Radiation Oncology/Breast/Breast overview

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Front Page: Radiation Oncology | RTOG Trials

Breast: Main Page | Staging | Breast Overview | Prevention | Benign | DCIS | LCIS | Paget's | Phyllodes tumor | Early stage | Advanced stage | Post mastectomy | Inflammatory | Partial breast irradiation | Regional lymphatics | Hormonal therapy | Chemotherapy | RT technique | Recurrence | Toxicity of RT | Randomized | NSABP trials

This chapter deals with general concepts of breast cancer treatment, not related to more specific chapters dealing with treatment of different presentations of breast cancer.

Contents 1 Epidemiology 2 Screening 2.1 Mammography 2.2 MRI 3 Pathology 3.1 Infiltrating Lobular Carcinoma 3.2 Special histologic types 3.3 Tissue microarray (TMA) profiling 3.4 Cancer stem cells 3.5 Extensive in-situ component (EIC) 4 Anatomy 5 Natural History 5.1 Tumor Size 5.2 Doubling Time 5.3 LN Status 5.4 Bone Marrow Mets 5.5 Distant Mets 5.6 Untreated Patients 5.7 BRCA Mutations 6 Work-up 7 Prognostic factors 8 Unknown primary with axillary lymphadenopathy 9 Quality of Life 9.1 Hot Flashes 9.2 Exercise

[edit] Epidemiology

• 2007 American Cancer Society PMID 17237035 -- "Cancer statistics, 2007." (Jemal A, CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66.)
  • Incidence: 178,500 (#1 for women, accounting for ~25%)
  • Prevalence: 2,385,000 (#1 for all) - based on NHIS 2003 data
  • Deaths: 40,500 (#2 for women, accounting for ~15%)
• 2002 IARC Worldwide data
  • Incidence: 1,151,000 (#1 for women, accounting for ~23%)
  • Deaths: 411,000 (#1, accounting for ~14%)

• Risk factors
  • Gender: 100x more frequent in women
  • Age: Incidence rises steeply until ~50 (menopause), then more slowly 50-75, then essentially flat 75+
  • Ethnicity: In US, incidence highest in Caucasians (141/100,000), then African-Americans (119/100,000), Asian Americans (97/100,000), Hispanics (901/100,000), American Indians (55/100,000)
  • Breast density: by mammogram
  • Benign Breast Disease: Proliferative with atypia RR 4, proliferative without atypia RR 2, nonproliferative no increase
  • Personal h/o BCA: invasive contralateral risk 1%/year premenopausal, 0.5%/year postmenopausal
  • Family history: age-dependent
  • Genetic mutations: BRCA1/BRCA2, p53 (Li-Fraumeni Syndrome), ATM (Ataxia-Telangiectasia), PTEN (PTEN Hamartoma Tumor Syndrome)
  • Hormone exposure: Age at menarchy, age at menopause, parity, age at first birth, hormone replacement therapy; breastfeeding protective
  • Lifestyle: see Harvard Nurses study below
  • Diet: see Harvard Nurses study below
  • Exposure to RT: Highest risk pre-pubertal, no excess risk after 45

• Risk factors for men
  • Klinefelter's syndrome,
  • Family history
  • Genetic mutations: BRCA2
  • Testicular or liver disease

• Patient age and relation to tumor features - PMID 8164038

• 'Harvard Nurses'' Health Study NHS I (1976 - 1996), NHS II (1989 - )
  • 2005 (Review): PMID 15864280 — "The Nurses' Health Study: lifestyle and health among women."
  • 121,700 women. Designed to test oral contraceptive use on breast cancer. Questionnaire every 2 years.
  • Increased risk:
    • High/moderate alcohol use is associated with the highest increase in risk. Also increases colon cancer risk.
    • Hormone replacement has an increased risk of 1.2 with estrogen only or 1.7 for estrogen + progestin. Increased risk with high hormonal levels of estrogen, testosterone, insulin-like growth factor 1 (IGF1) in pre-menopausal women, and prolactin levels in post-menopausal women.
    • Body-mass index associated with increased risk (but less of a risk factor when increased estrogen levels are factored out).
    • Dense breasts> (assessed by mammography) have higher risk.
  • Past OC use had no increase in risk. Modest increase in risk for current OC users (but very low incidence in this age group). OC use protective against ovarian cancer (persists for many years) and colon cancer.
  • Decreased risk (protective):
    • Folate in diet and higher intake of vegetable fat. No associate with fat intake, meat or fish comsumption.
    • Physical activity results in 20% decrease in risk for 7 or more hours/week vs 1 hour or less/week.

