Tumorresponse monitoring in patients with breast cancer treated with primary systemic therapy: Towards predicting response in both the primary tumor and in axillary lymph nodes

The use of primary systemic therapy, or neoadjuvant chemotherapy, has gained an
important role in the treatment of breast cancer. Systemic therapy before
surgery has several advantages.

Firstly, the rate of breast-conserving surgery is increased after primary
systemic therapy, because of reduction of tumorload. In a meta-analysis, Mauri
et al. describe an increase in breast conserving surgery of 18%. A slightly
increased risk of local recurrence was found. However, these recurrences mainly
occurred in patients with clinically complete remission who only received
irradiation to the breast without surgical treatment.
Secondly, the tumor response to systemic therapy can be evaluated enabling
translational research which gives us more insight in the behavior of different
tumor subtypes Interim radiological evaluation during primary systemic therapy
creates the opportunity to switch to another regimen in case of unfavorable
response. The final tumor response remains based on pathological assessment
after surgery.
The ultimate goal of primary systemic therapy is to improve survival. However,
the advantage in survival after primary systemic therapy compared to adjuvant
systemic therapy remains to be proven. Patients with a pathological complete
remission after primary systemic therapy do have a better disease-free survival
than patients with incomplete remission.5 Also, several trials comparing
different chemotherapy regimes in a primary setting show a survival benefit for
the superior regimen.

Response monitoring of the primary tumor
Response monitoring is a crucial process in the neoadjuvant setting. It is
needed to select patients eligible for breast conserving therapies and to
distinguish between favourable and unfavourable response. It provides the
opportunity to switch the chemotherapy regimen in insufficiently responding
tumors at an early time point.

Response monitoring of lymph node metastasis
Axillary pCR is described in 22-38% of patients treated with primary systemic
therapy.15;16 Currently, this group of patients undergoes an axillary lymph
node dissection, which was not necessary on retrospect. Although there is
substantial similarity between axillary tumor response and response of the
primary tumor, this correlation is too weak to reliably predict axillary tumor
response solely based on primary tumor response. A reliable method to evaluate
the axillary tumor response is however essential in order to reduce the rate of
unnecessary ALND*s, without compromising oncological safety. We hypothesize
that including PET/CT imaging in response monitoring of breast and axilla could
help with identifying the patients that obtain a (near) pCR of the axilla, thus
identifying patients in which axillary lymph node dissection can be omitted. In
addition to response monitoring by PET we also propose a new method to evaluate
axillary tumor response. With this method, a proven positive lymph node is
marked prior to primary systemic therapy in order to obtain histopathological
proof of response. After primary systemic therapy, the marked lymph node is
removed for analysis. Based on pathological assessment of the tumor response in
the marked lymph node, a decision can be made whether to perform an ALND or
not.

The aim of this protocol is twofold.
• Firstly, we aim to combine the new response monitoring method (PET imaging)
with the present technique (dynamic CI-MRI imaging) in order to discriminate
between favourable and unfavourable response of the primary tumor during and
after neoadjuvant chemotherapy.
• Secondly, we aim to investigate whether the axillary tumor response to
primary systemic therapy can be reliably assessed.

Two types of patients, scheduled to receive primary systemic therapy according
to the N04POM trial, TRAIN trial and in the future the TIP trial, will be
included in this study:
1. cN0: patients with negative axillary ultrasound findings and an unknown
pathological nodal status.
2. cN+: patients with tumor positive cytology after FNA.

In the current protocol for neoadjuvant systemic treatment, dynamic CE-MRI
imaging is included for response monitoring of the primary tumor and these
findings will now be combined with the PET findings. All patients will receive
3 FDG/PET scans. Time point of the scans will be dependent on the type of
chemotherapy regimen and HER2 expression:

In Her2 negative patients, treated with an antracycline or taxane based regimen:
• One FDG-PET at baseline, before primary systemic therapy, together with MRI
• One FDG-PET after 1 cycle of primary systemic therapy
• One FDG-PET after 3 cycles of primary systemic therapy, together with MRI

In Her2 positive patients, treated with a weekly trastuzumab based regimen:
• One FDG-PET at baseline, before primary systemic therapy, together with MRI
• One FDG-PET after 3 cycles of primary systemic therapy
• One FDG-PET after 8 cycles of primary systemic therapy, together with MRI

In the group of cN+ patients, axillary tumor response will be evaluated also by
Radioactive seed localization (RSL). The tumor positive axillary lymph node
will be marked prior to primary systemic therapy. In the same session of
surgery for the breast tumor after systemic therapy, the marked lymph node will
be detected using a gamma-ray detection probeand selectively removed. After
removal of the marked lymph node, an ALND will be performed. The correlation
between the tumor response in the marked lymph node and tumor response in the
ALND specimen will be investigated.

Patients will receive three additional imaging examinations, namely three times
a FDG-PET scan. Furthermore, I-125 seeds will be placed in a suspect lymph
nodes in cN1 patients with a low risk on inflammation.