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Microwave Imaging in Breast Cancer – Results from the First-In-Human Clinical Investigation of the Wavelia System

Open AccessPublished:August 04, 2021DOI:https://doi.org/10.1016/j.acra.2021.06.012

      Rationale and Objectives

      Microwave Breast Imaging (MBI) is an emerging non-ionising technology with the potential to detect breast pathology. The investigational device considered in this article is a low-power electromagnetic wave MBI prototype that demonstrated the ability to detect dielectric contrast between tumour phantoms and synthetic fibroglandular tissue in preclinical studies. Herein, we evaluate the MBI system in the clinical setting. The capacity of the MBI system to detect and localise breast tumours in addition to benign breast pathology is assessed. Secondly, the safety profile and patient experience of this device is established.

      Materials and Methods

      Female patients were recruited from the symptomatic unit to 1 of 3 groups: Biopsy-proven breast cancers (Group-1), unaspirated cysts (Group-2) and biopsy-proven benign breast lesions (Group-3). Breast Density was determined by Volpara VDM (Volumetric Density Measurement) Software. MBI, radiological, pathological and histological findings were reviewed. Subjects were surveyed to assess patient experience.

      Results

      A total of 25 patients underwent MBI. 24 of these were included in final data analysis (11 Group-1, 8 Group-2 and 5 Group-3). The MBI system detected and localised 12 of 13 benign breast lesions, and 9 out of the 11 breast cancers. This included 1 case of a radiographically occult invasive lobular cancer. No device related adverse events were recorded. 92% (n = 23) of women reported that they would recommend MBI imaging to other women.

      Conclusion

      The MBI system detected and localized the majority of breast lesions. This modality may have the potential to offer a non-invasive, non-ionizing and painless adjunct to breast cancer diagnosis. Further larger studies are required to validate the findings of this study.

      Key Words

      INTRODUCTION

      Breast cancer is the most frequently occurring invasive cancer to affect women and the leading cause of cancer death among females worldwide (
      • Ferlay J
      • Soerjomataram I
      • Dikshit R
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      ). As many as 1.7 million new diagnoses of breast cancer, and in excess of 500,000 breast cancer related deaths are recorded annually (
      • Tao Z
      • Shi A
      • Lu C
      • et al.
      Breast cancer: epidemiology and etiology.
      ).
      Survival following a diagnosis of breast cancer is determined by the stage of the disease at the time of initial diagnosis, highlighting the importance of early detection (
      • Siegel RL
      • Miller KD
      • Jemal A
      • et al.
      Cancer statistics, 2019.
      ).
      Mammography remains the gold standard imaging modality for the investigation of symptomatic presentations of breast pathology in women aged over 40 years and also for whole population breast cancer screening (
      • Moloney BM
      • O'Loughlin D
      • Abd Elwahab S
      • et al.
      Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
      ). While mammography offers a cost-effective method of investigating breast cancer, its capacity is limited in identifying tumours that present without a characteristic mass, as is frequently the case with invasive lobular breast cancer, or without calcification, as can occur in entities like non-calcified ductal carcinoma (
      • Bartella L
      • Smith CS
      • Dershaw DD
      • et al.
      Imaging breast cancer.
      ). The sensitivity of screening mammography, which aims to detect pre-clinical breast cancer in asymptomatic women, is estimated to be as low as 68% in mammographically dense breasts. Even in women with lower breast density (> 75 years), the sensitivity for screening mammography is 88% (
      • Walter LC
      • Schonberg MA
      Screening mammography in older women: a review.
      ). This modality is further limited by patient discomfort with compression and the not insignificant risks associated with ionising radiation (

      RMK,MA, England A, McEntee MF, et al. Effective lifetime radiation risk for a number of national mammography screening programmes. Radiography (Lond) 2018;24:240-246.

      ).
      Microwave Breast Imaging (MBI) has been proposed as a promising adjunct modality to conventional breast imaging for the detection of diseased breast tissue, offering a potential non-ionising, non-compressive approach to breast cancer diagnosis (
      • Preece AW
      • Craddock I
      • Shere M.
      • et al.
      MARIA M4: clinical evaluation of a prototype ultrawideband radar scanner for breast cancer detection.
      ) and as a potential tool in the monitoring of neoadjuvant chemotherapy (
      • Meaney PM
      • Kaufman PA
      • Muffly LS
      • et al.
      Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience.
      ). Microwave imaging uses electromagnetic radiation at frequencies ranging between 0.5 GHz and 9.0 GHz to deduce the dielectric properties, or to identify the presence of dielectric contrasts, within an imaging domain as it propagates through and scatters from the tissue. Quantitative or qualitative algorithms are then employed to approximate the actual dielectric properties of the tissue, or to localize the dielectrically contrasted foci of scattered energy in the imaging domain, for image reconstruction (
      • Moloney BM
      • O'Loughlin D
      • Abd Elwahab S
      • et al.
      Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
      ).
      To date, a total of ten MBI system prototypes have been employed in human subject tests, to investigate the clinical utility of MBI (
      • Moloney BM
      • O'Loughlin D
      • Abd Elwahab S
      • et al.
      Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
      ,
      • Benny RA
      • Mythili P
      An overview of microwave imaging for breast tumor detection.
      ,
      • O'Loughlin D
      • O'Halloran M
      • Moloney BM
      • et al.
      Microwave breast imaging: clinical advances and remaining challenges.
      ). While some studies to date have been too small to determine clinical efficacy, larger-scale trials have been conducted with three state-of-the-art MBI system prototypes, with favourable preliminary results (
      • Meaney PM
      • Fanning MW
      • Raynolds T
      • et al.
      Initial clinical experience with microwave breast imaging in women with normal mammography.
      ,
      • Sani LG
      • Vispa A
      • Paoli M
      • et al.
      Novel microwave apparatus for breast lesions detection: Preliminary clinical results.
      ,
      • Shere M
      • Lyburn I
      • Sidebottom R
      • et al.
      MARIA(R) M5: A multicentre clinical study to evaluate the ability of the Micrima radio-wave radar breast imaging system (MARIA(R)) to detect lesions in the symptomatic breast.
      ). Despite encouraging clinical results being reported, several recurrent limitations, detailed in (Table 1) remain unresolved across most studies, likely hindering the translation of this modality to the clinical setting. Of these limitations, the accuracy of lesion localization in the breast has not been quantified by any group. The Wavelia system is a low-power electromagnetic wave MBI device, developed by MVG Industries (Villejust, France), which accurately demonstrated an ability to detect a dielectric contrast between tumour phantoms and synthetic breasts moulds (

