ESTRO 36 Abstract Book

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S252 ESTRO 36 2017
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Performed scans are summarized in table 1.
In total 22/32 patients (69%) showed hypoxia at baseline
in primary tumor and/or lymph nodes. In the 11 hypoxic
tumors a significant negative correlation was found
between baseline HX4-TBR and tumor blood flow (r=-
0.618, p=0.043) and blood volume (r=-0.736, p=0.010).
(Fig 1).
After nitroglycerin administration, 4 of the 15 patients
(27%) with a baseline hypoxic tumor and/ or nodes that
received a second HX4-scan could not be classified as
hypoxic anymore. In the group of tumors with baseline
hypoxia we found a significant negative correlation
between the change in blood volume and HX4-HF (r=-
0.829, p=0.042) and HX4-TBR (r=-0.829, p=0.042). In non-
hypoxic tumors there was no correlation between the HX4-
TBR and either of the perfusion parameters.Conclusion
In this trial 27 percent of patients with baseline hypoxic
tumors and nodes become normoxic after treatment with
nitroglycerin. Dynamic contrast enhanced CT-scans
demonstrate that this effect on hypoxic tracer uptake is
negatively correlated with an effect on tumor perfusion in
hypoxic tumors. These results support the hypothesis that
hypoxia scans and/or DCE-CT scans could form a tool to
select patients for a nitroglycerin patch adjuvant to anti-
cancer treatment (radiotherapy, chemotherapy, targeted
agents or immunotherapy). An animation summarizing our
results is available at
OC-0482 Interferon stimulated genes: a common
pathway in tamoxifen- and radioresistance in breast
cancer
A. Post1, M. Smid2, A. Nagelkerke1, J. Martens2, J.
Bussink1 , C. Sweep3, P. Span1
1 Radboud university medical center, Radiation Oncology,
Nijmegen, The Netherlands
2 Erasmus MC Cancer Institute, Department of Medical
Oncology and Cancer Genomics Netherlands, Rotterdam,
The Netherlands
3 Radboud university medical center, Laboratory
Medicine, Nijmegen, The Netherlands
Purpose or Objective
Treatment resistance is an important cause of adverse
outcome in breast cancer. Several mechanisms involved in
resistance to either radiotherapy or endocrine therapy
(tamoxifen) have been elucidated. Since tamoxifen
resistant breast cancer cells were found to be less
sensitive to irradiation, we aimed to investigate common
pathways involved in radiotherapy and tamoxifen
resistance.
Material and Methods
The estrogen receptor positive breast cancer cell line
MCF7 was grown to radioresistance by exposing them to
multiple fractions of 4 Gy irradiation, adding up to a total
dose of at least 50 Gy (MCF7RT). Tamoxifen resistant MCF7
cells were created by culturing with gradually increasing
concentrations of 4-hydroxy-tamoxifen up to 10 µM
(MCF7TAM). Changes in expression profiles in MCF7RT and
MCF7TAM cells compared to parental MCF7 cells were
investigated by RNA sequencing, and common pathways
identified. QPCR was used to confirm the RNA sequencing
data, and to investigate expression of genes of interest
after irradiation and tamoxifen treatment.
Results
Genes involved in interferon signaling were significantly
increased in both MCF7RT and MCF7TAM compared to
parental MCF7 cells. For further experiments, five
interferon stimulated genes (ISGs; representing different
parts of the signaling pathway) were evaluated, namely
DDX60, STAT1, OAS1, IFI6 and IFI27. Differential
expression of these five ISGs in the resistant MCF7 cells,
and in treatment resistant T47D cells (also an estrogen
receptor positive breast cancer cell line), was confirmed
by qPCR. Expression of ISGs was induced by treatment: all
five genes were increased 24h and 48h after irradiation
with 4 Gy. Tamoxifen treatment (1 or 10 mM for 24h) also
led to increased ISG expression.
In patients treated with tamoxifen (KMplot, n=849), high
expression of ISGs correlated with a worse outcome (figure
1). Additionally, in a cohort of advanced breast cancer
patients (n=344), ISGs were co-expressed and correlated
with a tumor infiltrating lymphocyte signature, which in
turn was associated with a shorter time to progression
after tamoxifen treatment in these patients.
Figure 1
Conclusion
We show here that expression of ISGs is increased in MCF7
cells resistant to radiotherapy or tamoxifen, compared to
parental MCF7 cells. Since the expression of ISGs already
increased after a single dose of irradiation or tamoxifen
treatment, we hypothesize that after extended treatment
the interferon signaling pathway is upregulated and
confers a survival advantage to the cells, ultimately
leading to treatment resistance. We are currently
investigating the effect of pathway inhibition on the
sensitivity of resistant MCF7 cells to irradiation and