Superparamagnetic iron oxide (SPIO) for axillary mapping in patients with ductal carcinoma in situ undergoing mastectomy: single-institution experience.

PURPOSE: Unnecessary axillary surgery can potentially be avoided in patients with DCIS undergoing mastectomy. Current guidelines recommend upfront sentinel lymph node biopsy during the index operation due to the potential of upstaging to invasive cancer. This study reviews a single institution's experience with de-escalating axillary surgery using superparamagnetic iron oxide dye for axillary mapping in patients undergoing mastectomy for DCIS. METHODS: This is a retrospective single-institution cross-sectional study. All medical records of patients who underwent mastectomy for a diagnosis of DCIS from August 2021 to January 2023 were reviewed and patients who had SPIO injected at the time of the index mastectomy were included in the study. Descriptive statistics of demographics, clinical information, pathology results, and interval sentinel lymph node biopsy were performed. RESULTS: A total of 41 participants underwent 45 mastectomies for DCIS. The median age of the participants was 58 years (IQR = 17; range 25 to 76 years), and the majority of participants were female (97.8%). The most common indication for mastectomy was diffuse extent of disease (31.7%). On final pathology, 75.6% (34/45) of mastectomy specimens had DCIS without any type of invasion and 15.6% (7/45) had invasive cancer. Of the 7 cases with upgrade to invasive disease, 2 (28.6%) of them underwent interval sentinel lymph node biopsy. All sentinel lymph nodes biopsied were negative for cancer. CONCLUSION: The use of superparamagnetic iron oxide dye can prevent unnecessary axillary surgery in patients with DCIS undergoing mastectomy.

In vivo lymph node CEST-Dixon MRI in breast cancer patients with metastatic lymph node involvement.

PURPOSE: Axillary lymph nodes (LNs) often present a reservoir for metastatic breast cancer, yet metastatic LN involvement cannot be discerned definitively using diagnostic imaging. This study investigated whether in vivo CEST may discriminate LNs with versus without metastatic involvement. METHODS: 3T MRI was performed in patients with breast cancer before clinically-indicated mastectomy or lumpectomy with LN removal, after which LN metastasic involvement was determined using histological evaluation. Non-contrast anatomical imaging, as well as B0 and B1 field maps, were acquired in sequence with three-point CEST-Dixon (3D turbo-gradient-echo; factor = 25; TR/TE1/ΔTE = 851/1.35/1.1 ms; spatial-resolution = 2.5 × 2.5 × 6 mm; slices = 10; four sinc-gauss pulses with duty-cycle = 0.5, total saturation duration = 701.7 ms; B1 = 1.5 µT; saturation offsets = -5.5 to +5.5 ppm; stepsize = 0.2 ppm; scan duration = 6 min 30 s). The mean z-spectrum from LNs with (n = 20) versus without (n = 22) metastatic involvement were analyzed and a Wilcoxon rank-sum test (significance: p < 0.05) was applied to evaluate differences in B0, B1 , and magnetization transfer ratio (MTR) in differing spectral regions of known proton exchange (nuclear Overhauser effect [NOE], amide, amine, and hydroxyl) between cohorts. RESULTS: No difference in axillary B1 (p = 0.634) or B0 (p = 0.689) was observed between cohorts. Elevated MTR was observed for the NOE (-1.7 ppm; MTR = 0.285 ± 0.075 vs. 0.248 ± 0.039; p = 0.048), amine (+2.5 ppm; MTR = 0.284 ± 0.067 vs. 0.234 ± 0.31; p = 0.005), and hydroxyl (+1 ppm; MTR = 0.394 ± 0.075 vs. 0.329 ± 0.055; p = 0.002) protons in LNs from participants with versus without metastatic involvement. CONCLUSIONS: Findings are consistent with a unique metastatic LN microenvironment detectable by CEST-Dixon and suggest that CEST MRI may have potential for mapping LN metastasis non-invasively in vivo.

Soft Tissue Monitoring of the Surgical Field: Detection and Tracking of Breast Surface Deformations.

