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Edwin Smith (1822-1906) Papyrus, ca. 1500 a.C. lungo circa 4,5 metri e largo 33 centimetri

Descrive 8 casi di tumori o ulcere della mammella che erano trattati con la cauterizzazione utilizzando una “punta di fuoco”

Galeno di Pergamo (129-216 d.C.)

La teoria umorale di Ippocrate fu ulteriormente supportata da Galeno, e ha dominato per tutto il Medioevo. Galeno attribuiva l’origine del tumore mammario ad una sorta di “melanconia morbosa” e consigliava il trattamento con diete specifiche.

Dal 476 d.C. la medicina diventa appannaggio quasi esclusivo dei religiosi, soprattutto di alcuni ordini monastici, in particolare benedettini. La malattia è considerata una punizione divina e quindi la sua guarigione può essere ottenuta non con le cure ma con le preghiere, dirette al Santo protettore: S. Agata per la mammella, S. Biagio per la gola, S. Lucia per gli occhi, ecc. Al più si può ricorrere a blande terapie dietetiche e fisiche, o all’erboristeria utilizzando estratti delle piante officinali.

DIDEROT, 1780 Encyclopédie ou Dictionnaire raisonné des sciences, des arts et des métiers

1600-1699

William Stewart Halsted in camera operatoria, 1892

“All-Star Operation” from William Stewart Halsted by W. G. MacCallum (Johns Hopkins Press, 1930).

Nel 1894 W. S. Halsted

pubblica i primi risultati ottenuti trattando il carcinoma della mammella con l’intervento di

MASTECTOMIA RADICALE

asportazione in blocco della mammella, dei muscoli pettorali e dei linfonodi ascellari

The Johns Hopkins Hosp. Rep.:

4, 297, 1894

Ormonoterapia del carcinoma della mammella

Data prima publicazione

1896 1922 1939 1944 1951 1952 1953 1953

Tipo di terapia Ovariectomia Irradiazione ovarica Androgeni Estrogeni sintetici Progestinici Irradiazione ipofisi Adrenalectomia

Ipofisectomia

Sino agli anni ’60 Non era previsto alcuna terapia medica dopo l’intervento chirurgico di mastectomia radicale o radicale modificata

Storia della terapia medica del carcinoma della mammella

Intorno agli anni ‘70 si ebbe una svolta grazie alle

migliori conoscenze biologiche Affermazione della terapia medica, come terapia sistemica, ad integrazione della terapia chirurgica e della radioterapia come trattamenti loco-regionali

Storia della terapia medica del carcinoma della mammella

yesterday ….

Human breast cancer, tumor cells are ER positive

today ….

yesterday ….

today ….

yesterday ….

The Molecular Portrait Hypothesis

You can recognize the Mona Lisa by her smile and her nose and her eyes

and even her hands, but not by the sky or the trees

Breast Cancer: not one disease!

today ….

Annals of Oncology 24: 2206–2223, 2013

Breast cancer subtypes today ….

yesterday ….

yesterday ….

Annu Rev Med. 1975;26:353-63.

yesterday ….

Tamoxifen given for approximately five years after surgery to patients with early, estrogen-receptor-positive breast cancer is the current standard of care worldwide. This approach reduces the risk of death by about 25%, a reduction that translates into an absolute improvement in 10-year survival of more than 10% for patients N+ and 5% for patients N-

Early Breast Cancer

Trialists’Collaborative Group

Lancet, May 1998

yesterday ….

today ….

C. Palmieri et al. / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

Milestones in the development of treatment of HR-positive metastatic breast cancer

yesterday ….

yesterday ….

The five-year results of a prospective randomised trial of radical mastectomy (179 patients) versus radical mastectomy followed by adjuvant chemotherapy (207 patients) were analysed. Chemotherapy consisted of 12 monthly cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF).

yesterday ….

CA Cancer J Clin 1986;36;42-47

For premenopausal women with positive nodes, regardless of hormone receptor status, treatment with established combination chemotherapy should become standard care.

For premenopausal women with negative nodes, adjuvant therapy is not generally recommended. For certain high-risk patients in this group, adjuvant chemotherapy should be considered.

For postmenopausal women with positive nodes and positive hormone receptor levels, tamoxifen is the treatment of choice.

For postmenopausal women with positive nodes and negative hormone receptor levels, chemotherapy may be considered but cannot be recommended as standard practice.

For postmenopausal women with negative nodes, regardless of hormone receptor levels, there is no indication for routine adjuvant treatment. For certain high-risk patients in this group, adjuvant therapy may be considered.

yesterday ….

today ….

St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013

Annals of Oncology 24: 2206–2223, 2013

today ….

