments Post-Operatively
    1. Radiation usually given to control local nodal and total ipsilateral breast recurrence [30]
    2. Whole breast radiation (fractionated) traditionally used
    3. Focal irradiation and electron beam radiation being developed [1]
    4. Overall reduction in local recurrence from 27% to 9% at 10 years [55]
    5. Radiation schedule of 40 Gy in 15 fractions provides similar control and tolerability as the standard schedule of 50 Gy in 25 fractions [8]
    6. Lesion-targeted additional 16 Gy radiation (after standard 50 Gy) reduces local recurrence 40-50%
    7. Radiation therapy added to tamoxifen (TAM) in high risk (Stage II or III) and in T1 or T2 LN-negative postmenopausal patients reduced risk of locoregional recurrence ~80% [6]
    8. Improved disease free survival (10 year followup) by 33%
    9. Overall survival at 10 years 37.1% with radiation versus 35.9% without it [55]
    10. In premenopausal women with early LN+ disease, increases survival ~30%
    11. Local ± regional radiation should be considered for all who receive adjuvant chemo
  4. Radiotherapy of Bone Lesions
    1. Metastasis to bone may be presenting symptom in stage IV disease
    2. These metastases are extremely painful
    3. May also cause pathologic fractures and/or hypercalcemia
    4. Radiation therapy directed at lesion can be very effective
    5. Addition of chronic bisphosphonate therapy reduces risk of fractures and new bone mets

