• Information
  1. Introduction
  2. Risk Factors for Breast Ca
  3. Risk Reduction And Prevention
  4. Genetics of Breast Ca
  5. Carcinoma in Situ
  6. Invasive
  7. Screening
  8. Diagnosis
  9. Staging
  10. Prognostic Indicators

A. Introduction

1. Over 200,000 new cases annually in USA alone
   1. Estimated 1998 women with new breast Ca diagnosis: ~178,000
   2. Estimated 1998 men with new breast Ca diagnosis: ~1,600
   3. In 1997, over 44,000 deaths due to breast Ca
2. Over 370,000 new cases of Breast Ca in Europe in 2004; ~130,000 deaths [1]
3. During lifetime, ~11% of women will develop breast Ca
   1. Majority have Stage I, localized disease, and will be "cured"
   2. Over 1 million women have Stage II or III disease; recurrence is major problem
   3. The remainder have metastatic breast Ca (Stage IV)
   4. Median age at diagnosis is ~55 years
   5. ~75% are >50 years at diagnosis
4. Overall, ~75% of breast Ca are cured with current therapy
   1. Early detection and improved therapy including hormonal ablation, biologics
   2. Role of adjuvant therapy in LN-negative Ca being evaluated
   3. Unclear how long the followup period should be after therapy
   4. Late (>10-15 year) apparent recurrences have been reported
   5. Survival rates for Stage III and IV disease are <50% and <20% respectively
5. Breast Ca in Men [2]
   1. ~0.8% of breast Ca are in men, peaks age ~70
   2. Risk Factors: testicular or benign breast disease, family history, Jewish, Klinefelter Syndrome
   3. BRCA2 inovlved in ~10% of cases
   4. 80% are estrogen receptor (ER) positive, 75% progesterone receptor (PR) positive
   5. Prognostic factors and treatment similar to breast Ca in women
   6. Hormone therapy is mainstay of metastatic disease; chemotherapy for relapse
6. Pathogenesis of Breast Ca is Poorly Understood [1,22]
   1. Disease occurs in mammary epithelium
   2. Atypical duct hyperplasia was believed to be metaplastic intermediate but is histologically identical to small foci of ductal carcinoma in situ (DCIS)
   3. DCIS (or lobular CIS) may be precursor lesion but not all CIS progress
   4. Frank invasive carcinoma evolves over years
7. Risk reduction (prevention) is possible and should be considered by all women [3]

B. Risk Factors for Breast Ca [4]

1. Family History
   1. Risk primarily for women with one first-degree relative with breast ca
   2. Risks range from ~2.1X to 13X increased with one first degree relative with breast ca
   3. About 25% of the risk for breast Ca in families is due to heritable factors [5]
   4. Only 11% of women with breast Ca have an affected mother, sister or daughter [6]
   5. Familial Ca syndromes
   6. Expression of mutant BRCA1 or 2 increases risk of breast and ovarian Ca [7]
   7. Mutations in TP53 (p53) gene relatively common in early onset (<30 years) breast Ca [70]
   8. Other familial syndromes (see below)
2. Estrogen [9,11]
   1. Estrogen and metabolites associated with initiation and progression of breast Ca
   2. Activity through nuclear estrogen receptors alpha and beta, and through membrane signaling (kinase) pathways
   3. Age: 6.5X increase in women age 50 or older versus those <50 years
   4. Early Menarche: risk increased 1.2-1.5X by age at menarche <12 versus >13 years
   5. Late menopause: risk increased 1.5-2.0X by menopause 55 or older versus <55 years
   6. Late age at first live birth: risk increased 1.3-2.2X in >30 versus <20 year old mothers
   7. Overweight women produce more estrogen
   8. Elevated serum estrogen levels has 3-7X increased risk versus low levels [10]
   9. Elevated testosterone levels associated with 3.3Xrisk compared with low levels
   10. Black women have a lower frequency of hormone receptor positive tumors versus white
   11. Placental weight >700gm associated with up to 2X risk of breast Ca [8]
   12. Antiestrogenic drugs tamoxifen and raloxifene reduce risk of primary breast Ca to a similar extent [38] with distinct side effect profiles [39]
   13. Raloxifene reduced risk of breast Ca 75% in women with high serum estrogen levels [10]
3. Hormone Repalcement Therapy (HRT) [15,73,74,78]
   1. Breast Ca risk 1.24-3X higher in post-menopausal women on HRT versus non-users
   2. Increased risk with oral or transdermal preparations, estrogen ± progesterone [78]
   3. Major increased risk is for invasive lobular breast Ca [15,74]
   4. Use of conjugated estrogen alone (0.625mg/day) for up to 7 years in women with hysterectomy showed no increase in breast ca, possible slight reduction [24]
   5. Progesterone with estrogen does not reduce the risk of breast Ca in post-menopausal women [15,16] and may increase it [78]
   6. HRT also increases risk of abnormal mammogram necessitating biopsies [73]
4. Oral Contraceptives (OCP)
   1. Low-dose estrogen oral contraceptive pills (OCP) have unclear or low contribution
   2. Second and third generation OCP have lower or no increased risk in women with family history [13]
   3. Case-control study confirms no increased risk of breast Ca with ANY OCP use [14]
5. No increase in risk in women whose pregnancies end in spontaneous or induced abortion [85]
6. Lifestyle [3]
   1. High fat diet is most likely a risk for breast Ca
   2. Anorexia and severe caloric restriction associated with reduced breast Ca risk [84]
   3. Increased fruit and vegetable use not associated with reduction in breast Ca risk [17]
   4. Decreased exercise level is a risk
   5. Increasing exercise reduces risk of breast Ca ~20%
   6. Slightly increased risk (~1.5X) of breast Ca with increasing alcohol intake [19]
   7. Increasing risk with increased body weight
   8. Caffeine intake is not associated with breast Ca risk
7. Benign Breast Disease [20,22,92]
   1. Nonproliferative changes on biopsy: 1.27X risk
   2. Proliferative changes without atypia: 1.88X risk
   3. Proliferative changes with atypia: 4.0-4.4X risk
   4. Family history of breast cancer was a risk independent of biopsy findings
   5. In women with nonproliferative changes but no family history, there was no increased risk
   6. Relative risks are determined based on a cohort without benign breast disease findings
8. Breast Implants [82]
   1. May reduce sensitivity of self-exam screening for breast Ca
   2. Appear to reduce sensitivity of screening mamography
   3. No effect on false positive rate or prognostic variables in breast Ca
9. Antibiotic use associated with 1.4-2.1X increased risk of breast Ca [83]
10. History of Carcinoma in Situ (CIS) [86]
    1. Risk of subsequent invasive breast Ca after ductal CIS was 4.5X
    2. Risk of subsequent invasive breast Ca after lobular CIS was 4.0X
11. Radiation without chemotherapy for Hodgkin's Lymphoma in young women [77]
12. Prediction of Breast Ca Risk [4]
    1. Several equations are available for calculating risks
    2. Most easily calculated using program available from National Cancer Institute
    3. See web site: http://cancernet.nci.nih.gov/h_detect.html