• Tyrer-Cuzick Model (Cancer.org.uk, 2004) PMID 15057881 -- "A breast cancer prediction model incorporating familial and personal risk factors." (Tyrer J, Stat Med. 2004 Apr 15;23(7):1111-30.)
  • Model incorporating BRCA genes, a low penetrance gene, and personal risk factors

• BRCAPRO Model (Duke, 1998) PMID 9443863 -- "Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2." (Parmigiani G, Am J Hum Genet. 1998 Jan;62(1):145-58.)
  • Model for evaluating a probablity that a woman is a BRCA1/BRCA2 carrier
  • Variables: FH of breast and ovarian CA in 1st and 2nd degree relatives. Relationships, ages of onset, and ages of no disease important

• Claus Model (Yale, 1994) PMID 8299086 -- "Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction." (Claus EB, Cancer. 1994 Feb 1;73(3):643-51.)
  • Tables for age-specific risk of BCA in women with FH of BCA

• Gail Model (1989) - PMID 2593165 Full text (PDF) — "Projecting individualized probabilities of developing breast cancer for white females who are being examined annually." Gail MH et al. J Natl Cancer Inst. 1989 Dec 20;81(24):1879-86.
  • Risk factors: age at menarche, age at first live birth, number of previous biopsies, and number of first-degree relatives with breast cancer

[edit] Screening

• US Preventive Services Task Force; 2009 Full Report
  • Age 40-49: No routine screening mammography; decision to start screening should be individual one
  • Age 50-74: Biennial screening mammography
  • Age >=75: Insufficient evidence for mammography
  • Insufficient evidence for digital mammography or breast MRI over film mammography
  • Evidence for additional benefit/harm of clinical examination (in addition to mammography) is insufficient
  • Recommend against teaching breast self-examination

[edit] Mammography

• UC Davis, 2007 (1998-2002) PMID 17409321 -- "Influence of computer-aided detection on performance of screening mammography." (Fenton JJ, N Engl J Med. 2007 Apr 5;356(14):1399-409.)
  • Retrospective. Screening data from 43 facilities and 429,345 mammograms.
  • Implementation of computer-aided detection: specificity decreased 90% to 87% (SS), sensitivity remained unchanged, PPV decreased 4.1% to 3.2% (SS), rate of biopsy increased 20% (SS). No difference in cancer detection rate (4 per 1000 screening mammograms)
  • Conclusion: Computer-aided detection resulted in reduced accuracy. Increased rate of biopsy was not associated with improved detection

• Toronto, 2007 PMID 17229950 -- "Mammographic density and the risk and detection of breast cancer." (Boyd NF, N Engl J Med. 2007 Jan 18;356(3):227-36.)
  • Case-control. 1112 pairs. Evaluated % density and risk of BCA
  • Risk of BCA: low density (<10%) vs. high density (>75%) OR 4.7 (SS), persisted >8 years after study entry
  • In younger women (<56): 26% of BCA and 50% of CA detected <1 year after negative screen were in density >50%
  • Conclusion: extensive mammographic density associated with risk of BCA

[edit] MRI

American Cancer Society Guidelines

• 2007 PMID 17392385 -- "American cancer society guidelines for breast screening with MRI as an adjunct to mammography." (Saslow D, CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89.)
  • Annual Screening (Based on Evidence): BRCA mutatation, 1st degree relative of BRCA carrier, lifetime risk >=20% by models
  • Annual Screening (Based on Expert Opinion): Chest RT age 10-30, Li-Fraumeni syndrome and 1st BCA degree relatives, Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndromes and 1st degree BCA relatives
  • Insufficient Evidence: lifetime risk 15-20%, LCIS/ALH, ADH, dense breasts on mammography, personal history of BCA
  • No MRI Screening: <15% lifetime risk

Of the contralateral breast in women newly diagnosed with breast cancer:

• ACRIN 6667 (2003-4)
  • 969 women. Diagnosed with unilateral breast cancer. Negative mammogram and clinical exam of contralateral breast. Considered positive for cancer if histologic evidence of malignancy within 1 yr of exam.
    • MRI detected occult malignancy of the contralateral breast in 3.1% (30/969). Sensitivity 91%, Spec 88%, NPV 99%. Biopsy for positive MRI finding in 12.5% (121/969); 24% of these were positive (30/121); 18 of 30 were invasive. Mean size of invasive tumors 10.9 mm.
  • Conclusion: MRI can detect cancers missed by mammography.
  • PMID 17392300, 2007 — "MRI Evaluation of the Contralateral Breast in Women with Recently Diagnosed Breast Cancer." Lehman CD et al. New Engl J Med. 2007 Mar 29;356(13):1295-1303.

[edit] Pathology

• Non-invasive
  • Lobular carcinoma in-situ (LCIS)
  • Ductal carcinoma in-situ (DCIS)
• Invasive (infiltrating)
  • Ductal carcinoma
  • Lobular carcinoma
  • Others below

[edit] Infiltrating Lobular Carcinoma

• About 10% of invasive carcinomas. Bilateral in 6-28%.
• Higher frequency of skeletal, visceral, serosal and retroperitoneal mets.
• Early prognosis significantly better than IDC, but late prognosis significantly worse than IDC

• International BCSG trials; 2008 (1978-2002) PMID 18458044 -- "Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials." (Pestalozzi BC, J Clin Oncol. 2008 Jun 20;26(18):3006-14. Epub 2008 May 5.)
  • Retrospective. 12,206 patients on 15 trials. Categorized as ILC (6%), IDC (71%), or other/mixed (23%). Median F/U 13 years
  • ILC patient characteristics: older age, larger tumors, better differentiated, ER+, less LVI+. Mastectomy used more frequently (SS)
  • ILC outcome: significantly better early DFS/OS advantage, but significantly worse late (6 and 10 years) DFS/OS. Similar outcome when stratified by ER status
  • Conclusion: Infiltrating lobular carcinoma carries distinct prognostic and biologic implications

[edit] Special histologic types

Need to have > 90% predominant pattern.

Most have better prognosis (80-90% 10-year survival)

• Tubular carcinoma - 1.3% of all breast cancer cases. Older median age (67), 74% detected by mammography, remainder with palpable mass, 92% Estrogen receptor positive; bilateral presentation in 8%; indolent natural history with rare distant metastases
  • PMID 11899414 -- "Tubular breast cancer experience at Washington University: a review of the literature." (Holland DW, Clin Breast Cancer. 2001 Oct;2(3):210-4).
• Mucinous carcinoma (colloid) - excellent prognosis. 1-6%.
• Medullary carcinoma - excellent prognosis. 5-7%.
• Cribriform carcinoma -
• Invasive papillary carcinoma

Similar prognosis (as IDC)

• Secretory carcinoma
• Metaplastic carcinoma

Worse prognosis

• Micropapillary carcinoma (PMID 16196516)
  • Predominant or focal papillary clusters, devoid of fibrovascular core with empty lacunar spaces
  • On histology frequently with high proliferation index, p53+ and ER-; however, no basal-like staining pattern
  • Frequent LVI+, nodal mets and poor prognosis
  • Also present in lung, ovary, bladder, and salivary gland. If metastatic deposit, should evaluate those organs as primary site

[edit] Tissue microarray (TMA) profiling

References: see PMID 15328174 (Nielsen TO 2004), PMID 10963602 (Perou 2000), PMID 11553815 Full text (Sorlie T 2001), PMID 12829800 Full text (Sorlie T 2003), PMID 12429812 (Korsching E 2002), PMID 14519755 (Foulkes 2003)

5 groups by tissue microarray:
Typical IHC pattern listed)

• Luminal A - high ER expression
• Luminal B - high ER expression
• HER2 overexpressing
• Normal breast-like
• Basal type ("triple-negative") - expression of CK 5/6 or 17 but low expression of luminal CK 8/18. Since staining by IHC may be insensitive, can identify these by having CK5/6 and/or HER1 but negative for ER and HER2. Are often high grade, high frequency of BRCA1 mutation
  • Heterogenous group, both molecular and clinical (including adenoid cystic, medullary, etc)

luminal keratins (simple epithelial) - cytokeratins 7, 8, 18, and 19
basal epithelial cells (stratified epithelial cytokeratins) - 5, 6, 14, 15, and 17

Prognosis is worst for HER2 overexpressing and the basal type, best for Luminal A, and intermediate for Luminal B.