D. Adjuvant Chemo [1,11,58,63] navigator

  1. Significant distant recurrence rate over 20 years with initially localized disease
    1. This is highly stage dependent
    2. Also depends on biological markers in individual's tumor
    3. Overall, 15% risk of relapse in Stage I disease
    4. Overall, 30% risk of relapse in Stage II disease
    5. Oncotype Dx 21 multigene assay can aide in relapse risk assessment [30]
    6. Calculation of recurrence risk based on clinicopathological criteria can be done on the Internet at www.adjuvantonline.com [85]
    7. Broad gene expression profiles add prognostic and chemotherapy response predictions to standard clinicopathological risk scores for early breast ca [88]
  2. Adjuvant therapy has been shown to decrease recurrence rates [64]
    1. For Stage II and any high risk (defined above) Stage I
    2. 6-months of FAC or FEC (see below) reduce death rate ~38% over 15 years in age <50 years and ~20% for age 50-69 years [12]
    3. Women <50 years derive 10.3 months more relapse-free and 5.4 months overall survival
    4. Women 50-69 years derive 6.8 months relapse-free and 2.9 months overall survival
    5. Age alone did not significantly impact breast Ca specific (disease free) survival [18,38]
    6. Her2/neu overexpressing breast Ca benefit from 1-year of adjuvant trastuzumab after adjuvant chemo: ~35% reduction in mortality at 2 years [9,10]
    7. Paclitaxel should be included in adjuvant chemo in all HER2+ tumors and in HER2-ER- tumors with positive LN [38]
    8. Weekly paclitaxel is superior to paclitaxel q3 weeks (12 weeks total) and weekly docetaxel on improving progression free survival and mortality [89]
    9. Adjuvant chemo clearly safe and effective in ER-/ERpoor breast Ca for age <70 [11]
    10. Nearly all patients will benefit from adjuvant chemo [8,11]
  3. Six cycles of chemo with multiple agents over 3-6 months recommended
  4. Various different regimens are used, administered every 3-4 weeks
    1. Anthracyclines ± taxanes are generally standard of care
    2. CAF - cyclophosphamide, adriamycin (doxorubicin), fluorouracil (5FU)
    3. CEF - cyclophosphamide, epirubicin, 5FU (currently in favor)
    4. AC ± T - cyclophosphamide with adriamycin, then followed by paclitaxel [1,63]
    5. TAC - docetaxel (Taxotere®), adriamycin, cyclophosphamide [43,44]
    6. Docetaxel followed by CEF (3 cycles each) superior to vinorelbine followed by CEF for LN+ or high risk LN- early stage breast ca [9]
    7. CMF - cyclophosphamide, methotrexate, 5FU (rarely used) [12]
    8. E+CMF - epirubicin followed by CMF (4 cycles each), superior to 8 cycles CMF alone [35]
    9. TAM should always be added to adjuvant chemo in young women with ER+ breast ca [56]
    10. Addition of anti-her2/neu Ab to standard chemo reduces recurrence in HER2+ disease
    11. Tumors with HER2 amplification respond to anthracycline-containing adjuvant chemo (CEF is generally favored); CMF should generally not be used [69]
    12. Patients with positive LN and HER2 amplification (or HER2 normal and ER-) benefit from addition of paclitaxel after 4 cycles of AC adjuvant chemo [38]
  5. Estrogen Blockade Combined with Chemo
    1. Ovarian ablation in premenopausal women
    2. TAM, a selective estrogen receptor (ER) modulator, reduces recurrence and death by ~30% annually in ER+ tumors [12]
    3. Exemestane should be used after 2-3 years of TAM in post-menopausal tumors [7]
    4. These agents are mainly effective in post-menopausal women with ER+ tumors
    5. Only TAM is approved for treatment of breast Ca
    6. Ovariectomy surgically or with medications are required in premenopausal women
  6. Efficacy of Adjuvant Chemo or Hormonal Therapies [8,85]
    1. Current cytotoxic chemo decrease recurrence rates and improve survival
    2. Addition of local radiotherapy to adjuvant chemo also shown to improve survival
    3. Adjuvant chemo reduces recurrence in node negative disease by 10-30%
    4. Adjuvant chemo benefits nearly all early breast Ca patients [8,11]
    5. Women <50-65 years derive greatest benefit from adjuvant chemo [8,18] but age alone is not a contraindication [19]
    6. Usual high doses of adjuvant therapy should definitely be used (especially Stage II)
    7. Chemo for 12 weeks followed by radiotherapy is preferred treatment sequence
    8. Anthracyclines are most beneficial in her2/neu (erbB2) amplified tumors [69]
    9. CEF and TAC are superior to CMF but unclear whether CEF is superior to CAF [50,69]
    10. CEF for 9 cycles (3 weeks/cycle) is superior to and better tolerated than high dose chemo with progenitor cell rescue in Stage II or III disease [60]
    11. TAC is superior to CAF for disease-free and overall survival in operable LN+ breast ca but with increased asthenia, amenorrhea, edema, myalgia, other side effects [44]
    12. TAC (with AC q2 weeks) is superior to CAF for disease-free and overall survival in LN+, ER- breast Ca [68]
    13. TAC and CAF or CEF are reasonable for adjuvant therapy in high risk breast ca [43]
    14. Trastuzumab for 1 year considered in any (especially LN+) HER2+ tumors [9,85]
  7. Neoadjuvant Chemo
    1. Given prior to local surgery and/or radiation to shrink tumor
    2. Increasingly investigated to shrink large tumors
    3. Appears to improve survival particularly in patients with some ER or PR expression [1]
  8. Side Effects of Adjuvant Chemo [63]
    1. Nausea and vomiting - low risk (<5%) of severe symptoms with current treatment
    2. Myelosuppression - low risk (<2%) of severe neutropenia
    3. Increased risk of neutropenia and life-threatening sepsis with TA [76]
    4. Neurologic toxicity - mainly taxanes, both sensory and motor peripheral neuropathy
    5. Weight gain - AC has less weight gain than CMF
    6. Ovarian failure - 40% in women <40 years, 70% in >40 years, after CMF
    7. Cardiac toxicity - mainly doxorubicin, particularly with trastuzumab added
    8. Fatigue - may be severe in 65% of patients
    9. Second cancers - only endometrial Ca risk increased with TAM

