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![Case 45: “Bulging tumors of the breast”
Possible estrogen excess from
schistosomiasis-related liver insufficiency?
“If thou examinest a man
having bulging tumors on
his breast, (and) though
findest that [swellings]
have spread over his
breast...and if thou findest
them very cool…
Edwin Smith Papyrus
~3000-1600 BC
Dawson PJ. A history of cancer of the male breast.
Advances in Oncobiology: Breast Cancer vol 2, 1998, 1998](https://image.slidesharecdn.com/2011menandbreastcancerdr-frankieannholmes-111026112110-phpapp01/75/Men-Breast-Cancer-Dr-Frankie-Ann-Holmes-7th-Annual-Breast-Health-Summit-35-2048.jpg)
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Men & Breast Cancer, Dr. Frankie Ann Holmes - 7th Annual Breast Health Summit
The document summarizes information about male breast cancer. Some key points: 1) Male breast cancer is considered a rare or "orphan" disease that affects about 1 in 1000 men annually in the US, with estimated new cases of 2,140 and deaths of 450 in 2011. 2) The causes of male breast cancer include gene mutations like BRCA2 and PTEN, as well as factors like estrogen exposure. 3) Male breast cancer has some similarities to female breast cancer, especially the luminal/hormone receptor positive subtype, but the incidence peaks about 10 years later in men at age 75 compared to age 61 in women. 4) Treatment options are generally the same as for
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Similar to Men & Breast Cancer, Dr. Frankie Ann Holmes - 7th Annual Breast Health Summit
Men & Breast Cancer, Dr. Frankie Ann Holmes - 7th Annual Breast Health Summit
- 1. Men & BreastCancer Orphan disease or variations on a theme? Memorial Hermann Breast Health Summit 10-20-2011 Frankie Ann Holmes, MD Malecare.org
- 2. What’s an “orphan”disease? “Rare” • Rare Diseases Act 2002: “affects < 200,000” • USA: 1 in 1500 • Japan: 1 in 2500 • Europe: < 1 in 2000 “low prevalence..special combined efforts… needed to address” 2011 Male Breast Ca Estimates • New cases: 2,140 Malecare.org • Deaths: 450 Raredisese.info.nih.gov/RareDiseaseList.aspx?PageID =1; wikipedia.com; www.cancer.gov
- 3. Learning Objectives Male Breast Cancer • Incidence: orphan disease? • Causes: Genes, Estrogen, Radiation • Comparison to Female Breast Cancer: variations on a theme? • Diagnosis: Awareness • Treatment • Summary
- 4. What are theannual age-adjusted cancer incidence rates? 2006 (updated 2011) data Breast Cancer Incidence/100,000 Women 124 MEN Men 1 WOMEN Jemal A. CA Cancer J Clin 2010; 60:277-300; www.seer.cancer.gov/statfacts/html/breast.html
- 5. Has the incidenceof male breast cancer changed similar to changes in female? Conflicting data International population based registery study (date registry began) thru 2007: NO • Denmark (1943), Finland (1953), Norway (1952), Sweden (1958), Geneva (1970), Singapore (1968) • Patients: Female: 459, 846; Male 2,665 • Incidence per 100,000 thru 2000 • Female: 50%: 51 80 • Male: No change: 0.4 Miao H. J Clin Oncol 2011; 29; online 10-3-2011
- 6. Has the incidenceof male breast cancer changed like female has? NO Miao H. J Clin Oncol 2011; 29; online 10-3-2011
- 7. Has the incidenceof male breast cancer changed similar to changes in female? Conflicting data: YES, small sample sizes • SEER data, UK: cancers per 100,000 men • 1970s: 1.0 • 2000-2004: 1.2 • Regional/Racial variation: • US: 1%; African American: 1.4 (1993) 1.8% (2010) • India: 2.5%; Pakistan: 5.9% • US Women: change in incidence for Post- menopausal breast cancer: 2o HRT • Premenopausal breast cancer: stable Miao H. J Clin Oncol 2011; 29; online 10-3-2011
