Resultados para el objetivo específico N° 02

2.1 Background

2.1.Î What do markers of tumour biology measure?

W hile m arkers o f tum our biology are o f considerable prognostic value, the actual relationship to cancer grow th

in-vivo

has not been established. T um our metastasis is a com plex m ultistep process (H art and Saini 1992) in which the cell adhesion m olecules may pro vide a unifying hypothesis as to how cancer cells adhere, invade, m igrate, gain access to the lym phovascular circulation, and subsequently seed at the secondary site. T he integrins w ere selected for study as they are the largest superfam ily o f the adhesion m olecules, with a versatile range o f function governing interaction betw een cells and to the extracellular m atrix. As the steps surrounding the initial process o f tum our invasion are com plex, experim ental m ethods to evaluate the m etastatic cascade require to focus on individual events. This thesis concentrates on the relationship betw een cell-m atrix adhesion in benign and m alignant breast disease with particular em phasis on cell attachm ent to the basem ent m em brane and interstitial m atrix proteins in the developm ent o f breast cancer m etastasis.

2.1.Ü Clinical evaluation of women with breast cancer

The clinical evaluation o f patients with breast cancer focuses on the prim ary tum our and the extent o f m etastatic spread. This is established by a full history and physical exam ination, supplem ented by im aging investigations (m am m ography or ultrasonography) and fine needle aspiration cytology (Gui

et al

1995). In com bination, the "triple test" o f clinical assessm ent, im aging and cytology has a very high diagnostic accuracy (H erm ansen

et al

1987). Investigations to detect distant metastasis can include a chest X -ray, bone scan, liver ultrasound exam ination and serum liver enzym e biochem istry. C ontroversy surrounds the m anagem ent o f the axilla for diagnosis as well as surgical treatm ent.

Lym ph node status and tum our size are independent but additive prognostic indicators in breast cancer (H aybittle

et al

1982). T um our grade is also o f independent p ro gnostic value (Elston and Ellis 1991) with tubule form ation, cellular pleom orphism and m itotic rate as com m only used histological criteria (Elston 1987). N odal status, tum our size and tum our grade are com bined to form the N ottingham P rognostic Index (H aybittle

et al

1982), which may also be used as a m ethod o f patient selection for adjuvant therapy (M organ

et al

1993).

2.1.ÎÜ The dilemma of the axilla in human breast cancer

The dilem m a as to w hether the axilla should be sam pled, cleared surgically or not treated at all rem ains a m atter o f great debate (Sacks

et al

1992, F entim an and M ansel 1991). It is w idely accepted that the only way to accurately stage the axilla is by pathological assessm ent o f the axillary nodes. The Early Breast Cancer T rialists’ C ollaborative G roup (1992) m eta-analysis o f 133 random ized trials involving 75 000 w om en confirm s the survival benefit o f polychem otherapy as adjuvant treatm ent for node positive pre-m enopausal as well as perim enopausal w om en. T his is o f clinical relevance for node positive w om en in the 50-69 year old age gro up , w ho m ight in the past have only been placed on adjuvant tam oxifen after prim ary surgical treatm ent b ut m ay now also benefit from additional chem otherapy. F u rth er prospective trials are necessary to confirm these findings but know ledge o f their nodal status has becom e im portant clinical inform ation in order to select older w om en for adjuvant chem otherapy.

In term s o f treatm ent, only node positive w om en benefit from axillary clearance surgery to p rev ent the risk o f regional disease (C arpenter

et al

1992). This may lead to overtreatm ent o f the axilla in approxim ately 60% o f w om en if a uniform policy o f axillary clearance surgery is imposed on all w om en w ith breast cancer. R andom ized clinical trials testing the value o f surgical dissection against radiotherapy o f the axilla has show n no survival benefit from either m odality o f treatm ent (Fisher

et al

1985). The com bination o f axillary dissection and radiotherapy predisposes to

lym phoedem a (Kissin

et al

1986). A xillary clearance surgery provides m ore com plete inform ation on nodal status and prognosis, and may reduce the need for extensive radiotherapy to the axilla (Sacks

et al

1992).

2.1.ÎV Potential benefits of predicting nodal status without surgery to the axilla

If a m ethod o f reliably predicting patients with axillary nodal m etastasis from p rim ary breast cancer can be established, then patients at low risk o f having nodal disease m ay be offered a low axillary sam ple o r even spared axillary surgery altogether, reserving axillary clearance surgery for patients at high risk o f having positive nodes. The m echanism s that govern m etastatic capability is likely to lie in the biological characteristics o f the prim ary cancer cell. The adhesion m olecules are potential candidates to fulfil at least part o f this role as le^s adhesive cancer cells are m ore likely to m etastasize. Loss o f integrin expression may provide a means o f predicting nodal status thus allow ing patient selection for axillary surgery and adjuvant therapy protocols.

2.1.V Current knowledge of the integrins in human breast cancer

T he present understanding o f the role o f the integrins in breast cancer is limited to studies o f expression in hum an tissue sections and functional assays using propagated cell lines. The im m unochem istry o f hum an breast cancer integrin expression based on the results o f recent publications is discussed in C hapter l.I X .ii and l.IX .iii but the conclusions that can be draw n from these studies are limited by several factors. T he sam ples studied w ere sm all, the range o f subunits investigated varied and none considered the av|35 integrin despite its recognised presence in carcinom a cells (Cheresh

et al

1989). In addition, not all groups used special stains for the basem ent m em brane to distinguish

in-situ

from invasive disease. These lim itations and variation o f study design are sum m arised in Table 2 .1. W hile lim itations on the accessibility to the new er |86-j88 integrin subunits still apply, a m onoclonal antibody to is now available.

Table 2.1 Studies evaluating integrin expression in breast cancer D ’Ardenne et al 1991 Pignatelli et al 1991 Pignatelli e ta l 1992b Koukoulis et al 1991 n Subunits studied 26 a l- a ô 43 al,a2,j81 37 a2,0£6,av,/31,/33,j84 54 al-a6,av,j81,j83,i84

Basal layer stains

Laminin, Collagen

None

None

Myosin

T here has hitherto been no published study reporting a relationship betw een integrin expression in breast cancer and nodal status at the tim e o f clinical presentation. W hile

in-vitro

assessm ent o f integrin function in breast cancer cell lines have been described, there is no data to relate integrin expression to integrin function using patient derived breast cancer cells from w om en with know n histological param eters and nodal status. There has also been no com prehensive study o f integrin regulated cell adhesion and invasion in breast cancer cell lines. The cellular aspects o f integrin m odulation are im portant if we are to accept integrin expression as a means o f assessing nodal status and tum our progression in w om en with breast cancer.

2.n.

Experimental design

In document Dinámica familiar y comportamiento de los estudiantes del 4to y 5to de la I E S de San Jerónimo de jornada escolar completa Asillo 2017 (página 64-80)