OBJECTIVE: Deformable object tracking is common in the computer vision field, with applications typically focusing on nonrigid shape detection and usually not requiring specific three-dimensional point localization. In surgical guidance however, accurate navigation is intrinsically linked to precise correspondence of tissue structure. This work presents a contactless, automated fiducial acquisition method using stereo video of the operating field to provide reliable three-dimensional fiducial localization for an image guidance framework in breast conserving surgery. METHODS: On n = 8 breasts from healthy volunteers, the breast surface was measured throughout the full range of arm motion in a supine mock-surgical position. Using hand-drawn inked fiducials, adaptive thresholding, and KAZE feature matching, precise three-dimensional fiducial locations were detected and tracked through tool interference, partial and complete marker occlusions, significant displacements and nonrigid shape distortions. RESULTS: Compared to digitization with a conventional optically tracked stylus, fiducials were automatically localized with 1.6 ± 0.5 mm accuracy and the two measurement methods did not significantly differ. The algorithm provided an average false discovery rate <0.1% with all cases' rates below 0.2%. On average, 85.6 ± 5.9% of visible fiducials were automatically detected and tracked, and 99.1 ± 1.1% of frames provided only true positive fiducial measurements, which indicates the algorithm achieves a data stream that can be used for reliable on-line registration. CONCLUSIONS: Tracking is robust to occlusions, displacements, and most shape distortions. SIGNIFICANCE: This work-flow friendly data collection method provides highly accurate and precise three-dimensional surface data to drive an image guidance system for breast conserving surgery.

Incorporating heterogeneity and anisotropy for surgical applications in breast deformation modeling.

BACKGROUND: Simulating soft-tissue breast deformations is of interest for many applications including image fusion, longitudinal registration, and image-guided surgery. For the surgical use case, positional changes cause breast deformations that compromise the use of preoperative imaging to inform tumor excision. Even when acquiring imaging in the supine position, which better reflects surgical presentation, deformations still occur due to arm motion and orientation changes. A biomechanical modeling approach to simulate supine breast deformations for surgical applications must be both accurate and compatible with the clinical workflow. METHODS: A supine MR breast imaging dataset from n = 11 healthy volunteers was used to simulate surgical deformations by acquiring images in arm-down and arm-up positions. Three linear-elastic modeling approaches with varying levels of complexity were used to predict deformations caused by this arm motion: a homogeneous isotropic model, a heterogeneous isotropic model, and a heterogeneous anisotropic model using a transverse-isotropic constitutive model. FINDINGS: The average target registration errors for subsurface anatomical features were 5.4 ± 1.5 mm for the homogeneous isotropic model, 5.3 ± 1.5 mm for the heterogeneous isotropic model, and 4.7 ± 1.4 mm for the heterogeneous anisotropic model. A statistically significant improvement in target registration error was observed between the heterogeneous anisotropic model and both the homogeneous and the heterogeneous isotropic models (P < 0.01). INTERPRETATION: While a model that fully incorporates all constitutive complexities of anatomical structure likely achieves the best accuracy, a computationally tractable heterogeneous anisotropic model provided significant improvement and may be applicable for image-guided breast surgeries.

Supine magnetic resonance image registration for breast surgery: insights on material mechanics.

Purpose: Breast conserving surgery (BCS) is a common procedure for early-stage breast cancer patients. Supine preoperative magnetic resonance (MR) breast imaging for visualizing tumor location and extent, while not standard for procedural guidance, is being explored since it more closely represents the surgical presentation compared to conventional diagnostic imaging positions. Despite this preoperative imaging position, deformation is still present between the supine imaging and surgical state. As a result, a fast and accurate image-to-physical registration approach is needed to realize image-guided breast surgery. Approach: In this study, three registration methods were investigated on healthy volunteers' breasts ( n = 11 ) with the supine arm-down position simulating preoperative imaging and supine arm-up position simulating intraoperative presentation. The registration methods included (1) point-based rigid registration using synthetic fiducials, (2) nonrigid biomechanical model-based registration using sparse data, and (3) a data-dense three-dimensional diffeomorphic image-based registration from the Advanced Normalization Tools (ANTs) repository. Additionally, deformation metrics (volume change and anisotropy) were calculated from the ANTs deformation field to better understand breast material mechanics. Results: The average target registration errors (TRE) were 10.4 ± 2.3 , 6.4 ± 1.5 , and 2.8 ± 1.3 mm (mean ± standard deviation) and the average fiducial registration errors (FRE) were 7.8 ± 1.7 , 2.5 ± 1.1 , and 3.1 ± 1.1 mm for the point-based rigid, nonrigid biomechanical, and ANTs registrations, respectively. The mechanics-based deformation metrics revealed an overall anisotropic tissue behavior and a statistically significant difference in volume change between glandular and adipose tissue, suggesting that nonrigid modeling methods may be improved by incorporating material heterogeneity and anisotropy. Conclusions: Overall, registration accuracy significantly improved with increasingly flexible and data-dense registration methods. Analysis of these outcomes may inform the future development of image guidance systems for lumpectomy procedures.