      Fasoula A, Duchesne L, Gil Cano JD, et al. On-site validation of a microwave breast imaging system, before first patient study. Diagnostics 2018;8.

      ). In this study we present the findings of the first trial of the Wavelia MBI system in the clinical setting. The capacity of the Wavelia MBI System to detect and localise breast tumours in addition to benign breast pathology is assessed. Furthermore, the safety profile and patient experience of this novel device is catalogued.
      Table 1Current Unresolved Limitations to Reported MBI Technologies.
      Shortcomings to State-of-the-art Microwave Breast Imaging
      A non-negligible false positive rate.
      The challenges of managing a wide range of breast sizes with the same MBI system.
      The automated and repeatable/consistent detection of breast pathologies of various types in breasts of various levels of density.
      Factor analysis (breast density, breast size, age, cancer type and stage) in the absence of consistent datasets from larger-scale MBI clinical trials
      Identifying cases where MBI would offer a useful adjunct to detect or characterise breast pathology.
      The detectability of small, non-palpable, breast pathologies.
      The achievable accuracy of lesion localization in the breast has not been quantified with MBI by any group.
      The standardization of the patient positioning and scan process.

      MATERIALS AND METHODS

      Ethical Approval and Trial Registration

      Ethical approval was granted by the local Clinical Research and Ethics Committee and authorised by the Health Products Regulatory Authority (HPRA), Dublin, Ireland. Ethical standards complied with international guidelines including the Declaration of Helsinki and in accordance with the ethical principles underlying European Union (EU) Directive 93/42/EEC and EN ISO 14155. The study was registered with the U.S. National Library of Medicine (ClinicalTrials.gov NCT03475992).

      The Wavelia Microwave Breast Imaging System Prototype

      The Wavelia system is a low-power electromagnetic wave breast imaging device which was installed at the host institution for the duration of this study (Sept 2018 – Dec 2019) (

      Fasoula A, Duchesne L, Gil Cano JD, et al. On-site validation of a microwave breast imaging system, before first patient study. Diagnostics 2018;8.

      ). Wavelia consists of 2 distinct subsystems, integrated in 2 identical examination tables and both performing a non-compressive, non-invasive breast examination, illustrated in (Fig 1).
      The first subsystem, the Optical Breast Contour Detection (OBCD) subsystem, consists of a 3D stereoscopic camera placed below the examination table at a distance of approximately 40cm from the breast. An azimuthal scan of the camera allows the external surface of the breast to be reconstructed and breast volume to be calculated. Following initial OBCD examination, MBI is performed on an identical examination table, as illustrated in (Fig 1). During MBI, low-power, non-ionizing electromagnetic waves at microwave frequency range propagate through the breast with the patient lying in a prone position (Fig 2).
      Figure 2
      Figure 2Positioning during microwave breast imaging examination.
      The Wavelia MBI system operates using 18 equally-spaced wideband Vivaldi-type probes arranged in a circle in a horizontal plane outside a cylinder containing coupling fluid. Each probe illuminates the imaging domain individually, while the remaining probes receive the electromagnetic scattering at various angles around the circle, in a multistatic radar system configuration. With the patient lying prone on the examination table, the probe array moves vertically below the table and illuminates the breast at 5mm intervals, capturing the dielectric contrast for the entirety of the breast. Coronal sections of the breast, of thickness 10mm (ie, centre of the probe ± 5mm) are generated using the MBI data at each vertical scan position of the probe array. Overlapping consecutive coronal breast sections, formed per azimuthal sector of illumination (partial images), are integrated to form the 3D MBI image, based on multi-static radar imaging technology (TR-MUSIC imaging algorithm).
      The technical principles and algorithms of the multistatic radar detection technology involved in MBI image formation are previously described (Fig 3) (

      Fasoula A, Duchesne L, Gil Cano JD, et al. On-site validation of a microwave breast imaging system, before first patient study. Diagnostics 2018;8.