C. Risk Reduction And Prevention

1. Lifestyle
   1. Exercise associated with 14-33% risk reduction in postmenopausal women [80,81]
   2. Maintain normal body weight (BMI<25kg/m2)
   3. Dietary fat intake should be low to moderate
   4. Increased duration of breast feeding associated with substantially reduced risk [25]
2. Mastectomy [7]
   1. Should be considered in women with BRCA1 or BRCA2 mutations, reduces risk >90%
   2. Total mastectomy with nipple reconstruction preferred over subcutaneous mastectomy
3. Bilateral Oopherectomy
   1. Goal is estrogen ablation in general population
   2. This provides a moderate reduction of risk (~20%)
   3. Prophylactic bilateral salpingo-oopherectomy in women with BRCA1 or 2 mutations Reduces risk of ovarian Ca >80% [100] and breast Ca >50% [27]
4. Tamoxifen (TAM) [3]
   1. Selective estrogen receptor modulators (SERMs) preferred in high risk patients
   2. 30-50% reduction for new breast Ca (mainly ER+) when given over 4 years [28]
   3. Reduced risk of breast ca in contralateral breast in BRAC1/2+ Ca [29]
   4. Reduced incidence of ER+ breast Ca in healthy women with BRCA2 mutations 62% [30]
   5. No effect on incidence of ER+ breast Ca in healthy women with BRCA1 mutations [30]
   6. Increased endometrial hyperplasia, frank endometrial Ca, thromboembolic events [28]
   7. Associated with overall increased mortality risk, mainly due to clots [28]
5. Raloxifene (RAL) [3,31]
   1. ~45-75% reduction in breast Ca over 4-8 years [31,77,101]
   2. No effect on primary cardiac events, but slightly increased stroke [101]
   3. Increases bone density, reduces fractures [101]
   4. Does not cause endometrial hyperplasia or Ca [39]
   5. Increased deep venous thrombosis (DVT) risk 44% versus placebo
   6. Slightly higher non-significant risk of non-invasive breast ca than TAM in 4-5 year prevention trials (STAR 1 and 2) [38,77]
   7. RAL had lower uterine ca, DVT, pulmonary embolism, cataracts, than TAM [39,98]
   8. Consider SERMs (mainly RAL) for all post-menopausal women at increased risk
6. ASA use associated with 25% reduced risk of ER+ or PR+ breast Ca [87]
7. In general, women with relative risk >1.66X general population should consider TAM if clot risk is acceptable (or RAL, though data are not yet complete on RAL)