Tumor deformation correction for an image guidance system in breast conserving surgery.

Breast cancer is the most common cancer in women, and surgical resection is standard of care for the majority of breast cancer patients. Unfortunately, current reoperation rates are 10-29%. Uncertainty in lesion localization is one of the main factors contributing to these high reoperation rates. This work uses the linearized iterative boundary reconstruction approach to model patient breast deformation due to abduction of the ipsilateral arm. A preoperative supine magnetic resonance (MR) image was obtained with the patient's arms down near the torso. A mock intraoperative breast shape was measured from a supine MR image obtained with the patient's arm up near the head. Sparse data was subsampled from the full volumetric image to represent realistic intraoperative data collection: surface fiducial points, the intra-fiducial skin surface, and the chest wall as measured with 7 tracked ultrasound images. The deformed preoperative arm-down data was compared to the ground truth arm-up data. From rigid registration to model correction the tumor centroid distance improves from 7.3 mm to 3.3 mm, average surface fiducial error across 9 synthetic fiducials and the nipple improves from 7.4 ± 2.2 to 1.3 ± 0.7, and average subsurface error across 14 corresponding features improves from 6.2 ± 1.4 mm to 3.5 ± 1.1 mm. Using preoperative supine MR imaging and sparse data in the deformed position, this modeling framework can correct for breast shape changes between imaging and surgery to more accurately predict intraoperative position of the tumor as well as 10 surface fiducials and 14 subsurface features.

Breast image registration for surgery: Insights on material mechanics modeling.

Breast conserving surgery (BCS) is a common procedure for early-stage breast cancer patients. Supine preoperative magnetic resonance (MR) breast imaging for visualizing tumor location and extent, while not standard for procedural guidance, more closely represents the surgical presentation compared to conventional diagnostic pendant positioning. Optimal utilization for surgical guidance, however, requires a fast and accurate image-to-physical registration from preoperative imaging to intraoperative surgical presentation. In this study, three registration methods were investigated on healthy volunteers' breasts (n=11) with the arm-down position simulating preoperative imaging and arm-up position simulating intraoperative data. The registration methods included: (1) point-based rigid registration using synthetic fiducials, (2) non-rigid biomechanical model-based registration using sparse data, and (3) a data-dense 3D diffeomorphic image-based registration from the Advanced Normalization Tools (ANTs) repository. The average target registration errors (TRE) were 10.4 ± 2.3, 6.4 ± 1.5, and 2.8 ± 1.3 mm (mean ± standard deviation) and the average fiducial registration errors (FRE) were 7.8 ± 1.7, 2.5 ± 1.1, and 3.1 ± 1.1 mm (mean ± standard deviation) for the point-based rigid, nonrigid biomechanical, and ANTs registrations, respectively. Additionally, common mechanics-based deformation metrics (volume change and anisotropy) were calculated from the ANTs deformation field. The average metrics revealed anisotropic tissue behavior and a statistical difference in volume change between glandular and adipose tissue, suggesting that nonrigid modeling methods may be improved by incorporating material heterogeneity and anisotropy. Overall, registration accuracy significantly improved with increasingly flexible registration methods, which may inform future development of image guidance systems for lumpectomy procedures.