      ,
      • Fasoula A
      • Moloney BM
      • Duchesne L
      • et al.
      Super-resolution radar imaging for breast cancer detection with microwaves: the integrated information selection criteria.
      ). In summary, the Wavelia MBI system generates a set of parametric MBI images under various assumptions on the percentage of fibro-glandular tissue (pc_fib) along the propagation path within the breast, from a given transmitting antenna to the interrogated imaging pixel and back to a given receiving antenna. For each pc_fib value, the dielectric properties of the breast tissue along the path are defined as a weighted average (weighting by pc_fib) of the adipose tissue and fibro-glandular tissue ‘mean’ dielectric properties, as derived by Sugitani et al. (
      • Sugitani T
      • Kubota SI
      • Kuroki SI
      • et al.
      Complex permittivities of breast tumor tissues obtained from cancer surgery.
      ). Higher pc_fib values indicate denser breast tissue, with higher dielectric constant. The generated set of parametric images are further refined by incorporating image focusing measures, described by Pertuz et al. (
      • Pertuz S
      • Puig D
      • Garcia MA
      • et al.
      Analysis of focus measure operators for shape-from-focus.
      ). The optimal assumption pc_fib is automatically selected based on maximization of the focusing capability of the imaging algorithm. Considering the heterogeneity of breast tissue, the pc_fib parameter is assessed independently for each partial image of the breast, in each imaging sector. Multiple pc fib search ranges are employed to obtain a more complete representation of a lesion and substantiate the presence of a detected breast lesion, based on its persistence across multiple search ranges of the pc_fib parameter.
      Figure 3
      Figure 3MBI image formation based on multi-static radar imaging technology (TR-MUSIC imaging algorithm). Sectorization and partial image formation using multiple pc_fib search ranges: proprietary patented technology by MVG Industries.

      MBI Image Formation and Morphological Image Post-Processing

      The unknown dielectric properties of healthy breast tissue was deduced by assessing the pc_fib independently in each sub-image and while employing:
      • 2 wide search ranges: [10:60]% and [20:50]%, and
      • 3 narrow search ranges: [10:20]%, [30:40]% and [50:60]%;
      A total number of5 full 3D MBI images (‘Raw MBI images’) were formed per patient's breast, 1 for each pc_fib parameter search range. Morphological image post-processing was then applied to detect Region-Of-Interest (ROIs) persistently present in the set of 5 ‘Raw’ MBI images.
      The morphological characteristics of a ROI were assessed, and a ROI detection was validated in a given pc_fib search range if the following criteria were satisfied:
      • ROI measuring greater than 1cm3
      • Minimum solidity of 30% - This criterion was determined as the quantitative setting to support the differentiation of a breast mass from a focal asymmetry.
      • Minimum intensity contrast of 5% - This criterion was determined to allow isolation of a single dominant and persistent ROI.
      The persistent detection of a ROI in three or greater pc_fib search ranges was considered indicative of an association with a physical object and was included in the final morphological image (Fig 4). For iterative image thresholding, a progressive increase of the image threshold setting was applied, starting from null threshold and up to reaching a stop value based on the maximum accepted size (3 cm3) of ‘connected’ objects, defining a breast mass. The presence of a ROI in less than three pc_fib search ranges was considered artefact and was not reported for clinical data analysis.
      Figure 4
      Figure 4Morphological breast lesion detection based on persistence: proprietary patented technology by MVG Industries. Foot note: 1) Image threshold setting based on the maximum accepted size (3 cm3) of ‘connected’ objects, defining a breast mass.

      Patient Recruitment Process

      For this study, all patients were recruited following a symptomatic presentation to the Symptomatic Breast Unit. Eligible patients were invited to participate in the clinical investigation and written informed consent obtained.

      Selection of Study Population

      Inclusion and Exclusion criteria, applicable to all 3 groups of patients, are detailed in (Table 2).
      Table 2Inclusion and Exclusion Criteria Set Out for the Study.
      Inclusion Criteria
      1. Symptomatic presentation with a palpable breast lump.
      2. Mammography performed at time of presentation (< 6 weeks prior to MBI)
      3. Capable of comfortably lying in a prone position for 15 minutes.
      4. Subjects with bra size larger than 32B and cup size larger or equal to B.
      5. Subjects whose submerged breast would allow a sufficient margin to accommodate the transition liquid around the breast within the cylindrical container. Satisfaction of criteria determined by the clinician at time of initial clinical assessment.
      Exclusion Criteria
      1. Pregnant or breast-feeding.
      2. Previous surgery to the breast.
      3. Previously received chemotherapy or radiotherapy to the breast.
      4. Subjects who have had a breast biopsy within the previous two weeks.
      5. Subjects with any active or metallic implant or bearing any nonremovable object.
      6. Post-biopsy patients whose breast tissue is not healed sufficiently.
      7. Breast cyst aspiration before MBI.
      8. Significant co-morbidities.
      9. Prior or concurrent malignancy.
      10. Under the age of 18 years old.
      11. Inflammation and/or erythema of the breast and/or break in the skin.
      Three groups of patients were identified for inclusion in the study:
      • Group 1: Patients with pre-diagnosed breast cancer (core needle biopsy performed ≥14 days before the microwave breast investigation).
      • Group 2: Patients with breast cyst. No prior biopsy.
      • Group 3: Patients with pre-diagnosed benign lesion (Core needle biopsy performed ≥14 days before the microwave breast investigation).
      The 14-day time lapse was considered sufficient to allow healing of the biopsy site in the breast. Due to the high dielectric constant of the blood (
      • Salahuddin S
      • Farrugia L
      • Sammut CV
      • et al.
      Dielectric properties of fresh human.
      ), residual hematoma at the biopsy site could impact MBI images, generating high signal not associated with the pathological tissue.

