Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial.

BACKGROUND: In high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC), nanoparticle albumin-bound (nab)-paclitaxel showed promising efficacy versus solvent-based (sb)-paclitaxel in neoadjuvant trials; however, optimal patient and therapy selection remains a topic of ongoing research. Here, we investigate the potential of Oncotype DX® recurrence score (RS) and endocrine therapy (ET) response (low post-endocrine Ki67) for therapy selection. PATIENTS AND METHODS: Within the WSG-ADAPT trial (NCT01779206), high-risk HR+/HER2- EBC patients were randomized to (neo)adjuvant 4× sb-paclitaxel 175 mg/m2 q2w or 8× nab-paclitaxel 125 mg/m2 q1w, followed by 4× epirubicin + cyclophosphamide (90 mg + 600 mg) q2w; inclusion criteria: (i) cN0-1, RS 12-25, and post-ET Ki67 >10%; (ii) cN0-1 with RS >25. Patients with cN2-3 or (G3, baseline Ki67 ≥40%, and tumor size >1 cm) were allowed to be included without RS and/or ET response testing. Associations of key factors with pathological complete response (pCR) (primary) and survival (secondary) endpoints were analyzed using statistical mediation and moderation models. RESULTS: Eight hundred and sixty-four patients received neoadjuvant nab-paclitaxel (n= 437) or sb-paclitaxel (n = 427); nab-paclitaxel was superior for pCR (20.8% versus 12.9%, P = 0.002). pCR was higher for RS >25 versus RS ≤25 (16.0% versus 8.4%, P = 0.021) and for ET non-response versus ET response (15.1% versus 6.0%, P = 0.027); no factors were predictive for the relative efficacy of nab-paclitaxel versus sb-paclitaxel. Patients with pCR had longer distant disease-free survival [dDFS; hazard ratio 0.42, 95% confidence interval (CI) 0.20-0.91, P = 0.024]. Despite favorable prognostic association of RS >25 versus RS ≤25 with pCR (odds ratio 3.11, 95% CI 1.71-5.63, P ≤ 0.001), higher RS was unfavorably associated with dDFS (hazard ratio 1.03, 95% CI 1.01-1.05, P = 0.010). CONCLUSIONS: In high-risk HR+/HER2- EBC, neoadjuvant nab-paclitaxel q1w appears superior to sb-paclitaxel q2w regarding pCR. Combining RS and ET response assessment appears to select patients with highest pCR rates. The disadvantage of higher RS for dDFS is reduced in patients with pCR. These are the first results from a large neoadjuvant randomized trial supporting the use of RS to help select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- EBC.

Correction of linear system drifts in magnetic particle imaging.

Magnetic particle imaging (MPI) is a tracer-based imaging technique that can be used for imaging vessels and organ perfusion with high temporal resolution. Background signals are a major source for image artifacts and in turn restrict the sensitivity of the method in practice. While static background signals can be removed from the measured signal by taking a dedicated background scan and performing subtraction, this simple procedure is not applicable in case of non-stationary background signals that occur in practice due to e.g. temperature drifts in the electromagnetic coils of the MPI scanner. Within this work we will investigate a dynamic background subtraction method that is based on two background measurements taken before and after the object measurement. Using first-order interpolation it is possible to remove linear background changes and in turn significantly suppress artifacts. The method is evaluated using static and dynamic phantom measurements and it is shown that dynamic background subtraction is capable of reducing the artifact level approximately by a factor of four.

Human-sized magnetic particle imaging for brain applications.

Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmolFe ml-1, which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.

Hybrid system calibration for multidimensional magnetic particle imaging.

Magnetic particle imaging visualizes the spatial distribution of superparamagnetic nanoparticles. Because of its key features of excellent sensitivity, high temporal and spatial resolution and biocompatibility of the tracer material it can be used in multiple medical imaging applications. The common reconstruction technique for Lissajous-type trajectories uses a system matrix that has to be previously acquired in a time-consuming calibration scan, leading to long downtimes of the scanning device. In this work, the system matrix is determined by a hybrid approach. Using the hybrid system matrix for reconstruction, the calibration downtime of the scanning device can be neglected. Furthermore, the signal to noise ratio of the hybrid system matrix is much higher, since the size of the required nanoparticle sample can be chosen independently of the desired voxel size. As the signal to noise ratio influences the reconstruction process, the resulting images have better resolution and are less affected by artefacts. Additionally, a new approach is introduced to address the background signal in image reconstruction. The common technique of subtraction of the background signal is replaced by extending the system matrix with an entry that represents the background. It is shown that this approach reduces artefacts in the reconstructed images.

Two dimensional magnetic particle spectrometry.

Magnetic particle spectrometry (MPS) is an excellent and straight forward method to determine the response of magnetic nanoparticles to an oscillating magnetic field. Such fields are applied in magnetic particle imaging (MPI). However, state of the art MPS devices lack the ability to excite particles in multidimensional field sequences that are present in MPI devices. Especially the particle behavior caused by Lissajous sequences cannot be measured with only one excitation direction. This work presents a new kind of MPS which features two excitation directions to overcome this limitation. Both field coils can drive AC as well as DC currents and are thereby able to emulate the field sequences for arbitrary spatial positions inside an MPI device. Since the DC currents can be switched very fast, the device can be used as system calibration unit and acquire system matrices in very short time. These are crucial for MPI image reconstruction. As the signal-to-noise-ratio provided by the MPS is approximately 1000 times higher than that of actual imaging devices, the time space analysis of particle signals is more precise and easier done. Four system matrices are presented in this paper which have been measured with the realized multidimensional MPS. Additionally, a time space comparison of the particle signal for Lissajous, radial and spiral trajectories is given.

Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer.

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERalpha) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERalpha is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERalpha and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher's exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERalpha and PR positive and low grade than advanced stages.