Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience
© Meaney et al.; licensee BioMed Central Ltd. 2013
Received: 13 July 2012
Accepted: 8 March 2013
Published: 24 April 2013
Microwave tomography recovers images of tissue dielectric properties, which appear to be specific for breast cancer, with low-cost technology that does not present an exposure risk, suggesting the modality may be a good candidate for monitoring neoadjuvant chemotherapy.
Eight patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer were imaged longitudinally five to eight times during the course of treatment. At the start of therapy, regions of interest (ROIs) were identified from contrast-enhanced magnetic resonance imaging studies. During subsequent microwave examinations, subjects were positioned with their breasts pendant in a coupling fluid and surrounded by an immersed antenna array. Microwave property values were extracted from the ROIs through an automated procedure and statistical analyses were performed to assess short term (30 days) and longer term (four to six months) dielectric property changes.
Two patient cases (one complete and one partial response) are presented in detail and demonstrate changes in microwave properties commensurate with the degree of treatment response observed pathologically. Normalized mean conductivity in ROIs from patients with complete pathological responses was significantly different from that of partial responders (P value = 0.004). In addition, the normalized conductivity measure also correlated well with complete pathological response at 30 days (P value = 0.002).
These preliminary findings suggest that both early and late conductivity property changes correlate well with overall treatment response to neoadjuvant therapy in locally advanced breast cancer. This result is consistent with earlier clinical outcomes that lesion conductivity is specific to differentiating breast cancer from benign lesions and normal tissue.
Neoadjuvant chemotherapy (NCT) for breast cancer has become an increasingly important treatment option  that offers potential therapeutic advantages. Various clinical trials have demonstrated that treatment response, including tumor shrinkage, leads to substantial downstaging of disease which in turn allows for increased use of more limited surgery . In such cases, breast conservation strategies such as lumpectomies and radiotherapy can be used instead of more comprehensive radical mastectomies . By monitoring the patient's response to systemic therapy before tumor resection, prediction of longer term prognosis or identification of the need for additional or alternative treatment may be possible. Data have suggested that patients receiving neoadjuvant therapy with pathologic complete response have better survival outcomes [1, 3].
While NCT is emerging as a promising treatment strategy for locally advanced breast cancer, deploying monitoring methods during the course of therapy is important for making further advances. Magnetic resonance (MR) and fluorodeoxyglucose positron emission tomography (FDG PET) have been evaluated in several clinical trials and have proven useful in this setting, but both also come at considerable cost and inconvenience [3–8]. Conventional breast imaging modalities, such as ultrasound and mammography, have been disappointing in detecting the extent of residual disease during treatment . Studies have also been conducted using Doppler ultrasonography, diffuse optical spectroscopy and tomography and scintimammography [10–13]. Assessing tumor shrinkage by clinical breast examination is possible as well but is poorly correlated with treatment response .
Microwave imaging is in the early stages of clinical evaluation and most of the work has focused on breast tumor detection. Impressive technical developments based on active microwave radar concepts have been reported [14–18]. Passive microwave radiometry has also been investigated [19–21]. However, only a modest number of clinical microwave tomographic (MT) breast examinations have been conducted [22–24]. Our early clinical experience with MT has demonstrated statistically significant differences in the electrical conductivity of breast tumors greater than 1 cm in diameter relative to the normal breast and other benign abnormalities . We have also shown strong associations between whole breast radiographic density designations as well as focal patterns of dense fibroglandular tissue and the imaged microwave property distributions .
We are currently evaluating women undergoing NCT for the treatment of locally-advanced breast cancer with MT performed at regular intervals from the start of treatment to the time of surgery. In the following sections, we describe the methods used in the study related to patient recruiting, imaging modalities, pathology and image analysis. In the Results section, we examine two cases in detail (one complete responder and a second non-responder) to provide an appreciation of the information contained in the images and their progression during treatment. In addition, we also include a representative sequence of images from the contralateral breast for one patient during the course of treatment as an example of the more limited changes observed in the non-cancerous breast. Finally, we statistically analyze the results for the eight patients in this study.
Materials and methods
Summary of patient data
7 × 6.5
5 × 3
No substantial response (MRI)
4 × 4
5 × 5
8 × 7
No substantial response (MRI)
1 × 1
IDC, ER equivocal/PR-/HER2neu+
10 × 9
4 × 4
No substantial response (MRI)
For each TM session, patients lie prone on a padded table with one breast pendant through an aperture into a coupling liquid. An array of monopole antennas with fixed radial positions on a 15.2 cm diameter circle are moved up from the base of the imaging tank into a position surrounding the breast close to the chestwall. Data are acquired over multiple frequencies (700 to 1,700 MHz in 200 MHz increments) with each antenna sequentially acting as the transmitter and the remaining complement serving as receivers for a total of 240 (16 transmitters × 15 receivers) measurements at each frequency. The antennas are subsequently moved to six lower positions in 1 cm increments (or less depending on the overall breast length) where the data acquisition sequence is repeated to provide coverage of the breast. After data acquisition is completed on one breast, the patient is repositioned and the contralateral breast is imaged under the same protocol for a total examination time of approximately 15 minutes (approximately 5 minutes of data acquisition time per breast and 5 minutes for breast positioning).
