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optimizing treatment in luminal breast
cancer
13IN INTRODUCTION: LUMINAL A AND B: HOW CURABLE ARE
THEY?
A. Di Leo 1 , N.H. Turner 1 , L. Malorni 1 , C. Guarducci 2
1 Oncology- Istituto Toscano Tumori, Ospedale di Prato Sandro Pitigliani Med.
Oncology Unit, Prato, ITALY, 2 Ospedale di Prato, Translational Research Unit,
Prato, ITALY
Hormone receptor positive (HR+) breast cancers can be separated by molecular
subtyping into luminal A breast cancer (LUM A), which is more prevalent though
less aggressive, and luminal B breast cancer (LUM B), which is associated with
higher grade, increased proliferation rates, and an overall poorer prognosis. Other
than genetic molecular subtyping, which can be expensive and not readily available,
it may be possible to differentiate between these two subgroups using
immunohistochemical assessment of the proliferative marker Ki67, as reported by
Cheang et al, where a cut off of Ki67 14% was used. This method of assessment
demonstrated utility in providing prognostic information, however the false positive
and false negative rates were around 25%, suggesting there is significant room for
improvement within such a method, and thus highlighting an area for ongoing
research. Methodology aside, differentiation of HR+ breast cancers by molecular
subgroups is critical, in order to identify appropriate treatment options for patients.
Generally, endocrine therapy alone would be recommended for LUM A, which
carries an excellent ten year breast cancer specific survival rate of approximately 90%.
However, tumor dormancy and late recurrences beyond 10 years are characteristic of
LUM A. There is a significant lack of knowledge of the mechanisms behind tumor
dormancy, highlighting a crucial area for further research. Additionally, the optimal
manner and duration of endocrine therapy in either pre- or postmenopausal women
is, as yet, unknown; extension of endocrine treatment beyond 5 or even 10 years, as
well as the most effective endocrine therapy agent, requires ongoing study to better
define treatment algorithms for LUM A. LUM B, which is inherently more
aggressive, requires more aggressive therapy and thus is generally treated with both
endocrine therapy and chemotherapy, though this approach is not always effective.
Potential alternate or additional treatment options may include targeting of other
pathways of importance in this subgroup. This therefore requires firstly identification
of pathways active in LUM B, and secondly, development and assessment of targeted
agents against these pathways. The utility of inhibitors against mTOR, PI3K or
IGFR-1 is of particular interest.
Disclosure: All authors have declared no conflicts of interest.
14IN HOW TO OPTIMISE ENDOCRINE THERAPY
S.R.D. Johnston
Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UNITED
KINGDOM
For post-menopausal women with early stage ER+ breast cancer, aromatase
inhibitors are recommended to be part of adjuvant endocrine therapy either as
up-front therapy or as a switch strategy following initial tamoxifen therapy. Both
approaches are equally effective, and both are superior to tamoxifen alone for 5
years. The current duration for aromatase inhibitors given as adjuvant therapy is 5
years based on current safety and efficacy data. However, the optimal duration of
adjuvant endocrine therapy is currently unknown, and extended adjuvant therapy
with aromatase inhibitors after tamoxifen is an increasingly utilised strategy for
reducing ongoing risk of recurrence, especially for those deemed to be at greater
risk such as those with node-positive disease or other indicators for late relapse. In
pre-menopausal women with ER+ early breast cancer the added benefit of ovarian
suppression over and above tamoxifen remains unknown. In women aged 10% the tumor is very unlikely to fall into the
lowest relapse risk category at post neoadjuvant endocrine therapy surgery
(preoperative endocrine prognostic index zero or PEPI-0 (defined as ER+ Stage 1 or
2A, Ki67 < 2.7%) and therefore not suitable for continued neoadjuvant endocrine
therapy (since one of the objectives of our studies is to avoid chemotherapy in AI
sensitive tumors). We have recently completed a successful pilot of triaging 35
patients with an early on treatment high Ki67 values to chemotherapy with the
efficacy results to be reported at the San Antonio Breast Cancer Symposium. The
ALTERNATE trial is based on these principles (ALTernate approaches for clinical
stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment) and
will screen over 2000 patients to identify up to 400 cases of ER+ HER2- AI resistant
breast cancer who will be suitable candidates for investigational neoadjuvant
approaches to improve outcomes in this understudied group of high risk patients.
Patients with PEPI-0 disease will be managed without adjuvant chemotherapy with a
prospective plan to demonstrate that the 5 year relapse rate is 5% or less.
Disclosure: The author has declared no conflicts of interest.
16IN NEW TARGETED AGENTS IN LUMINAL BC
J. Baselga
Massachusetts General Hospital Cancer Center and Harvard Medical School,
Boston, MA, UNITED STATES OF AMERICA
In recent years the description of well-defined molecular subtypes of breast cancer,
together with the identification of driving genetic alterations and signaling
pathways, has led to the clinical development of a number of successful molecular
targeted agents. Among them, luminal B breast cancer is emerging as an important
subset of ER+ tumors that are less responsive to hormonal therapy. Novel targets
under exploration in this group of patients include inhibitors of the
PI3K-AKT-mTOR. In this regard, a recently reported phase III study the mTOR
inhibitor everolimus and exemestane to exemestane and placebo in 724 patients
with HR+ breast cancer refractory to nonsteroidal aromatase inhibitors showed that
the combination of everolimus and exemestane resulted in marked improvement in
progression-free survival as determined by local investigator assessment (6.9 vs. 2.8
months; hazard ratio [HR], 0.43; P = 1.4 × 10 −15 ) 1 .The clinical benefit observed in
the combination arm also far exceeds the clinical benefit of single-agent everolimus
in a similar population of patients. In addition novel PI3K inhibitors are being
tested in patients with breast cancer including PI3K alpha specific agents that have
shown activity in patients with breast cancer harboring PI3K mutations. Other
approaches include inhibitors against the MEK pathways, as well as receptor
tyrosine kinase inhibitors such as the Insulin-like growth factor receptor (IGF-1R)
and the fibroblast growth factor receptor (FGFR). The clinical development of these
agents will require a change from the current large randomized trials in unselected
patient populations to smaller trials in molecular defined tumor types that
incorporate tumor biomarker endpoints as well as functional imaging. New
challenges include the appearance of resistance either by acquired secondary
mutations, or via induction of adaptive activation of compensatory pathways that
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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