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Annals of Oncology
and 2 GSs were associated in both ER+ and ER-/HER2+ groups with pathologic
complete response (pCR) (e.g. T-cell activation and differentiation) and residual
disease (RD) (e.g. Cell-cell junction) respectively (combined p ≤ .001). We also noted
ER specific associations with pCR or RD. For instance, 18 GSs were associated with
pCR in ER-/HER2+ (p ≤ .001) but not in ER + /HER2+ tumors (e.g. chemochine
C-C binding and activity, phospholipid catabolic process).
Conclusions: Among HER2+ tumors, ER- and ER+ cancers represent distinct
molecular subtypes. Immune signatures predict for good prognosis and higher
chemotherapy sensitivity in HER2+ cancers regardless of ER status.
Disclosure: All authors have declared no conflicts of interest.
173O OPTIMIZING THERAPEUTIC COMBINATIONS OF A
SELECTIVE MEK 1/2 INHIBITOR (PIMASERTIB) WITH PI3K/
MTOR INHIBITORS OR WITH MULTI-TARGETED KINASE
INHIBITORS IN PIMASERTIB-RESISTANT HUMAN LUNG
AND COLORECTAL CANCER CELLS
E. Martinelli 1 , T. Troiani 1 , F. Morgillo 1 ,E.D’Aiuto 2 , L. Ciuffrida 3 , S. Costantini 3 ,
L. Vecchione 4 , V. De Vriendt 4 , S. Tejpar 4 , F. Ciardiello 1
1 Division of Medical Oncology, Department of Experimental and Clinical Medicine
and Surgery “F. Magrassi and A. Lanzara”, Second University of Naples, Naples,
ITALY, 2 Immunology Department, Second University of Naples, Naples, ITALY,
3 Pharmacology Department, Second University of Naples, Naples, ITALY,
4 Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM
Background: The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR
pathways are key intracellular signal transduction pathways for the control of survival
and proliferation in human cancer cells. Selective inhibitors of different transducer
molecules in these pathways have being developed as molecular targeted anti-cancer
therapies.
Methods: The in vitro and in vivo antitumor activity of pimasertib, a selective MEK
½ inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR
inhibitor (everolimus), or with multitargeted kinase inhibitors (sorafenib and
regorafenib) were tested in a panel of eleven human lung and colon cancer cell lines.
Results: Following pimasertib treatment, the cancer cell lines were classified as
pimasertib-sensitive (IC 50 for cell growth inhibition of approximately 0.001 µM) or
pimasertib-resistant (IC 50 for cell growth inhibition above 3 µM). Evaluation of basal
gene expression profiles by microarrays identified a series of genes that were
up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/
RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of
combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or
regorafenib were conducted, demonstrating a synergistic effect in cell growth
inhibition, G1 phase arrest and induction of apoptosis with a sustained blockade in
MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human
colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude
mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the
combination treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor)
or with sorafenib caused significant tumor growth delays and increase in mice
survival as compared to single agent treatment.
Conclusion: These results suggest that it is possible to overcome intrinsic resistance
to MEK inhibition by the dual blockade of MAPK and PI3K pathways.
Disclosure: All authors have declared no conflicts of interest.
174O VEGF-A-INDUCED TREG PROLIFERATION, A NOVEL
MECHANISM OF TUMOR IMMUNE ESCAPE IN COLORECTAL
CANCER: EFFECTS OF ANTI-VEGF/VEGFR THERAPIES
M. Terme, S. Pernot, E. Marcheteau, O. Colussi, F. Sandoval, N. Benhamouda,
E. Tartour, J. Taieb
Parcc-european Georges Pompidou Hospital, INSERM U970, Paris, FRANCE
Background: Regulatory T cells (Treg) are suspected of hindering an effective
antitumor immune response in cancer. Multi-target anti-angiogenic tyrosine kinase
inhibitors (TKI) that are routinely used as first or second line treatment of cancer
patients, have been shown to decrease Treg proportion in tumor-bearing mice and
metastatic renal cancer patients. However, the role of VEGF/VEGFR blockade in this
effect is still debatable, and the direct impact of VEGF-A on Treg has not been studied.
Methods: Treg proportion, number were analyzed by flow cytometry in peripheral
blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, and
in CT26 tumor-bearing mice treated with drugs targeting the VEGF axis. The direct
impact of VEGF on Treg increase in cancer was also studied.
Results: Sunitinib (a TKI targeting VEGFR, PDGFR, c-kit), and anti-VEGF-A
antibody both decreased Treg in CT26 tumor-bearing mice. Masitinib, a TKI that does
not target VEGFR, did not reduce Treg proportion in CT26 bearing mice.
Bevacizumab, an anti-VEGF-A monoclonal antibody, reduced Treg proportion in
peripheral blood of mCRC patients. Proliferation of Treg was enhanced in CT26
tumor-bearing mice compared to tumor-free mice and was decreased after
anti-VEGF-A treatment. Furthermore, in vitro experiments have shown that VEGF-A
could directly induce Treg proliferation. VEGFR1 and 2 were expressed on Treg in the
presence of a tumor. Anti-VEGFR2 antibody administration reduces Treg proportion
and also proliferation in CT26 bearing mice, but anti-VEGFR1 antibody did not,
suggesting that VEGF-A-induced Treg proliferation was dependent on VEGFR2
expression. In metastatic CRC patients, Treg proliferation was also enhanced
compared to healthy volunteers and was blocked by bevacizumab treatment.
