Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery.

PURPOSE: Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20-40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. METHODS: We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. RESULTS: Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81-5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. CONCLUSIONS: Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

Correction to: Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery.

The article Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery, written by Barbara L. Smith et al., was originally published electronically on the publisher's internet portal on January 2, 2020, without open access.

Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery.

BACKGROUND: Obtaining tumor-free margins is critical to prevent recurrence after lumpectomy for breast cancer. Unfortunately, current approaches leave positive margins that require second surgeries in 20-40% of patients. We assessed the LUM Imaging System for real-time, intraoperative detection of residual tumor. METHODS: Breast lumpectomy cavity walls and excised specimens were assessed with the LUM Imaging System after 1 mg/kg intravenous LUM015, a protease-activatable fluorescent agent. Fluorescence at potential sites of residual tumor in lumpectomy cavity walls was evaluated intraoperatively with a sterile hand-held probe, with real-time predictive results displayed on a monitor intraoperatively, and later correlated with histopathology. RESULTS: In vivo lumpectomy cavities and excised specimens were imaged after LUM015 injection in 45 women undergoing breast cancer surgery. Invasive ductal and lobular cancers and intraductal cancer (DCIS) were included. A total of 570 cavity margin surfaces in 40 patients were used for algorithm development. Image analysis and display took approximately 1 s per 2.6-cm-diameter circular margin surface. All breast cancer subtypes could be distinguished from adjacent normal tissue. For all imaged cavity surfaces, sensitivity for tumor detection was 84%. Among 8 patients with positive margins after standard surgery, sensitivity for residual tumor detection was 100%; 2 of 8 were spared second surgeries because additional tissue was excised at sites of LUM015 signal. Specificity was 73%, with some benign tissues showing elevated fluorescent signal. CONCLUSIONS: The LUM015 agent and LUM Imaging System allow rapid identification of residual tumor in the lumpectomy cavity of breast cancer patients and may reduce rates of positive margins.

Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity walls using a novel cathepsin-activated fluorescent imaging system.

PURPOSE: Obtaining tumor-free surgical margins is critical to prevent recurrence in breast-conserving surgery but it remains challenging. We assessed the LUM Imaging System for real-time, intraoperative detection of residual tumor. METHODS: Lumpectomy cavity walls and excised specimens of breast cancer lumpectomy patients were assessed with the LUM Imaging System (Lumicell, Inc., Wellesley MA) with and without intravenous LUM015, a cathepsin-activatable fluorescent agent. Fluorescence at potential sites of residual tumor was evaluated with a sterile hand-held probe, displayed on a monitor and correlated with histopathology. RESULTS: Background autofluorescence was assessed in excised specimens from 9 patients who did not receive LUM015. In vivo lumpectomy cavities and excised specimens were then imaged in 15 women undergoing breast cancer surgery who received no LUM015, 0.5, or 1 mg/kg LUM015 (5 women per dose). Among these, 11 patients had invasive carcinoma with ductal carcinoma in situ (DCIS) and 4 had only DCIS. Image acquisition took 1 s for each 2.6-cm-diameter surface. No significant background normal breast fluorescence was identified. Elevated fluorescent signal was seen from invasive cancers and DCIS. Mean tumor-to-normal signal ratios were 4.70 ± 1.23 at 0.5 mg/kg and 4.22 ± 0.9 at 1.0 mg/kg (p = 0.54). Tumor was distinguished from normal tissue in pre-and postmenopausal women and readings were not affected by breast density. Some benign tissues produced fluorescent signal with LUM015. CONCLUSION: The LUM Imaging System allows rapid identification of residual tumor in the lumpectomy cavity of breast cancer patients and may reduce rates of positive margins.

Oncologic Safety of Nipple-Sparing Mastectomy in Women with Breast Cancer.

BACKGROUND: Nipple-sparing mastectomy (NSM) has gained popularity for breast cancer treatment and prevention. There are limited data about long-term oncologic safety of this procedure. STUDY DESIGN: We reviewed oncologic outcomes of consecutive therapeutic NSM at a single institution. Nipple-sparing mastectomy was offered to patients with no radiologic or clinical evidence of nipple involvement. RESULTS: There were 2,182 NSM performed from 2007 to 2016. Long-term outcomes were assessed in the 311 NSM performed in 2007 to 2012 for Stages 0 to 3 breast cancer; 240 (77%) NSM were for invasive cancer and 71 (23%) were for ductal carcinoma in situ. At 51 months median follow-up, 17 patients developed a recurrence of their cancer. Estimated disease-free survival was 95.7% at 3 years and 92.3% at 5 years. There were 11 (3.7%) locoregional recurrences and 8 (2.7%) distant recurrences; 2 patients had simultaneous locoregional and distant recurrences. There were 2 breast cancer-related deaths in patients with isolated distant recurrences. No patient in the entire 2,182 NSM cohort has had a recurrence in the retained nipple-areola complex. CONCLUSIONS: Rates of locoregional and distant recurrence are acceptably low after nipple-sparing mastectomy in patients with breast cancer. No patient in our series has had a recurrence involving the retained nipple areola complex.

