1. Novel pre- and intraoperative imaging techniques for improved breast cancer management
- Author
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Jurrius, Patriek, Purushotham, Anand David, and Pinder, Sarah Elizabeth
- Abstract
Introduction: Breast cancer is the most common cancer in women worldwide, affecting 1 in 7 women in the UK. Most women with invasive breast cancer will undergo either primary systemic therapy, typically neoadjuvant chemotherapy (NACT), or primary surgery. For both treatment routes there are challenges in assessing their effectiveness. In the UK at present, the response of a woman's breast cancer to NACT is assessed by changes in tumour size, contrast avidity, and lymph node involvement based on magnetic resonance imaging (MRI) with or without ultrasound pre-, mid-, and post-treatment. This means exposing women to at least 3 cycles of NACT prior to the assessment of response at mid-treatment and yet one-third of these women will have no discernible effect of their treatment. In breast-conserving surgery (BCS) failure to obtain clear margins is the main risk factor for local and distant recurrence. Due to a lack of adequate intraoperative tools to identify and assess tumour excision margins, ~20% of patients currently need to undergo a reoperation because of positive resection margins on routine postoperative histopathology. Various novel preoperative and intraoperative imaging techniques were investigated to assess treatment effectiveness, thereby improving breast cancer management. Material & Methods: Preoperative magnetic resonance elastography (MRE), incorporated into a routine MRI scanner, was developed to generate mechanical waves for quantification of the viscoelastic properties of breast cancer and investigated as an imaging biomarker to assess the response to NACT early i.e., after only 1 cycle of NACT. Changes in biomechanical properties, in particular the phase angle of the tumour after 1 cycle of NACT relative to the pre-treatment biomechanics, were used to determine treatment response. MRE findings were then correlated with response to NACT, as determined by standard-of-care MRI assessment. For the intraoperative assessment of excision margins flexible autoradiography (FAR), confocal microscopy (Histolog® Scanner), and fluorescence imaging of a targeted probe (EMI-137) and enzyme-activated spray dyes (HMRef-⍺Man and gGlu-2OMe SiR600) were investigated. The performance of FAR and confocal microscopy was assessed by comparing the outcome to standard-of-care histopathology results. The studies on the fluorescence imaging of EMI-137 and the enzyme-activated spray dyes were aimed to establish safety, optimal imaging procedures and feasibility. In the first-in-human multicentre feasibility FAR study, patients received an intravenous injection of fluorine-18 fluorodeoxyglucose (18F-FDG) pre-operatively. Following surgical excision, a thin flexible scintillating film was applied to the wide local excision (WLE) specimens, cavity shavings and excised lymph nodes. The scintillating film converted β+- particles from the 18F in the tumour cells to visible scintillations, which were imaged by an ultra-sensitive camera system intraoperatively. In a multicentre feasibility study the Histolog® imaging system was used for confocal microscopy to generate subcellular histopathology-like images of excision margins. In the first-in-woman feasibility fluorescence imaging studies, different fluorescent probes were investigated. EMI-137 is a c-Met targeting fluorescent probe, imaged using a bespoke imaging system: the Quest Spectrum Platform, whereas the spray dyes HMRef-⍺Man and gGlu-2OMe SiR600 are activated by enzymes, α-mannosidase 2C1 (MAN2C1) and γ-glutamyl transpeptidase (GGT), respectively, overexpressed in breast cancer, amongst other solid cancers. Concurrent use of both dyes facilitates discriminating between normal, benign and malignant breast tissue. Results: In women who had a partial or complete response to their first NACT regimen, the phase angle increased following one cycle of NACT relative to the pre-treatment MRE scan. In women who had stable disease or disease progression whilst undergoing their first NACT regimen, the phase angle decreased after 1 cycle compared to their pretreatment scan. Known clinical trends for receptor status and residual cancer burden in relation to treatment response were also observed in the relative change of phase angle. Relative changes in a tumour's phase angle as assessed by MRE after only 1 cycle of neoadjuvant chemotherapy (NACT) correlates with the radiological response to treatment, allowing for early assessment of a patient's response to NACT. Identification of women with radiological stable disease or disease progression and therefore likely to respond poorly to NACT after 1 cycle, instead of after 3-4 cycles as is the current standard, facilitates an early switch to the second chemotherapeutic regimen, thereby preventing unnecessary treatment delays, side-effects, and toxicity from continuing an inefficacious chemotherapy regimen or alternatively, where appropriate, non-responding patients maybe considered for early surgical intervention. Both FAR and confocal microscopy assessment of wide-local excision specimens and cavity shavings achieved good specificities (81.7% and 78.3%, respectively) and NPVs (98.4% and 92%, respectively), however, the sensitivities remained suboptimal (71.4% and 21%). For FAR the diagnostic accuracy improved in women who received an injected 18F activity ≥242 MBq; for confocal microscopy the diagnostic accuracy improved after implementation of a standardised image assessment method and scoring system. Due to the expiry date of EMI-137 and the SARS-CoV-2 pandemic, only 1 patient was imaged using the optimised study design and bespoke imaging system. In this patient, good correlation was found with histopathology for both invasive cancer and DCIS on the wide-local excision specimen as well as excised axillary lymph nodes. The spray dyes were proven to be safe; the optimal imaging procedures were established and the initial two WLE specimens were successfully imaged using the HMRef-⍺Man dye. Conclusion: All investigated preoperative and intraoperative imaging techniques showed promising initial results. Larger studies, based on the recommendations from this thesis, should be considered to possibly improve the technique and assess the performance more robustly. The recruitment into the MRE study has continued, with an amended study design to allow for extra tumour tissue biopsies to be collected for correlation of biological tumour markers to the biomechanical markers. For intraoperative margin assessment, the findings from the FAR study have guided the design and setup of a subsequent interventional study, in which FAR is combined with Cerenkov luminescence imaging (CLI), exploiting the advantages of each technique.
- Published
- 2023