- 8. Did the incidencein breast cancer change in the US in 2003? Yes, but only in 50 yr+ subset? Women’s Health Initiative “WHI” report 2002: Post- menopaus al E + P hormones assoc’d with Ravdin P. New Engl J Med 2007; 356: 1670 Breast Ca
- 9. Did ALL 50+yr old pts have a decrease? NO, only ER+ subset; ER neg NO CHANGE Women’s Health Initiative “WHI” report 2002: Post- menopaus al E + P hormones assoc’d with Ravdin P. New Engl J Med 2007; 356: 1670 Breast Ca
- 10. 5 “subtypes” ofbreast cancer Luminal A: ER+ PR+; Luminal B: ER+ PR- “Normal”: enigma HER2 positive Basal-like; “triple negative” ER neg, PR neg, HER2 neg
- 11. Perou (Sorlie, Stanford PNAS 2003; 100-8418) 5 types LuminalA Luminal B HER2/neu Basal Normal
- 12. 2 main flavorsof breast cancer: Luminal “ER pos” & Basal “ER neg”. Male Br Ca is like “Luminal ER pos” ER + ER -
- 13. Are the changesin incidence large? NO, small trends Anderson JF. J Clin Oncol 2010; 28:232
- 14. Age-standardized incidence rates1974-2005 Anderson JF. J Clin Oncol 2010; 28:232
- 15. What age domen get breast cancer compared to women? Older: 67 vs 61 yrs Women: 2 peaks young & old “Clemmensen’s hook” ★ Men: single peak, age 75 yr Korde LA. J Clin Oncol 2010; 28:2114
- 16. What is the“bend” in the incidence curve for women? What’s the biologic significance? “Clemmesen’s hook” • Change in incidence rate associated with menopause • Not seen in men • 2 types of breast cancer in women • Young • Old • Male breast ca ~ to older female type Anderson JF. J Clin Oncol 2010; 28:232
- 17. Age specific incidencerates peaked at 2000 and have declined slightly since
- 18. Is death frombreast cancer decreasinging for both men & women? YES, but less for men MEN WOMEN Anderson JF. J Clin Oncol 2010; 28:232
- 19. Learning Objectives Male Breast Cancer • Incidence: orphan disease? • Causes: Genes, Estrogen, Radiation • Comparison to Female Breast Cancer: variations on a theme? • Diagnosis: Awareness • Treatment • Summary
- 20. Why do menget breast cancer? Known Gene mutations: ~10% BRCA (mostly BRCA2) PTEN (Cowden’s), CHEK2, p53 Unknown gene issues: family history, race Estrogen excess or testosterone low Klinefelter’s syndrome (XXY) 3-7.5% Liver disease Testicular injury, dysfunction Environmental: Radiation, Exhaust (PAH) Gynecomastia? A marker not cause Korde LA. J Clin Oncol 2010; 28:2114 Fentimen IS. Lancet 2006; 367:595
- 21. BRCA genes: essential forprecise DNA repair Friedenson F. BMC Cancer 2007; 7:152
- 22. BRCA2 gene longarm chromosome 13 “13q12.3” is more common in Male Breast Ca From base pair 32,889,616 to 32,973,808 Nat Rev Ca
- 23. What is theprevalence of BRCA gene mutations in Male Breast Ca? 10-30% N BRCA1 BRCA2 aChodick, 2008 Israel 261 3% 8% bTchou, 2007 USA 41 10% 27% Basham, 2002 UK 94 0% 5% Frank, 2002 Myriad 76 11% 18% Friedman, 1997 USA 54 0% 4% aAshkenazi founder mutations only. Prevalence the same for Jewish and non-Jewish men in Israel bNo large genomic rearrangements found D Euhus MD Chodick. Eur J Med Genetis 208; 51:141 Tchou, J Clin Breast Cancer 2007; 7:627
- 24. What is thelifetime risk by age 70 for breast cancer in men with BRCA mutations? BRCA1: 1.2%; BRCA2: 6.8% NCI Cancer Genetics Network 1939 families with complete pedigrees 676 Ashkenazi Jewish Identified via high-risk counseling clinics 87 (4.5%) families: 97 male breast ca pts BRCA2 26% (23/87); BRCA1 7% (6/87)* 3 key findings: 1) BRCA2 more common* 2) BRCA2 risk (~7%) > BRCA1 (~1%) 3) Highest risk ages 30-40, decreases after • RR @ age 30 = 22.3x RR @ age 70! Tai WY. J Natl Cancer Inst 2007; 99:1811
- 25. Cumulative onset breastcancer in 508 BRCA2 carriers. By age = 70 7.1%, age 80 = 8.4% Evans DGR. J Med Genet 2010; 47:710
- 26. What other cancersoccur in BRCA2 carriers? Evans DGR. J Med Genet 2010; 47:710
- 27. Cowden’s syndrome: skinsign (loss of PTEN) Papules in flexor crease Amer M. Int J Derm 2011; 50
- 28.
