1. Qué es el Cáncer, Cuáles son las Estadísticas en Puerto Rico & Cómo podemos prevenir,detectar y manejar el Cáncer de Seno? Raúl H. Morales-Borges, M.D . Instituto de Hematologia & Oncologia Ashford

2. LA VIDA Y LA ESPERANZA SON MUY BONITAS Y NO PODEMOS NEGARLA. RHMB 2005

3. Prevención es lo mejor para gozar de una vida saludable. RHMB 2005

12. Muertes por Cáncer PR 2002 Hombres 2,667 Mujeres 1,948 Próstata 21% Pulmón 14% Colorectal 12% Estómago 6% Hígado 6% Esófago 5% Páncreas 4% Linfóma 3% Leucemia 3% Laringe 2% Otras Localizaciones 24% 20% Mama 13% Colorectal 10% Pulmón 7% Estómago 5% Hígado 4% Páncreas 4% Ovario 4% Linfóma 3% Cervix 3% Cuerpo útero, NOS 27% Otras Localizaciones

13. Tasa de Muerte por Cancer*, Todas las localizaciones, Puerto Rico 1990-2002 Hombres Ambos sexos Tasa por 100,000 Mujeres *Tasas ajustadas por edad a la población Estándar Millón de PR año 2000. Fuente: Registro Central de Cáncer de PR, 2004

14. Tasa de Mortalidad por Cáncer*, en Hombres, Puerto Rico,1990-2002 Tasa por 100,000

15. Tasa de Mortalidad por Cáncer*, en Mujeres, Puerto Rico, 1990-2000 Tasa por 100,000

16. Casos de Cáncer en Puerto Rico, 2000* *Excluye los tumores de piel de células basales y escamosas y el carcinoma in situ de cuello uterino. Hombres5,156 Mujeres 5,131 Próstata 32% Colorectal 13% Pulmón 7% Vejiga Urinaria 4% Estómago 4% Linfóma 4% Hígado 4% Leucemia 3% Esófago 3% Laringe 3% Otras Localizaciones 24% 35% Mama 14% Colorectal 6% Cuerpo útero 4% Cervix 4% Pulmón 4% Linfóma 3% Tiroides 3% Ovario 3% Estómago 2% Leucemia 22% Otras Localizaciones

17. Tasas de Incidencia de Cáncer* para Hombres, Puerto Rico, 1990-2000 Próstata Pulmón Colorectal Vejiga Uriraria Estómago Tasa por 100,000 *Tasas ajustadas por edad a la población Estándar Millón de PR año 2000. Fuente: Registro Central de Cáncer de PR, 2004

18. Tasas de Incidencia de Cáncer* para Mujeres, Puerto Rico, 1990-2000 *Age-adjusted to the 1970 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1973-1998, Division of Cancer Control and Population Sciences, National Cancer Institute, 2001. Tasa por 100,000

26. 2007 Estimated US Cancer Cases* * Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. American Cancer Society, Cancer Facts & Figures 2007 Women 678,060 Breast 26% Lung and bronchus 15% Colon and rectum 11% Uterine corpus 6% Melanoma of skin 4% Non-Hodgkin’s 4% lymphoma Thyroid 4% Ovary 3% Kidney and renal pelvis 3% Leukemia 3% All Other Sites 21%

27. 2007 Estimated U.S. Cancer Deaths* Women 270,100 Lung & bronchus 26% Breast 15% Colon & rectum 10% Pancreas 6% Ovary 6% Leukemia 4% Non-Hodgkin’s 3% lymphoma Uterine corpus 3% Brain and other 2% nervous system Liver and intrahepatic 2% bile duct

29. Cáncer de Seno con evidencia de engrosamiento de la piel y cambios inflamatorios

31. Cáncer de Seno en Hombre en los 1800’s

33. SIN LUZ SEGUIREMOS EN LAS TIENIEBLAS RHMB 2005 RHMB 2005

34. Prevención, Diagnóstico y Manejo del Cáncer de Seno

36. Adapted from American Cancer Society (2006) and Hulka et al. (2001).

40. Hartmann, L. et al. N Engl J Med 2005;353:229-237 BENIGN BREAST DISEASES (FIBROCYSTIC BREAST DISEASE)

42. Accurate clinical staging for breast cancer has always been considered essential before surgery is undertaken ( Sobin & Wittekind, 2002) . However, i t is important to remember the clinical signs of breast cancer that would invalidate surgical attempts at cure. In these instances, initial referral to a clinical oncologist would be more relevant.

