Il carcinoma della mammella costituiva fino a non molti anni fa un Big Killer. In oncologia si definiscono big killer quei tumori con grande aggressività e poche possibilità di guarigione

I carcinomi della mammella oggi sono ancora i primi tumori per prevalenza ed incidenza nelle donne ma stanno pian piano facendo posto ai tumori del polmone i quali a causa dell’aumento del numero di fumatrici nel mondo stanno crescendo rapidamente nel sesso femminile essendo quindi in contro tendenza con la diminuzione osservata nel sesso maschile per riduzione in questo sesso del numero di fumatori.

Il carcinoma della mammella è un tumore di origine o epiteliale ghiandolare duttale o lobulare a seconda che le aree d’origine colpiscano i dotti oppure i lobuli. Infatti la mammella è una ghiandola tuboloalveolare composta che presenta un’ altissima plasticità fenotipica relazionata al gran numero di recettori per gli estrogeni, progesterone e la prolattina che contiene. Questo fa della mammella un organo in continua evoluzione e modificazione durante tutto l’arco della vita (pre menarca, vita fertile e post-menopausa) così come durante tutta la più semplice fase del ciclo ovarico che accade ogni 28 giorni. Essendo quindi un organo ormono sensibile è estremamente dinamico.

Questo è un primo punto a favore del cancro il quale notoriamente in tessuti ad alto turnover citologico e certa tendenza trasformativa è più incline a svilupparsi. Ciò ovviamente non basta per generare un carcinoma della mammella ma certamente in parte giustifica quella serie di comunissime alterazioni epitelio stromali benigne della mammella come cisti colloidi oppure fibroadenomi. Il carcinoma della mammella quindi è una malattia che si genera su un organo suscettibile di trasformazione patologica e ciò giustifica ad es. parte della sua epidemiologia. Se continuiamo ad osservare l’epidemiologia notiamo che il carcinoma mammario è tipico o quasi dell’età adulta post-menopausale. Ciò poiché gli estrogeni durante la menopausa decadono verticalmente a causa di un blocco della produzione degli ormoni da parte dell’ovaio.

La caduta verticale dei livelli di estradiolo ed estrone è responsabile delle sindromi post menopausali tipiche come l’osteoporosi nonché dei  maggiori rischi di natura cardiovascolare  come i fenomeni protrombotici e sintomi quali  vampate di calore, nausea etc. D’altro canto però è stato visto che gli estrogeni sembrano favorire lo sviluppo del carcinoma, cosa evidenziata dal fatto che nelle persone con menopausa tardiva e pubertà precoce cioè le donne che sono state esposte per più tempo agli estrogeni c’è un maggior rischio si sviluppo dei tumori mammari. Tutto ciò è importante per capire la terapia per questa malattia.

La terapia dei carcinomi della mammella è quanto di più avanzato e ricercato ci sia. I primi farmaci ormonali introdotti nella cura di questo tumore furono i SERM (modulatori selettivi del recettore estrogenico) alla fine degli anni ’70 tra cui il Tamoxifene e il Toremifene, inibitori del recettore degli estrogeni. Questi farmaci costituiscono la terapia ormonale nel carcinoma della mammella la quale ultimamente si avvale anche di SERD (inibitori selettivi del numero di recettori degli estrgeni) come il Fulvestrant oppure inibitori dell’aromatasi che converte gli androgeni in estrogeni cioè Aminoglutemide (non più usata), il Fomestrano oppure il Letrozolo, Anastrazolo ed Exemestano che sono di 3° generazione. Altri farmaci ormonali sono ad es. gli analoghi del GnRH propriamente detti come la Goserelina, Buserelina, Leuprolide etc. che inibiscono down-regolandoli i recettori ipofisari LH e FSH detti ormoni gonadotropi per azione trofica sulla regolazione del ciclo ovarico (FSH) nonché la produzione di androgeni (cellule tecali stromali ovariche sotto stimolo di LH) e della loro aromatizzazione centrale a estrogeni (cellule granulosa sotto stimolo FSH) e gli antagonisti puri del GnRH come Abarelix e Ganirelix che sono attivi come gli analoghi anche contro il carcinoma prostatico ( si associano ai SARM cioè antagonisti selettivi androgenici come Bicalutamide, Flutamide, ciproterone acetato).

Tutti questi farmaci da soli non sono efficaci. Il carcinoma per essere efficacemente trattato infatti deve seguire 3 step:

  • Chirurgia quando la massa è resecabile
  •  Terapia ormonale e chemioterapica
  •  terapia Biologica

Ora, l’approccio chirurgico del carcinoma mammario è quello che ha fatto la storia. E’ ad Umberto Veronesi e molti medici italiani che si deve la nascita della chirurgia conservativa con quadrantectomie e l’idea del linfonodo sentinella cioè quello o quelli verso cui il tumore metastatizza per prima. Tale approccio però è ormai una pagina di storia. La rivoluzione moderna invece viene dalla scoperta di una proteina espressa selettivamente dalle cellule dei carcinomi mammari e cioè Her2. Infatti si vide che i tumori Her2+ erano più aggressivi ed a prognosi peggiore. Ciò ha fatto nascere l’idea di usare un farmaco che bloccasse questo recettore appartenente alla famiglia dell’EFGR con conseguente congelamento del potere proliferativo della massa per i fenomeni noti di oncogene addiction. Pertanto è stato sviluppato il Trastuzumab, commercializzato come Herceptin, un anticorpo monoclonale che lega ed inattiva il recettore (che per funzionare deve eterodimerizzare) aumentandone anche l’internalizzazione con degradazione e che ha portato nelle pazienti con carcinoma ad alto staging ed Her2+ ad una percentuale remissione nella politerapia superiore all’80 % (prima dell’Herceptin era intorno al 25-30% o meno). Naturalmente questo è stato un passo avanti da gigante che ha permesso una seria possibilità di guarigione in queste pazienti, anche aventi una forma molto avanzata di malattia.

Quindi per concludere il take home message è il seguente: il cancro è una malattia curabile. Tutto ciò che sembra impossibile oggi probabilmente non lo sarà domani

Redazione | Nato a Torre del greco il 27/03/1992 5°anno facoltà di medicina e chirurgia Federico II Napoli Appassionato di molte discipline diverse la medicina rappresenta sicuramente la più importante. Non disdegno alcun settore ma le branche che più mi interessano sono quelle della diagnostica clinica, della dermatologia, della ricerca oncologica, della farmacologia, della pediatria e della medicina interna. La mia idea di medico è quella di un lavoro di gruppo che possa essere parte di un team multidisciplinare ben strutturato che garantisca ai pazienti un iter di cura completo ed efficace. Spero un giorno di poter fare esperienze anche in zone di guerra specialmente in medio oriente magari con MSF o Emergency

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