Bypassing Mechanisms of Resistance: Introduction

Carlos H. Barrios, MD
PUCRS School of Medicine Porto Alegre, Brazil

Chemotherapy: EBCTCG - 2011

EBCTCG, Lancet 2011.

Breast Cancer Adjuvant Chemotherapy: Treatment Evolution

100%

Trastuz DD TAC
84%

Antra
CMF Surgery

%Disease Free Survival

67% 62%
50%

35% 32% 26%

0%
1 3 5 7 9 11 13 15 years

Bonadonna. NEJM, 2006. EBCTCG, Lancet, 2011. Bonilla, JNCI, 2010.

Martin, ASCO 2010. Slamon, NEJM 2011

Map of 157 chromosomal breakpoints in the MCF-7 breast cancer cell line

Hampton, et al. Genome Res, 2009.

Basal-like Breast Cancer and Genomic Instability

Array CGH in 89 LABC:

% DNA copy number alterations

Red=gain Green=loss Genome-wide aberrations

Chromosome
Bergamaschi et al, Genes Chromosomes Cancer, 2006.

Bypassing Mechanisms of Resistance

Recognize that tumor progression leads to new molecular alterations
Treatment itself induces changes leading to resistance Mechanisms of resistance are not uniform Are we addressing these issues appropriately?

How to Move Forward?

Need to address the ever increasing heterogeneity in molecular subtypes
Recognize and characterize both primary and secondary resistance Challenge of biomarker development Challenge of new (re-)biopsies:
Neo-adjuvant scenario represents a helpful platform but certainly does not cover all the required aspects (ie, dormancy, late relapses, etc.) Mandatory requirement for certain (metastatic) clinical trials?

A Long Time Ago But Not So Far Away From Here

Voltaires Challenge Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing
Franois-Marie Arouet, Voltaire (1694-1778)

Plenary II: Agenda

09:10-09:35 Personalized Care of Breast Cancer Patients: Hope and Hype. Edith Perez
09:35-10:00 New Insights into Mechanisms of Resistance to Chemotherapy. Charles Swanton 10:00-10:30 Closing Cancer Escape Routes: PI3Kinase and mTOR inhibition. Howard Burris

10:30-11:00 Panel Discussion Dennis Slamon, Angelo Di Leo, Masakazu Toi