[edit] Cancer stem cells

• Growing evidence suggests only small subclass of cancer cell within a given tumor are actually tumorigenic. In breast cancer, these cells carry CD44+/CD24- phenotype
• These cells are self-renewing, and persist in small numbers through passaging
• A gene signature differentiating these cells from normal breast epithelium is able to select patients with poor overall survival and poor mets-free survival. It probably does this by identifying tumors that have a high proportion of cancer cells with invasive phenotype

• Marseille, 2007 PMID 17476019 -- "A gene signature in breast cancer." (Bertucci F, N Engl J Med. 2007 May 3;356(18):1887-8; author reply 1887-8.)
  • Comment on PMID 17229949. Use of IGS profile on basal and luminal samples
  • 89% of genes overexpressed in cancer stem cells also overexpressed in basal samples
  • Conclusion: Basal-cell BCA enriched in tumorigenic BCA cells or have similar tumorigenic capability, which partially explains poor prognosis of basal cell BCA

• Michigan, 2007 PMID 17229949 -- "The prognostic role of a gene signature from tumorigenic breast-cancer cells." (Liu R, N Engl J Med. 2007 Jan 18;356(3):217-26.)
  • Comparison of gene expression profile in tumorigenic ("cancer stem cells") CD44+/CD24- cells and normal breast epithelium. 186 gene signtaure generated (IGS = invasiveness gene signature).
  • 10-year outcome stratification: OS 98% vs. 62%, and mets-free survival (82% vs. 54%)
  • Also associated with prognosis in medulloblastoma, lung CA, and prostate CA

• Michigan, 2003 PMID 12629218 -- "Prospective identification of tumorigenic breast cancer cells." (Al-Hajj M, Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8.)
  • BCA model: human breast cancer cells grown in immunocompromised mice.
  • Only minority of cells had ability to form new tumors: CD44+/CD24-
  • As few as 100 cells could for tumors in mice, while >10,000 cells of other phenotypes couldn't form tumors
  • Self renewing; persist through passaging

[edit] Extensive in-situ component (EIC)

• Invasive tumor in which > 25% is DCIS, and DCIS extends beyond edges of tumor.
• Initially seen to have higher rate of LR in pts treated with breast conservation, because role of surgical margin was not clear
• Some institutions could not demonstrate EIC impact on LR, partly due to variability in amount of tissue removed during surgery (thus making SM- more likely)
• Ultimately it was demonstrated that if SM-, EIC status is irrelevant. Thus, EIC serves as a marker for high DCIS burden in the breast and higher rate of local failure, but if margins can be cleared, breast conservation + RT is reasonable

• Harvard
  • 1994 (1982-1985) PMID 8082077 -- "The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy." (Schnitt SJ, Cancer. 1994 Sep 15;74(6):1746-51.)
    • Retrospective. 181 patients with Stage I-II invasive BCA, treated with surgery + RT >=60 Gy. Median F/U 7.2 years
    • Recurrence rate EIC-: no difference if SM+ vs. SM- (<10%)
    • Recurrence rate EIC+: if SM+ 50% vs. SM- 0%
    • Conclusion: BCS reasonable option for EIC+ if SM-; LR very high if EIC+ and SM+
  • 1990 (1968-1982) PMID 2173044 -- "Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy." (Boyages J, Radiother Oncol. 1990 Sep;19(1):29-41.)
    • Retrospective. 783 patients treated with gross excision (margins not routinely assessed) + RT >=60 Gy
    • 5-year recurrence: EIC+ 24% vs. EIC- 6% (SS)
    • "True recurrence" (same quadrant): EIC+ 88% vs. EIC- 55%
  • 1984 PMID 6318957 -- "Pathologic predictors of early local recurrence in Stage I and II breast cancer treated by primary radiation therapy." (Schnitt SJ, Cancer. 1984 Mar 1;53(5):1049-57.)
    • Retrospective. 231 patients histology reviewed, and 5-year LR calculated
    • EIC defined

[edit] Anatomy

Lymphatic drainage:

• PMID 14745331 (Full text) (2004), Netherlands — "Lymphatic drainage patterns from the breast." Estourgie SH et al. Ann Surg. 2004 Feb;239(2):232-7.
  • Lymphatic mapping using sentinal lymph node technique. Provides maps of lymphatic drainage from each of 5 quadrants of the breast.