Conclusions: We identified a new mechanism by which VEGF-A induced by the
tumor could stimulate Treg proliferation. VEGF-A/VEGFR2 blockade reduced Treg
proportion and proliferation in tumor-bearing mice and metastatic CRC patients
suggesting that combination of anti-VEGF-A/VEGFR2 therapies with immunotherapeutic
approaches in the future might be particularly relevant in CRC patients.
Disclosure: J. Taieb: advisory role, Roche; research grant, Roche. All other authors
have declared no conflicts of interest.
175PD EFFECTS OF CHEMOTHERAPY ON IPILIMUMAB-MEDIATED
INCREASES IN ABSOLUTE LYMPHOCYTE COUNT AND
ACTIVATION OF T CELLS
S.D. Chasalow 1 , J.D. Wolchok 2 , M. Reck 3 , S. Maier 4 , V. Shahabi 5
1 Bioinformatics, Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF
AMERICA, 2 Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY,
UNITED STATES OF AMERICA, 3 Thoracic Oncology, Hospital Grosshansdorf,
Grosshansdorf, GERMANY, 4 Global Clinical Research, Bristol-Myers Squibb,
Lawrenceville, NJ, UNITED STATES OF AMERICA, 5 Oncology Biomarkers,
Bristol-Myers Squibb, Princeton, NJ, UNITED STATES OF AMERICA
Background: Ipilimumab (IPI) is a fully human monoclonal antibody that binds
CTLA-4 to augment an antitumor T-cell response. Consistent with the expected
immune-stimulating effect, increases in absolute lymphocyte count (ALC) and
activation of peripheral-blood T cells frequently have been observed in patients (pts)
treated with IPI as monotherapy. Such changes thus appear to be indicators of the
biological activity of IPI. Combining IPI with other treatments, such as
chemotherapy (CT), may have the potential to enhance efficacy. However, CT may
also interfere with the immune-stimulating effects of IPI. The current analysis
investigated the effect of IPI on ALC and T cell activation in the presence of CT.
Methods: ALC was measured in 3 trials of IPI + CT (n = 887). In CA184024, IPI or
placebo (PLB) was combined with dacarbazine (DTIC) in metastatic melanoma
(MM) pts. In CA184041, IPI in 2 different dosing schedules or PLB was combined
with carboplatin/paclitaxel (CP) in lung cancer (NSCLC and SCLC) pts. In
CA184078, IPI was combined with PLB, CP, or DTIC in MM pts. ALC assessments
from baseline through the end of a 12- or 18-week dosing period were included. In
CA184078, frequency of peripheral-blood activated (HLA-DR + ) T cells at 0, 3, and
11 weeks from first treatment was assessed by flow cytometry. Extended linear
models were used to estimate mean ALC and T cell frequencies as a function of time
and treatment group.
Results: In all 3 studies, mean ALC increased significantly (p < 0.0001 to p = 0.027)
over time after initiation of treatment in the IPI-containing arms, with or without
CT, but not in the PLB arms. In the IPI arms, mean ALC changes from baseline to
the end of IPI dosing ranged from 0.45 to 0.75 x 10 9 cells/L. ALC increases were
temporally associated with IPI, but not CT, dosing. In CA184078, mean relative and
absolute frequencies of activated CD4 + and CD8 + T cells increased significantly after
start of IPI treatment similarly in the 3 arms.
Conclusions: Mean increases in ALC and activated T cells, similar to those seen with
IPI monotherapy, were observed after treatment with IPI combined with CP or
DTIC. This suggests that IPI maintains biological activity when administered with
CT, thus supporting continued clinical evaluation of IPI/CT combination therapy.
Disclosure: S.D. Chasalow: Employment by Bristol-Myers Squibb, Bristol-Myers
Squibb stock ownership. J.D. Wolchok: I am a consultant to Bristol-Myers Squibb,
Merck and Glaxo Smith Kline. I have research support from Bristol-Myers Squibb.
M. Reck: Consultant/advisor to Bristol-Myers Squibb, Hoffmann-La Roche, Eli Lilly,
Pfizer, AstraZeneca, and Daiichi Sankyo; compensated, self. S. Maier: Employment
by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership. V. Shahabi:
Employment by Bristol-Myers Squibb, Bristol-Myers Squibb stock ownership.
176PD PREDICTION OF LATE BREAST CANCER RECURRENCE BY
THE ROR (PAM50) SCORE IN POSTMENOPAUSAL WOMEN
IN THE TRANSATAC COHORT
J. Cuzick 1 , I. Sestak 1 , S. Ferree 2 , J.W. Cowens 2 , M. Dowsett 3
1 Centre for Epidemiology Mathematics and Statistics, Queen Mary University of
London, London, UNITED KINGDOM, 2 Nanostring Technologies, NanoString
Technologies, Seattle, WA, UNITED STATES OF AMERICA, 3 Academic
Department of Biochemistry, Breakthrough Research Centre, London, UNITED
KINGDOM
Background: Adjuvant endocrine therapy beyond 5 years is known to be of benefit
to some oestrogen receptor (ER) positive breast cancer patients. We have shown
previously that the IHC4 score and the ROR score are significantly correlated with
distant recurrence in the cohort from the TransATAC study. Here we assess the
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds391 | ix75