E. Systemic Chemonavigator

  1. Often given to women after relapse from hormonal ablation therapy [1,58]
    1. AC ± 5-FU often used primarily
    2. Added paclitaxel or docetaxel to AC has benefit
    3. Bevacizumab (Avastin®) + paclitaxel approved first line therapy in HER2 negative disease [90]
    4. Trastuzumab (Herceptin®) for systemic therapy for tumors overexpressing her2/neu [62]
    5. Additional active agents may be used on relapse
  2. Active Agents
    1. Paclitaxel, docetaxel, doxorubicin (Dox), epirubicin, vinorelbine have good activity
    2. Liposomal dox, gemcitabine also have good activity
    3. Paclitaxel (Taxol®) - used for initial therapy of high risk patients in some centers [52]
    4. Paclitaxel-albumin bound (Abraxane®) - approved for 2nd line metastatic disease [24]
    5. Docetaxel (Taxotere®) - synthetic taxoid, used for relapsed/progressive breast Ca [20]
    6. Other active agents: methotrexate, cyclophosphamide, mitoxantrone
    7. Vinorelbine+platinum+5-FU used when anthracyclines to be avoided [1]
    8. Dox + taxol ± cyclophosphamide increasingly used [52]
    9. Capecitabine (Xeloda®) - oral, 5-FU prodrug, approved for recurrent metastatic Ca [33]
    10. Ixabepilone (Ixempra®) - semisynthetic epothilone, combine with capecitabine [87]
    11. Addition of TAM to chemotherapy usually beneficial
  3. Efficacy of Combination Chemo for Metastatic Breast Ca (see below)
    1. Partial or complete responses occur in >50% of patients with modern therapy
    2. Complete remission (disappearance of all clinical disease) occurs in ~15% of patients
    3. Time to initial response is 4-8 weeks
    4. Median duration of response is 5-13 months
    5. Median survival of responders is 15-33 months
  4. Gene expression profile pretreatment can used to predict response to docetaxel [17]

F. Hormone Ablation Therapy [2,25] navigator

  1. Types of Agents
    1. Aromatase Inhibition - anastrazole, letrozole, vorozole
    2. Estrogen Blockade - TAM (see below), toremifine, raloxifene
    3. Progesterones - megesterol (now second or third line)
    4. GnRH Antagonists - leuprolide and goserelin
    5. Women who relapse on one therapy often respond to a different hormonal ablation
    6. Hot flashes often occur and may be treated as in menopause
  2. Aromatase Inhibitors [21]
    1. Aromatase is enzyme in periphery which converts androgens to estrogens
    2. In postmenopausal women, estrogen is made peripherally (nonovarian) using aromatase
    3. Most breast Ca cells depend on estrogens for growth
    4. Somewhat effective after progression on TAM
    5. Letrozole and anastrozole are more effective first line than TAM
    6. Less thromboemboli and vaginal bleeding than TAM
  3. Anastrozole (Arimidex®) [4,27,61]
    1. Highly selective aromatase inhibitor suppresses estrogen to 1-10% of baseline levels
    2. Effective in advanced as well as early breast Ca
    3. Indicated for first line therapy in Stage IV breast Ca in postmenopausal women
    4. More effective and better tolerated hormonal therapy than progestins and TAM [4,22]
    5. More effective than TAM as adjuvant therapy in postmenopausal women with localized breast Ca [14,22]
    6. Reduced morbidity and mortality in postmenopausal women with early breast ca when given after 2 years of TAM, compared with maintaining TAM [77]
    7. Reduced thromboembolic events, hot flashes, endometrial Ca, vaginal bleeding compared with TAM [61]
    8. No suppression of mineralocorticoid or glucocorticoid activity
    9. Dose 1mg po qd
    10. Fewer endometrial Ca, thromboembolism, hot flashes, weight gain, and vaginal bleeding and discharge compared with TAM
    11. Compared with TAM, reduces bone density, increases fractures [77]
  4. Letrozole (Femara®) [25]
    1. Highly selective aromatase inhibitor, more effective than TAM [21,45]
    2. Following 5 years of TAM therapy, letrozole for a mean of 2.4 years reduced the recurrence of or new primary breast ca compared with placebo by ~40% [29]
    3. Letrozole superior to TAM on mortality and recurrent disease after 5 years [45]
    4. Side effects: musculoskeletal pain, nausea, high cholesterol
    5. Dose is 2.5mg po qd
  5. Exemestane (Aromasin®) [7,23]
    1. FDA approved for postmenopausal advanced breast Ca which has failed TAM
    2. Irreversible aromatase inhibitor derived from androstenedione
    3. Significantly improved disease free survival in post-menopausal women when given after 2-3 years of TAM versus full 5 years of TAM [23]
    4. Dose 25mg po qd
  6. Vorozole (Rivizor®)
    1. Highly selective aromatase inhibitor
    2. Same indications as anastrozole
    3. Not yet FDA approved
  7. Toremifine (Fareston®) [34]
    1. Triphenylethylene derivative, with direct antiestrogenic activty on breast
    2. Agonist activity on endometrium
    3. Dose is 60mg po qd
    4. Side effects similar to TAM
    5. No demonstrable benefit over TAM
  8. Fulvestrant (Faslodex®) [73]
    1. Pure, potent estrogen receptor antagonist
    2. For hormone receptor positive metastatic breast ca in postmenopausal women
    3. Effective after TAM failure
    4. Median time to progression 16.7 months compared with anastrozole 13.6 months
    5. Injection agent 250mg IM monthly
    6. Probably should be used after progression on TAM
    7. Fulvestrant versus TAM for first line treatment is being evaluated
  9. Raloxifene (Evista®) [26]
    1. Nonsteroidal benzothiophene with selective estrogen receptor interactions
    2. Agonist effects on bone and probably vascular endothelium; improves lipid profiles
    3. Antagonist effects on uterus, without causing endometrial hyperplasia or cancer
    4. Reduction in risk of new invasive breast Ca by ~75% over ~3.5 year study [41]
    5. FDA approved for prevention of post-menopausal osteoporosis
    6. Does not cause endometrial problems and therefore may soon be preferred to TAM
    7. Like TAM, increases risk of venous thromboembolism by ~3 fold
  10. Progestins
    1. Examples: Medroxyprogesterone Acetate and Megestrol Acetate (Megace®)
    2. These agents are now third line therapy, used after direct aromatase inhibitors
    3. Also for patients in whom TAM has failed
    4. However, initial response to megestrol (~30%) is similar to that for TAM
    5. Stimulates appatite and causes weight gain; increases thromboembolic risk
    6. High dose megestrol also causes adrenal insufficiency; slow tapers should be used
  11. Goserelin (Zoladex®)
    1. GnRH (LHRH) analogue approved for treatment of advanced breast Ca
    2. Blocks estrogen production; alternative to oopherectomy
    3. Overall, LHRH agonists plus chemo or TAM reduced death or recurrence in ER+ tumors [22]

