Men & Breast Cancer, Dr. Frankie Ann Holmes - 7th Annual Breast Health Summit

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Men & Breast Cancer, Dr. Frankie Ann Holmes - 7th Annual Breast Health Summit

  1. 1. Men & Breast Cancer Orphan disease or variations on a theme? Memorial Hermann Breast Health Summit 10-20-2011 Frankie Ann Holmes, MDMalecare.org
  2. 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: 2,140Malecare.org • Deaths: 450Raredisese.info.nih.gov/RareDiseaseList.aspx?PageID=1; wikipedia.com; www.cancer.gov
  3. 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. 4. What are the annual age-adjusted cancer incidence rates? 2006 (updated 2011) data Breast Cancer Incidence/100,000 Women 124 MEN Men 1 WOMENJemal A. CA Cancer J Clin 2010; 60:277-300;www.seer.cancer.gov/statfacts/html/breast.html
  5. 5. Has the incidence of male breast cancerchanged similar to changes in female? Conflicting dataInternational population based registerystudy (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: 0.4Miao H. J Clin Oncol 2011; 29; online 10-3-2011
  6. 6. Has the incidence of male breastcancer changed like female has? NO Miao H. J Clin Oncol 2011; 29; online 10-3-2011
  7. 7. Has the incidence of 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: stableMiao H. J Clin Oncol 2011; 29; online 10-3-2011
  8. 8. Did the incidence in 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. 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. 10. 5 “subtypes” of breast cancer Luminal A: ER+ PR+; Luminal B: ER+ PR- “Normal”: enigma HER2 positive Basal-like; “triple negative” ER neg, PR neg, HER2 neg
  11. 11. Perou(Sorlie,StanfordPNAS 2003;100-8418)5 typesLuminal ALuminal BHER2/neuBasalNormal
  12. 12. 2 main flavors of breast cancer: Luminal“ER pos” & Basal “ER neg”. Male Br Ca is like “Luminal ER pos” ER + ER -
  13. 13. Are the changes in incidence large? NO, small trends Anderson JF. J Clin Oncol 2010; 28:232
  14. 14. Age-standardized incidence rates 1974-2005 Anderson JF. J Clin Oncol 2010; 28:232
  15. 15. What age do men 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. 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. 17. Age specific incidence rates peaked at2000 and have declined slightly since
  18. 18. Is death from breast cancer decreasinging for both men & women? YES, but less for men MEN WOMENAnderson JF. J Clin Oncol 2010; 28:232
  19. 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. 20. Why do men get 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. 21. BRCA genes:essential for preciseDNA repair Friedenson F. BMC Cancer 2007; 7:152
  22. 22. BRCA2 gene long arm chromosome 13“13q12.3” is more common in Male Breast Ca From base pair 32,889,616 to 32,973,808Nat Rev Ca
  23. 23. What is the prevalence of BRCA gene mutations in Male Breast Ca? 10-30% N BRCA1 BRCA2aChodick, 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 samefor Jewish and non-Jewish men in IsraelbNo large genomic rearrangements found D Euhus MD Chodick. Eur J Med Genetis 208; 51:141 Tchou, J Clin Breast Cancer 2007; 7:627
  24. 24. What is the lifetime 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. 25. Cumulative onset breast cancer in 508 BRCA2 carriers. By age = 70 7.1%, age 80 = 8.4%Evans DGR. J Med Genet 2010; 47:710
  26. 26. What other cancers occur in BRCA2 carriers?Evans DGR. J Med Genet 2010; 47:710
  27. 27. Cowden’s syndrome: skin sign (loss of PTEN) Papules in flexor crease Amer M. Int J Derm 2011; 50
  28. 28. Cowden’s syndrome: PapulesWikipedia.org
  29. 29. What is Cowden’s Disease? 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. 30. Cumulative risk of any cancer by age 70 in Cowden Syndrome. Female- red; Male-blueRiegert-Johnson.Hereditarycancer inclinical practice2010; 8:6
  31. 31. CHEK2 Gene:another essentialfor precise DNArepair Friedenson F. BMC Cancer 2007; 7:152
  32. 32. What is the function of Chek2? Arrests cells with damaged DNA from dividingcancer • 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. 33. Increased risk of breast cancer in CHEK2 mutations. • Low frequency ~2% • Risk increased 2X • Br Ca Cases attributable 0.7% M+FCHEK2 Breast Cancer Case-Control Consortium. AmJ Hum Genet 2004; 74:1175
  34. 34. Undiscovered genes? Family history 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 3.96-23.96Brinton LA. J Natl Cancer Inst 2008;100:1477
  35. 35. Case 45: “Bulging tumors of the breast”Possible estrogen excess fromschistosomiasis-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. 36. Are hormones a risk 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 • OrchitisKorde LA. J Clin Oncol 2010; 28:2114
  37. 37. What is Kleinfelter’s Syndrome? 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. 38. Lancet 2011 Apr 9; 377:1211. PMID 21461690www.iom.edu/reports/2011/The-Health-of-Lesbian_Gay-Bisexual-and-Transgender-People
  39. 39. Dose breast cancer occur 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 availablePritchard TJ. JAMA 259; 2278
  40. 40. Is breast cancer seen 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 yrShao T. Clinical Breast Ca 2011 doi10.1016/j.clbc.2011.06.006;Burcombe RJ. Breast
  41. 41. How does testosterone cause breastcancer? Converted to estradiol byaromatase• 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. 42. Was Male Breast Cancer 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 womenRon E. J Natl Cancer Inst 2005; 97:603