D. Genetics of Breast Ca [1,32]

1. Genetic Pathways in Breast Ca
   1. All breast Ca have multiple somatic abnormalities
   2. Familial breast Ca are associated with specific germline mutations
   3. BRCA1 mutations in ~50% of familial breast Ca
   4. Rare, high penetrance BRCA1 or 2 mutations found in 12% of familial breast ca [21]
   5. Similar clinical outcomes with BRCA1 or 2 mutations versus other breast ca [36]
   6. Both somatic and germline p53 (TP53) mutations including rare familial breast ca [21]
   7. Her2/neu is a growth factor receptor involved in autocrine cancer cell growth
   8. Her2/neu amplification in ~25%, associated with aggressive, often ER- tumors [35]
   9. CHEK2 mutations found in ~5% of non-BRCA1/2 familial breast ca [21]
   10. Cyclin E overexpression is associated with increased risk of death [33]
   11. Genomic profiling has aided in understanding gene expression changes in spontaneous and familial breast Ca [34]
2. BRCA1 Mutations
   1. BRCA1 is a 1863 amino acid protein involved in DNA repair pathway
   2. BRCA1 mutations in <3% of women with breast Ca, ~1% of DCIS [12]
   3. ~85% of BRCA1 mutated breast ca is ER negative [30]
   4. BRCA1 mutations confer an overall risk of breast Ca of 56-87% and ovarian Ca of 16-60%
   5. In breast Ca patients with strong family history, ~25% have BRCA1 mutations
   6. In women age <35 yrs with breast Ca, BRCA1 mutations occur in ~10%
   7. In women with breast AND ovarian Ca, >13% have BRCA1 mutations
   8. Screening for BRCA1 mutations in the general population is not warrented
   9. African American women have lower incidence of deleterious mutations and higher incidence of sequence variations in BRCA1 and 2 compared with European women [95]
3. BRCA2 [43]
   1. Gene localized to 13q12-q13 codes for 2329 amino acid protein
   2. Required for normal efficient DNA repair, found in complex with BRCA1
   3. Involved in ~15% patients with young onset, familial breast Ca
   4. Found in 2.4% of DCIS [12]
   5. ~75% of BRCA2 associated breast ca is ER+ [30]
   6. Risk of breast Ca with BRCA2 999del5 mutation is 17% at 50, 37% at 70 years
4. Prohibitin Alleles [40]
   1. Chromosome 17q21; common (C) and less common (T) alleles
   2. Function: binding RB family (RB1, p107, p130), blocking E2F transcription, cell cycle
   3. Deletions: familial and sporadic breat cancer
   4. Mutations: T allele of prohibitin lacks G1/S blocking effects
   5. Familial Syndrome: increased risk of familial breast Ca independent of BRCA genes
5. Genetic Syndromes with Increased Breast Ca Risk [70,89]
   1. Li-Fraumeni Syndrome - mutations in p53
   2. Multiple Hamartoma Syndrome - PTEN mutations
   3. Peutz-Jegers Syndrome - STK11 mutations
   4. Ataxia - Telangiectasia - ATM mutations
   5. HNPCC (Muir-Torre) Syndrome - mismatch repair gene mutations
   6. Cowden disease
6. See http://cancernet.nci.nih.gov/genesrch.shtml for genetic testing centers
7. Cancer Information Service (1-800-4-CANCER, 1-800-422-6237) also available

E. Carcinoma in Situ (CIS) [22,42]

1. Epidemiology of Ductal CIS (DCIS) [41]
   1. Most common type of CIS ~70%; around 24,000 new cases per year in USA
   2. Incidence is increasing since institution of routine mammography
   3. Accounts for ~20% of new cases of breast Ca
   4. About 9% of women in autopsy series have DCIS (~1.5 have frank carcinoma)
   5. Carries ~4.5X risk of invasive Ca (in either breast)
   6. BRACA1 or 2 mutations present in ~3% of DCIS [12]
2. Characteristics of DCIS
   1. Mass within ducts, has not yet penetrated basement membrane
   2. DCIS is similar to atypical duct hyperplasia and may evolve to frank invasive ductal carcinoma (IDC)
   3. Bloody discharge from nipple may occur
   4. Diagnosis: palpation (usually ~5mm); calcification (stellate) on mammogram
   5. Surgical biopsy and pathological analyiss required for diagnosis
3. Treatment of DCIS
   1. Lumpectomy with radiation therapy is now standard treatment (without LN dissection)
   2. Radiation reduced both recurrent DCIS and IDC by 30-40% in ipsilateral breast [44,75]
   3. For margin width >10mm at surgery, radiation does not reduce recurrence risk
   4. For margin width <1mm, radiation reduced local recurrence by ~50% over 8 years
   5. Mastectomy is not necessary for treatment unless margin contains DCIS cells
   6. Axillary lymph node dissection is not required (only ~1% would be positive)
   7. Tamoxifen alone or added to radiation therapy after lumpectomy was not beneficial overall in one study [75] but clear benefits in high risk patients with DCIS, particularly ER+ [80]
   8. Variable course of DCIS and 98% 10 year survival rate make optimal treatments difficult
4. Lobular CIS (LCIS)
   1. Usually diagnosed as an incidental finding on biopsy examination
   2. "Indian file" cells around ducts, have not penetrated into ducts
   3. Carries a 4.5X increased risk of IDC in either breast
   4. Therefore, LCIS is considered to be a marker for generalized breast tissue dysplasia
   5. Bilateral mastectomy is sometimes recommended due to high risk of contralateral Ca

