Breast Cancer Clinical Trial
Official title:
Feasibility Study of Motility Contrast Tomography for Predicting Therapeutic Response
Millions of cancer patients every year receive chemotherapy with only a 20-60% probability of
pathological response, while most experience adverse side effects that lower quality of life
without prolonging it. Reliable identification of ineffective therapies can eliminate
needless human suffering while increasing overall probability of positive response to
treatment. Chemotherapy resistance profiling entails testing whether a patient exhibits
strong resistance to a therapy prior to its final selection by the oncologist. However, there
are no effective methods for quickly assessing patient chemotherapy resistance. Patient
Derived Xenograft (PDX) models have replaced older Chemotherapy Sensitivity and Resistance
Assays (CSRAs) to some degree, but both technologies suffer from long testing times, high
cost, and/or low accuracy.
Motility Contrast Tomography (MCT) has recently emerged as a technology that measures the
biodynamic response of intact tumor biopsies to applied therapeutics by using Doppler
detection of infrared light scattered from intracellular motions inside living tissue.
Several small scale animal, xenograft, and human studies have shown this phenotypic profiling
technique to be highly accurate in prediction of response and resistance to chemotherapy.
This project will be the first human trial of biodynamic phenotyping to predict chemotherapy
response among breast cancer patients. Specifically, the study cohort will include patients
selected for neoadjuvant chemotherapy treatment, because this setting offers the opportunity
for near-term outcome measurement at the time of post-chemo surgery. Pre-therapy fresh tumor
specimens will be imaged using MCT, and the resulting bio-dynamic signatures will be compared
to confirmed pathological response at the time of surgery. Observation of a high predictive
value will provide the basis for expanded clinical trials and prompt commercialization of a
biodynamic chemotherapy selection assay for breast and other cancer patients.
STUDY RATIONALE: The demonstrated ability of MCT to accurately assess tumor xenografts may
establish it as a reliable technique for patient tumor stratification based on predicted
response to therapy, which could enable a treatment selection based on the personal needs of
an individual patient. This study is designed to assess MCT as an assay for predicting
chemosensitivity to treatment with chemotherapy agents routinely used in the neoadjuvant and
adjuvant treatment of breast cancer. If positive, the results of this study will provide the
basis for expanded clinical trials and use of MCT in therapy selection.
BACKGROUND: Live cell imaging has become the standard for high-content analysis and drug
discovery applications. The most common assays on live cells include viability, proliferation
and cytotoxicity assays as cellular physiology and function are measured responding to
applied perturbations of xenobiotics. Cellular and tissue viability assays are typically
measured using exogenous vital dyes as biomarkers of membrane integrity or cellular metabolic
activity. However, dyes are invasive, potentially toxic, and often require fixing of the
tissue or permeabilization of the membranes [1, 2]. Furthermore, the common format of high
content analysis and flow cytometry requires isolated cells, or cells distributed on flat
hard surfaces. Isolated cells lack many of the biologically-relevant intercellular
connections and communications that are hallmarks of healthy tissue [3, 4], and flattened
cells on plates have pathological shapes and anisotropic cellular adhesions [5].
Discovery of technology that can predict response to cancer therapy is an urgent priority.
While many technologies exist to evaluate early response to drugs ex vivo, the need to
perform viability, cytotoxicity and proliferation assays in three-dimensional tissue or
culture has become increasingly urgent [6, 7], as drug response in 2D is often not the same
as drug response in biologically-relevant three dimensional culture. This is in part because
genomic profiles are not preserved in monolayer cultures [8-10]. There have been several
studies that have tracked the expression of genes associated with cell survival,
proliferation, differentiation and resistance to therapy that are expressed differently in 2D
cultures relative to three-dimensional culture. For example, cell lines of epithelial ovarian
cancer [11, 12], hepatocellular carcinoma [13-15] or colon cancer [16] display expression
profiles more like those from tumor tissues when measured in three-dimensional culture, but
not when grown in 2D. In addition, the three-dimensional environment of 3D culture presents
different pharmacokinetics than 2D monolayer culture and produce differences in cancer drug
sensitivities [17-20]. Finally, most current technologies rely on destructive end-point
assessment, preventing meaningful longitudinal observation of therapy response over time.
One of the main challenges to migrating drug-response assays to the third and fourth
dimensions has been to find a means to extract vital information from deep (up to a
millimeter) inside living tissue. Tissue is translucent and light can propagate diffusively
many centimeters. Furthermore, the dynamic motions of living cells cause dynamic light
scattering that produces phase fluctuations on the scattered light fields that can be
measured as dynamic speckle in diffusely reflected light from tissue. This is the basis of
diffusing wave spectroscopy (DWS) [21, 22] and diffusion correlation spectroscopy (DCS)
[23-26], but these techniques lack depth resolution. A powerful tool in the characterization
of light propagation in tissues is the use of interferometry [27]. Interferometric detection
is the underlying process in optical coherence tomography (OCT) [28-31], which is a
point-scanning technique that suppresses speckle [32-34], although speckle decorrelation in
OCT data can provide similar information as provided by DCS. This has been used to measure
intracellular rheology [35] and to find dynamic signatures of apoptosis [36]. Transport also
can be detected at cellular resolution using phase contrast microscopy [38], but this
approach cannot be used in thick tissues.
Dr. Nolte and colleagues have developed volumetrically-resolved tissue dynamic imaging that
uses the advantages of depth selectivity from low-coherence interferometry, combined with
high speckle contrast in broad-illumination digital holography. The technique is called
Motility Contrast Tomography (MCT) and uses low-coherence digital holography to penetrate up
to 1 millimeter into living tissue to measure speckle dynamics from light scattering from
dynamic motion in living cells [37]. It was previously applied as a cytotoxicity assay to
study the efficacy of anti-mitotic drugs [40]. In essence, the technology works by profiling
the 'movement' of cellular organelles. Specific changes in organelle motion are detectable
very early in cells undergoing response to chemotherapy treatment, and may be usable as an
early predictor of chemotherapy response.