HERA TRIAL DESIGN

Women with HER2 POSITIVE invasive

breast cancer IHC3+ or FISH+ centrally confirmed

Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy

Stratification

Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age,

region

Randomization

Trastuzumab

8 mg/kg 6 mg/kg

3 weekly x 2 years

Trastuzumab

8 mg/kg 6 mg/kg

3 weekly x 1 year

Observation

today ….

ASCO, Scientific Session, May 16, 2005

A 2008 Lifetime Television movie, directed by Dan Ireland, starring Harry Connick, Jr. The film is based on the true life story of Dr. Dennis Slamon.

Development of treatment of HER2+ metastatic breast cancer

The light microscope remains the central cancer diagnostic tool for 400 years

Zacharias and Hans Jansen (ca 1595)

Modern microscope (ca 1995)

Today’s cancer diagnostic lab

Cellular Phenotyping Microscopy (histology/cytology) Immunohistochemistry Flow Cytometry

Genetic tests Cytogenetics Molecular Genetics Genotyping for specific mutations (PCR/RT-PCR) Minimal Residual Disease monitoring (CGH and SNP/LOH genotyping) (Gene Expression Profiling)

Genome Sequencing

Sanger (capillary) sequencing

2015 ? ~1day ?? $100

2005 ~3 years

~$ 20million

2010 ~1month

$9,500 (Illumina)

AM

L

Me

lanom

a

Sm

all-

cell

lung

Bre

ast

2008 ~4 months

~$ 1.5million

Lun

g (

NS

S)

Cancer Genomics

2000 ~10 years

~$ 3.5 billion

Myelo

ma

Hepato

ce

llula

r

CLL

Mo

use A

ML

Next generation sequencing

Diagnostic whole genome sequencing

Constitutional genome

Cancer genome

Compare

Clinical Report

Other diagnostic data

Somatic mutations Subclonal heterogeneity

Substitutions Indels

Copy number changes Translocations

Inherited mutations & polymorphisms

Cancer

Normal tissues

DNA with tumour-specific mutation

Plasma DNA

Slide courtesy of Dr Peter Campbell

Nuove opzioni terapeutiche

“terapie mirate” ovvero

la personalizzazione della cura

Triangolo Terapeutico

PAZIENTE

TUMORE FARMACO TERAPIA

RESISTENZA

INTERAZIONI FARMACO-TUMORE

INTERAZIONI OSPITE-TUMORE

INTERAZIONI FARMACO-OSPITE

Approccio multidisciplinare carcinoma della mammella

PAZIENTE

TUMORE FARMACO

Anatomia Patologica Biologia Molecolare Cardiologia Chirurgia Senologica Chirurgia Plastica Dermatologia Farmacia Genetica Medica Ginecologia Medicina di Base Medicina Nucleare Medicina di Laboratorio Medicina Palliativa Oncologia Medica Ortopedia Radiologia Radioterapia ………….

How breast cancer subtypes influence treatment

Turner N C , Jones A L BMJ 2008;337:bmj.a540

Breast cancer mortality has dropped by

nearly one-third since 1990

Akt

SOS

RAS

RAF

MEK

VEGF

MAPK P

P

P P

Receptor-specific

ligands

HER1, HER2,

HER3, or HER4

HER2

HER1

(EGFR)

HER2 HER4 HER3

Tyrosine kinase

domains

Plasma

membrane

PI3K

Cell proliferation

Cell survival

Cell mobility and invasiveness

Cytoplasm

Nucleus

Transcription

Signal Transduction Pathways by the HER Family

Ross JS, et al. The Oncologist. 2009;14:320-368.

Signal Transduction Pathways by estrogen receptors

A. Friedman and N. Perrimon, Cell 128, January 26, 2007

Pathway vs. Network signaling

Network “Chaotic”

Pathway “Newtonian”

Puglisi et al, Drugs 2012

Therapies targeting downstream HER2-pathways in clinical trial in breast cancer

C. Palmieri et al. / Molecular and Cellular Endocrinology xxx (2013) xxx–xxx

Targeted therapies in clinical trial with endocrine therapy in breast cancer

The Future?

Cancer Patient

Surgery/Biopsy

Cancerous Tissue

Array Analysis

Tumor Fingerprint

Individualized Treatment

• Imaging

• Multiparametric/miniature testing of serum on a protein array

• Mass spectrometric serum/urine proteomic pattern generation

General Population

Screen-positive patients

Prevention; Effective Therapy

The Future?

Asymptomatic individuals

Predisposition to certain disease

Prevention (drugs; lifestyle) Surveillance

The Future?

Whole genome SNP analysis