      Patient Experience

      Each patient who underwent MBI was invited to complete an ad-hoc questionnaire investigating their experience with MBI. 4 areas, comprising 10 questions in total, were targeted for evaluation. These included 1) Experience with the coupling liquid [1(A) Temperature of the coupling liquid; 1(B) Smell of the coupling liquid; 1(C) Ease of cleaning coupling liquid from the breast post-examination], 2) Comfort during MBI examination [2(A) Comfort of examination table; 2(B) Comfort maintaining body position during the examination], 3) Device factors [3(A) Noisiness of device, 3(B) Device vibrations, 3(C) Examination duration], and finally, the Process of MBI Imaging [4(A) Process easy to understand, 4(B) Is MBI recommendable]. The questionnaire was completed in person or over the telephone with each patient.

      Radiological and Histological Data Collection

      All mammographic studies were undertaken with full field digital mammography (FFDM) systems [GE Senographe Essential (Chicago, Illinois, United States) and Hologic Selenia Dimension (Marlborough, Massachusetts, United States)]. Ultrasound was performed with the patient in the supine or decubitus position using a high-resolution 12.5 MHz linear array transducer (Philips EPIQ 5W; Amsterdam, Netherlands). In Group 1 and Group 3, ultrasound guided biopsies were retrieved using a TruCore II biopsy gun (Argon Medical; Frisco, Texas, USA) or a Achieve automatic biopsy device (Merit Medical; Galway, Ireland) with a fourteen-gauge automated needle. The radiological database (AGFA IMPAX, Agfa-Gevaert, Mortsel, Belgium) was assessed and all conventional imaging (mammography and ultrasonography) studies reviewed.
      Mammographic location, BIRADS category for density and BIRADS category for predication of malignancy were recorded. The fifth edition of the American College of Radiology (ACR) BI-RADS was employed (
      • Rao AA
      • Feneis J
      • Lalonde C
      • et al.
      A pictorial review of changes in the BI-RADS fifth edition.
      ). Mammographic breast density was assessed using Volpara® Volumetric Density Measurement (VDM) Software. Sonographic lesion location was recorded.
      All personal or identifying details were removed from patient data, and a trial number assigned, ensuring anonymity. The anonymised data was kept in a secure database designed and maintained by the Clinical Research Facility of the host institution.

      Imaging and Data Analysis

      As this study was undertaken to address early feasibility, the number of subjects included in the study (n = 25) was limited and not intended to permit a clinically meaningful statistical analysis.
      MBI image formation and morphological post-processing for persistent breast lesion (ROI) detection and characterization was performed offsite by the MVG group. Given that this was a First-in-Human (FiH) investigation for the Wavelia MBI modality, the MBI data processing chain progressively evolved, throughout patient recruitment, before stabilization for final data analysis at patient group level. 3 interim data reviews were performed to assess and confirm the clinical relevance of the MBI findings based on the available reference clinical data.

      RESULTS

      Patient Demographics

      A total of 24 female patients with a palpable breast lump were included in final analysis. 1 patient who underwent MBI was excluded from the final data and imaging analysis. This case was a patient who presented with a palpable lump which was determined to be normal breast tissue. This patient had small scattered cysts identified in a different breast quadrant, and as a result was erroneously enrolled in Group 2 prior to imaging.
      The mean age (range) was 50.5 years (35 - 83). A further breakdown of age in each patient group is detailed in (Table 3). There were 11 cases of invasive carcinoma [6 invasive ductal carcinoma (IDC), and 5 invasive lobular carcinoma (ILC)], 8 patients with an underlying breast cyst, 4 cases of benign breast disease (fibroadenoma) and 1 case of a complicated cyst. The tumour characteristics are detailed in (Table 3).
      Table 3Clinicopathological and Tumour Characteristics of the Patients who Underwent MBI and were Included in the Final Data Analysis.
      Clinicopathological Details of Patients
      GroupNumber (n = 24)Age (range)
      1 – Invasive Cancer1164.6 (42 – 83)
      2 – Cyst838.3 (35 – 49)
      3 – Fibroadenoma437.5 (36 – 39)
      3 – Complicated cyst147
      Tumour Characteristics (Group 1)
      FeatureGroupingNumber (n = 11)
      Histological TypeDuctal6
      Lobular5
      Tumour GradeI1
      II9
      III1
      Nodal StatusPositive3
      Negative8
      BI-RADS Lesion Classification (At initial Triple Assessment)56
      4/51
      41
      3/41
      11
      01

      Morphological MBI Post-Processing: Lesion Detection based on Persistence

      5 MBI images associated with 5 distinct search ranges for the parameter pc_fib (percentage fibroglandular), were formed in each case (2 wide and 3 narrow search ranges). Lesions morphologically detected in at least three of the 5 pc_fib search ranges under evaluation were considered persistent. This method of image generation is detailed, using Case 1 as an example.