MCT is based on optical coherence imaging (OCI) [38]. OCI is a full-field short-coherence
holography [39] that collects backscattered speckle. With the help of coherence gating, OCI
can optically section tissue up to 1 mm deep. MCT specifically uses intracellular motion as
the endogenous contrast to characterize submicron subcellular motion inside three-dimensional
living tissue [42].
Figure 1 shows the holographic recording principle of MCT. After calibration, the short
coherence light is first divided into an object beam and a reference beam. The object beam
hits the living tissue sample, and backscattered speckles from the tissue are collected by
the lens L1. The living tissue sample locates at the focal plane of the lens L1, so L1 also
performs an optical Fourier transform of the backscattered light. The charge coupled device
(CCD) locates at the other focal plane of L1, so it captures the Fourier transformed
scattering light from the tissue. The reference beam is controlled by a delay stage (not
shown in the figure) to adjust the path length of the reference beam to perform a zero-path
match between the object and reference beams. The beam splitter combines both beams and
because they are zero-path matched, they interfere at the CCD plane. The reference beam is
tilted by 20° in an off-axis configuration, and the spacing of the interference fringes (Λ)
is 3 pixels (24 μm). The speckle size (aspec) is adjusted to be 3 fringes wide (70 μm).
Additional details about the experimental setup can be found in reference [41].
Fig.1. The principle of MCT on multicellular tumor spheroids. The biological sample is
located at the image plane of lens L1. The back scattered light from the sample is Fourier
transformed by L1 and interfered with reference beam on the CCD chip. The speckle hologram is
recorded on the Fourier plane with a 20 crossing angel with the reference beam. Examples of
a) Raw digital hologram; b) reconstructed image; c) MCI image. O.A.: optical axis; I.P.:
image plane; L1: lens; BS: beam splitter; CCD: charge coupled device.
EX VIVO CANCER CHEMOSENSITIVITY ANALYSIS MCT was previously applied to study the efficacy of
anti-mitotic drugs using multicellular tumor spheroids [40]. When applying MCT to tumor
xenografts, it is also capable of showing a significantly different response between two cell
lines under cisplatin. After applying the drug, the normalized standard deviation (NSD) value
of the platinum-sensitive cell line (A2780) drops from 0.7 to 0.1 in 8 hours. In contrast,
the NSD value of the platinum-resistant cell line (A2780-CP70) remains nearly constant (0.81
to 0.80) 9 hours after applying drug. The NSD value of normal mouse tissue attached to the
tumor xenograft decreases only a little (0.6 to 0.52) compared with A2780. Fig. 2 shows the
cisplatin drug response curves. The NSD value of each point is averaged over the entire
target. The time between measurements is 24 minutes for A2780-CP70 and normal mouse tissue
and is 12 minutes for A2780. The 20 μM cisplatin was applied at time t = 0, and the
measurements lasted 9 hours for A2780-CP70 and normal mouse tissue, and lasted 8 hours for
A2780. At time=0, the aggressive cell line A2780-CP70 has the highest NSD and the normal
mouse mesenterium tissue has lowest NSD (0.6). The NSD of the platinum-sensitive cell line
A2780 lies in the middle: 0.7. After applying cisplatin, the NSD curve of A2780 drops
immediately. The NSD value of the A2780-CP70 almost doesn't change.
Fig. 2 Motility metric (NSD) of ovarian cancer tumor xenografts responding to 20 μM
cisplatin. The x-axis is time (minute), the y-axis is NSD value. The sensitive tumor is
A2780, while the insensitive tumor A2780-CP70. Both tumor tissues begin with higher motility
than normal mouse tissue. The cisplatin was added at time t=0. The NSD of A2780 dropped very
fast and after 8 hours it dropped to 0.1. The NSD of the insensitive tumor A2780-CP70 didn't
change during 9 hour peroid. The NSD of normal mouse tissue dropped a little compared with
the A2780.
In a further study in a veterinary clinical setting, MCT has been used to predict patient
outcome for canine non-Hodgkin's lymphoma. Canine non-Hodgkin's lymphomas are initially
characterized by tumoral infiltration of peripheral lymph nodes. Canine non-Hodgkin's
lymphomas are diverse in their clinical aggressiveness and response to chemotherapy. The only
current biomarker for chemoresponsiveness is tumor cell immunophenotype (i.e. T-cell vs.
B-cell origin), but chemoresponsiveness varies tremendously within immunophenotype, which
reduces the clinical utility of this biomarker. In our study, we used MCT to measure the
heterogeneous response of canine lymphoma biopsies to the standard-of-care doxorubicin. The
biodynamic signatures of doxorubicin responsivity ex vivo were correlated with canine patient
outcome. These studies have demonstrated, for the first time, the utility of label-free
intracellular biodynamic markers to predict therapeutic efficacy for cancer treatment in
dogs.
SPECIFIC AIMS The primary study objective is to examine the feasibility of using MCT as a
chemosensitivity assay among breast cancer patients receiving neoadjuvant chemotherapy by
comparing MCT patterns consistent with chemotherapy response or resistance ex-vivo to
confirmed response or resistance to chemotherapy as measured by Response Evaluation Criteria
in Solid Tumors (RECIST) v1.1 criteria.
PRIMARY ENDPOINT: Objective pathological response measured at the time of surgery.
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