- 29. What is Cowden’sDisease? Mutation in PTEN tumor suppressor gene. Clinically presents as “multiple hammartomas” & diagnostic skin lesions Thyroid disease, mucocutaneous lesions, lipomas, AVM, GI polyps, uterine fibroids, fibrocystic breast disease, renal cancer Head circumference >58 cm F, 61 cm M PTEN mutation calculator: http://www.lerner.ccf.org/gmi/ccscore/ Autosomal dominant; multiple cancers Lifetime risk female breast cancer 81% Amer M. Internatl J Derm 2011; 50:516; wikipedia
- 30. Cumulative risk ofany cancer by age 70 in Cowden Syndrome. Female- red; Male-blue Riegert- Johnson. Hereditary cancer in clinical practice 2010; 8:6
- 31. CHEK2 Gene: another essential forprecise DNA repair Friedenson F. BMC Cancer 2007; 7:152
- 32. What is thefunction of Chek2? Arrests cells with damaged DNA from dividingcancer • DNA damage by IR Ionizing Radiation or UV Radiation • Collaborates with ATM & p53, other ca-assoc’d gene mut’n Chehab NH. Gene Dev 2000; 14:278
- 33. Increased risk ofbreast cancer in CHEK2 mutations. • Low frequency ~2% • Risk increased 2X • Br Ca Cases attributable 0.7% M+F CHEK2 Breast Cancer Case-Control Consortium. Am J Hum Genet 2004; 74:1175
- 34. Undiscovered genes? Familyhistory is a risk factor relative risk “RR” 95% CI 1st degree relative: 1.92 1.19 - 3.09 Mother only 1.15 0.53 - 2.49 Sister only 2.25 1.13 - 4.47 Mother & Sister 9.73 3.96-23.96 Brinton LA. J Natl Cancer Inst 2008; 100:1477
- 35. Case 45: “Bulgingtumors of the breast” Possible estrogen excess from schistosomiasis-related liver insufficiency? “If thou examinest a man having bulging tumors on his breast, (and) though findest that [swellings] have spread over his breast...and if thou findest them very cool… Edwin Smith Papyrus ~3000-1600 BC Dawson PJ. A history of cancer of the male breast. Advances in Oncobiology: Breast Cancer vol 2, 1998, 1998
- 36. Are hormones arisk for male breast cancer? YES, Estrogen-testosterone imbalance • Kleinfelter syndrome: XXY • Cirrhosis (?schistosomiasis?) • Obesity • Physical inactivity • Alcohol – not as potent as in women • Exogenous estrogen or androgen • Prostate cancer • Transgender individuals • Testicular abnormality or injury • Orchitis Korde LA. J Clin Oncol 2010; 28:2114
- 37. What is Kleinfelter’sSyndrome? XXY chromosome abnormality • 1/500-650 men • May not be clinically obvious • 1o hypogonadism low testosterone levels • Relatively estrogen levels • Prevalence of male breast cancer ~ 7.5% Hultborn R. Anticancer • RR 50 x Res 1997; 17(6D) 4293
- 38. Lancet 2011 Apr 9; 377:1211. PMID 21461690 www.iom.edu/reports/ 2011/The-Health-of- Lesbian_Gay-Bisexual- and-Transgender- People
- 39. Dose breast canceroccur in transgender pts? YES, 3 pts with Male to Female “MtF” • 35 yr, oral estrogen x 10 yr, +FH Mother 4 cm IDC with 1/28 LN; ER neg PR pos by sucrose density gradient • 2 pts each 30 yr, oral estrogen 5 yr, no FH available Pritchard TJ. JAMA 259; 2278