We utilized either 80% or 86% glycerin coupling baths for patient examinations. At the first pre-therapy imaging session, baseline data were acquired with both baths for each patient. We determined the optimal bath for a given subject by evaluating the measured data and image quality from both acquisitions . Given the variability of the average microwave properties of the breast, especially with respect to its density and the patient's age, we compared the recovered images empirically on a patient-by-patient basis in order to determine the best mixture for future examinations . Once the bath of choice was established, the liquid was recycled and used only for the subsequent examinations of that individual patient.
Permittivity and conductivity images were reconstructed post-examination for associated frequencies and antenna positions. Each image was processed in less than two minutes on a Dell Blade workstation using our two-dimensional finite difference time domain (FDTD)-based algorithm which has been described in detail elsewhere [27–30].
Clinical (MR) imaging
MR breast images were acquired in a 1.5T scanner (GE Signa, GE Healthcare, Waukesha, WI, USA) for standard clinical indications or a 3T (Philips Achieva, Philips Healthcare, Andover, MA, USA) system for research studies. Dedicated breast coils were used with sub-millimeter in-plane resolution and slice thicknesses of < 3 mm (T1-weighted) and < 5 mm (T2-weighted). T1 and T2 scans provided detailed maps of tissue structure which were used to differentiate breast tissue types. Three dimensional gradient echo T1-weighted sequences with chemical fat suppression were performed prior to and at one to two minute intervals following the injection of a bolus of contrast (Gadodiamide, Omniscan, GE Healthcare) of 0.1 mmol per kilogram of body weight to identify suspicious enhancement foci. The first post-contrast scan was initiated 40 seconds after injection. Subtraction images were generated with the pre-contrast gradient echo T1 image as the reference to assess the Gd washout behavior.
Standard surgical pathology analysis of the excised tissues was used to assess subject outcomes. The subjects compared in this pilot study underwent surgical mastectomy . The mastectomy specimens were sectioned fresh, medial to lateral, in the sagittal plane. Each tissue slice was examined grossly and photographed for image correlation. Areas of treatment response, residual tumor and normal breast were sampled and processed for microscopic analysis per standard laboratory protocols (formalin fixation, dehydration, paraffin-embedding, 4 micron sectioning and H & E stain). Complete pathologic response (pCR) was defined as a complete absence pathologically of cancer in the breast after extensive sampling.
Results and discussion
Case I - complete response
The first patient had a locally advanced cancer on the right side. At diagnosis, the right breast mammogram showed linear and pleomorphic micro-calcifications in a segmental distribution over the lower-central and entire lower-inner gradient while also demonstrating skin thickening in overlying zones. The tumor measured 6.5 × 3.7 × 7.1 cm by MRI. Biopsy demonstrated an intermediate grade invasive ductal carcinoma with a component of ductal carcinoma in situ (DCIS), estrogen receptor positive (ER(+)), progesterone receptor negative (PR(-)), human epidermal growth factor receptor-2 (HER-2)/neu(+) (HER-2:CEP-17 14.2). The patient was treated with four cycles of doxorubicin and cyclophosphamide, followed by four cycles of weekly paclitaxel and traztuzumab (PT) and then underwent modified radical right mastectomy. Surgical pathology revealed a complete pathologic response.
For the right (diseased) breast images prior to treatment, the coronal perimeters are more uneven with elevated property zones in the lower quadrants and increased properties on the breast boundary likely corresponding to the tumor, skin thickening and edema appearing in the MRI, respectively. At day 44 (Figure 3c) the baseline MT images have changed significantly and show: (1) improved delineation of the breast boundary, (2) diminished tumor size and property intensity, and (3) reduced property intensity along the lower breast edge. All three findings appear to correspond well with the clinical tumor size reduction, skin thinning and decrease in subdermal edema. At the end of treatment, the breast outline is even more regular than in the previous images, the recovered tumor enhancement is further reduced and no enhancement appears near the breast perimeter.