Computational Imaging to Compensate for Soft-Tissue Deformations in Image-Guided Breast Conserving Surgery.

OBJECTIVE: During breast conserving surgery (BCS), magnetic resonance (MR) images aligned to accurately display intraoperative lesion locations can offer improved understanding of tumor extent and position relative to breast anatomy. Unfortunately, even under consistent supine conditions, soft tissue deformation compromises image-to-physical alignment and results in positional errors. METHODS: A finite element inverse modeling technique has been developed to nonrigidly register preoperative supine MR imaging data to the surgical scene for improved localization accuracy during surgery. Registration is driven using sparse data compatible with acquisition during BCS, including corresponding surface fiducials, sparse chest wall contours, and the intra-fiducial skin surface. Deformation predictions were evaluated at surface fiducial locations and subsurface tissue features that were expertly identified and tracked. Among n = 7 different human subjects, an average of 22 ± 3 distributed subsurface targets were analyzed in each breast volume. RESULTS: The average target registration error (TRE) decreased significantly when comparing rigid registration to this nonrigid approach (10.4 ± 2.3 mm vs 6.3 ± 1.4 mm TRE, respectively). When including a single subsurface feature as additional input data, the TRE significantly improved further (4.2 ± 1.0 mm TRE), and in a region of interest within 15 mm of a mock biopsy clip TRE was 3.9 ± 0.9 mm. CONCLUSION: These results demonstrate accurate breast deformation estimates based on sparse-data-driven model predictions. SIGNIFICANCE: The data suggest that a computational imaging approach can account for image-to-surgery shape changes to enhance surgical guidance during BCS.

Impact of deformation on a supine-positioned image-guided breast surgery approach.

PURPOSE: To reduce reoperation rates for image-guided breast-conserving surgery, the enhanced sensitivity of magnetic resonance (MR) supine imaging may be leveraged. However, accurate tissue correspondence between images and their physical counterpart in the surgical presentation is challenging due to breast deformations (e.g., from patient/arm position changes, and operating room table rotation differences). In this study, standard rigid registration methods are employed and tissue deformation is characterized. METHODS: On n = 10 healthy breasts, surface displacements were measured by comparing intraoperative fiducial locations as the arm was moved from conventional MR scanning positions (arm-down and arm-up) to the laterally extended surgical configuration. Supine MR images in the arm-down and arm-up positions were registered to mock intraoperative presentations. RESULTS: Breast displacements from a supine MR imaging configuration to a mock surgical presentation were 28.9 ± 9.2 mm with shifts occurring primarily in the inferior/superior direction. With respect to supine MR to surgical alignment, the average fiducial, target, and maximum target registration errors were 9.0 ± 1.7 mm, 9.3 ± 1.7 mm, and 20.0 ± 7.6 mm, respectively. Even when maintaining similar arm positions in the MR image and mock surgery, the respective averages were 6.0 ± 1.0 mm, 6.5 ± 1.1 mm, and 12.5 ± 2.8 mm. CONCLUSION: From supine MR positioning to surgical presentation, the breast undergoes large displacements (9.9-70.1 mm). The data also suggest that significant nonrigid deformations (9.3 ± 1.7 mm with 20.0 mm average maximum) exist that need to be considered in image guidance and modeling applications.

Radiotherapy after breast-conserving surgery for elderly patients with early-stage breast cancer: A national registry-based study.