F. Invasive (Frank) Carcinoma

1. Histology
   1. Ductal Carcinoma: >80% breast Ca
   2. Lobular Carcinoma: 5-10% of breast Ca
   3. Mucinous Carcinoma: ~3% of breast Ca
   4. Paget's Disease: ~2.5% of breast Ca
   5. Medullary Cancer
   6. Inflammatory Carcinoma: ~2% of breast Ca
2. Ductal Ca
   1. Most common; constant incidence over last 20 years [69]
   2. Early stage disease restricted to ipsilateral breast
   3. Usually best prognosis of common disease types
3. Lobular Ca
   1. Second most common
   2. Incidence rates increasing 1.65X over past 20 years [69]
   3. Usually a marker for bilateral neoplastic breast disease
   4. Bilateral mastectomy is highly recommended due to risk of contralateral neoplasia
4. Mucinous Ca
   1. Ductal type of carcinoma
   2. Approximately 3% of all CAs of breast
   3. Usually slow growing, better prognosis than other ductal Ca
5. Paget's Disease of the Nipple
   1. Nipple proximal ducts involved
   2. Clear cells, called "Paget Cells" found either lining ducts or invading
   3. Highly malignant, aggressive tumor
   4. Mastectomy strongly recommended
6. Medullary Ca
   1. Circumscribed lesions, may become large
   2. Slow growing tumor, low grade infiltration
7. Inflammatory Breast Ca
   1. ~2% of invasive CA
   2. Massive lymphocytic infiltration with marked pain
   3. Breast looks like "Peau-d'Orange" (orange-peel)
   4. Warm, erythematous breast
   5. Poor prognosis: immediate chemotherapy (CAF) then surgery and radiation recommended

G. Screening

1. Most patients still detected when symptoms occur rather than through screening [47,48]
   1. Mammography is the best method for screening currently available
   2. Contrast enhanced MRI should be used for screening in women with high familial breast cancer risk [89,91]
   3. Patients with delays of 3 months or more have 7-12% lower 5 year survival in most studies
   4. Routine screening for BRCA1/2 mutations is not indicated in general population [93,94]
   5. Screening reduces breast ca death ~46% [97]
2. Self Breast Exam
   1. Strongly advocated but reduction in mortality due to this exam is unclear [48]
   2. Exam should include nipple irregularities
   3. At least two positions (arms raised and at sides), in front of mirror should be included
3. Health Care Professional Exam
   1. Clinical examination at least once per year by a health care professional
   2. At least two positions should be done
   3. Should include thorough lymph node examination
   4. Cervical, supraclavicular, infraclavicular, and axillary node palpation
   5. About 13% of breast exams over a 10 year period lead are falsely positive [51]
   6. Either fine-needle aspiration biopsy or ultrasonography for palpable breast abnormality [79]
   7. Diagnostic mammography does not help determine if palpable breast mass should be biopsied [79]
4. Mammography [41,52,53,54,71,104]
   1. Strongly recommend exams every 1-2 years begining at age 49-50
   2. Mortality reduction 25-30% with mammography begun at age 50 years
   3. Trend (19%) mortality reduction with screening begun age 39-41 [52]
   4. Screening for low or average risk women in their 40s is controversial [48,52,55,56,71]
   5. Therefore, each woman should decide when, between ages 40 and 50, to begin [71,104]
   6. High risk patients should have screening exam age 35 and 40, rescreening q1-2 years after
   7. About 23% of mamographic exams over a 10 year period are falsely positive [57]
   8. Overall positive predictive value of initial screening mammography is 3-4% [41,58]
   9. Some benefit to continuing mammography >69 years, particularly in women with higher bone mineral density (thought to reflect estrogen effects) [53,59]
   10. HRT use may reduce sensitivity of mamography [60]
   11. Cancer detection rates in women with first degree relative with breast Ca similar to those in women a decade earlier with no family history [58]
   12. Detection of cancers with mammographic screening associated with reduced risk of distant metastases compared with similar sized tumors discovered otherwise [88]
   13. Mammography for age >50 advocated strongly pending further studies [4,41,54]
   14. Screening mammography is cost effective in women >65 years old without clinically significant comorbidity [23]
   15. Digital and film mammography have similar accuracy overall, but digital is more accurate in women <50 years, with dense breasts, or premenopausal [96]
   16. Extensive (>75%) mammographic density associated with ~4.7X increased odds of breast ca and had poorer detection on mammography [26]
   17. Positive predictive value (PPV) of mammography is 22% in one study [31]
   18. Ultraound plus mammography detects >5 cancers/1000 women but reduces PPV to 11% [31]
   19. Breast implants make diagnosis by both clinical exam and mamography less sensitive
5. Action based on Mammography Screening Results [79]
   1. Suspicious abnormalities or highly suggestive of malignancy: undergo biopsy
   2. Core needle or surgical biopsy may be performed
   3. Need additional imagining evaluation: undergo diagnostic mammography or ultrasonography
   4. Probably benign finding: low risk malignancy, can safely repeat in 6 months
6. Magnetic Resonance Imaging (MRI) versus Mammography [46,90]
   1. Sensitivity is superior to mammography (~90%); specificity 68-88%
   2. Characteristics independent of breast density, tumor type, menopausal status
   3. Does not obviate need for breast biopsy
   4. Screening BRCA1/2 carriers with MRI is superior to mammography, ultrasound, clinical breast examination [89,106] and is cost effective in these patients [99]
   5. Contrast enhanced MRI is now standard screening for BRCA1/2 carriers and other very high risk subgroups [91,106]
7. Metastatic Disease
   1. Bone pain is major symptom (see below)
   2. Lung metastases including lymphangitic spread, pleural effusions
   3. Hypercoagulable state, tumor microemboli
   4. Central nervous system metastases common
8. Serum Markers for Breast Ca
   1. Some breast Ca express: CA-125, carcinoembryonic antigen (CEA), CA-15.3
   2. The CA27.29 antigen is a glycoprotein mainly found on breast Ca cells
   3. CA27.29 can be measured with Truquant BR® and predicts recurrent disease

