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Study to Assess Response to Tamoxifen in (cT3)/ Inoperable Locally Advanced / Metastatic ER-positive BC by the 'Tamoxifen Activity Score' Based on Drug Interaction and Polymorphisms in Genes Coding for Tam. Metabolising Enzymes.

18 Years
Open (Enrolling)
Breast Neoplasm, Female

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Trial Information

Study to Assess Response to Tamoxifen in (cT3)/ Inoperable Locally Advanced / Metastatic ER-positive BC by the 'Tamoxifen Activity Score' Based on Drug Interaction and Polymorphisms in Genes Coding for Tam. Metabolising Enzymes.

This multi-centre open label single arm non randomized observational study will compare the
efficacy in terms of overall response rate and progression free survival of tamoxifen as
first line therapy in 3 groups of postmenopausal women with measurable hormone dependent
large, locally advanced or metastatic breast cancer. The 3 groups are women with a normal
and those with a low 'tamoxifen activity score' based on genetic polymorphisms for CYP2D6
and other genes that are important in the metabolism of tamoxifen using SEQUENOM's MassARRAY

The study is subject to Ethical Commission approval and patient consent. The study will
necessitate collection of blood for genetic analyses.

We will investigate the relation between the studied genotype, the use of drugs that
interfere with tamoxifen and tamoxifen-related endpoints like regression of metastatic or
locally advanced or large oestrogen receptor positive breast cancer in tamoxifen users. The
'tamoxifen activity score' has been used by a group in the US showing a link with tamoxifen
compliance. The score will be adapted to the Belgian situation based on the prevalence of
polymorphism in a Belgian population. The efficacy of tamoxifen will be correlated with a
predefined 'tamoxifen activity score' which is based on the presence of single nucleotide
polymorphisms (SNP) in relevant genes combined with the effect of well known drugs that
interfere with the metabolism of tamoxifen.

The study will be conducted in several clinical sites in Belgium. All patients will receive
tamoxifen 20mg daily. Patients with a large operable or inoperable non-metastatic breast
cancer will be considered for surgery no more than 4 months on tamoxifen. If operable, they
will postoperatively receive the most appropriate adjuvant therapy and for hormone therapy
either continue tamoxifen or receive an oral aromatase inhibitor as decided by the
clinician. If women with a locally advanced inoperable breast cancer are not operable after
the 4 months of neo-adjuvant therapy, another appropriate salvage therapy will be proposed.
Women with metastatic breast cancer will continue treatment until clinical or imaging
progression or unacceptable toxicity development. Patients that experience progression of
their disease as defined by RECIST criteria will receive salvage therapy by an oral
aromatase inhibitor if tamoxifen is given in first line but some patients may require
another therapy like chemotherapy. The study will require approximately 14 months to recruit
and another 7 months to events/data analyses as the estimated time to progression in this
setting is 9-12 months if tamoxifen is given as first line endocrine therapy for those in
the metastatic setting

Inclusion Criteria:

- - Female > 18 years of age

- Written and voluntary informed consent understood signed and dated

- Histologically or cytologically confirmed measurable invasive adenocarcinoma of the
breast either large (cT3), locally advanced stage IIIB/C inoperable, or metastatic
and not amenable to curative therapy with surgery or radiotherapy.

- Measurable disease is defined as follows: CT scan for metastatic or locally advanced
stage IIIB disease and ultrasound of the breast for operable large size breast
cancers where tamoxifen is given for neoadjuvant endocrine therapy .

- Patients must be postmenopausal as defined by criteria in appendix 1.

- Breast cancer should be considered as oestrogen receptor positive by the clinician
using immunohistochemistry readings as is standard procedure for local pathologist

- Prior endocrine tamoxifen therapy in the adjuvant setting is allowed if there is more
than 12 months after completion of adjuvant tamoxifen.

- Prior radiotherapy is allowed but evaluable lesions that have been irradiated need to
be progressive before starting in the study

- Concurrent use of bisphosphonates is allowed if they are started 2 weeks before study
start and these drugs should be continued as planned throughout the study

- Adequate renal and liver function Serum creatinine and serum bilirubin ≤ 1.5 X ULN
Serum ALT and AST ≤ 2.5 X ULN (or ≤ 5 in case of liver metastases)

- Serum calcium should be ≤ 11,6 mg/dl

- ECOG performance status 0,1,2 (appendix 2)

Exclusion Criteria:

- - Male

- Life threatening disease requiring a quick response (eg, extensive hepatic or
pulmonary involvement)

- CNS involvement

- Less than 12 months since stopping tamoxifen in the adjuvant setting

- Previous chemotherapy, tamoxifen or more than one line hormone therapy or targeted
therapy for locally advanced/ metastatic breast cancer

- Bone lesions only

- One line of prior endocrine therapy with an oral aromatase inhibitor for locally
advanced or metastatic breast cancer is not allowed also not if there is clear
progression according to RECIST and the clinician judges tamoxifen an appropriate
second line therapy

- Contra indication for tamoxifen: history of DVT/vaginal bleeding of unknown origin

- Dementia

- History of other malignancy that may interfere with at least 6 months of tamoxifen

Type of Study:


Study Design:

Observational Model: Case-Only, Time Perspective: Prospective

Outcome Measure:


Outcome Time Frame:

3 months/ 6 months

Safety Issue:


Principal Investigator

Patrick Neven

Investigator Role:

Principal Investigator

Investigator Affiliation:

UZ Leuven


Belgium: Federal Agency for Medicinal Products and Health Products

Study ID:




Start Date:

February 2009

Completion Date:

Related Keywords:

  • Breast Neoplasm
  • Female
  • Breast Neoplasms
  • Neoplasms