- 40. Is breast cancerseen in “FtM” transgender inviduals? YES – 3 reports FtM • 53 yr, testosterone x 5 yr, +FH Aunt, age 32 & Mat GM but he was BRCA neg 0.9 cm IDC Gr 2 with 0/3 SLN; ER 90% PR 0% HER2=3+ • 27 yr, testosterone x 6 yr, +FH MGM but he was BRCA neg 2.5 cm IDC Gr 3 with 1/14 LN, ER 90% PR 10% HER2=3+ Ki67 90%yr, oral estrogen 5 yr, no FH available • ? Age, subcutaneous mastectomy, testosterone x 10 yr Shao T. Clinical Breast Ca 2011 doi 10.1016/j.clbc.2011.06.006;Burcombe RJ. Breast
- 41. How does testosteronecause breast cancer? Converted to estradiol by aromatase • Consider bilateral mastectomy for FtM • Consider “AI” aromatase inhibitor • BRCA evaluation Shao T. Clinical Breast Ca 2011 doi 10.1016/j.clbc.2011.06.006
- 42. Was Male BreastCancer increased in atomic bomb survivors? YES • Hiroshima-Nagasaki Tumor Registries • Estab 1958; persons alive & cancer free • BIAS: no data from 1st 13 yrs after exposure • Population: 45,880 males 32,411 known radiation doses; 2,978 unk 10,491 men not in city at bombing • Exposed: 9 MBC; Non-exposed 3 • Long latency & later than in women Ron E. J Natl Cancer Inst 2005; 97:603
- 43. Learning Objectives Male Breast Cancer • Incidence: orphan disease? • Causes: Genes, Estrogen, Radiation • Comparison to Female Breast Cancer: variations on a theme? • Diagnosis: Awareness • Treatment • Summary
- 44. What are differencesin Male vs Female Br Ca? Slide credit D EuhusMale Postmen Fem Median Age 67 62 High Grade 40% 37% DCIS 4 - 10% 25 – 30% Lobular Histology 1% 8% Papillary 2 – 5% 1 – 2% Lymph Node Pos 40% 29% Estrogen ER (+) 88% 80% PR(+) 86% 68% Androgen AR (+) 39 – 95% 48 – 78% Her-2/neu (+) 2 - 5% 20 – 25%
- 45. Why is lobularcancer less frequent in males? “The male breast is like pre-pubescent girl: not many ducts or lobules Ron E JNCI 2005;97:603 Female Breast Male Breast
- 46. OncotypeDX Genes inMale (347) & Female (82,434) Breast Cancers: SAME ER-group HER Prolif’n INV Shak S. ASCO 2009 #549
- 47. What were themain findings in the OncotypeDX study? • Lobular breast cancer less frequent in men • Distribution of Recurrence Scores: same • Average expression of ER, PR, SCUBE2, STM73 and 5 proliferation genes were HIGHER in males; as clinically observed • Differences in QUANTITATIVE ER gene expression vary by age in men vs women • These data SUPPORT present practice of EXTRAPOLATING treatment for Male Breast Cancer from Female Br Cancer Shak S. Proc ASCO 2009; #549
- 48. Learning Objectives Male Breast Cancer • Incidence: orphan disease? • Causes: Genes, Estrogen, Radiation • Comparison to Female Breast Cancer: variations on a theme? • Diagnosis: Awareness • Treatment • Summary
- 49. Diagnosis and Treatment • Awareness • Imaging • Biopsy-surgery • Adjuvant Treatment • Metastatic Disease
- 50. Men need toknow that men get breast cancer! “It’s tax time…my accountant…looks tired, and different…. “I just finished my 2nd round of chemo…I had a modified radical mastectomy.” “In the parking lot, I check my breasts…behind the Breast cancer: not for nipple, hard as a women only rock…What are the Michael Hayes Samuelson. odds?...I had a Lancet 2006; 367:605
- 51. • June 11,1991 John W Nick at the age of 58 died of Male Breast Cancer. • Nancy Nick promised her father the world would know that “Men Get Breast Cancer Too!” • If this information had been available to John Nick, he could have detected his cancer early… • Awareness saves lives!!!
