Systemic therapy with or without Up front surgery of the primary tumor in Breast cancer patients with distant Metastases at Initial presenTation (SUBMIT, BOOG 2010-05)

Patients with breast cancer are treated with surgery of the breast tumor if
there is no evidence of distant metastases. However, 5% of all patients with
breast cancer present with primary distant metastases (metastases at initial
presentation). Because metastatic breast cancer is considered to be an
incurable disease, the aim of the treatment is to provide palliation. Therefore
systemic therapy is used. Breast surgery is only performed if the tumor is
symptomatic. Until recently, it is believed that, once distant metastases have
occurred, (aggressive) local therapy provides no survival advantage and should
not be the aim of the treatment. Nevertheless, women who have primary
metastatic disease and survive several years following this diagnosis may
benefit from elimination of the primary tumor as a source of re-seeding of
distant sites.

Recent retrospective studies have demonstrated that (complete) resection of the
primary tumor significantly improves the outcome of patients with primary
metastatic breast cancer. The hazard ratios for overall survival vary from 0,47
to 0,71. Furthermore, in studies taking into account surgical resection
margins, better survival was only observed in patients whose primary breast
lesion had been removed with free surgical margins.

It has to be mentioned that in several studies potential confounders can be
identified: age, site of metastases and surgical margins. Most retrospective
studies adjusted for age, hormone receptor status and site of metastases, but
hardly any study adjusted for factors such as comorbidity or selection criteria
for surgical treatment.

Also, three recent studies showed that different forms of bias may explain the
observed survival benefit in patients who underwent surgery. This concerns
stage migration bias, case selection bias and coding errors based on the
retrospective character of the studies.

Given the results of these retrospective studies, it is not possible to answer
the question whether up front surgery of the primary tumor does improve overall
survival. A randomized controlled trial (RCT) should therefore be performed.

In a randomized controlled trial effective local therapy, meaning a resection
with free surgical margins, should be performed (in case of randomization for
surgical treatment) and at the same time the study protocol should allow
flexibility in the choice of systemic therapy regimens.

Up front breast surgery in patients with primary distant metastatic breast
cancer, will result in an improvement of the 2-year survival compared to the
survival achieved with systemic therapy and delayed local treatment or systemic
therapy alone.

The objective of the study is to test the following hypotheses:

I Up front breast surgery in patients with primary distant metastatic breast
cancer, will result in a significant improvement of the 2-year survival
compared to the survival achieved with palliative systemic therapy followed by
delayed local treatment or systemic therapy alone.

II Local tumor control in these patients will be superior in case of up front
breast surgery compared to patients who receive systemic treatment with delayed
local therapy or systemic therapy alone.

III Better local control, by the use of up front breast surgery, results in a
better quality of life in patients with Stage IV breast cancer, compared to
patients who receive systemic treatment with delayed local therapy or systemic
therapy alone.

In a separate side study the association of HER2 status on CTCs with outcome on
hormonal treatment and chemotherapy will be assessed.

This study is a multicenter, open-label, randomized controlled trial of 516
patients.

Patients with primary distant metastatic breast cancer, diagnosis confirmed
with biopsy, including estrogen- and progesteronreceptor status and HER2Neu
status, can be included in the study.

Screening for metastases should take place in patients with a T2 tumor > 3 cm,
patients with a T3 or T4 tumor and/or patients with clinical pathological
axillary lymph nodes.

Patients with a T1-T3 tumor and a resectable T4 tumor can be included.

Patients either randomize for up front surgery of the breast tumor (UFS)
followed by systemic therapy or they randomize for systemic therapy (ST)
possibly followed by local treatment of the breast tumor.
1. Up front breast surgery (UFS) followed by systemic therapy (group A)
2. Systemic therapy (ST) possibly followed by local treatment of the breast
tumor (group B)

Patients who randomize for surgery are treated with the intent of a radical
resection of the breast tumor. Furthermore, all patients will be treated with
systemic treatment according to local practice.

In case of local progression, all patients can be treated with local treatment
(surgery/radiotherapy) to establish local control.

The aim of this study is to determine the effect of up front surgery of the
primary tumor on survival in patients with primary metastatic breast cancer.
According to randomization, half of the patients will undergo up front surgery
of the primary tumor.

Randomization:
A. Up front breast surgery (UFS) followed by systemic therapy
B. Systemic therapy (ST) potentially followed by delayed local treatment of the
breast tumor

Up front breast surgery:
Depending on patient and tumor characteristics a lumpectomy or mastectomy of
the breast will be performed. Both types of surgery may be conducted as long as
the intention is a radical operation. The definition of radical resection in
this trial is free resection margins for the invasive component of the tumor.

In case of involved margins there are several options; perform a re-excision or
mastectomy (preferred options in UFS group), treat the patient with
radiotherapy or accept that a non-radical resection has been performed. This
decision is the responsibility of the treating physician; he or she is not
bound by restrictions in the protocol. Of note, radiotherapy can be postponed
after first-line chemotherapy has been delivered. Concurrent radiotherapy and
chemotherapy is not allowed because of expected excessive toxicity.

The choice to perform an axillary lymph node dissection is left to the
discretion of the treating physician, but is highly recommended if palpable
(and tumor positive) lymph nodes in the axillary region are present.

In case of local progression at any time, local treatment at another point than
scheduled (= up front or after 5-6 months of systemic therapy) to gain local
control is allowed. Local progression is defined as progression of the primary
tumor during systemic therapy, in which case the tumor can cause wound problems
or ulceration. To prevent this, local treatment should be considered.

Surgical treatment or (stereotactic) radiotherapy of oligometastases can be
considered after systemic therapy (after 5-6 months).

Last but not least, breast surgery is an accepted treatment for patients
without distant metastases; it is a relatively safe operation, without chance
of major complications.

The extent of the burden regarding the visits to the out-patient clinic and
completing quality of life questionnaires is estimated below:

Visits to out-patient clinic; questions about trial,
inclusion, baseline criteria, randomization 30 min.

1/2e of all patients: preoperative assessment,
surgery, visit for check-up after surgery, result
of pathologic examination tissue 60 min. + admission in hospital for surgery
(72 hours)

8 x Quality of life questionnaire 80 min.
________

Total: 170 min. + possible admission in hospital for surgery (72 hours)

Additional visits to the out-patient clinic are comparable with patients with
primary metastatic breast cancer who do not participate in this trial.

If patients give their informed consent an additional 20 ml of blood will be
collected during a standard vena punction.

The risks associated with participation of this trial are the risks caused by
surgery. The patients randomized for surgery have the same risks as breast
cancer patients without distant metastases, who undergo surgery as a standard
part of their treatment. These risks include postsurgical bleeding, wound
infection and the development of a hematoma or a seroma. Risks associated with
anesthesia should also be considered. Breast surgery is in medical terms a
relative minor operation with little chance of complications, and it is very
unlikely that severe complications occur.