# Radiation Oncology/Breast/Breast overview

* 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.

## 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), PALB2
** Hormone exposure: Age at menarche, 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.

### Predictive Models

* 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

### Obesity

* Danish DBCG; 2010 (1977-2006) PMID 21115856 -- "Effect of obesity on prognosis after early-stage breast cancer." (Ewertz M, J Clin Oncol. 2011 Jan 1;29(1):25-31. Epub 2010 Nov 29.)
** Registry study. 18,967 women, early stage BCA, BMI available, complete follow-up to 10 years
** Outcome: 10-year DM risk increased by 46% if BM >30 kg/m2, risk of death increased by 38%. No impact on loco-regional recurrences
** Conclusion: Obesity independent prognostic factor for development of distant mets and breast cancer death. Effect of adjuvant therapy less in obese patients

## Screening

* ACR Appropriateness Guidelines; 2012 Full Report
** Annual Screening Mammography Recommended starting at 1) Age 40 for general population; 2) age 25-30 for BRCA carriers and untested relatives; 3) Age 25-30 or 10 years earlier than the age of the affected relative at diagnosis for person with first degree relative with pre-menopausal breast cancer or for women with lifetime risk > 20%; 4) 8 years after radiation therapy but not before age 25 for women who received mantle radiation between ages 10-30; 5) Any women with biopsy proven lobular neoplasia, atypical ductal hyperplasia, DCIS, or invasive breast cancer.
* 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

### 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

### 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.

## Pathology

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

### 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

### Special histologic types

Need to have > 90% predominant pattern.
Most have better prognosis (80-90% 10-year survival)
Tubular:
* 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).
** Need for RT:
*** 2012: SEER PMID 22543207 -- "Adjuvant Radiation Therapy and Survival for Pure Tubular Breast Carcinoma-Experience From the SEER Database." (Li BInt J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):23-9.)
**** Conclusion: "Since sufficiently powered large scale clinical trials are unlikely, we would recommend that adjuvant radiation be considered in PTCB patients age 65 or younger, although consideration of the small absolute survival benefit is important. Adjuvant radiation can be omitted for patients older than 65."
*** MGH; 2005 (1980-2002) PMID 16142444 -- "Tubular carcinoma of the breast: a retrospective analysis and review of the literature." (Sullivan T, Breast Cancer Res Treat. 2005 Oct;93(3):199-205.)
**** Retrospective. 13 women treated without RT, none recurred.
*** 2005 (1972-2001) PMID 15730459 -- "Excision only for tubular carcinoma of the breast." (Leonard CE, Breast J. 2005 Mar-Apr;11(2):129-33.)
**** 44 pts. Median f/u 5.4 yr. 2 local recurrences, crude LC 96% (2/44).
*** 2003 (1987-1999) PMID 12846864 -- "Tubular carcinoma of the breast: an institutional experience and review of the literature." (Cabral AH, Breast J. 2003 Jul-Aug;9(4):298-301.)
**** Retrospective. 44 pts. 20 pts treated with breast conservation without RT: local recurrence in 1 of 20. Pts with RT: LR in 0 of 13. Second breast cancers developed in 16% of cases.
* Mucinous carcinoma (colloid) - excellent prognosis. 1-6%. usually ER+.
* Cribriform carcinoma - excellent prognosis. usually ER/PR+.
* Invasive papillary carcinoma
Similar prognosis (as IDC)
* Secretory carcinoma
* Metaplastic carcinoma
* Medullary carcinoma - traditionally felt to have excellent prognosis, despite being high grade. 5-7%. Most are triple negative. However, per NCCN guidelines (v.2.2010), medullary carcinomas have a risk for distant metastases similar to other high grade carcinomas, and thus should be treated similarly to other triple negative invasive breast cancers, rather than be treated per guidelines for favorable histology.
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
Intracystic papillary carcinoma
* Review, 2013: (Bahrain) PMID 23304242 -- "Intracystic papillary breast cancer: a clinical update." (Reefy SA, Ecancermedicalscience. 2013;7:286)
Solid papillary carcinoma
* Review, 2012: (U.Florida) PMID 23020734 -- "Solid papillary carcinoma of the breast: a pathologically and clinically distinct breast tumor." (Saremian J, Arch Pathol Lab Med. 2012 Oct;136(10):1308-11.)
Invasive Papillary Carcinoma
* SEER analysis, 2018: PMID 27819878 -- "Prognostic Factors, Treatment, and Outcomes in Early Stage, Invasive Papillary Breast Cancer: A SEER Investigation of Less Aggressive Treatment in a Favorable Histology." (Fakhreddine MH, Am J Clin Oncol. 2018 Jun;41(6):532-537)
** Lumpectomy + radiation is associated with superior OS for early-stage invasive papillary patients in this SEER-based retrospective study.
Reviews:
* 2012 PMID 22826373 -- "Management of unusual histological types of breast cancer." (Cadoo KA, Oncologist. 2012;17(9):1135-45.)
** Includes: adenoid cystic carcinoma, apocrine carcinoma, cribriform, metaplastic, squamous cell carcinoma (subtype of metaplastic), papillary cancer, and secretory breast cancer.
** Does not discuss radiotherapy management.