H. Diagnosis [1]

1. Fine Needle Aspiration or Core Needle Biopsy
   1. Pathological identification of breast Ca cells
   2. Assessment of specific histologic markers for typing breast Ca
   3. Assessment of selected prognostic markers
   4. Ultrasound guidance is being used increasingly
2. Lymph Node (LN) Analysis [61]
   1. Full axillary LN dissection (AND) for pathologic analysis usually done
   2. AND is standard of care with invasive breast Ca and >2.5cm noninvasive tumors [1]
   3. All LN in ipsilateral axilla are examined for tumor cells
   4. Increasingly, molecular markers for breast Ca cells are being evaluated in LN
   5. Immunohistochemistry for cytokeratins AE-1 and CAM 5.2 can detect occult LN metastases and aids in prognostic accuracy, particularly in postmenopausal women [62]
   6. Significant morbidity with increased infections, swelling, pain, nerve damage
   7. Analysis of single sentinal LN may be sufficient for accurate prognosis
3. Sentinel Node Biopsy [18,61,63,76]
   1. Dyes or radioactive tracers injected at breast tumor site localize to single major LN
   2. Single LN is called sentinel lymph node (SLN), which drains area where tracer is injected
   3. Most breast Ca which spread go directly to SLN
   4. In randomized trial, SLN performed as well as AND with less arm pain, mobility, edema [76]
   5. Overall accuracy of SLN ~96%
   6. Sentinal nodes were outside of axilla in ~5% of cases
   7. At trained centers, SLN can be used in place of AND
4. MRI of contralateral breast detects occult disease in 3% of recently diagnosted patients [46]
5. Evaluation of Metastatic Disease
   1. Bone Scan
   2. Chest Computerized Tomogram (CT)
   3. Liver CT Scan
   4. Head CT Scan

I. Staging (Based on TNM System)

1. Tumor (T), lymph node (N), and metastasis (M) are determined
2. Primary Tumor
   1. T0 - no evidence of primary tumor
   2. Tis - carcinoma in situ, DCIS, LCIS, or Paget's disease of the nipple with no tumor
   3. T1 - tumor 2cm or less in greatest dimension
   4. T1mic - microinvasion 0.1cm or less in greatest dimension
   5. T1a - tumor 0.1-0.5cm in greatest dimension
   6. T1b - tumor 0.5-1.0cm in greatest dimension
   7. T1c - tumor 1.0-2.0cm in greatest dimension
   8. T2 - tumor 2.0-5.0cm in greatest dimension
   9. T3 - tumor >5.0cm in greatest dimension
   10. T4 - tumor any size with direct extension to chest wall or skin
   11. T4a - extension to chest wall
   12. T4b - edema (including peau d'orange) or ulceration of skin
   13. T4c - both T4a and T4b present
   14. T4d - inflammatory carcinoma (as defined above)
3. Regional LN
   1. N0 - no regional LN metastasis
   2. N1 - metastasis to movable ipsilateral axillary LN
   3. N2 - metastasis to ipsilateral axillary LN fixed to one another or to other structure(s)
   4. N3 - metastasis to ipsilateral internal mammary LN
4. Distant Metastasis
   1. M0 - no distant metastasis
   2. M1 - distant metastasis (includes metastasis to ipsilateral supraclavicular LN)
5. Stage 0: Tis N0 M0
6. Stage I: T1 (including T1mic) N0 M0
   1. Stage Ia: Tumor size <1cm have 20 year recurrence rate 14%
   2. Stages Ib and 1c: Tumor size 1-3cm have 20 year recurrence rate 31%
7. Stage II
   1. Stage IIA: T0 N1 M0; T1 N1 M0, T2 N0 M0
   2. Stage IIB: T2 N1 M0; T3 N0 M0
   3. Tumor size >3cm have 20 year recurrence rate >50%
8. Stage III
   1. Stage IIIA: T0,1,2 N2 M0; T3 N1,2 M0
   2. Stage IIIB: T4 Any N M0; Any T N3 M0
9. Stage IV - Any T, Any N M1