G. Tamoxifen (TAM, Nolvadex®) [12,34]navigator

  1. Selective estrogen receptor (ER) modulator (SERM)
  2. Mixed antagonist/agonist activity
    1. Specifically blocks ER, antagonistic activity on breast tissue
    2. Agonist (estrogenic) activity on uterus and bone
    3. Improvement in lipid profile similar to estrogen
  3. Utility
    1. TAM strongly recommended for breast ca with ANY level of ER positivity [13,18]
    2. Major utility is in treatment of ER and/or PR positive breast ca of ANY age
    3. Tumors that are ER and PR negative have little or no response (<5%) to TAM
    4. Approved for the treatment as well as the prevention of breast Ca
    5. 5 years of TAM reduces annual death rate ~30% [12]
    6. Reduces recurrence ~40% in patients with DCIS added to lumpectomy + radiation [42]
    7. After >2-5 years, many tumors no longer shrink with TAM
    8. After 2-3 years of TAM, anastrozole [77] or examestane [23] are superior to continued TAM for early disease
    9. Letrozole superior to TAM after 5 years; letrozole now first line [45]
    10. In general, all patients with ER+ or PR+ breast ca should receive TAM, letrozole, or anastrozole for 5 years [45,61,77]
  4. TAM dose 20-30mg po qd for 5 years (or 2 years followed by anastrozole or letrozole) [77]
  5. Side Effects
    1. "Menopausal" symptoms (hot flashes, anovulation, headaches)
    2. About 4X (small) increase in risk of endometrial Ca, usually low grade [46]
    3. Increases risk of uterine polyps, endometrial thickening, uterine dysplasia
    4. Use of TAM requires monitoring for uterine abnormalities (see below)
    5. Also increases thromboembolic risks to ~7% of patients on TAM
    6. Vaginal bleeding occurs in ~2.5% of patients
    7. Moderate thrombocytopenia and leukopenia have been reported, but rarely significant
    8. Raloxifene does not appear to cause uterine abnormalities
  6. Risk of Uterine Ca [46]
    1. Overall, 1.5-4X increased risk of endometrial Ca with use of TAM
    2. Endometrial ca in patients on TAM tend to be high grade and poor prognosis [57]
    3. Prior to treatment, Pap smear, pelvic exam, and careful history should be obtained
    4. Consider screening transvaginal ultrasound
    5. ANY uterine bleeding or discharge must be evaluated
    6. Consider endometrial biopsy in persons with >5mm endometrial thickness