Supraclavicular and Infraclavicular LNs

• Michigan, 2001 PMID 11687672 -- "Definition of the supraclavicular and infraclavicular nodes: implications for three-dimensional CT-based conformal radiation therapy." (Madu CN, Radiology. 2001 Nov;221(2):333-9.)
  • CT-based anatomic evaluations

[edit] Natural History

[edit] Tumor Size

• New Mexico, 2005 (1988-1997) PMID 15650642 -- "Modeling the effect of tumor size in early breast cancer." (Verschraegen, Ann Surg. 2005 Feb;241(2):309-18.)
  • Modeling. SEER data from 83,686 women with T1-2, ALND done (58,070 N0 and 25,616 N+), no mets
  • Tumor size independent predictor of survival, regardless of LN status.
    • Death rate for N0 patients: 0.3cm 10% vs. 5cm 25%
    • Death rate for N+ patients: 0.3cm 20% vs. 5cm 40%
  • Conclusion: Both tumor size and lymph node status independently predict for mortality, and probably represent different processes (growth velocity vs. metastatic potential)

[edit] Doubling Time

• BRCA carriers 45 days, high risk women 84 days
• <50 y/o 80 days, 50-70 y/o 157 days, >70 y/o 188 days

• Erasmus Univ, 2005 (Netherlands) PMID 15978801 -- "Hereditary breast cancer growth rates and its impact on screening policy." (Tilanus-Linthorst MM, Eur J Cancer. 2005 Jul;41(11):1610-7.)
  • 80 BRCA1/2 carriers and women at high risk for familial BCA; tumor doubling time (DT) estimated
  • Mean DT (BRCA/high risk): carriers 45 days, non-carriers 84 days (SS)
  • Only age correlated with DT: mean DT slowed to 50% in each successive decade-older group (75d premenopausal vs. 153d postmenopausal)
  • Conclusion: consider bi-annual screening for high risk women <40 years old

• Virginia, 1993 PMID 8443754 -- "Mammographic assessment of human breast cancer growth and duration." (Spratt JA, Cancer. 1993 Mar 15;71(6):2020-6.)
  • Sporadic BCA patients
  • Growth rates: 10 - 7051 days; no clear relationship to age

• Nijmegen (Netherlands), 1993 PMID 8490903 -- "Age-dependent growth rate of primary breast cancer." (Peer PG, Cancer. 1993 Jun 1;71(11):3547-51.
  • Data from screening program
  • Median DT: Women <50 80 days, women 50-70 157 days, women >70 188 days

• Diseases of the Breast (Haagensen CD ed, Philadelphia: WB Saunders, 1986)
  • ~5 years for tumor to reach palpable size

[edit] LN Status

• Axillary nodes
  • Newly diagnosed T1-T2 BCA have ~30% chance of axillary LN mets (function of age, size, grade)
  • Axillary clinical exam unreliable
    • If clinically negative axilla -> ~30% positive on dissection
    • If clinically positive axilla -> ~25% negative on dissection

• NSABP B-32 Abstract "Preliminary technical results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer patients [abstract]." (Julian TB, Breast Cancer Res Treat 2004, 88:S11-S12.)
  • Randomized. 5611 patients. Treated with 1) SLN alone or 2) SLN + axillary dissection. If SLN+, then complete axillary dissection
  • SLN+ in 26%; false negative rate 10% (in those who had SLN + ALND)
  • 0.6% had SLN+ outside of the axilla

• USC, 2001 PMID 11376414 -- "Predicting axillary nodal positivity in 2282 patients with breast carcinoma." (Silverstein MJ, World J Surg. 2001 Jun;25(6):767-72.)
  • Retrospective. 2282 ALND (391 DCIS, 1891 invasive). LN+ in 0.8% DCIS and 36% invasive
  • Predictors for LN+: LVI (16% vs. 2%), large tumors, high grade (8% G3 vs. 4%), palpable tumors (3% vs. 3%). If all factors negative, 3% LN+; if 3 factors negative 6%
  • Conclusion: Features can be used to estimate risk of ALN+