J. Prognostic Indicators [64]

1. Gross Aspects
   1. Tumor size (primary) - analysis of margins in resected specimen
   2. Lymph Node (LN) involvement (see above)
   3. Extranodal metastases
   4. Bone marrow analysis is experimental but appears
   5. Staging is therefore most comprehensive clinical indicator
2. Grade or Type
   1. Tubular, Papillary, or Typical Medullary good prognosis
   2. CIS better prognosis
   3. Nuclear Grade 1 better; 3 worst
3. Pathology: poorer prognosis
   1. Inflammatory infiltrates
   2. Comedonecrosis: web-like necrotic/fibrotic pattern
4. Estrogen (ER) / Progesterone (PR) Receptors
   1. Best Prognosis with PR+ (~50% of tumors are PR+) and ER+ (~65% of tumors are ER+)
   2. Blacks appear to have more ER- and PR- tumors than whites
   3. R/PR+ tumors show best responses to hormonal agents
   4. Women <35 years old with ER+ tumors have poorer outcomes than older women [65]
5. Proto-Oncogene HER2/neu (cErbB-2)
   1. HER2/neu protein is related to epidermal growth factor receptor
   2. Protein expression associated with good response to chemotherapy
   3. Gene amplification associated with poorer prognosis (increased recurrence)
   4. HER2/neu analysis is superior to S phase fraction and DNA ploidy (see below)
   5. Antibodies to Her2/neu induce a response in patients with overexpressing tumors
6. Gene Expression Signatures [49,66,72]
   1. Primary tumor gene expression profile used to predict clinical outcome
   2. Out of 25,000 genes, 21-130 gene prognosis profiles created
   3. These prognosis profiles were superior to all standard systems, including LN status
   4. Data indicate that primary tumor contains critical metastatic potential
   5. A 21-gene prediction set (Oncotype DX®) can be used for a recurrence score and is an independent prognistic marker in TAM-treated LN-negative breast Ca [37]
   6. The Oncotype DX test reclassifies some patients from high down to low risk, reducing the recommendation for unnecessary adjuvant chemotherapy [49]
   7. A 76-gene signature can be used to predict relapse in LN-negative breast Ca [67]
   8. A 70-gene signature (MammaPrint®) predicts survival in Stage I or II (<5cm) breast Ca [49]
   9. Good concordance (~80%) amongst different gene sets for prognostication [102]
   10. Invasiveness 186-gene signature derived from CD44+CD24- breast ca cells independently associated with overall and disease-free survival in breast and other cancers [103]
   11. Broader gene expression profiles add prognostic and chemotherapy response predictions to standard clinicopathological risk scores [50]
7. Other Markers for Prognosis and Treatment
   1. Generally of limited clinical decision making utility
   2. S phase fraction: low replicative fraction = better prognosis
   3. DNA ploidy: lower ploidy (diploid) = better prognosis
   4. p53 Gene mutation = poorer response to doxorubicin chemotherapy
   5. Cyclin E overexpression associated with 13X risk of death (high versus low levels) [33]
8. Bone Marrow (BM) Aspirates [68]
   1. Breast ca micrometastasis in the BM carries a 2-4X risk for breast ca recurrence/death [27,79]
   2. 30-40% clinically localized breast Ca have BM with cytokeratin positive (epithelial) cells
   3. After 21.5 years, relapse free survival was ~44% of patients with BM micrometastasis compared with 66% of patients without micrometastasis [51]
   4. BM positivity may not always be an independent risk factor for recurrence [66] but large pooled analysis has confirmed its independence [27]
9. Calculation of recurrence risk can be done on internet at www.adjuvantonline.com [45]

