Image-guided de-escalation of neoadjuvant chemotherapy in HER2-positive breast cancer: the TRAIN-3 study.

High pathological complete response (pCR)-rates are seen using different
neoadjuvant chemotherapy schedules with trastuzumab and pertuzumab in
HER2-positive stage II-III breast cancer patients. Total pCR rates in breast
and axilla have been described as high as 64%, and with an even higher rate of
>80% in patients with HER2-positive and hormone receptor (HR) negative tumors.
PCR is associated with better long-term outcomes in patients with HER2-positive
breast cancer. Three year progression-free survival ranges between 85-90%.
Neoadjuvant treatment of HER2-positive breast cancer typically consists of six
to nine cycles of treatment. Longer duration of treatment is associated with
higher pCR-rates but gives more toxicity. Pathological complete responses are
sometimes seen after only 10-12 days of neoadjuvant treatment. It is therefore
important to investigate which patients can safely be treated with less than
six cycles of chemotherapy and who requires more than six cycles for maximum
activity.
The radiologic response of a breast tumor after neoadjuvant therapy is
predictive of the pathologic response, although the accuracy differs between
breast cancer subtypes. It is hypothesized that patients with an early complete
radiologic response may not benefit from additional chemotherapy and can be
referred for early surgery. Patients who have not achieved pCR after early
surgery despite radiologic complete response (rCR) are candidates for further
adjuvant chemotherapy to complete the initially planned number of treatment
cycles and maintain maximum treatment activity. Imaged guided de-escalation in
which the number of treatment cycles is determined by the radiologic response
could thus reduce toxicity in neoadjuvant treatment while maintaining activity.
Patients who do not have a pathologically complete response after neoadjuvant
treatment are candidates for treatment with T-DM1. This gives a predicted
invasive disease-free survival of 11%.
This study will evaluate the efficacy of image-guided de-escalation of
neoadjuvant chemotherapy in patients with HER2-positive breast cancer.

This study has been transitioned to CTIS with ID 2024-516205-23-00 check the CTIS register for the current data.

To evaluate efficacy of image-guided de-escalating chemotherapy in the presence
of dual HER2-blockade with Herceptin® and pertuzumab in HER2-positive breast
cancer, as measured by three-year event-free survival.
Secondary objectives
• To evaluate 3-year overall survival
• To evaluate pCR rate in breast and axilla
• To evaluate 5-year, and 10-year overall and event-free survival rate
• To evaluate the association between pCR and long-term outcome
• To evaluate the association between radiologic complete response (rCR) and pCR
• To compare short-term and long-term efficacy by number of chemotherapy cycles
received
• To compare non-radical resection percentages between rCR and no rCR•
• To evaluate the association between VACBs and pCR
• To evaluate QoL after 3, 6 or 9 courses of chemotherapy

This is a multicenter, single arm, phase II study evaluating the efficacy of
image-guided de-escalating neoadjuvant treatment with paclitaxel, Herceptin®
(trastuzumab), carboplatin, and pertuzumab (PTC-Ptz) in stage II-III
HER2-positive breast cancer.
The primary endpoint of the study is the 3-year event-free survival rate.
Event-free survival will be calculated from time of registration to time of
first event. An event is defined as the earliest occurrence of disease
progression resulting in inoperability, invasive locoregional recurrence,
distant metastases, or death from any cause. Patients alive without an event as
of the analysis cutoff date will be censored at last study follow-up date.
Treatment regimen
The PTC-Ptz regimen consists of a maximum of nine cycles consisting of:
• Paclitaxel 80mg/m2 administered intravenously on day 1 and day 8
• Herceptin® 6mg/kg administered intravenously on day 1 (loading dose 8mg/kg)
or Herceptin® administered subcutaneously 600mg on day 1
• Carboplatin AUC 6mg•ml/min administered intravenously on day 1
• Pertuzumab 420mg administered intravenously on day 1 (loading dose 840mg)
• Treatment cycles are repeated on day 22

Number of neoadjuvant courses PTC-Ptz depends on the radiological response
during the tumor evaluation every 3 courses. The total number of chemotherapy
treatments depends on the eventual pathological complete response.

In addition to trastuzumab in the adjuvant setting pertuzumab is also given a
total of one year.

All patients with pCR continue with Herceptin® (trastuzumab) and pertuzumab
after surgery for a total of 12 months.
Patients who do not have pCR receive 14 cycles of adjuvant TDM1

All investigational products are registered for the neoadjuvant treatment of
HER2-postive breast cancer and considered regular care. Adjuvant pertuzumab and
TDM1 are not standard of care and will be provided until reimbursement.
Patients are at risk of developing treatment related toxicity. SAEs will be
monitored. Blood will be drawn for translational research, hematology and
chemistry.
Burden:
• Up to one or two times more often an MRI-scan of the breast and possibly an
ultrasound scan of the axilla.
• Take a biopsy of a lymph node of the axilla max. one or two times more often
than usual (this applies only to patients with proven lymph node metastasis at
diagnosis or in case of doubt to newly developed suspected lymph nodes)
• Treatment with pertuzumab up to one year after the start of treatment.
• When participating in biomarker research: three additional tumor biopsies
after three courses of therapy. *
• When participating in biomarker research: extra tubes of blood are drawn at
four timepoint simultaneously with the regular blood collection (before the
treatment, after one treatment, after three courses and before the operation) *
• VACBs will be taken in HR-positive patients with an early rCR to improve the
NPV of imaging alone to predict pCR. VACBs gives a small risk of hematoma,
bleeding or bruising.
• patients will be asked to fill in quality of life questionnaires four times
in total *

* If permission has been given separately