A Study of the Growth Patterns of Breast Carcinoma Using 3D Reconstruction: A Pilot Study.

Lumpectomy with microscopically clear margins is a safe and effective approach for surgical management of breast carcinoma. Margins are positive for tumor in 18-50% of lumpectomies, as it is not possible to accurately determine the shape or microscopic borders of a tumor preoperatively or intraoperatively. We examined the 3D microanatomy and growth patterns of common breast carcinoma subtypes to provide guidance for lumpectomy surgery. Prospective consent was obtained for the use of excess tissue from patients undergoing lumpectomy or mastectomy for breast carcinoma. Tissue blocks from nine breast carcinomas were serially sectioned. Hematoxylin and eosin-stained slides at 100 µm intervals were scanned using a Nanozoomer (Hamamatsu, Japan) microscopic-resolution scanner. Three-dimensional reconstructions of tumors were created from scanned images using Reconstruct, open-access software. Breast carcinoma subtypes demonstrated characteristic growth patterns within breast tissue, which may have implications for lumpectomy surgery. Invasive ductal carcinomas showed a spherical shape, with a spiculated surface representing tumor cells infiltrating into surrounding parenchyma. Ductal carcinoma in situ appeared to spread along the duct system, creating dilated, tortuous, tumor-filled ducts. The invasive lobular carcinomas examined had a haphazard, linear, infiltrative growth pattern, different from the shape seen in ductal carcinomas. Our preliminary work suggests that invasive ductal and invasive lobular carcinomas appear to have distinct growth patterns in three dimensions and ductal carcinoma in situ appears to grow in a linear fashion along the duct network. The microanatomy studies described have the potential to guide refinements in breast lumpectomy technique.

Factors Associated with Recurrence Rates and Long-Term Survival in Women Diagnosed with Breast Cancer Ages 40 and Younger.

BACKGROUND: Young age at breast cancer diagnosis has been associated with increased risk of recurrence and mortality. We reevaluated this assumption in a large, modern cohort of women diagnosed with breast cancer at age ≤40 years. METHODS: We identified women with breast cancer at age ≤40 years at a single institution from 1996-2008. We assessed locoregional recurrence (LRR), distant recurrence, disease-free survival (DFS), and overall survival (OS), and correlated patient and tumor characteristics with outcomes. RESULTS: We identified 584 women aged ≤40 years with breast cancer. Median age was 37 years, and median follow-up was 124 months; 61.5 % were stages 0-I and 38.5 % were stages II-III. Overall, 57.4 % had lumpectomies and 42.5 % mastectomies. DFS was 93 % at 5 years and 84.5 % at 10 years. OS was 93 % at 5 years and 86.5 % at 10 years. On multivariate analysis, worse DFS was associated with positive nodes (p = 0.002); worse OS was associated with larger tumor size (p = 0.042). When stratified by lumpectomy versus mastectomy, there were no significant differences in survival or recurrence. For lumpectomy patients, DFS was 96 % at 5 years and 88 % at 10 years; OS was 96 % at 5 years and 89 % at 10 years. For mastectomy patients, DFS was 89.5 % at 5 years and 79 % at 10 years; OS was 90 % at 5 years and 83 % at 10 years. Lumpectomy LRR rates were 1 % at 5 years and 4 % at 10 years. Mastectomy LRR rates were 3.5 % at 5 years and 8.7 % at 10 years. CONCLUSIONS: Outcomes for women with breast cancer at age ≤40 years have improved. Lumpectomy recurrence rates are low, suggesting that lumpectomy is oncologically safe for young breast cancer patients.

Should New "No Ink On Tumor" Lumpectomy Margin Guidelines be Applied to Ductal Carcinoma In Situ (DCIS)? A Retrospective Review Using Shaved Cavity Margins.