H. Trastuzumab (Herceptin®) [32,72,83] navigator

  1. Anti-HER2/neu monoclonal antibody
  2. 25-30% of patients with metastatic breast ca overexpress her2/neu
  3. Effective in patients with amplification or overexpression of her2/neu
    1. FDA approved for first line therapy of metastatic breast Ca
    2. May be used alone or in combination with paclitaxel (Taxol®) or with AC
    3. Effective as adjuvant therapy in LN+ or LN- disease [9,10]
  4. Efficacy in Metastatic Disease
    1. In recurrent metastatic disease, trastuzumab alone had 15% overall response rate [59]
    2. Combination therapy with trastuzumab increased duration of median response from
  5. 4 months to 13 months (median survival increased from 20.3 to 25.1 months)
    1. One year survival was 68% with chemotherapy alone, 79% with chemo + trastuzumab
    2. Trastuzumab combined with paclitaxel or AC improves mortality, objective response rate, and prolongs disease free interval for first line metastatic breast Ca [62]
  6. Efficacy in Adjuvant Setting
    1. Trastuzumab q3 weeks x 1 year after at least 4 cycles of anthracycline chemotherapy in patients with HER2+ breast Ca reduced cancer related events by ~45% [78]
    2. Trastuzumab x 1 year with paclitaxel both q3 weeks after doxorubicin-cyclophosphamide adjuvant therapy in HER2+ breast Ca reduced disease progression and death 33% [79]
    3. Trastuzumab x 1 year reduced overall mortality ~35% in adjuvant setting [10]
  7. May increase cardiotroxicity associated with athracyclines
    1. Use alone in adjuvant setting reported cardiac problems in ~0.5% of cases [78]
    2. Combination with paclitaxel in adjuvant setting reported heart failure in 4% of cases [79]
  8. Other Side Effects
    1. Chills, fever, asthenia, pain, nausea occurred in 40% of persons at first infusion
    2. About 25% of patients developed diarrhea
  9. Lapatinib (see below) has activity in trastuzumab resistance [84]

I. Metastatic Breast Ca [2] navigator

  1. Metastatic Disease Subdivisions [34]
    1. Indolent Disease
    2. Aggressive Disease
  2. Indolent Disease
    1. Disease-free interval >2 years after initial surgery AND/OR
    2. Soft-tissue, bone or nodular lung metastases AND
    3. Estrogen and/or progesterone receptor positive
    4. These patients have a good response to TAM
    5. After TAM, treat with secondary and then tertiary endocrine therapies
    6. When tumor fails to respond, then given systemic chemo
    7. Systemic chemo with AC or AC + T is usually used first line
    8. Bevacizumab + T approved first line for HER2 normal metastatic breast ca [90]
    9. Trastuzumab should be included first line when her2/neu is overexpressed [62]
  3. Aggressive Disease
    1. Combination therapy is used for metastatic breast Ca [1]
    2. Radiation therapy alone is often effective for one or a few bone lesions
    3. Chemo helps reduce pain and complications
    4. Bevacizumab (anti-VEGF Ab) plus paclitaxel improved progression-free survival versus paclitaxel alone (11.8 and 5.9 months); similar overall survival (~26 months) [86,90]
    5. Hormonal ablation therapy may also be helpful in aggressive disease
    6. TAM has benefits in pre-menopausal women who have had oopherectomy
  4. Relapsed Disease
    1. Docetaxel containing regimens often used
    2. Capecitabine (Xeloda®) approved for recurrent disease; may combine
    3. Carboplatin ± paclitaxel or gemcitabine may be used 2nd line
    4. Lapatinib (Tykerb®) is an oral EGF-R1 and EGF-R2 (HER2/neu) inhibitor [81,84]
    5. Lapatinib + capcitabine increased progression free-survival by 4 months, compared with capcitabine alone in trastuzumab refractory, HER2+ breast ca [81]
    6. Bevacizumab (Avastin®) has good activity with paclitaxel in relapsed breast ca [82]
  5. Bone Metastasis
    1. Extremely painful; pain should be controlled
    2. Bisphosphonate therapy may reduce new bony metastases in patients with breast Ca
    3. For multiple lesions, pamidronate infusions monthly reduces complications and pain
    4. Clodronate (Ostac®) reduces bone pain, hypercalcemia and pathologic fractures [31]
    5. Clodronate also significantly reduced the mortality rate versus standard care alone
  6. Pleural Disease
    1. Pleural effusion is common in advanced breast Ca
    2. Shortness of breath can develop
    3. Drainage of effusions is very effective for eliminating symptoms
    4. Pleurodesis may be carried out for recurrent pleural effusions
  7. High Dose Chemotherapy (HDC)
    1. Compared with 2 years of standard maintenance (CMF) therapy, HDC with stem cell rescue had reduced disease-free and overall survival [54]
    2. Trends to improvement with adjuvant therapy for >10 involved axillary LN found [15,16]
    3. Significant improvement in progression free and overall survival with HDC versus epirubicin/cyclophosphamide then CMF in patients with at least 9 positive LN [39]
    4. Review of early positive trials has shown major design and reporting flaws [51]
    5. HDC is NOT recommended and should be offerred only in experimental setting