References

1. Veronesi U, Boyle P, Goldhirsch A, et al. 2005. Lancet. 365(9472):1727
2. Fentiman IS, Fourquet A, Hortobagyi GN. 2006. Lancet. 367(9510):595
3. Chlebowski RT. 2000. NEJM. 343(3):191
4. Armstrong K, Eisen A, Weber B. 2000. NEJM. 342(8):564
5. Lichtenstein P, Holm NV, Verkasalo PK, et al. 2000. NEJM. 343(2):78
6. Collaborative Group on Hormonal Factors in Breast Cancer. 2001. Lancet. 358(9291):1389
7. Kennedy RD, Quinn JE, Johnston PG, Harkin DP. 2002. Lancet. 360(9338):1007
8. Cnattingius S, Torrang A, Ekbom A, et al. 2005. JAMA. 294(19):2474
9. Clemons M and Goss P. 2001. NEJM. 344(4):276
10. Cummings SR, Duong T, Kenyon E, et al. 2002. JAMA. 287(2):216
11. Yager JD and Davidson NE. 2006. NEJM. 354(3):270
12. Claus EB, Petruzella S, Matloff E, Carter D. 2005. JAMA. 293(8):964
13. Grabrick DM, Hartmann LC, Cerhan JR, et al. 2000. JAMA. 284(14):1791
14. Marchbanks PA, McDonald JA, Wilson HG, et al. 2002. NEJM. 346(26):2025
15. Chen CL, Weiss NS, Newcomb P, et al. 2002. JAMA. 287(6):734
16. Schairer C, Lubin J, Troisi R, et al. 2000. JAMA. 283(4):485
17. Smith-Warner SA, Spiegelman D, Yaun SS, et al. 2001. JAMA. 285(6):769
18. Davidson NE, Morrow M, Kopans DB, Koerner FC. 2005. NEJM. 353(20):2177 (Case Record)
19. Singletary KW and Gapstur SM. 2001. JAMA. 286(17):2143
20. Page DL, Schuyler PA, Dupont WD, et al. 2003. Lancet. 361(9352):125
21. Walsh T, Casadei S, Coats KH, et al. 2006. JAMA. 295(12):1379
22. Arpino G, Laucirica R, Elledge RM. 2005. Ann Intern Med. 143(6):446
23. Mandelblatt JM, Saha S, Teutsch S, et al. 2003. Ann Intern Med. 139(10):835
24. Stefanick ML, Anderson GL, Margolis KL, et al. 2006. NAMA. 295(14):1647
25. Collaborative Group on Hormonal Factors in Breast Cancer. 2002. Lancet. 360(9328):187
26. Boyd NF, Guo H, Martin LJ, et al. 2007. NEJM. 356(3):227
27. Braun S, Vogl FD, Naume B, et al. 2005. NEJM. 35398):793
28. IBIS Investigators. 2002. Lancet. 360(9336):817
29. Narod SA, Brunet JS, Ghadirian P, et al. 2000. Lancet. 356(9245):1876
30. King MC, Wieand S, Hale K, et al. 2001. JAMA. 286(18):2251
31. Cummings SR, Eckert S, Krueger KA, et al. 1999. JAMA. 281(23):2189
32. Haber D. 2000. NEJM. 343(21):1566
33. Keyomarsi K, Tucker SL, Buchholz TA, et al. 2002. NEJM. 347(20):1566
34. Hedenfalk I, Duggan D, Chen Y, et al. 2001. NEJM. 334(8):539
35. Hudis CA. 2007. NEJM. 357(1):39
36. Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. 2007. NEJM. 357(2):115
37. Paik S, Shak S, Tang G, et al. 2004. NEJM. 351(27):2817
38. Vogel VG, Costantino JP, Wickerham DL, et al. 2006. JAMA. 295(23):2727
39. Land SR, Wickerham DL, Costantino JP, et al. 2006. JAMA. 295(23):2742
40. Jupe ER, Badgett AA, Aneas BR, et al. 2001. Lancet. 357(9268):1588
41. US Preventive Services Task Force. 2002. Ann Intern Med. 137(5):344
42. Burstein HJ, Polyak K, Wong JS, et al. 2004. NEJM. 350(14):1430
43. Ryan PD, Haber DA, Shannon KM, et al. 2003. NEJM. 349(11):1076
44. Julien JP, Bijker N, Fentiman IS, et al. 2000. Lancet. 355(9203):528
45. Winer EP, Harris JR, Smith BL, et al. 2007. NEJM. 357(16):1640 (Case Record)
46. Lehman CD, Gatsonis C, Kuhl CK, et al. 2007. NEJM. 356(13):1295
47. Alexander FE, Anderson TJ, Brown HK, et al. 1999. Lancet. 353(9168):1903
48. UK Trial of Early Detection in Breast Cancer Group. 1999. Lancet. 353(9168):1909
49. Marchionni L, Wilson RF, Wolff AC, et al. 2008. Ann Intern Med. 148(5):358
50. Acharya CR, Hsu DS, Anders CK, et al. 2008. JAMA. 299(13):1574
51. Mansi JL, Gogas H, Bliss JM, et al. 1999. Lancet. 354(9174):197
52. Moss SM, Cuckle H, Evans A, et al. 2006. Lancet. 368(9552):2053
53. Humphrey LL, Helfand M, Chan BKS, Woolf SH. 2002. Ann Intern Med. 137(5):347