A significant reduction in the recovered dielectric properties occurred within the tumor region as treatment progressed. The post-surgical pathological evaluation confirmed a complete response. Larger areas of soft, grey-white tissue appear where the tumor had been treated. Microscopic analysis showed no signs of viable tumor with only stromal scarring, macrophages and inflammation in the treated areas. Dielectric probe measurements in pathology revealed that the treated tumor properties have not reverted back to values corresponding to fibroglandular zones in the contralateral breast as expected since the treated area is no longer representative of normal breast tissue.
Case II - non-responder
The second case was a woman who presented with locally advanced and metastatic breast cancer. Initial MRI showed a 4 × 2.5 × 4 cm irregular complex cystic mass in the upper outer quadrant of the left breast. Two smaller (1 cm) lesions were noted superior and anterior to the primary tumor. Core needle biopsy of the primary tumor demonstrated a high grade invasive ductal carcinoma with angiolymphatic invasion, weakly ER(+), PR(-), HER-2/neu(-) (HER-2:CEP-17 1.09). Left axillary lymph node biopsy was positive for metastatic disease. The patient was treated with four cycles of single agent weekly TOCOSOL paclitaxel (Eagle Pharmaceuticals, Belgrade, Serbia), followed by left simple mastectomy. Surgical pathology revealed a partial pathologic response with the treatment effect estimated as comprising > 50% but < 90% of the original tumor.
For the left breast images, the outer boundaries appear more disrupted than in the contralateral breast and significant internal zones of both permittivity and conductivity enhancement are evident. Enhancement occurs in the upper-central to upper-right regions in planes two to four of the permittivity and planes two to five of the conductivity images at the first two imaging dates (pre-chemotherapy and day 52). This visibility over multiple planes is indicative of a large tumor. The enhanced area in plane four of the permittivity image from the second examination is much more intense (higher values) than the corresponding plane for the first examination and appears to corroborate the MR observation that the tumor was growing. The microwave images obtained from the last examination suggest that the tumor has expanded significantly in size with the appearance of substantial enhancement in both planes five and six. The level of enhancement in the conductivity images has also increased correspondingly. These results correlate well with the clinical observations that the tumor spread anteriorly towards a satellite location and that the primary and secondary tumors had merged by the time of surgery.
We were not always able to collect as much data from the contralateral breast as for the ipsilateral (diseased) side for multiple reasons: (a) several patients had ports inserted in the contralateral breast for drug infusion that precluded imaging, (b) multiple experimental imaging modalities were involved in the study, so the total examination time allotted to MT was limited, and (c) some patients were simply feeling too ill to participate in more than a single-sided breast examination.
Summary of the eight patient study
The mean of the normalized permittivity ROI:background ratio for complete responders was not significantly different from that for incomplete-responders (P-value = 0.68) over the full treatment intervals. However, the corresponding normalized mean conductivity for the complete responders was significantly different from that for non-responders (P-value = 0.004). There were no significant time or interaction effects for either dielectric property in the study. We investigated whether other covariates, including body mass index (BMI), age and breast density (we grouped fatty and scattered density breasts into a single low density category, and heterogeneously dense and extremely dense breasts into one high density group, respectively) influenced the results. For both permittivity and conductivity, the effect of these factors was not significant (P-values for the three variables were 0.84, 0.36 and 0.32 for permittivity, respectively, and 0.41, 0.58 and 0.07 for conductivity, respectively). We also analyzed the interaction between the group and days from baseline variables and found no association (P-values of 0.14 and 0.28 for the permittivity and conductivity, respectively). These results are consistent with our prior experience in which conductivity was found to have a higher level of correlation with tumor presence than the corresponding permittivity values and would be expected to be the superior measure of tumor progression/regression . In addition, the normalized conductivity measure had a high level of association with complete tumor response at 30 days (P-value = 0.002) - a finding that could be clinically important because it would provide valuable early-stage information on tumor progression and whether the current therapy regimen should be continued or modified.
We have conducted a preliminary investigation using MT to monitor the progression of breast cancer response to neoadjuvant chemotherapy. Early indications show that the images are repeatable and sensitive to drug-induced breast changes. Of particular interest is the response at one month after the start of treatment where analysis of the conductivity in the ROI was found to distinguish statistically between the complete and incomplete (non)-responding patient groups. Early prediction of treatment success (or lack thereof) could provide useful information to medical oncologists with respect to altering treatment when a patient is not responding to the initial therapy. MT could be performed at numerous stages during treatment at relatively low cost and may be particularly attractive for this type of longitudinal monitoring where the conventional imaging alternatives (for example, MR; FDG PET) are less feasible because of cost and inconvenience.
- FDG PET:
fluorodeoxyglucose positron emission tomography
- H & E:
hematoxylin and eosin
human epidermal growth factor receptor-2
paclitaxel and traztuzumab
regions of interest.
This work was sponsored by National Institutes of Health/National Cancer Institute grant # PO1-CA080139.
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