Considerable controversies exist regarding whether elderly patients with early-stage breast cancer receiving breast-conserving surgery (BCS) should forgo radiotherapy. We utilized the National Cancer Database to analyze data of 115 516 women aged ≥70 years, treated with BCS for T1-2N0-1M0 breast cancer between 2004 and 2014. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality 3, 5 and 10 years after 90 days of BCS associated with radiotherapy. Patients who received no radiotherapy had a higher mortality rate than those who received radiotherapy (5-year survival rate: 71.2% vs 83.8%), with multivariable-adjusted HRs of 1.65 (95% CI: 1.57-1.72) for 3-year mortality, 1.53 (1.47-1.58) for 5-year mortality and 1.43 (1.39-1.48) for 10-year mortality. The association held even for patients ≥90 years. This association was observed in all strata by reasons for radiotherapy omission, receipt of endocrine therapy or chemotherapy, calendar period and other clinical characteristics, with 40% to 65% increased 5-year mortality for patients without radiotherapy. This positive association persisted when analyses were restricted to patients with T1N0 and estrogen-receptor-positive disease who had received endocrine therapy (5-year mortality: HR 1.47 [1.39-1.57]) and in propensity score weighted analyses. Our study shows, in routine practice, elderly patients who received no post-BCS radiotherapy had higher total mortality than those who received radiotherapy. These findings suggest that the current recommendation of omission of post-BCS radiotherapy for elderly women with early-stage breast cancer may need to be reconsidered, particularly for those without contraindication.

Metabolic Heterogeneity in Patient Tumor-Derived Organoids by Primary Site and Drug Treatment.

New tools are needed to match cancer patients with effective treatments. Patient-derived organoids offer a high-throughput platform to personalize treatments and discover novel therapies. Currently, methods to evaluate drug response in organoids are limited because they overlook cellular heterogeneity. In this study, non-invasive optical metabolic imaging (OMI) of cellular heterogeneity was characterized in breast cancer (BC) and pancreatic cancer (PC) patient-derived organoids. Baseline heterogeneity was analyzed for each patient, demonstrating that single-cell techniques, such as OMI, are required to capture the complete picture of heterogeneity present in a sample. Treatment-induced changes in heterogeneity were also analyzed, further demonstrating that these measurements greatly complement current techniques that only gauge average cellular response. Finally, OMI of cellular heterogeneity in organoids was evaluated as a predictor of clinical treatment response for the first time. Organoids were treated with the same drugs as the patient's prescribed regimen, and OMI measurements of heterogeneity were compared to patient outcome. OMI distinguished subpopulations of cells with divergent and dynamic responses to treatment in living organoids without the use of labels or dyes. OMI of organoids agreed with long-term therapeutic response in patients. With these capabilities, OMI could serve as a sensitive high-throughput tool to identify optimal therapies for individual patients, and to develop new effective therapies that address cellular heterogeneity in cancer.

Textual fiducial detection in breast conserving surgery for a near-real time image guidance system.

Breast cancer is the most common cancer in American women, and is the second most deadly. Current guidance approaches for breast cancer surgery provide distance to a seed implanted near the tumor centroid. Large deformations between preoperative imaging and surgical presentation, coupled with the lack of tumor extent information leads to difficulty in ensuring complete tumor resection. Here we propose a novel image guidance platform that utilizes character-based fiducials for easy detection and small fiducial points for precise and accurate localization. Our system is work-flow friendly, and near-real time with use of stereo cameras for surface acquisition. Using simple image processing techniques, the proposed technique can localize fiducials and character labels, providing updates without relying on video history. Character based fiducial labels can be recognized and used to determine correspondence between left and right images in a pair of stereo cameras, and frame to frame in a sequence of images during a procedure. Letters can be recognized with 89% accuracy using the MATLAB built in optical character recognition function, and an average of 81% of points can be accurately labeled and localized. The stereo camera system can determine surface points with accuracy below 2mm when compared to optically tracked stylus points. These surface points are incorporated to a four-panel guidance display that includes preoperative supine MR, tracked ultrasound, and a model view of the breast and tumor with respect to optically tracked instrumentation.

Sex Disparity Observed for Oncotype DX Breast Recurrence Score in Predicting Mortality Among Patients with Early Stage ER-Positive Breast Cancer.