• Eindhoven, 2000 (Netherlands), PMID 10989986 -- "The risk of nodal metastases in breast cancer patients with clinically negative lymph nodes: a population-based analysis." (Voogd AC, Breast Cancer Res Treat. 2000 Jul;62(1):63-9.)
  • Population-based study 1984-1997, 7680 patients with invasive BCA, 6663 axillary dissection
  • 34% positive LN
  • Predictors: type, size, location, number of nodes examined

• IM nodes
  • By SLN mapping: <1% localized to IM in NSABP B-32, 14% in Spanish study
  • If SLN localized to IM or dissection with medial tumors: ~10% LN+
  • Thus, overall <1% positive (10% of 1-14%)
  • Possibly outdated info (because of mammography) from surgical series in 1960-80's
    • If axilla LN- -> ~10% positive
    • If axilla LN+ -> ~30% positive

• Barcelona, 2004 (Spain) PMID 15465187 -- "Incidence of internal mammary node metastases after a sentinel lymph node technique in breast cancer and its implication in the radiotherapy plan." (Farrus B, Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):715-21.)
  • Prospective. 225 patients with SLN mapping for early BCA
  • IM nodes: 31/225 (14%) SLN drainage to IM. No biopsy attempted by design in 11 cases. Biopsy performed successfully in 14/20 cases (69%). LN+ in 2/14 (14%). Overall LN+ 2/116 (1.7%)
  • RT to IM not recommended unless pathologically proven

• Milan, 2002 PMID 12417517 -- "Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients." (Galimberti V, Ann Surg Oncol. 2002 Nov;9(9):924-8.)
  • Retrospective. 182 patients biopsied after SLN or because medial tumor
  • IMN+ in 9%; of these axilla LN- in 4/14 and LN+ in 10/14
  • Conclusion: IMN technically easy, and 10% results in upstaging with modified RT and chemo treatments

• British Columbia, 2000 (1989-1995) PMID 10920130 -- "Relationship between tumor location and relapse in 6,781 women with early invasive breast cancer." (Lohrisch C, J Clin Oncol. 2000 Aug;18(15):2828-35.)
  • Retrospective. Early BCA. Grouped by low risk/high risk, and systemic chemo/no chemo
  • High risk, adjuvant chemo patients: medial location associated with 50% excess risk of systemic relapse (33% vs. 26%, SS) and BCA-death (25% vs. 20%, SS), compared to lateral location
  • Low risk, or high risk with no adjuvant chemo: no difference
  • Conclusion: 2X risk of relapse and BCA-death possibly due to occult spread to IM nodes

[edit] Bone Marrow Mets

• While conceptually interesting, in the US it is felt that it may not add addition value in current management with aggressive chemotherapy. Also, QA of testing was extremely difficult

• Multinational, 2005 PMID 16120859 -- "A pooled analysis of bone marrow micrometastasis in breast cancer." (Braun S, N Engl J Med. 2005 Aug 25;353(8):793-802.)
  • Meta-analysis. Individual data from 9 studies involving 4703 patients. Stage I, II, or III breast CA. Median F/U 5.2 years
  • Prevalence: overall 31%; present in women with larger tumors, higher grade, LN+, and ER-
  • Prevalence by subgroup: T1 25%, T2 33%, T3 38%, T4 60%; Grade 1 22%, Grade 2 30%, Grade 3 35%; N0 26%, N1 30%, N2 40%, N3 50%; ER/PR/her2- 34%, at least one positive 29%; pT1N0 without systemic therapy 22%
  • Prognosis: worse OS (mortality ratio 2.1) and worse BCA-specific survival (mortality ratio 2.4)

• LMU (Germany) 2001 PMID 11230493 -- "Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy." (Braun S, J Clin Oncol. 2001 Mar 1;19(5):1468-75.)
  • Prospective. 150 node-negative patients with Stage I/II. Anti-CK staining for micromets
  • Micromets in: Bone marrow 29%, LN 9%, both 1%
  • Bone marrow micromets independent risk factor for cancer-related death (HR 6.1)