### 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, her 2 neu negative, low Ki-67
* Luminal B - high ER expression AND often her 2 neu positive, Ki-67 and grade higher than luminal A
* HER2 overexpressing - ER/PR negative, her 2 neu positive and Ki-67 high
* 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, often EGFR positive
** 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.
clinical stratifications of each:
* Luminal A: most common, low grade, responsive to anti-hormonals, not that responsive to chemo
* Luminal B: Variable grade, variable chemo response, usually anti-hormonal responsive
* Her-2-Neu: usually high grade, lymph nodes positive at presentation, chemotherapy responsive, often trastuzamab and lapatinib responsive
* Basal: high grade, premenopausal african american women, BRCA 1 associated, chemo responsive

### 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

### 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

## Anatomy

* Please see the RT Technique page

## Natural History
### 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)

### 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

### LN Status

See also: Radiation_Oncology/Breast/Regional_Lymphatics
* 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

### 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)

### 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

### 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%

### BRCA Mutations

    For BRCA in male breast cancer, see Radiation Oncology/Breast/Male breast cancer
    See also page at Radiation_Oncology/Breast/Early_breast/BCT#BRCA1/BRCA2
* Review; 2011 PMID 21134653 -- "Radiotherapy in the treatment of hereditary breast cancer." (Pierce LJ, Semin Radiat Oncol. 2011 Jan;21(1):43-50.)
* Netherlands; 2014 (1980-2011) PMID 24947112 -- "Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: A prospective analysis." (A M Heemskerk-Gerritsen B, Int J Cancer. 2014 Jun 20. -- [Epub ahead of print])
** 583 pts with BRCA-associated breast cancer. 42% (242 pts) treated with contralat mastectomy; 341 without.
** Median f/u 11.4 yr. Lower incidence of contralat breast cancer (2% vs 19%: mastect vs control). Lower mortality (HR 0.49)
** Conclusion: "We conclude that CRRM is associated with improved overall survival in BRCA1/2 mutation carriers with a history of PBC."
* U. Toronto; 2014 PMID 24519767 -- "Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis." (Metcalfe K, BMJ. 2014 Feb 11;348:g226.)
** Retrospective. 390 women with Stage I-II BRCA-associated breast cancer, treated with mastectomy. Compared outcomes of those who had mastectomy of the contralateral breast (181 pts) vs those who did not (209 pts).
** Median f/u 14.3 yr. 20-yr survival 88% (contralat mastectomy) vs 66% (without). Ccontralat mastectomy was associated with a 48% reduction in death from breast cancer
** Conclusion: "This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. Given the small number of events in this cohort, further research is required to confirm these findings."
* Dutch MRISC Screening Study; 2010 (1999-2006) PMID 21079137 -- "BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study." (Rijnsburger AJ, J Clin Oncol. 2010 Dec 20;28(36):5265-73. Epub 2010 Nov 15.)
** Prospective screening study. 2,157 women, >15% cumulative lifetime risk of BCA (CLTR). Group 1: BRCA1/BRCA2 carriers, Group 2: high CLTR (30-50%), Group 3: moderate CLTR (15-30%). Biannual clinical breast exam, annual MRI and mammography screening. Median F/U 5 years
** Outcome: MRI sensitivity better than mammography for invasive cancer, no difference for DCIS. BRCA1 results worse than BRCA2 results. 6-year OS Group 1 84%, Group 2 93% and Group 3 100%
** Conclusion: Screening results worse in BRCA1 mutation carriers, but 6-year OS high in all groups
* U. Michigan; 2010 PMID 20411323 -- "Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy." (Pierce LJ, Breast Cancer Res Treat. 2010 Jun;121(2):389-98.)
** 655 pts with BRCA1/2 mutations and breast cancer, 302 treated with BCT and 353 with mastectomy.
** 15-yr local failure (as first failure) 23.5% (BCT) vs 5.5% (M). If BCT + chemotherapy, decreased risk of 11.9%. Most were second primary cancers rather than true local recurrences. Contralateral breast cancer risk 40% in all groups, not affected by use of RT. No differences in regional or distant recurrence rates or overall survival.
** Conclusion: Similar survival whether treated with M or BCT. Women treated with BCT have elevated risk of ipsilateral breast recurrence. Risk of ipsilateral recurrence with BCT reduced by use of chemotherapy. High rate of contralateral cancers.
* Multicenter; 2009 (1996-2008) PMID 19858402 -- "Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers." (Graeser MK, J Clin Oncol. 2009 Dec 10;27(35):5887-92.)