      Case 1

      Case 1 was a 51-years old patient presenting with a mass palpated deep to the left nipple, in a central position of the left breast. The OBCD reconstruction for the prone breasts in this case demonstrated the nipple to be off-centre to the left-hand side (Fig 5). The conventional imaging, along with MBI localisation is illustrated in (Fig 6). This patient subsequently underwent primary surgery, where a 37mm IDC was confirmed on final histology.
      Figure 5
      Figure 5OBCD reconstruction of the outer contours of the breast for Case 1.
      Figure 6
      Figure 6Case 1: From left; Mammography (mediolateral oblique and craniocaudal projections), ultrasonography (transverse and longitudinal), and MBI localisation (sagittal and coronal images) of the area of interest in the left breast.
      The MBI images associated with the 5 pc-fib search ranges, which were systematically employed for all the patients, are illustrated in (Fig 7) for Case 1. In this case, a cluster of significant radar target echoes outstanding from the surrounding breast parenchyma were identified in a region deep to the left of the nipple. This lesion satisfied the morphological criteria and persisted across all pc_fib search ranges. The subsequent morphological image was generated demonstrating the persistent region of interest.
      Figure 7
      Figure 7IDC morphological detection based on persistence.

      Summary of Results of Wavelia MBI

      Group 1: Invasive Carcinomas

      The detection rate for the persistent morphologically-extracted breast lesions, their locations and the corresponding location on conventional imaging for Group 1 are detailed in (Table 4). In Group 1, persistent lesion detection was validated for 9 of the 11 invasive carcinomas. This included persistent detection in 4 of 6 IDC and 5 of 5 ILC. In case 043, the ILC was occult on both mammography and ultrasonography. With MBI, this lesion was correctly identified and localised. The location of 7 out of the 9 validated lesion detections was correctly approximated, assuming the site identified on conventional imaging to be correct. The two lesions that were not detected were ≤ 10 mm on post-surgery histology.
      Table 4Persistent Morphological Breast Lesion detections for Group 1. Footnotes: (1) The Extracted ROI was Persistent in 2 out of the 5 pc_fib Search Ranges only, but Exceptionally Retained, as this Finding was Deemed Clinically Relevant. (2) In Case 032, the Patient had a Complete Response to Neoadjuvant Chemotherapy. The Size Provided (30mm), is the Maximum Size of the Lesion, Recorded with MRI Prior to the Treatment. (3) MBI Location was Correct, with Reference to Site of Lesion at Time of Surgery.
      Histology SubtypePatient IDPathological Lesion Size (mm)pc_fib:ROI Detection RatePersistent Lesion DetectionConventional Imaging LocationMicrowave Imaging LocationAccurate MBI Location
      [n][Clock Face Position]
      Ductal002405/532
      010375/51212
      027154/5119
      029354/555
      013100/59OccultN/A
      0419.50/512OccultN/A
      Lobular039324/51010
      004525/5129
      008352/51-88
      0323023/51212
      043654/5Occult93

      Groups 2 & 3: Benign Breast Lesions

      Persistent morphological breast lesions, their locations and the corresponding location on conventional imaging for Group 2 and 3 is detailed in (Table 5). In Group 2 and Group 3, persistent lesion detection was validated for 12 of the 13 breast lesions. Case 023, which was not detectable with Wavelia MBI, was a 12-mm fibroadenoma, also occult to mammography (36 years-old patient with dense breasts, BIRADS Category C).
      Table 5Persistent Morphological Breast Lesion detections for Group 2 and Group 3. Footnotes: (1) The Extracted ROI was Persistent in 2 out of the 5 pc_fib Search Ranges only, but Exceptionally Retained, as Clinically Relevant. (2) Small Lesion Persistent Over Varying pc_fib Search Range, but Volumetric Size too Small (<1 cm3). As Such, Volume min= 0.5 cm3 Exceptionally Used at Morphological Processing.
      GroupPatient IDLesion Size (Conventional Imaging, mm)pc_fib: ROI Detection RatePersistent Lesion DetectionConventional Imaging LocationMicrowave Imaging LocationAccurate MBI Location
      [n][Clock Face Position]
      Group 2030145/533
      009164/523
      040253/51212
      012133/522
      00692/51-1010
      019104/599
      036103/52CentralCentral
      003313/51212
      Group 3017265/51111
      031195/534
      037255/5CentralCentral
      023120/56OccultN/A
      033175/5118
      The location of 10 out of the 12 validated lesion detections was correctly approximated, with the 2 remaining cases localized within the correct breast quadrant.

      Patient Experience and Safety Profile

      The patients' responses to the 10-question questionnaire are presented in the form of a cumulative bar graph (Fig 8). 92% (n = 23) of women reported that they would recommend MBI imaging to other women. 96% (n = 24) reported that the process was clear and well-understood. A majority agreement, indicating a favourable patient experience, was recorded for all questions regarding the coupling fluid (Question 1A, 1B and 1C) and the examination table (Question 2A and 2B). When asked if the scan was too loud (Question 3A) or if the vibrations were too strong (Question 3B) a majority disagreement was recorded. 40% of patients (n = 10) who underwent MBI reported a neutral feeling when asked if the scan duration was too long (Question 3C). The average MBI imaging duration was approximately 7 minutes per breast. The average duration of the full MBI examination, including patient positioning and potential imaging repetitions, was 50 minutes. Imaging was repeated if deemed necessary based on the outputs of a scan quality check integrated with the MBI system software.
      In terms of the safety profile of the Wavelia System, a single adverse event was recorded. A patient underwent MBI with a pre-existing hordeolum (stye) of the left eye. As this infection was still present when the patient completed the follow-up visit, this was recorded as an ongoing adverse event of mild severity, unrelated to the clinical investigation. No Adverse Device Effects, Serious Adverse Events or Serious Adverse Device Effects were recorded. The power emitted within the breast by this first-generation prototype was consistently less than 50mW. The calculated maximum value of localized Specific Absorption Rate (SAR) in the breast amounts to 0.50W/kg, at 4GHz and for average within 10g of breast tissue mass.