43. The staging systems currently in use are based on the clinical size and extent of invasion of the primary tumour (T), the clinical absence or presence of palpable axillary lymph nodes and evidence of their local invasion (N), together with the clinical and imaging evidence of distant metastases (M). *For T1–3: 'a' indicates no attachment to underlying muscles; 'b' indicates attachment. Adapted from Sobin & Wittekind (2002).

44. The TNM classificatio has been subdivided into four broad categories by the Union Internationale Contre Cancer. *Many expert groups include T2 tumors in stage I. Adapted from Sobin & Wittekind (2002).

45. Conocimiento de Receptores Hormonales

46. cAMP, cyclic AMP; E 2 , oestrogen; 4-OH-E 2 , 4-hydroxyestradiol; ER, oestrogen receptor; EGFR, epidermal growth factor receptor; IGF-1, insulin-like growth factor; MAPK, mitogen-actived protein kinase; mRNA, messenger RNA; PI3K, phosphoinositide 3-kinase; mtProteins, mitochrondrial proteins; Shc, Src homology 2 domain-containing protein; pShc, phosphorylated Shc protein; Ras, GTP-binding protein; Raf, serine/threonine kinase; Src, protein tyrosine kinase. Dashed line arrows indicate putative pathways. Reproduced with permission from Yager & Davidson (2006).

47. Oestrogens cause activation of various protein kinases, such as mitogen-activated protein kinases (MAPK), and increase levels of second messengers, such as cAMP. EGF, epidermal growth factor; IGF-1, insulin-like growth factor 1; PI3K, phosphoinositide 3-kinase; ERK, extracellular signal-activated protein kinase; JNK, c- jun N-terminal kinase. Reproduced with permission from Yager & Davidson (2006).

48. Growth factor reduction of progesterone receptor (PR) via direct inhibition of PR gene transcription and induction of membrane-initiated oestrogen receptor (ER) signalling. E 2 , oestradiol; ERK1/2, extracellular regulated kinase 1/2; HB-EGF, heparin-binding epidermal growth factor; HER, human epidermal growth factor receptor; IGF-IR, insulin-like growth factor-1 receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; SERM, selective oestrogen receptor modulator; Tam, tamoxifen. Reproduced with permission from Cui et al. (2005).

49. Binding of epidermal growth factor (EGF) to the human epidermal growth factor receptor (EGFR) activates a cellular pathway, with induction of phosphorylation by intracellular kinases, leading to nuclear signals that increase cell proliferation. Based on Lo et al. (2006).

50. Epidermal growth factor receptor (EGFR) family members are dysregulated in many human cancers, suggesting a pivotal role in tumorigenesis ( Grünwald & Hidalgo, 2003) .

51. A tumour's hormone receptor status can be determined by immunohistochemistry. This photomicrograph demonstrates strong positive nuclear staining (brown or black) for oestrogen receptors in an infiltrating ductal carcinoma.` Reproduced with permission from Dietz J et al. Atlas of Cancer.

52. Tumours that express ER and/or PR are deemed to be endocrine responsive, while those expressing neither receptor are endocrine unresponsive. ER, oestrogen receptor; PR, progesterone receptor; +, positive (Allred score ≥2); –, negative (Allred score <2); ?, unknown. *Calculated from the Nurses' Health Study (2096 incident breast cancer cases during 1,029,414 person-years of follow-up). Data from Colditz et al . (2004).

53. Endocrine responsiveness is an important prognostic marker in breast cancer. ER, oestrogen receptor. Reproduced with permission from Hess et al. (2003).

54. All patients were treated with systemic endocrine therapy (tamoxifen in >90%). ER+, oestrogen receptor positive; ER–, oestrogen receptor negative; PR+, progesterone receptor positive; PR–, progesterone receptor negative. Reproduced with permission from Cui et al. (2005).

55. Many hormones influence breast development and function, including oestrogens, progesterone, androgens, prolactin, and luteinising hormone-releasing hormone (LHRH). FSH, follicle-stimulating hormone; LH, luteinising hormone; ACTH, adrenocorticotrophic hormone. Based on Dickson (2000) & Russo and Lamarque (1984) .

56. *The relative risk was calculated with the low-risk group as the reference group. †There is no association between the risk of breast cancer and oophorectomy performed at 35 years of age or older. Reproduced with permission from Clemons & Goss ( 2001).