[edit] Distant Mets

• Milan; 2007 PMID 17952122 -- "Breast cancer metastases are molecularly distinct from their primary tumors." (Vecchi M, Oncogene. 2007 Oct 22; [Epub ahead of print])
  • 26 matched primary breast tumors and LN mets to identify 270 discriminating probesets. Further independent 81 breast tumors and 32 distant mets to refine 126 probeset. Verified on independent 57 primary tumors and matched LN mets. 1/3 of differentially expressed genes were from epithelial component. Two of these modified cell motility in vitro
  • Conclusion: Breast CA mets are molecularly distinct from their primary tumors

• Gustave-Roussy (France)
  • 4000 patients treated for BCA 1954-1975; no adjuvant chemo. Follow-up 15-30 years
  • 1999 PMID 9989510 -- "The link between local recurrence and distant metastases in human breast cancer." (Koscielny S, Int J Radiat Oncol Biol Phys. 1999 Jan 1;43(1):11-24.)
    • If no local recurrence (LR), monthly mets rate decreases continuously
    • If local recurrence, excess mets seeded after initial treatment (from residual disease)
    • Each year, a small proportion of grade 1 residual disease progresses to grade 2, and significantly increases chance of distant mets
    • 20-year outcome
      • LR- patients: 25% develop distant mets
      • LR+ patients: Grade 1 - 70%(due to residual disease grade progression)), Grade 2/3 - 90% develop distant mets
  • 1991 PMID 1756255 -- "Natural history of human breast cancer: recent data and clinical implications." (Tubiana M, Breast Cancer Res Treat. 1991 Aug;18(3):125-40.)
    • For tumors of a given size, strong correlation between grade and development of distant mets
    • Similarly, low grade tumors need to be significantly larger than high grade tumors before development of distant mets
    • Proportion of grade 1 tumors higher in smaller tumors; suggests that tumors progress toward higher grade during growth (~20% of grade 1 progress to grade 2 per year)
  • 1989 PMID 2744888 -- "Growth rate, kinetics of tumor cell proliferation and long-term outcome in human breast cancer." (Tubiana M, Int J Cancer. 1989 Jul 15;44(1):17-22.)
    • Cells with rapid growth rate (high thymidine labelling index) have higher rates of distant mets
    • LI and grade two most important prognostic indicators for relapse or death
  • 1989 PMID 2736212 -- "The natural history of human breast cancer. The relationship between involvement of axillary lymph nodes and the initiation of distant metastases." (Koscielny S, Br J Cancer. 1989 May;59(5):775-82.)
    • For tumors of a given size, strong correlation between number of LN+ and development of distant mets
    • Lymphatic spread is on average acquired much earlier than hematogenous spread
  • 1984 PMID 6733019 -- "Breast cancer: relationship between the size of the primary tumour and the probability of metastatic dissemination." (Koscielny S, Br J Cancer. 1984 Jun;49(6):709-15.)
    • Retrospective. 2648 patients treated 1954-1972 without chemotherapy
    • Proportion of patients with distant mets increases with tumor size. This suggests "threshold volume" (median 3.5cm, log-normal distribution) for each tumor, when first remote met is initiated (ie BCA not immediately metastatic, and local cure is possible)
    • Threshold volume correlated with grade and number of +LN

[edit] Untreated Patients

• 1962 PMID 13870135 -- "Natural history of untreated breast cancer (1805-1933). Comparison of untreated and treated cases according to histological grade of malignancy." (Bloom HJ, Br Med J. 1962 Jul 28;2(5299):213-21.)
  • Retrospective. 250 patients with pathologic diagnosis of breast CA. Manchester system Stage II 2.4%, Stage III 23%, Stage IV 74%
  • 10-year OS: 3.6%

[edit] BRCA Mutations

• Harvard; 2007 (1999-2007) PMID 17761984 -- "Primary fallopian tube malignancies in BRCA-positive women undergoing surgery for ovarian cancer risk reduction." (Callahan MJ, J Clin Oncol. 2007 Sep 1;25(25):3985-90.)
  • Retrospective. 122 BRCA+ patients with prophylactic ovarian CA surgery. Median age 46 years
  • Outcome: 6% early malignancy, 100% (n=7) originated in distal fallopian tube, 2 already surface implants on the ovary
  • Conclusion: Distal fallopian tube dominant site of origin for BRCA+ women at risk for GYN carcinomas