** Retrospective, multicenter cohort study. 2020 pts with BRCA+ breast cancer.
** Risk of contralateral breast cancer 47.4% at 25 yrs. Higher risk (1.6x) for BRCA1 vs BRCA2. Higher risk with younger age at diagnosis for BRCA1 pts: 62.9% 25-yr risk if age <40, vs. 19.6% if age >50.
** Conclusion: contralateral breast cancer risk depends on age at first breast cancer diagnosis.
* 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
* U. Michigan; 2006 PMID 16636335 -- "Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer." (Pierce LJ, J Clin Oncol. 2006 Jun 1;24(16):2437-43.)
** Retrospective. 160 BRCA+ breast ca pts matched with controls, all treated with BCS.
** No significant difference in ipsilateral breast tumor recurrence: 10-yr: 12% (BRCA+) vs 9%; 15-yr 24% vs 17%. BRCA+ pts had a higher risk of contralateral breast cancer: 39% vs 7% at 15 yrs.
** Conclusion: IBTR risk similar between carriers and controls. Increased risk of contralateral breast cancers.
* France; 2005 PMID 16140006 -- "Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy." (Kirova YM, Eur J Cancer. 2005 Oct;41(15):2304-11.)
** 131 pts with family history "non-carriers" (including 27 with BRCA1/2 mutations "carriers"; 20.6%) compared with 261 matched controls with breast cancer. Cancers were more likely to be high grade and ER-negative in those with BRCA mutations. Median f/u 8 yrs.
** No significant differences in breast cancer recurrence as first event seen between BRCA1/2 tumors and controls or non-carriers and controls. Higher rate of contralateral breast cancer in all pts with a family history and in those with BRCA1/2 mutations vs non-carriers. Ipsilateral breast cancer recurrence not higher for BRCA1/2 mutations vs non-carriers
** Conclusion: "These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term."
* Toronto; 2004 PMID 15197194 -- "Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers." (Metcalfe K, J Clin Oncol. 2004 Jun 15;22(12):2328-35.)
** 491 women with Stage I-II breast cancer with BRCA1/2 mutation.
** Risk of contralateral breast cancer was 29.5% at 10 years. In women who not have an oophorectomy or take tamoxifen, the risk of contralateral cancer was 43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers.
** Substantial risk of contralateral breast cancer at 10 yrs
Effect of Radiotherapy:
* 2000 PMID 11013276 -- "Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations." (Pierce LJ, J Clin Oncol. 2000 Oct 1;18(19):3360-9.)
** Conclusion: "There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years."
MRI Screening in BRCA Mutation Carriers:
* Toronto; 2011 No PMID yet -- "Prospective Study of Breast Cancer Incidence in Women With a BRCA1 or BRCA2 Mutation Under Surveillance With and Without Magnetic Resonance Imaging." (Warner E, J Clin Oncol. online before print; 2011 Mar 28)
** Total of 1275 women with BRCA mutation -- 445 on an MRI screening protocol and 830 controls not screened with MRI.
** Conclusion: annual surveillance with MRI is associated with a significant reduction in the incidence of advanced-stage breast cancer in BRCA1 and BRCA2 carriers.
BRCA-Associated gynecologic malignancies: See page at: Radiation Oncology/Ovary/Epithelial ovarian#BRCA Mutations

## 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

## 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

## 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.
* Australia; 2000 PMID 10758316 -- "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.
* MDACC; 2010 PMID 20564117-- "Population-based analysis of occult primary breast cancer with axillary lymph node metastasis." Walker et al. Cancer. 2010 Jun 8.
** SEER analysis of 750 cases of occult breast cancer. Mastectomy or ALND w/ RT (n = 470) had a 10-year OS rate of 65% vs 59% for patients who underwent ALND only (n = 126) vs 48% for patients who underwent observation only (n = 94). Mastectomy showed no difference in OS or CSS over ALND with RT.

## Quality of Life
### 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 antidepressants (Paxil, Effexor, Prozac)

### Exercise

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

## EBCTCG trials

The EBCTCG meta-analyses (a.k.a. "Oxford overviews") are referenced in the following chapters:
* Early breast/BCT (under subheading "meta-analyses")
* Post-mastectomy (under subheading "meta-analysis")
* Breast chemotherapy
* Breast hormonal therapy

## Other Resources

* ASTRO/ARRO Journal Club Webinar 2011 - "Association Between the 21-Gene Recurrence Score Assay and Risk of Locoregional Recurrence in Node-Negative, ER–Positive Breast Cancer: Results From NSABP B-14 and NSABP B-20" with Thomas Buchholz, MD