PURPOSE: Prognostic value of Oncotype DX Breast Recurrence Score (RS) in male patients with breast cancer is understudied. We evaluated associations of RS with overall mortality in male patients with breast cancer and compared it with female counterparts. EXPERIMENTAL DESIGN: With a cohort of 848 male and 110,898 female patients with breast cancer identified from the National Cancer Database (2010-2014), we estimated HRs and 95% confidence intervals (CI) for overall mortality associated with RS using Cox regression models. RS was evaluated continuously, as well as by categorization following respective traditional (≤17, 18-30, and ≥31) and TAILORx (≤10, 11-25, and ≥26) cutoffs. RESULTS: RS was positively associated with mortality in male patients (HR = 1.13; 95% CI, 1.02-1.26 per unit RS increment) up to RS > 21, after which the risk plateaued. Among female patients, mortality began to increase with RS only when RS > 23 (HR = 1.02; 95% CI, 1.01-1.02 per unit of RS increment). The intermediate- (HR = 5.37; 95% CI, 1.79-16.11) and high-risk diseases (HR = 4.28; 95% CI, 1.22-14.97) defined by TAILORx, but not traditional cutoffs established for female patients, were associated with elevated mortality risk in men even after adjustment for demographic, clinical characteristics, and treatments, except chemotherapy. CONCLUSIONS: RS is associated with mortality in male patients with breast cancer at a much lower threshold than that for female patients. Studies are needed to establish specific guidelines for RS thresholds for male patients with breast cancer.

Overall Mortality After Diagnosis of Breast Cancer in Men vs Women.

IMPORTANCE: Survival differences between male and female patients with breast cancer have been reported, but the underlying factors associated with the disparity have not been fully studied. This understanding is fundamental to developing strategies for cancer treatment and survivorship care. OBJECTIVE: To compare mortality between male and female patients with breast cancer and quantitatively evaluate the factors associated with sex-based disparity in mortality. DESIGN, SETTING, AND PARTICIPANTS: This large, nationwide, registry-based cohort study used the National Cancer Database to identify and obtain data on patients who received a breast cancer diagnosis between January 1, 2004, and December 31, 2014. After exclusions, the final study population comprised 1 816 733 patients. Statistical analyses were conducted from September 1, 2018, to January 15, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival. Secondary outcomes were 3-year and 5-year mortality. Mortality differences were evaluated by Kaplan-Meier analysis. The roles of race/ethnicity, clinical characteristics, treatments, and access-to-care factors in the association between sex and mortality were estimated by nested Cox proportional hazards regression models with adjustment for age. RESULTS: In total, 16 025 male (mean [SD] age, 63.3 [13.0] years) and 1 800 708 female (mean [SD] age, 59.9 [13.3] years) patients with breast cancer were included in the study. Compared with female patients, male patients had higher mortality across all stages. For men, the overall survival rate was 45.8% (95% CI, 49.5-54.0; P < .001), the 3-year rate was 86.4% (95% CI, 85.9-87.0; P < .001), and the 5-year rate was 77.6% (95% CI, 76.8-78.3; P < .001). For women, the overall survival rate was 60.4% (95% CI, 58.7-62.0; P < .001), the 3-year rate was 91.7% (95% CI, 91.7-91.8; P < .001), and the 5-year rate was 86.4% (95% CI, 86.4-86.5; P < .001). Overall, clinical characteristics and undertreatments were associated with a 63.3% excess mortality rate for male patients. A higher proportion of excess deaths in men were explained by these factors in the first 3 years after breast cancer diagnosis (66.0%) and in all patients with early-stage cancer (30.5% for stage I and 13.6% for stage II). However, sex remained a significant factor associated with overall mortality (adjusted hazard ratio [HR], 1.19; 95% CI, 1.16-1.23) as well as mortality at 3-year (adjusted HR, 1.15; 95% CI, 1.10-1.21) and 5-year (adjusted HR, 1.19; 95% CI, 1.14-1.23) analyses, even after adjustment for clinical characteristics, treatment factors, age, race/ethnicity, and access to care. CONCLUSIONS AND RELEVANCE: This study found that mortality after cancer diagnosis was higher among male patients with breast cancer compared with their female counterparts. Such disparity appeared to persist after accounting for clinical characteristics, treatment factors, and access to care, suggesting that other factors (particularly additional biological attributes, treatment compliance, and lifestyle factors) should be identified to help in eliminating this disparity.

Molecular determinants of post-mastectomy breast cancer recurrence.

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Toward quantitative quasistatic elastography with a gravity-induced deformation source for image-guided breast surgery.