J. Chemoprevention [34,36]navigator

  1. TAM for 5 years reduced risk of contralateral breast cancer by 47% [36]
  2. Women at high risk who took TAM (average 3.5 yrs) had 45% decrease in breast Ca [1]
  3. BRCA1/2 Breast Cancer
    1. TAM reduced incidence of ER+ breast cancer in healthy women with BRCA2 mutations by 62% [66]
    2. TAM had no effect on incidence of ER+ breast cancer in healthy women with BRCA1 mutations [66]
  4. TAM reduced risk of fractures, but increased risk of endometrial cancer [1,34]
  5. Raloxifene reduced incidence of new invasive breast cancer by ~55% over 4 year study

K. Follow-Up [67]navigator

  1. Evaluation of efficacy with intensive follow-up evaluations
    1. Overall 5 year mortality following initial surgery in women <71 years ~20%
    2. Overall 10 year mortality following initial surgery in women <71 years ~33% [70]
    3. All patients had no evidence of metastatic disease at initial surgery
    4. No improvement in survival with intensive (versus usual) follow-up
  2. Current Professional Society Recommendations for Followup of Early Stage Breast Ca [31]
    1. intensive monitoring of no benefit
    2. History and physical exam q4-6 months x 1 year, then annu
    3. Chest Radiation and Bone Scan q6 months
    4. Mammography annually
    5. Liver Ultrasound with g-glutamyl transferase and alkaline phosphatase determinations
  3. CA27.29 tumor marker assay is now FDA approved for predicting relapses

L. Survival Ratesnavigator

  1. Stage I - 80-84% [71]
  2. Stage II - 64-71% [71]
  3. Stage III - 48%
  4. Stage IV - 18%
  5. Blacks Versus Whites
    1. Mortality appears to be higher in black patients than in whites
    2. This is likely due to more aggressive tumors in blacks, rather than delayed diagnoses
  6. Overall mortality is 15-20% over 5 years

References navigator

  1. Veronesi U, Boyle P, Goldhirsch A, et al. 2005. Lancet. 365(9472):1727 abstract
  2. Smith IE. 2002. Lancet. 360(9335):790 abstract
  3. Goodwin PJ, Leszcz M, Ennis M, et al. 2001. NEJM. 345(24):1719 abstract
  4. Buzdar A, Howell A, Cuzick J, et al. 2006. Lancet Oncology. 7:633 abstract
  5. Holmes MD, Chen WY, Feskanich D, et al. 2005. JAMA. 293(20):2479 abstract
  6. Fyles AW, McCready DR, Manchul LA, et al. 2004. NEJM. 351(10):963 abstract
  7. Coombs RC, Hall E, Gibson LJ, et al. 2004. NEJM. 350(11):1081
  8. START Trialists' Group. 2008. Lancet. 371(9618):1098 abstract
  9. Joensuu H, Kellokump-Hehtinen PL, Bono P, et al. 2006. NEJM. 354(8):809 abstract
  10. Smith I, Procter M, Gelber RD, et al. 2007. Lancet. 369(9555):29 abstract
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