Prediction of Response Of horMOnal Treatment in advanced and recurrent Endometrial cancer

Endometrial cancer (EC) is the fourth most common malignancy in Europe, with a
current incidence of 18/100,000 women per year in the European Union, resulting
in a total of 65,000 new cases per year. The incidence of endometrial cancer is
rising and is expected to continue rising in the coming years due to an
increased life expectancy and increased prevalence of obesity. Endometrial
cancer in general has a relatively good outcome, since most patients present
with stage I disease. If this group of patients is successfully treated, they
have a five year survival of 90%. However, 20% of patients present with
advanced stage or have a recurrence; prognosis for these patients is poor with
few curative treatment options. Curative treatment for advanced stage disease
is surgery and chemotherapy. Hormonal therapy is an alternative treatment
option for those women who are medically unfit for surgery or chemotherapy.
Recurrent endometrial cancer can only be cured in case of a local recurrence
with (extensive) surgery or radiotherapy. Systemic recurrences are incurable
and can be treated with chemotherapy or hormonal therapy. In this setting,
chemotherapy has a response rate (RR) ranging from 20% in patients with prior
chemotherapy to around 40% in chemotherapy naïve patients. However chemotherapy
results in severe side effects with 26% of patients experiencing neurotoxicity
of grade 2 and higher and 18% having to discontinue treatment due to toxicity.
The RR for hormonal therapy ranges from 20% to 40%, with adverse events
occurring in less than 5% of patients. Therefore, hormonal treatment can be a
realistic alternative in both advanced and recurrent disease. However, there is
no consensus on the position of hormonal treatment in relation to chemotherapy.
In a retrospective analysis of pre-treatment tumour samples of patients with
advanced or recurrent EC (PROMOTE-R), the hormonal biomarkers oestrogen
receptor (ER) expression, progesterone receptor (PR) expression, androgen
receptor expression (AR) and oestrogen receptor (ER) pathway activity were
related to response to hormonal therapy. Based on these analyses, a
response-prediction algorithm was developed to improve patient selection for
hormonal therapy using the most promising markers PR expression and ER pathway
activity. PR expression was used as first test using a cut-off value of 50%
since PR expression <=50% did not result in response in any patients. For
patients with PR expression >50%, the RR was 50%. Among patients with PR
expression>50%, a positive ER pathway activity increased the RR to 57.6%. The
primary objective of this prospective study is to validate the response
prediction algorithm with RR as primary outcome and progression free survival
(PFS) and clinical benefit rate (CBR) as secondary outcomes.
In recent years, genomic analysis of ECs have resulted in identification of
molecular aberrations that were associated with prognosis. Specific aberrations
can be used for targeted treatment, but associations with response to hormonal
therapy is currently unclear. In the PROMOTE-P study, exploratory analyses will
be performed to relate molecular biomarkers with response to hormonal therapy.
Next, blood samples will be collected for exploration of the serum steroid
analysis for response prediction. Serum steroids have been associated with
prognosis, but not yet with response to hormonal therapy. In addition, blood
serum provides an opportunity to identify predictive biomarkers in cell free
tumour DNA. Aside from response to hormonal therapy, it is also important to
evaluate the patient perspective on hormonal therapy as currently there is no
information on this subject available. Chemotherapy was shown to lower the
quality of life at least in the short term in patients who had received
adjuvant chemoradiotherapy in a study with curative intent (11). The
health-related Quality of Life (HR-QoL) was reported to improve with time, but
progression free interval are shorter for patients with advanced stage and
recurrent EC treated with palliative chemotherapy (12). It is therefore
important to assess HR-QoL in patients with advanced or recurrent endometrial
cancer to better compare hormonal therapy with chemotherapy in this setting.

Primary Objective:
Validation of the response prediction algorithm to hormonal therapy defined as
response rate, progression free survival (PFS) and clinical benefit rate (CBR).

Secondary Objectives:
• Health-related quality of life in patients with advanced or recurrent
endometrial cancer receiving hormonal therapy.
• Evaluation of the relation between the molecular markers and the response to
hormonal therapy

Prospective observational study

The validated PROMOTE algorithm will be used to improve patient selection for
hormonal therapy. This could potentially prevent patients from receiving
hormonal therapy and its side effects when the chance of response is slim. On
the other side, it could also show that hormonal therapy is just as effective
as chemotherapy for that individual patient, thereby preventing (severe) side
effects associated with chemotherapy.