  43. 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. 44. What are differences in Male vs Female Br Ca?Slide credit D EuhusMale Postmen FemMedian Age 67 62High 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. 45. Why is lobular cancer 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. 46. OncotypeDX Genes in Male (347) & Female (82,434) Breast Cancers: SAME ER-group HER Prolif’n INVShak S. ASCO2009 #549
  47. 47. What were the main 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 CancerShak S. Proc ASCO 2009; #549
  48. 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. 49. Diagnosis and Treatment• Awareness• Imaging• Biopsy-surgery• Adjuvant Treatment• Metastatic Disease
  50. 50. Men need to know that men get breast cancer!“It’s tax time…myaccountant…lookstired, and different….“I just finished my 2ndround of chemo…I hada modified radicalmastectomy.”“In the parking lot, Icheck mybreasts…behind the Breast cancer: not fornipple, hard as a women onlyrock…What are the Michael Hayes Samuelson.odds?...I had a Lancet 2006; 367:605
  51. 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. 52. Diagnostic Evaluation• Same as for women• Bilateral mammos• Ultrasound if needed• Biopsy Doyle S. Clin Radiol 2011; 66:1079
  53. 53. MammogramMale BreastwithGynecomastiaLEFT lowerinnerquadrantmass Doyle S. Clin Radiol 2011; 66:1079
  54. 54. Corresponding Ultrasoundshowing 3 cm spiculated massDoyle S. Clin Radiol 2011; 66:1079
  55. 55. What surgical options are 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. 56. Operable breast cancer: T1, T2, T3Credit: Breast. In: Greene FL et al, eds. AJCC CancerStaging Atlas. New York: Springer, 2006: 219-233.©American Joint Committee on Cancer.
  57. 57. NOT Operable “LABC” pT4a & pT4b Locally Advanced Breast Cancer Skin edema, “peau d’orange”Credit: Breast. In: Greene FL et al, eds. AJCC CancerStaging Atlas. New York: Springer, 2006: 219-233.©American Joint Committee on Cancer.
  58. 58. www.cancer.gov; male breast cancer Small breast means skin or chest wall involvement may be more common “T4”
  59. 59. Is Sentinel Lymph Node (SLN) Biopsy in MaleBreast Cancer as effective as in Women? YES MDACC MSKCC Male Female MaleNumber 30 2,784 78SLN Identification 100% 98.3% 97%Mean # SLN 3.0 3.5 2.8SLN (+) Rate 37.0% 22.3% 49%Non-SLN(+) rate 62.5% 20.7%Median largest met 10 mm 3 mmBoughey JC. J Am Coll Surg 2006;203:475-480Flynn LW, J Am Coll Surg 2008;206:616-621Slide credit D Euhus
  60. 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. 61. Operable Male Breast Ca Treatment GuidelinesSurgery • 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 LNChemo- >1 cm; LN (+); ER neg; HER2 pos;therapy OncotypeDX; other (proliferation)Hormonal Tamoxifen for ER (+)Therapy Slide credit D Euhus
  62. 62. What if the tumor is inoperable?Consider preoperative therapy Reasons for inoperability • T4 • Skin, chest wall involvement • Bulky or N3 lymph nodes
  63. 63. What extent of lymph node involvement makes patients inoperable? cN2, cN3N1: mets in N2a: “matted LN’s” N2b: ipsilat movable ipsilat mets fixed to other IMC LN axillary LN’s LN or structuresCredit: Breast. In: Greene FL et al, eds. AJCC Cancer Staging Atlas. NewYork: Springer, 2006: 219-233. ©American Joint Committee on Cancer.
  64. 64. What other areas of lymph nodes involvement are inoperable? cN3N3a: 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. 65. AJCC TNM version 7 Staging. Operable?Clinical Tumor Node Met Operable?IA T1 N0 M0 YesIB T0, T1 N1mi M0IIA T0, T1 N1 M0 Yes T2 N0 M0IIB T2 N1 M0 T3 N0 M0IIIA T0, T1, T2 N2 M0 Possibly T2, T3 N2 M0 Possibly T3 N1 M0 YIIIB T4 Any N M0 NoIIIC 65 Any T N3 M0 No
  66. 66. Inoperable Male Breast Cancer Treatment GuidelinesER pos Tamoxifen Surgery Radiation & or Chemo TamHER2  Addpos Trastuzuma bER neg  Chemo Surgery RadiationMetastatic disease Per NCCN Guidelines for Female except “AI”Fentiman IS. Lancet 2006; 367:595
  67. 67. What hormone therapies have 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. 68. Male Sex Hormone Environment Peripheral Conversion of Androgens • 80% of Estradiol • 98% of Estrone • 80% of DHT Dihydrotestost • <5% of Testosterone Central Production >95% of TestosteroneCentral production 15 - 20% of Estradiolof sex hormones is 20% of DHTlife long and Adapted from Nordman I,independent of Breast J 2008;14:562-569aromatization. Slide credit D Euhus
  69. 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 malesNahleh Z. Nat Clin Prac Oncol 2006; 3:428
  70. 70. What are 2 issues 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. 71. What is the 2nd issue unique totargeting 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 settingNordman IC. Breast J 2008; 14:562Slide credit D Euhus
  72. 72. Why is aromatase inhibition (AI) controversial in MaleBreast 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:e42Conclude –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. 73. Is the survival of male breast cancer worse than in women? Overall Survival “appears worse” but…Korde LA. JCO 2010;28:2114
  74. 74. “Relative” survival adjusts for older age at dx, poorer life expectancy in men and is SAME or BETTERKorde LA. JCO 2010; 28:2114
  75. 75. Summary of Male Breast 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. 76. Summary of Male Breast 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”

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