- 52. Diagnostic Evaluation • Sameas for women • Bilateral mammos • Ultrasound if needed • Biopsy Doyle S. Clin Radiol 2011; 66:1079
- 53. Mammogram Male Breast with Gynecomastia LEFT lower inner quadrant mass Doyle S. Clin Radiol 2011; 66:1079
- 54. Corresponding Ultrasound showing 3cm spiculated mass Doyle S. Clin Radiol 2011; 66:1079
- 55. What surgical optionsare available? • BREAST: Due to the tumor-breast ratio, many men need mastectomy No contraindication to conservative therapy, but Cosmetic issues differ from women • LYMPH NODES Sentinel lymph node procedure Level I, II axillary lymph node
- 56. Operable breast cancer:T1, T2, T3 Credit: Breast. In: Greene FL et al, eds. AJCC Cancer Staging Atlas. New York: Springer, 2006: 219-233. ©American Joint Committee on Cancer.
- 57. NOT Operable “LABC”pT4a & pT4b Locally Advanced Breast Cancer Skin edema, “peau d’orange” Credit: Breast. In: Greene FL et al, eds. AJCC Cancer Staging Atlas. New York: Springer, 2006: 219-233. ©American Joint Committee on Cancer.
- 58. www.cancer.gov; male breastcancer Small breast means skin or chest wall involvement may be more common “T4”
- 59. Is Sentinel LymphNode (SLN) Biopsy in Male Breast Cancer as effective as in Women? YES MDACC MSKCC Male Female Male Number 30 2,784 78 SLN Identification 100% 98.3% 97% Mean # SLN 3.0 3.5 2.8 SLN (+) Rate 37.0% 22.3% 49% Non-SLN(+) rate 62.5% 20.7% Median largest met 10 mm 3 mm Boughey JC. J Am Coll Surg 2006;203:475-480 Flynn LW, J Am Coll Surg 2008;206:616-621 Slide credit D Euhus
- 60. Learning Objectives Male Breast Cancer • Incidence: orphan disease? • Causes: Genes, Estrogen, Radiation • Comparison to Female Breast Cancer: variations on a theme? • Diagnosis: Awareness • Treatment • Summary
- 61. Operable Male BreastCa Treatment Guidelines Surgery • Modified radical mastectomy • Total Mastectomy + SLN Bx Nipple preservation has been reported in 7 cases with no LR (Breast 2007;16:653-6) Radiation T3 or T4; close or involved margins > 4 involved LN Chemo- >1 cm; LN (+); ER neg; HER2 pos; therapy OncotypeDX; other (proliferation) Hormonal Tamoxifen for ER (+) Therapy Slide credit D Euhus
- 62. What if thetumor is inoperable? Consider preoperative therapy Reasons for inoperability • T4 • Skin, chest wall involvement • Bulky or N3 lymph nodes
- 63. What extent oflymph node involvement makes patients inoperable? cN2, cN3 N1: mets in N2a: “matted LN’s” N2b: ipsilat movable ipsilat mets fixed to other IMC LN axillary LN’s LN or structures Credit: Breast. In: Greene FL et al, eds. AJCC Cancer Staging Atlas. New York: Springer, 2006: 219-233. ©American Joint Committee on Cancer.
