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how to integrate new drugs in the
current therapeutic landscape of
metastatic triple negative breast
cancer
18IN INTRODUCTION: RECENT FAILURES IN DRUG DEVELOPMENT
FOR TN MBC
F. André
Breast Cancer Unit, Department of Medical Oncology, Institut de Cancérologie
Gustave Roussy, Villejuif Cedex, FRANCE
Several compounds have been developed in the recent years in triple negative BC.
Although associated with promising initial results, they all failed to be fully
implemented. Iniparib failed because the compound was not fully characterized, and
because phase II trials amplified the effect of the drug. Olaparib failed because it
targeted a rare population, and partially because its position in the therapeutic
sequence was unclear. Finally, bevacizumab, although registered, was not fully
optimized in the practice. Overall, these failures are illustrative of current questions
in drug development. The first relates to the amount of information needed before
moving to registration trials: is the compound characterized in preclinical models?
Do we have evidence for bioactivity in early trials? Are phase II randomized trials
optimal for decision to phase III? The second relates to the difficulties to develop
drug in small populations defined by a biomarker: how to develop a predictive test?
How to organize clinical research when less than 1 out of 10 patients screened will
enter the trial? What is the path to registration for a drug targeting a rare
population?
Disclosure: F. André: advisory board : SANOFI, Roche, Astrazeneca, novartis
speaker bureau: Novartis
19IN DOES MOLECULAR TRIAGE HELP TO IDENTIFY HIGHLY
SENSITIVE DISEASE?
L. Pusztai
Medical Oncology, Yale University, New Haven, CT, UNITED STATES OF
AMERICA
It is helpful to consider predictive biomarkers within three distinct categories that
also represent different degrees of difficulty in terms of the predictor discovery
process. (1) There are broad treatment response markers that are based on detecting
a fundamental biological process that is relevant for the action of a class of drugs.
Such markers have a large transcriptional (or other molecular) footprint and hence
represent relatively low hanging fruits in the discovery process. For example, high
tumor proliferation is such a marker for general chemotherapy sensitivity or for
worse baseline prognosis. It may be possible in the future to discover similar broad
markers for metabolism-targeted agents or for immunotherapies. (2) There are drug
class-specific predictors such as estrogen receptor (ER) expression or human
epidermal growth factor 2-receptor (HER2) amplification or activating mutations in
critical signaling genes (e.g EGFR, bRAF, c-KIT, etc..) that represent singular driver
events in tumors. These alterations reflect partial dependence on a given molecular
pathway and can predict sensitivity to a variety of agents that target the involved
pathway. Similar driver events for distinct small subsets of cancers are likely to be
discovered in the next decade and could yield predictors with clinically useful
negative predictive value. (3) Single drug-specific response markers that could be
used to select one agent over another have remained elusive despite extensive
research efforts. This may be due to the case-to-case heterogeneity of molecular
mechanisms that can converge to cause sensitivity or resistance to a particular
molecule. Molecular markers under points (2) and (3) and their combinations exist
and are useful to select adjuvant therapies in breast cancer (e.g. Ki67, OncotypeDX,
MammaPrint, ER, HER2, PAM50) or triage patients to clinical trials who are
unlikely to do well with existing treatment modalities. Prospectively designed
molecular triaging studies that directly test the positive predictive value of candidate
response markers also remain an important research strategy to rapidly assess the
clinical utility of predictive markers.
Disclosure: The author has declared no conflicts of interest.
Annals of Oncology 23 (Supplement 9): ix29–ix30, 2012
doi:10.1093/annonc/mds372
20IN DEVELOPMENT OF NEW TARGETED AGENTS FOR TNBC
N. Turner
Breakthrough Breast Cancer, Institute of Cancer Research, London, UNITED
KINGDOM
Triple negative breast cancers are a highly diverse and heterogenous group of
tumours. A number of different approaches to tackling this heterogeneity are
emerging for the targeted treatment of TNBC. Targeting common genetic events
of TNBCs. TNBCs have a high frequency of TP53 mutations in ∼60% of TNBC,
a rate substantially higher than other breast cancer subtypes. Targeting TP53
inactivation has historically been challenging, although preclinical data suggests
that combinations of DNA damaging chemotherapy with CHK1 or WEE1
inhibitors has the potential to target TP53 deficiency. Other common targetable
events include genetic activation of the PI3 kinase pathway in ∼15-20% cancers,
through PTEN deletions/ inactivating mutations and PIK3CA activating mutations,
and loss of HR based DNA repair, though mutation of BRCA1/2 and BRCA1
promoter methylation, that could be targeted with PARP inhibitors. A further
potentially targetable common event includes loss of the phosphatase PTPN12 and
upregulation of specific receptor tyrosine kinases. Targeting TNBC subtype specific
features. Gene expression studies have revealed multiple different gene expression
subtypes in TNBC. The luminal AR subtype expresses the androgen receptor (AR)
and now both preclinical and tentative clinical data to support AR as a
therapeutic target. Mesenchymal-like basal TNBC express autocrine FGF2 ligand
that is important for their biology.
Targeting individual rare events. A diverse set of potentially targetable oncogenic
mutations and amplifications occur in TNBC that are likely important
therapeutic targets for individual cancers, but these present a substantial
challenge to drug development due to their individual rarity. Through such
strategies to sub-segment TNBC progress will be made in delivering targeted
therapies for TNBC.
Disclosure: N. Turner: Dr Nicholas Turner has received honoraria from Novartis,
Astra Zeneca, Roche, Clovis, EOS
21IN IS THERE A ROLE FOR NEW CYTOTOXIC AGENTS IN TNBC?
J. Cortes
Medical Oncology Department, Vall d’Hebron Institute of Oncology, Vall
d’Hebron University Hospital, Barcelona, SPAIN
Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all
cases of breast cancer, is characterized by having estrogen-receptor
(ER)-negative and progesterone-receptor (PR)-negative and has no
overexpression of human epidermal growth factor receptor 2 (HER2). It is an
aggressive subtype of breast cancer marked by higher rates of visceral and
central nervous system metastases and poor disease-free survival compared with
hormone receptor-positive sybtypes. In recent years, an increasing appreciation
and identification of somatic mutations and other genetic aberrations that drive
human malignancies have led us within reach of personalized cancer medicine.
However, after a high expectation with iniparib, a non optimal PARP inhibitor,
final data from a randomized phase III trial did not demonstrate this drug to
improve outcomes in combination with chemotherapy in patients with advanced
TNBC and bevacizumab is the only “targeted” agent which has shown to
improve outcomes in combination with chemotherapy in patients with
metastatic TNBC. Thus, chemotherapy continues to be the standard of care in
these patients. Although taxanes and anthracyclines are still the most important
compounds for patients with metastatic TNBC, the majority of them will
progress and patients will need new chemotherapeutic drugs. Thus, new
cytotoxic drugs are being studied in patients with TNBC in late-line. Among
them, new antimicrotubule agents such as eribulin mesylate have shown to
increase survival versus the treatment of physiciańs choiceandseemstobe
active also in this tumor type. Other agents which seem to play a role are
vinflunine and KNTR-102, a new polymeric conjugate of irinotecan, both in
phase III trials. NKTR-102 has shown an impressive response rate in patients
with very heavily pretreated TNBC, including taxanes, anthacyclines and
capecitabine.
Disclosure: J. Cortes: Consultant: Roche, Novartis, Celgene Honoraria: Roche,
Celgene, Novartis, Cephalon/Teva
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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