      DISCUSSION

      In this FiH clinical trial in a patient cohort, the Wavelia System demonstrated the capacity to detect and approximate underlying breast abnormalities to the appropriate location in patients with biopsy confirmed invasive carcinoma and benign breast lesions such as cysts and fibroadenomas. This is the first study, to our knowledge, where the accuracy of an MBI prototype to localise breast lesions has been reported. These promising findings suggest that Wavelia MBI may represent a viable, non-ionising, user independent adjunct to conventional breast imaging and warrants further evaluation in the clinical setting.
      Microwave breast imaging (MBI) has been investigated as a novel modality for the detection of breast disease, offering a non-ionising, non-compressive approach (
      • Preece AW
      • Craddock I
      • Shere M.
      • et al.
      MARIA M4: clinical evaluation of a prototype ultrawideband radar scanner for breast cancer detection.
      ), and as a potential diagnostic management strategy in the monitoring of neoadjuvant chemotherapy (
      • Meaney PM
      • Kaufman PA
      • Muffly LS
      • et al.
      Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience.
      ). Despite extensive efforts to harness the potential of this modality, spanning 40 years, a pertinent clinical application for this modality has yet to be identified (
      • O'Loughlin D
      • O'Halloran M
      • Moloney BM
      • et al.
      Microwave breast imaging: clinical advances and remaining challenges.
      ,
      • Kwon S
      • Lee S
      Recent advances in microwave imaging for breast cancer detection.
      ,
      • Larsen L
      • Jacobi J
      Microwaves offer promise as imaging modality.
      ). Multiple distinct approaches, both in terms of integrated hardware components and imaging algorithm design have been reported, including bed-based, hand-held, and wearable MBI systems, each with distinct patient positioning (
      • O'Loughlin D
      • O'Halloran M
      • Moloney BM
      • et al.
      Microwave breast imaging: clinical advances and remaining challenges.
      ). Most of those systems use a transition liquid as an interface between the antenna array and the breast, while other MBI systems feature a dry interface setup (
      • Moloney BM
      • O'Loughlin D
      • Abd Elwahab S
      • et al.
      Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
      ,
      • O'Loughlin D
      • O'Halloran M
      • Moloney BM
      • et al.
      Microwave breast imaging: clinical advances and remaining challenges.
      ). In terms of the imaging algorithm being employed, radar and tomography-based systems have been reported. Data can be acquired in the time or the frequency domain, and also in a monostatic or multistatic manner. Reported systems have also differed in terms of probe design, probe array shape, the movement of the array, the number of array elements, and the working frequency bandwidth (
      • Moloney BM
      • O'Loughlin D
      • Abd Elwahab S
      • et al.
      Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
      ,
      • O'Loughlin D
      • O'Halloran M
      • Moloney BM
      • et al.
      Microwave breast imaging: clinical advances and remaining challenges.
      ). The most up-to-date system reported, the MARIA5 by Micrima Ltd., is in use in several symptomatic breast units in the North Bristol Trust in the United Kingdom (
      • Shere M
      • Lyburn I
      • Sidebottom R
      • et al.
      MARIA(R) M5: A multicentre clinical study to evaluate the ability of the Micrima radio-wave radar breast imaging system (MARIA(R)) to detect lesions in the symptomatic breast.
      ). The sensitivity of this system is reported to be 79% for cancers in dense tissue, with the system detecting underlying cancer in 26 of 33 patients with a BIRAD breast density classification of C or D. In this study the Wavelia system demonstrated comparable sensitivity, correctly detecting the abnormality in 21 of the 24 patients (87.5%). Of 11 patients with biopsy confirmed invasive carcinoma, 9 of 11 lesions were detectable, 7 of which were approximated to the appropriate location. Of the patients presenting with benign breast lesions such as simple cysts and fibroadenomas, 12 of 13 were detectable with MBI, 10 of which were approximated to the appropriate location.
      In this study, 5 of the eleven invasive carcinomas included were ILC. This is an unusually high proportion, considering in normal practice, ILC accounts for 10-15% of all invasive breast cancers (
      • Li CI
      • Uribe DJ
      • Daling JR
      • et al.
      Clinical characteristics of different histologic types of breast cancer.
      ). In contrast to IDC which are usually well demarcated, ILC proliferation patterns are more typically diffuse with an irregular growth pattern and minimal desmoplastic reaction (
      • Gannon LM
      • Cotter MB
      • Quinn CM
      • et al.
      The classification of invasive carcinoma of the breast.
      ). Often, other than a slightly firm consistency, no mass may be identifiable clinically or radiologically until an advanced stage, due to the subtle insidious proliferative pattern of this subtype (
      • Moloney BM
      • McAnena PF
      • Ryan EJ
      • et al.
      The impact of preoperative breast magnetic resonance imaging on surgical management in symptomatic patients with invasive lobular carcinoma.
      ). Of the 5 cases of ILC, the Wavelia MBI system accurately identified all tumours. Of note, the cases of ILC were of a larger size than the cases of IDC, as determined at postoperative histopathology (Table 4). Interestingly, in case 043, the ILC was occult on both mammography and ultrasonography. With MBI, this lesion was correctly identified and localised. The sensitivity of conventional mammography in detecting ILC is reported as between 57%–81% (
      • Johnson K
      • Sarma D
      • Hwang ES
      Lobular breast cancer series: imaging.
      ), suggesting that the addition of MBI could improve the existing diagnostic paradigm for this clinically relevant subtype of breast cancer. Of the 6 cases of IDC, 4 cases were detectable with MBI. The remaining 2 lesions that were not detected were small in size (≤ 10 mm on post-surgery histology), and too small for detection with the current Wavelia prototype. Similarly, amongst the benign lesions, the Wavelia prototype failed to detect a 12-mm fibroadenoma. In this case, the lesion was mammographically occult, but visible with sonography. Of note, the breast density in this case was heterogeneously dense (BIRADS Category C).
      This study highlights the safety profile of the Wavelia MBI system. No clinical trial related adverse event was recorded. Furthermore, no device deficiencies occurred, underlining the robustness of this prototype. The calculated maximum value of localized SAR (0.50W/kg, at 4GHz, averaged within a 10g mass of tissue) complies with the guidelines of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the EU Council Recommendation 1999/519/EC on the limitation of exposure of the general public to electromagnetic fields (recommended maximum value of localized SAR<2W/kg averaged within a 10g mass of tissue). With this exposure, this non-ionizing technology could offer the possibility for regular follow-up with MBI scan repetitions, with minimal risk for the patient.
      Crucially, the initial participant's feedback for the Wavelia MBI prototype was favourable. A major benefit of this MBI system is the non-compressive nature of the examination, which is likely to be partly responsible for the majority (92%) of women reporting that they would recommend MBI imaging to other women. A significant amount of breast compression is required to obtain mammograms of acceptable image quality, to separate overlapping structures, and to minimise motion artefact and radiation dose (
      • Eklund GW
      Mammographic compression: science or art?.
      ). For most women, breast compression is an uncomfortable experience. In a study of 954 patients, Keemers-Gels et al. (
      • Keemers-Gels ME
      • Groenendijk RP
      • van den Heuvel JH
      • et al.
      Pain experienced by women attending breast cancer screening.
      ) found that as many as 79% of patients undergoing breast cancer screening found mammography to be mildly to severely painful. Additionally, the authors established that the pain associated with breast compression during mammography as the main deterrent for women who indicated that they would not attend further screening.