54. Nystrom L, Andersson I, Bjurstam N, et al. 2002. Lancet. 359(9310):909
55. Miller AB, To T, Baines CJ, Wall C. 2002. Ann Intern Med. 137(5):305
56. Gertzsche PC and Olsen O. 2000. Lancet. 355(9198):129
57. Elmore JG, Barton MB, Moceri VM, et al. 1998. NEJM. 338(16):1089
58. Kerlikowske K, Carney PA, Geller B, et al. 2000. Ann Intern Med. 133(11):855
59. Kerlikowski K, Salzmann P, Phillips KA, et al. 1999. JAMA. 282(22):2156
60. Kavanagh AM, Mitchell H, Giles GG. 2000. Lancet. 355(9200):270
61. McMasters KM, Giuliano AE, Ross MI, et al. 1998. NEJM. 339(14):990
62. Cote RJ, Peterson HF, Chaiwun B, et al. 1999. Lancet. 354(9182):896
63. Krag D, Weaver D, Ashikaga T, et al. 1998. NEJM. 339(14):941
64. Dowsett M. 1998. Lancet. 351(9118):1753
65. Aebi S, Gelber S, Castiglione-Gertsch M, et al. 2000. Lancet. 355(9218):1869
66. Van de Vijver MJ, He YD, Van't Veer LJ, et al. 2002. NEJM. 347(25):1999
67. Wang Y, Klijn JGM, Zhang Y, et al. 2005. Lancet. 365(9460):671
68. Braun S, Pantel K, Muller P, et al. 2000. NEJM. 342(8):525
69. Li CI, Anderson BO, DalingJR, Moe RE. 2003. JAMA. 289(11):1421
70. Lalloo F, Varley J, Ellis D, et al. 2003. Lancet. 361(9363):1101
71. Fletcher SW and Elmore JG. 2003. NEJM. 348(17):1672
72. Huang E, Cheng SH, Dressman H, et al. 2003. Lancet. 361(9369):1595
73. Chlebowski ST, Hendrix SL, Langer RD, et al. 2003. JAMA. 289(24):3243
74. Li CI, Malone KE, Porter PL, et al. 2003. JAMA. 289(24):3254
75. UK Coordinating Committee on Cancer Research. 2003. Lancet. 362(9378):95
76. Veronesi U, Paganelli G, Viale G, et al. 2003. NEJM. 349(6):546
77. Travis LB, Hill DA, Dores GM, et al. 2003. JAMA. 290(4):465
78. Million Women Study Collaborators. 2003. Lancet. 362(9382):419
79. Kerlikowske K, Smith-Bindman R, Ljung BM, Grady D. 2003. Ann Int Med. 139(4):274
80. McTiernan A, Kooperberg C, White E, et al. 2003. JAMA. 290(10):1331
81. Thune IT, Brenn T, Lund E, Gaard M. 1997. NEJM. 336(18):1269
82. Miglioretti DL, Rutter CM, Geller BM, et al. 2004. JAMA. 291(4):442
83. Velicer CM, Heckbert SR, Lampe JW, et al. 2004. JAMA. 291(7):827
84. Michels KB and Ekbom A. 2004. JAMA. 291(10):1226
85. Collaborative Group on Hormonal Factors in Breast Cancer. 2004. Lancet. 363(9414):1007
86. Cuzick J, Forbes J, Edwards R, et al. 2002. Lancet. 360:817
87. Terry MB, Gammon MD, Zhang FF, et al. 2004. JAMA. 291(20):2433
88. Joensuu H, Lehtimaki T, Holli K, et al. 2004. JAMA. 292(9):1064
89. Warner E, Plewes DB, Hill KA, et al. 2004. JAMA. 292(11):1317
90. Bluemke DA, Gatsonis CA, Chen MH, et al. 2004. JAMA. 292(22):2735
91. MARIBS Study Group. 2005. Lancet. 365:1769
92. Hartmann LC, Sellers TA, Frost MH, et al. 2005. NEJM. 353(3):229
93. US Preventive Services Task Force. 2005. Ann Intern Med. 143(5):355
94. Nelson HD, Huffman LH, Fu R, Harris EL. 2005. Ann Intern Med. 143(5):362
95. Nanda R, Schumm IP Cummings S, et al. 2005. JAMA. 294(15):1925
96. Pisano ED, Gatsonis C, Hendrick E, et al. 2005. NEJM. 353(17):1773
97. Berry DA, Cronin KA, Plevritis SK, et al. 2005. NEJM. 353(17):1784
98. Raloxifene for Breast Cancer Prevention. 2006. Med Let. 48(1234):37
99. Plevritis SK, Kurian AW, Sigal BM, et al. 2006. JAMA. 295(20):2374
100. Finch A, Beiner M, Lubinski J, et al. 2006. JAMA. 296(2):185
101. Barrett-Connor E, Mosca L, Collins P, et al. 2006. 355(2):125
102. Fan C, Oh DS, Wessels L, et al. 2006. NEJM. 355(6):560
103. Liu R, Wang X, Chen GY, et al. 2007. NEJM. 356(3):217
104. Qaseem A, Snow V, Sherif K, et al. 2007. Ann Intern Med. 146(7):511
105. Berg WA, Blume JD, Cormack JB, et al. 2008. JAMA. 299(18):2151
106. Warner E, Messersmith H, Causer P, et al. 2008. Ann Intern Med. 148(9):671