- 64. What other areasof lymph nodes involvement are inoperable? cN3 N3a: mets in N3b: mets in N3c: ipsilat only ipsilat BOTH Ax & IMC supraclav LN infraclav LN’s Credit: Breast. In: Greene FL et al, eds. AJCC Cancer Staging Atlas. New York: Springer, 2006: 219-233. ©American Joint Committee on Cancer
- 65. AJCC TNM version7 Staging. Operable? Clinical Tumor Node Met Operable? IA T1 N0 M0 Yes IB T0, T1 N1mi M0 IIA T0, T1 N1 M0 Yes T2 N0 M0 IIB T2 N1 M0 T3 N0 M0 IIIA T0, T1, T2 N2 M0 Possibly T2, T3 N2 M0 Possibly T3 N1 M0 Y IIIB T4 Any N M0 No IIIC 65 Any T N3 M0 No
- 66. Inoperable Male BreastCancer Treatment Guidelines ER pos Tamoxifen Surgery Radiation & or Chemo Tam HER2 Add pos Trastuzuma b ER neg Chemo Surgery Radiation Metastatic disease Per NCCN Guidelines for Female except “AI” Fentiman IS. Lancet 2006; 367:595
- 67. What hormone therapieshave been used for Male Breast Cancer? Surgical endocrine ablation (historical) Orchiectomy (first performed 1941) Adrenalectomy Hypophysectomy LHRH agonist +/- antiandrogen (cyproterone) SERMs (Tamoxifen) Aromatase Inhibitors +/- LHRH Agonist(controversial) Anti-estrogens (untested) Nahleh Z. Nat Clin Prac Oncol 2006; 3:428
- 68. Male Sex HormoneEnvironment Peripheral Conversion of Androgens • 80% of Estradiol • 98% of Estrone • 80% of DHT Dihydrotestost • <5% of Testosterone Central Production >95% of Testosterone Central production 15 - 20% of Estradiol of sex hormones is 20% of DHT life long and Adapted from Nordman I, independent of Breast J 2008;14:562-569 aromatization. Slide credit D Euhus
- 69. What is aromatase? “estrogen synthase”, made by CYP19 gene controls peripheral conversion of androgen to estrogen Anatomic locations in men: hypothalamus, liver, adipose, normal breast, muscle Distribution varies by 1) AMOUNT of fat, 2) LOCATION of fat High: in buttock, thigh (female pattern) Low: breast, abdomen (male fat pattern) • This may explain lower activity of AI in males Nahleh Z. Nat Clin Prac Oncol 2006; 3:428
- 70. What are 2issues unique to targeting aromatase in men compared to women? Intratumoral Aromatase: “home brew” 75% of female breast cancers express aromatase in the stroma & tumor compared to 100% of male breast cancers. J Clin End Metabol 1996;81:3063-3067 May be effective in advanced 1o male BC Suzuki T. Biomed & Pharmacother 2003; 57:460
- 71. What is the2nd issue unique to targeting aromatase in men compared to women? Peripheral Aromatase Android obesity (visceral adipose) is associated with reduced aromatase activity and reduced testosterone in men. May not be effective in metastatic or adjuvant setting Nordman IC. Breast J 2008; 14:562 Slide credit D Euhus
- 72. Why is aromataseinhibition (AI) controversial in Male Breast Cancer? Feedback loop Test Estrogen Animal Data Reduced estradiol FSH testicular Testosterone FSH E2 AI’s in Healthy Men E2 AI 50% but Testosterone E2 16 Reports of AI: 12 no T response; 4 response 4 Reports: LHRH agonist + AI 2 resp; 2 no resp –J Clin Oncol 2006;24:e42 Conclude –J Clin Oncol 2007;25:3787 • Tamoxifen is 1st line hormonal rx in men • Letrazole + Leuprolide may be 2nd line Slide credit: D Euhus; Nordman IC. Breast J 2008; 14:562
- 73. Is the survivalof male breast cancer worse than in women? Overall Survival “appears worse” but… Korde LA. JCO 2010; 28:2114
- 74. “Relative” survival adjustsfor older age at dx, poorer life expectancy in men and is SAME or BETTER Korde LA. JCO 2010; 28:2114
- 75. Summary of MaleBreast Cancer • “Stuff” happens. BE AWARE • Orphan disease, but increasing • Like female breast cancer, potentially curable & survival similar • Hormonally driven • Genetic causes: evaluate & screen for other associated primary cancers • Aromatase inhibitors controversial • RESEARCH needed: target the “killer molecules”
- 76. Summary of MaleBreast Cancer • Male Breast Cancer happens. • Orphan disease, but increasing • Like female breast cancer, potentially curable & survival similar • Hormonally driven • Genetic causes: evaluate & screen for other associated primary cancers • Aromatase inhibitors controversial • RESEARCH needed: target the “killer molecules”