      Limitations

      This is an early-phase, first-in-human study limited to symptomatic presentations with palpable breast lumps. The 24-patient cohort was too limited to allow for factor analysis. Future investigations with larger sample sizes, a wider range of lesion types (malignant versus benign, IDC versus ILC, mass-like versus non mass-like) and various breast densities is required to delineate the cases where the Wavelia MBI modality may offer a beneficial adjunct to current diagnostic protocols.
      A significant limitation of the current generation is the inability to detect lesions less than 10mm. In current practice, with clinical outcomes from breast cancer determined by the size of the lesion at presentation (
      • Verschraegen C
      • Vinh-Hung V
      • Cserni G
      • et al.
      Modeling the effect of tumor size in early breast cancer.
      ), the importance in considerably reducing the minimal size in subsequent prototype generations cannot be overstated.
      A further limitation of the current MBI prototype is the range of breast sizes which can be assessed. The current system is unsuitable for patients with a small breast (A-cup size). This is due to the necessity for the breast to have a pendulous reach in the prone position in order to undergo imaging. With case 003, only two MBI coronal sections of the breast could be reconstructed, thwarting a 3D reconstruction and rendering interpretation of MBI findings challenging. Further Wavelia MBI prototypes will necessitate the inclusion of all breast cup sizes if the system is to hold any potential clinical utility.
      The current prototype has limited ability to detect abnormal tissue in immediate proximity of the pectoralis major. This is due to 3-4cm between the uppermost breast scanning position and the thoracic wall. The next generation of the prototype will in some part address this concern via miniaturisation of the microwave sensors allowing inclusion of more of the axillary tail of the breast. As MBI is performed with the patient lying prone, the authors postulate that examination of the retro-areolar region will be unrestricted with the Wavelia system. Carcinoma in the retroareolar region account for 8% of all breast cancers, and often represent more of a diagnostic challenge than cancers elsewhere in the breast (
      • Ferré R
      • Paré M
      • Smith L
      • et al.
      Retroareolar carcinomas in breast ultrasound: pearls and pitfalls.
      ).
      The long duration of the examination procedure is an additional limitation of this first MBI prototype. Second generation prototype development is underway where a major aim is to reduce the time duration of the procedure in future clinical investigations. The acceleration of the MBI scan will also have a beneficial effect on the stability of the recorded signals, by limiting any environmental factors and sensor drifts that may degrade the quality of the scan data.

      CONCLUSIONS

      The Wavelia MBI system, while still in a developmental prototype stage, holds significant potential for detecting breast abnormalities while offering the patient a favourable experience over conventional mammography. This novel modality may also add significant value to the existing detection paradigm for ILC which can evade conventional imaging. Future studies incorporating a larger cohort of patients with a variety of breast pathology will offer greater insight into its sensitivity and specificity. Should future investigations validate these initial promising results this novel imaging modality may have the potential to be introduced in clinical practice to further optimize the detection and management of breast cancer.