• Haifa, 2007 (Israel)(1987-1988) PMID 17625123 -- "Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations." (Rennert G, N Engl J Med. 2007 Jul 12;357(2):115-23.)
  • Population-based study. 1545 women with medical records and paraffin-embedded tumor blocks. BRCA1 or BRCA2 mutation in 10% of women with Ashkenazi Jewish ancestry
  • Outcome: HR for death comparable for carriers and non-carriers
  • Conclusion: BCA-specific death rate similar for carriers of BRCA founder mutations and non-carriers

[edit] Work-up

• Switzerland, 2007 PMID 17693646 -- "Therapeutic impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography in the pre- and postoperative staging of patients with clinically intermediate or high-risk breast cancer." (Klaeser B, Ann Oncol. 2007 Aug;18(8):1329-34.)
  • Retrospective. 114 patient with clinically intermediate or high-risk BCA, 73 PET prior to surgery, 41 after surgery.
  • Change in treatment: overall 32%; curative vs. palliative change 20% , RT planning 27%, surgical planning 8%, chemotherapy 11%, bisphosphonates 13%
  • Conclusion: PET may have substantial impact, including RT planning

[edit] Prognostic factors

CAP Consensus Statement

• CAP 2000 PMID 10888772 -- "Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999" (Fitzgibbons PL, Arch Pathol Lab Med. 2000 Jul;124(7):966-78.
  • Category I (proven and useful): TNM, histologic grade, histologic type, mitotic count, ER/PR status
  • Category II (not yet validated): Her2/neu, proliferation markers, LVI, p53
  • Category III (unclear): bunch of stuff

Extracapsular extension of lymph node metastases:

• Harvard, 2000 - PMID 1065636 — "The significance of extracapsular extension of axillary lymph node metastases in early-stage breast cancer." Hetelekidis S et al. Int J Radiat Oncol Biol Phys. 2000 Jan 1;46(1):31-4.
  • 368 pts treated with BCT. 122 had ECE.
  • ECE did not predict for poor DFS or OS, or local, nodal, or distant failures. ECE correlates with the number of involved LN.

Plasma Testosterone

• Milan, 2007 (Italy) PMID 17548841 -- "Plasma testosterone and prognosis of postmenopausal breast cancer patients." (Micheli A, J Clin Oncol. 2007 Jul 1;25(19):2685-90.)
  • Retrospective. 194 patients, T1-2N0, no chemotherapy
  • Outcome: high testosterone (>= 0.4 ng/ml) resulted in significantly lower EFS (HR 2.05, SS). 5-year EFS: 83% vs. 76%; 10-year 70% vs. 52%; 15-year 67% vs. 36%
  • Conclusion: Testosterone levels should be determined as part of prognostic workup

[edit] Unknown primary with axillary lymphadenopathy

When there is axillary lymphadenopathy but no known breast primary, mammography discovers an occult breast cancer ~ 25% of the time, and MRI of the breast about 75% of the time. A breast primary was identified in 61% of mastectomy specimens on combined analysis of nine published series.

• PMID 10758316, 2000 (Australia) - "Occult breast carcinoma presenting as axillary metastases." Foroudi et al. Int J Radiat Oncol Biol Phys. 2000 Apr 1;47(1):143-7.
  • reviewed 20 cases of occult breast cancer. For pts who did not have treatment of the breast, 5 of 6 (83%) had failure in the breast; compared to 3 of 12 (25%) who had breast XRT and 0 of 2 with mastectomy.

[edit] Quality of Life

[edit] Hot Flashes

• Please see the Hot Flashes section
• No benefit shown in randomized trials for acupuncture, soy phytoestrogens, red clover, black cohosh
• Vitamin E showed a statistically significant, but clinically small benefit of one hot flash reduction/day compared to placebo
• Gabapentin can reduce hot flash frequency by ~50%
• Significant benefit shown for several antidepresants (Paxil, Effexor, Prozac)

[edit] Exercise

• Please see details at the Supportive care/exercise page
• Several randomized trials have shown that exercise during/after breat cancer therapy is benefitical. However, compliance can be a problem