Biomechanical breast models have been employed for applications in image registration and diagnostic analysis, breast augmentation simulation, and for surgical and biopsy guidance. Accurate applications of stress-strain relationships of tissue within the breast can improve the accuracy of biomechanical models that attempt to simulate breast deformations. Reported stiffness values for adipose, glandular, and cancerous tissue types vary greatly. Variations in reported stiffness properties have been attributed to differences in testing methodologies and assumptions, measurement errors, and natural interpatient differences in tissue elasticity. Therefore, the ability to determine patient-specific in vivo breast tissue properties would be advantageous for these procedural applications. While some in vivo elastography methods are not quantitative and others do not measure material properties under deformation conditions that are appropriate to the application of concern, in this study, we developed an elasticity estimation method that is performed using deformations representative of supine therapeutic procedures. More specifically, reconstruction of mechanical properties appropriate for the standard-of-care supine lumpectomy was performed by iteratively fitting two anatomical images before and after deformations taking place in the supine breast configuration. The method proposed is workflow-friendly, quantitative, and uses a noncontact, gravity-induced deformation source.

A system for automatic monitoring of surgical instruments and dynamic, non-rigid surface deformations in breast cancer surgery.

When negative tumor margins are achieved at the time of resection, breast conserving therapy (lumpectomy followed with radiation therapy) offers patients improved cosmetic outcomes and quality of life with equivalent survival outcomes to mastectomy. However, high reoperation rates ranging 10-59% continue to challenge adoption and suggest that improved intraoperative tumor localization is a pressing need. We propose to couple an optical tracker and stereo camera system for automated monitoring of surgical instruments and non-rigid breast surface deformations. A bracket was designed to rigidly pair an optical tracker with a stereo camera, optimizing overlap volume. Utilizing both devices allowed for precise instrument tracking of multiple objects with reliable, workflow friendly tracking of dynamic breast movements. Computer vision techniques were employed to automatically track fiducials, requiring one-time initialization with bounding boxes in stereo camera images. Point based rigid registration was performed between fiducial locations triangulated from stereo camera images and fiducial locations recorded with an optically tracked stylus. We measured fiducial registration error (FRE) and target registration error (TRE) with two different stereo camera devices using a phantom breast with five fiducials. Average FREs of 2.7 ± 0.4 mm and 2.4 ± 0.6 mm with each stereo-camera device demonstrate considerable promise for this approach in monitoring the surgical field. Automated tracking was shown to reduce error when compared to manually selected fiducial locations in stereo camera image-based localization. The proposed instrumentation framework demonstrated potential for the continuous measurement of surgical instruments in relation to the dynamic deformations of a breast during lumpectomy.

Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.

Inhibition of proliferation in estrogen receptor-positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2-negative (HER2-) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.

Breast tissue stiffness estimation for surgical guidance using gravity-induced excitation.

Tissue stiffness interrogation is fundamental in breast cancer diagnosis and treatment. Furthermore, biomechanical models for predicting breast deformations have been created for several breast cancer applications. Within these applications, constitutive mechanical properties must be defined and the accuracy of this estimation directly impacts the overall performance of the model. In this study, we present an image-derived computational framework to obtain quantitative, patient specific stiffness properties for application in image-guided breast cancer surgery and interventions. The method uses two MR acquisitions of the breast in different supine gravity-loaded configurations to fit mechanical properties to a biomechanical breast model. A reproducibility assessment of the method was performed in a test-retest study using healthy volunteers and was further characterized in simulation. In five human data sets, the within subject coefficient of variation ranged from 10.7% to 27% and the intraclass correlation coefficient ranged from 0.91-0.944 for assessment of fibroglandular and adipose tissue stiffness. In simulation, fibroglandular content and deformation magnitude were shown to have significant effects on the shape and convexity of the objective function defined by image similarity. These observations provide an important step forward in characterizing the use of nonrigid image registration methodologies in conjunction with biomechanical models to estimate tissue stiffness. In addition, the results suggest that stiffness estimation methods using gravity-induced excitation can reliably and feasibly be implemented in breast cancer surgery/intervention workflows.