BACKGROUND: No consensus exists for clear margins for breast-conserving surgery for pure ductal carcinoma in situ (DCIS). We examined the implications of applying a "no ink on tumor" standard for pure DCIS by correlating clear margin width with rates of residual disease. METHODS: Lumpectomies with complete shaved cavity margins (SCMs) for pure DCIS at our institution from 2004 to 2007 were reviewed and patients with microinvasive cancer or multifocal disease requiring multiple wires excluded. Rates of residual disease in shaved margins were determined based on margin status of the main lumpectomy specimen using margin widths of "ink on tumor," ≤1, >1 to <2, and ≥2 mm. RESULTS: Overall, 182 women undergoing lumpectomy for pure DCIS met eligibility criteria. In patients with "ink on tumor" in the main lumpectomy specimen, 88 % had residual disease in the SCMs. Rates of residual disease in SCMs for lumpectomies with margins of <2 mm (but not on ink) were 52 % compared with 13 % for lumpectomies with margins ≥2 mm (p < 0.0005). Multivariate analyses confirmed the association of lumpectomy margin width and residual tumor in shaved cavity margins. Odds of residual disease in the SCM for postmenopausal patients were 74 % less than for pre/perimenopausal women (odds ratio 0.26; confidence interval 0.08-0.82). CONCLUSIONS: Application of a "no ink on tumor" lumpectomy margin standard to patients with DCIS results in a significant increase in the rates of residual disease in cavity margins compared with use of a ≥2-mm margin standard. Use of narrower margins may have important implications for use of adjuvant therapy.

Positive Nipple Margins in Nipple-Sparing Mastectomies: Rates, Management, and Oncologic Safety.

BACKGROUND: When a nipple margin of a nipple-sparing mastectomy (NSM) contains malignancy, current practice includes removal of the nipple or nipple areola complex (NAC). We evaluated rates and trends of positive nipple margins, subsequent management, and oncologic outcomes. STUDY DESIGN: A retrospective chart review of all NSM at our institution from 2007 to 2014 was performed. A descriptive analysis was performed of patients with positive nipple/subareolar margins. RESULTS: Among 1,326 NSM, 43 of 642 (6.7%) therapeutic and 3 of 684 (0.4%) prophylactic NSM had positive nipple margins. Nipple or NAC excision was performed for 39 of 46 (85%) positive nipple margins: 20 of 39 (51%) had nipple only and 19 of 39 (49%) had the entire NAC excised. Practice evolved to remove only the nipple and retain the areola for positive nipple margins: in 2007 to 2011, 7 of 17 (41%) underwent nipple-only excision compared with 14 of 22 (64%) in 2012 to 2014. Among 39 excised nipples/NAC, 28 (72%) contained no residual malignancy, while 8 contained ductal carcinoma in situ (DCIS), 2 had invasive lobular carcinoma, and 1 had invasive ductal carcinoma. With experience, rates of positive nipple margins for therapeutic NSM decreased from 11% (17 of 160) in 2007 to 2011 to 5.4% (26 of 482) in 2012 to 2014 (p < 0.05). At 36 month median follow-up, there were no recurrences in the nipple/NAC. CONCLUSIONS: Early results suggest that excision of the nipple with retention of the areola is a safe approach for management of a positive nipple margin after NSM. With experience, low rates of positive nipple margins are possible in therapeutic NSM. Overall risk of nipple/NAC recurrence after NSM remains extremely low.

Nipple-Sparing Mastectomy in Irradiated Breasts: Selecting Patients to Minimize Complications.

BACKGROUND: Nipple-sparing mastectomies (NSM) are increasingly common because of their cosmetic advantage. Radiotherapy (RT) has been a relative contraindication to immediate reconstruction because of concerns about increased complications. We aimed to evaluate outcomes of NSM plus immediate reconstruction in irradiated breasts and to determine additional risk factors for complications. METHODS: We retrospectively reviewed NSM with immediate reconstruction from 2007 to 2013 at our institution. Complications were broken down into several categories. Potential risk factors for complications were evaluated. RESULTS: There were 982 NSM: 816 had no RT, 67 had prior RT, and 97 had postmastectomy radiotherapy (PMRT). Compared to breasts with no RT, both prior RT and PMRT increased overall complications (10.2 vs. 21.7 and 17.5%, p = 0.003, 0.03, respectively) and nipple loss (0.9 vs. 4.3 and 4.1%, p = 0.04, 0.02, respectively), while PMRT increased rate of reconstruction failure (2.2 vs. 8.2%, p = 0.003). On multivariate regression analysis, prior RT [odds ratio (OR) 2.53, p = 0.006], PMRT (OR 2.29, p = 0.015), age >55 years (OR 2.03, p = 0.04), breast volume ≥800 cm(3) (OR 1.96, p = 0.04), smoking (OR 2.62, p = 0.001), and periareolar incision (OR 1.74, p = 0.03) were independent risk factors for complications requiring surgical revision. In irradiated breasts, complication rates were 13.4% without further risk factors and 17.5, 50, and 66.7% when 1, 2, and ≥3 additional independent risk factors were present, respectively (p < 0.001). CONCLUSIONS: Although complication rates were higher in irradiated breasts, reconstruction failure and nipple/areola necrosis was infrequent. RT should not be a contraindication to NSM. Preoperative identification of risk factors and appropriate patient selection may reduce complication rates.