      REFERENCES

        • Ferlay J
        • Soerjomataram I
        • Dikshit R
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: 359-386
        • Tao Z
        • Shi A
        • Lu C
        • et al.
        Breast cancer: epidemiology and etiology.
        Cell Biochem Biophys. 2015; 72: 333-338
        • Siegel RL
        • Miller KD
        • Jemal A
        • et al.
        Cancer statistics, 2019.
        CA Cancer J Clin. 2019; 69: 7-34
        • Moloney BM
        • O'Loughlin D
        • Abd Elwahab S
        • et al.
        Breast cancer detection-a synopsis of conventional modalities and the potential role of microwave imaging.
        Diagnostics (Basel). 2020; 10: 1-13
        • Bartella L
        • Smith CS
        • Dershaw DD
        • et al.
        Imaging breast cancer.
        Radiol Clin North Am. 2007; 45: 45-67
        • Walter LC
        • Schonberg MA
        Screening mammography in older women: a review.
        JAMA. 2014; 311: 1336-1347
      1. RMK,MA, England A, McEntee MF, et al. Effective lifetime radiation risk for a number of national mammography screening programmes. Radiography (Lond) 2018;24:240-246.

        • Preece AW
        • Craddock I
        • Shere M.
        • et al.
        MARIA M4: clinical evaluation of a prototype ultrawideband radar scanner for breast cancer detection.
        J Med Imaging (Bellingham). 2016; 3033502
        • Meaney PM
        • Kaufman PA
        • Muffly LS
        • et al.
        Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience.
        Breast Cancer Res. 2013; 15: 35
        • Benny RA
        • Mythili P
        An overview of microwave imaging for breast tumor detection.
        Prog Electromagn Res. 2020; 87: 30
        • O'Loughlin D
        • O'Halloran M
        • Moloney BM
        • et al.
        Microwave breast imaging: clinical advances and remaining challenges.
        IEEE Trans Biomed Eng. 2018; 65: 2580-2590
        • Meaney PM
        • Fanning MW
        • Raynolds T
        • et al.
        Initial clinical experience with microwave breast imaging in women with normal mammography.
        Acad Radiol. 2007; 14: 207-218
        • Sani LG
        • Vispa A
        • Paoli M
        • et al.
        Novel microwave apparatus for breast lesions detection: Preliminary clinical results.
        Biomed Signal Process Control. 2019; 52: 257-263
        • Shere M
        • Lyburn I
        • Sidebottom R
        • et al.
        MARIA(R) M5: A multicentre clinical study to evaluate the ability of the Micrima radio-wave radar breast imaging system (MARIA(R)) to detect lesions in the symptomatic breast.
        Eur J Radiol. 2019; 116: 61-67
      2. Fasoula A, Duchesne L, Gil Cano JD, et al. On-site validation of a microwave breast imaging system, before first patient study. Diagnostics 2018;8.

        • Fasoula A
        • Moloney BM
        • Duchesne L
        • et al.
        Super-resolution radar imaging for breast cancer detection with microwaves: the integrated information selection criteria.
        Conf Proc IEEE Eng Med Biol Soc. 2019; : 1868-1874
        • Sugitani T
        • Kubota SI
        • Kuroki SI
        • et al.
        Complex permittivities of breast tumor tissues obtained from cancer surgery.
        Appl Phys Lett. 2014; 1: 1-5
        • Pertuz S
        • Puig D
        • Garcia MA
        • et al.
        Analysis of focus measure operators for shape-from-focus.
        Pattern Recognit. 2013; 46: 1415-1432
        • Salahuddin S
        • Farrugia L
        • Sammut CV
        • et al.
        Dielectric properties of fresh human.
        blood. 2017; 1: 1-4https://doi.org/10.1109/ICEAA.2017.8065249
        • Rao AA
        • Feneis J
        • Lalonde C
        • et al.
        A pictorial review of changes in the BI-RADS fifth edition.
        Radiographics. 2016; 36: 623-639
        • Kwon S
        • Lee S
        Recent advances in microwave imaging for breast cancer detection.
        Int J Biomed Imaging. 2016; 20165054912
        • Larsen L
        • Jacobi J
        Microwaves offer promise as imaging modality.
        D I. 1982; 11: 44-47
        • Li CI
        • Uribe DJ
        • Daling JR
        • et al.
        Clinical characteristics of different histologic types of breast cancer.
        Br J Cancer. 2005; 93: 1046-1052
        • Gannon LM
        • Cotter MB
        • Quinn CM
        • et al.
        The classification of invasive carcinoma of the breast.
        Expert Rev Anticancer Ther. 2013; 13: 941-954
        • Moloney BM
        • McAnena PF
        • Ryan EJ
        • et al.
        The impact of preoperative breast magnetic resonance imaging on surgical management in symptomatic patients with invasive lobular carcinoma.
        BRCA. 2020; 141178223420948477
        • Johnson K
        • Sarma D
        • Hwang ES
        Lobular breast cancer series: imaging.
        Breast Cancer Res. 2015; 17: 94
        • Eklund GW
        Mammographic compression: science or art?.
        Radiology. 1991; 181: 339-341
        • Keemers-Gels ME
        • Groenendijk RP
        • van den Heuvel JH
        • et al.
        Pain experienced by women attending breast cancer screening.
        Breast Cancer Res Treat. 2000; 60: 235-240
        • Verschraegen C
        • Vinh-Hung V
        • Cserni G
        • et al.
        Modeling the effect of tumor size in early breast cancer.
        Ann Surg. 2005; 241: 309-318
        • Ferré R
        • Paré M
        • Smith L
        • et al.
        Retroareolar carcinomas in breast ultrasound: pearls and pitfalls.
        Cancers. 2016; 9