57. Oestradiol and, to a lesser degree, other steroid hormones (e.g., progesterone) drive breast cell proliferation, which facilitates mutation, enhances fixation of mutations or facilitates expression of genetic errors by loss of heterozygosity by defects in DNA repair. Germline mutations in relevant tumour-suppressor genes accelerate the transformation to the malignant phenotype. Reproduced with permission from Henderson et al . (2000).

58. *ACI denotes a cross between August and Copenhagen-Irish strains and SENCAR sensitive to carcinogenesis. Reproduced with permission from Yager & Davidson (2006).

59. Mamografía : Prueba Estandard para Cernimiento y Detección Tempara

61. Importancia de la Sonomamografía

62. El Uso del MRI en el Diagnóstico de Cáncer de Seno

64. Cirugía Conservadora del Seno

67. Nódulo Sentinela

68. A variety of reconstructive techniques are available today aimed at minimising the mutilation effect of mastectomy without compromising the oncological clearance (Ahmed et al, 2005).

69. (A) A schematic representation of the post-operative appearance after transverse rectus abdominis myocutaneous (TRAM) flap reconstruction. (B) A 35-year-old patient after skin-sparing mastectomy and immediate TRAM. Reproduced with permission from Dietz J et al. (2002).

70. (A) A schematic representation of latissimus dorsi (LD) flap breast reconstruction. (B) A 38-year-old patient after modified radical mastectomy with immediate reconstruction using the LD flap and submuscular saline implant. Reproduced with permission from Dietz J et al. (2002).

71. Data from Gazet et al . (1991,1996).

72. Careful attention to histopathology and quality assurance of treatment delivery is essential to ensure APBI is applied appropriately. To this end, both the American Brachytherapy Society ( Arthur et al ., 2002) and the American Society of Breast Surgeons ( ASBS, 2003) have published recommendations for patient selection criteria for accelerated partial breast irradiation (APBI).

73. The EBCTCG confirmed that polychemotherapy produced substantial and highly significant proportional reductions in relation to the risk of relapse and death from breast cancer. The effects of treatment were described as either proportional or absolute benefits. For women under 50 years at randomisation, the absolute reduction in risk of relapse was 10.4% for node-negative and 15.4% for node-positive disease. The reduction was also significant for mortality (absolute improvements in 10-year survival of 5.7% and 12.4% for node-negative and -positive disease, respectively). CMF, cyclophosphamide, methotrexate and 5-fluorouracil. Reproduced with permission from the EBCTCG (2005).

74. AC, doxorubicin, cyclophosphamide; FAC, 5-fluorouracil, cyclophosphamide, doxorubicin; FEC, 5-fluorouracil, cyclophosphamide, epirubicin; HR, hazard ratio; OS, overall survival; T, docetaxel; TAC, docetaxel, doxorubicin, cyclophosphamide; TC, docetaxol, cyclophosphamide. Data from Nabholtz et al . (2002), Jones et al . (2003), Roche et al . (2004), and Bear et al . (2003).

75. AC, doxorubicin, cyclophosphamide; HR, hazard ratio; OS, overall survival; T, paclitaxel. Data from Henderson et al . (2003) and Mamounas et al . (2003).

76. Following the success of trastuzumab in metastatic breast cancer, four large international multicentre trials were designed to test the efficacy of trastuzumab as adjuvant treatment either with or following chemotherapy. *Group B from N9831 and Group A from HERA were excluded from the analysis. AC, doxorubicin, cyclophosphamide; LN, lymph node. Data from Romond et al . (2005), Piccart-Gebhart et al . (2005), and Slamon et al . (2005).

77. Adapted from Piccart et al . (2005). There are international consensus guidelines based on clinicopathological features and outcomes, which are regularly updated to help inform local guidelines and individual clinicians. The 2005 St Gallen guidelines have defined low-, intermediate- and high-risk categories.

78. The 2005 St Gallen guidelines recommend adjuvant treatment according to risk and endocrine responsiveness. *Depending on clinician and patient discussion. ET, endocrine therapy; CT, chemotherapy. Adapted from Piccart et al . (2005).

79. AC, doxorubicin, cyclophosphamide; CAF, cyclophosphamide, doxorubicin, 5-fluorouracil; CEF, cyclophosphamide, epirubicin, 5-fluorouracil; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; CT, chemotherapy; FEC, 5-fluorouracil, cyclophosphamide, epirubicin; TAC, docetaxel, doxorubicin, cyclophosphamide. Adapted from Piccart et al . (2005).

82. Gracias …