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Open Access 01-06-2020 | Breast Cancer | Breast Oncology

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

Authors: Barbara L. Smith, MD, PhD, Conor R. Lanahan, BS, Michelle C. Specht, MD, Bridget N. Kelly, BA, Carson Brown, BA, MS, David B. Strasfeld, PhD, Jorge M. Ferrer, PhD, Upahvan Rai, BS, Rong Tang, MD, Travis Rice-Stitt, MD, Anna Biernacka, MD, Elena F. Brachtel, MD, Michele A. Gadd, MD

Published in: Annals of Surgical Oncology | Issue 6/2020

Abstract

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.

Fisher B, Anderson S, John Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002. https://doi.org/10.1056/NEJMoa022152.CrossRefPubMed

Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002. https://doi.org/10.1056/NEJMoa020989.CrossRefPubMed

Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Onc. 2011. https://doi.org/10.1200/JCO.2011.36.1105.CrossRef

Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005. https://doi.org/10.1016/S0140-6736(05)67887-7.CrossRefPubMed

Esbona K, Li Z, Wilke L. Intraoperative imprint cytology and frozen section pathology for margin assessment in breast conservation surgery: a systematic review. Ann Surg Oncol. 2012. https://doi.org/10.1245/s10434-012-2492-2.CrossRefPubMedPubMedCentral

Coopey SB, Smith BL, Hanson SA, et al. The safety of multiple re-excisions after lumpectomy for breast cancer. Ann Surg Oncol. 2011. https://doi.org/10.1245/s10434-011-1802-4.CrossRefPubMed

Coopey SB, Buckley JM, Smith BL, et al. Lumpectomy cavity shaved margins do not impact re-excision rates in breast cancer patients. Ann Surg Oncol. 2011. https://doi.org/10.1245/s10434-011-1909-7.CrossRefPubMed

Chagpar AB, Brigid K, Killelea BK, Tsangaris TN et al. A randomized, controlled trial of cavity shave margins in breast cancer. N Engl J Med. 2015. http://doi.org/10.1056/NEJMoa1504473.CrossRefPubMedPubMedCentral

McCahill LE, Single RM, Aiello Bowles EJ, et al. Variability in re-excision following breast conservation surgery. JAMA. 2012. https://doi.org/10.1001/jama.2012.43.CrossRefPubMed

10.

Riedl O, Fitzal F, Mader N, et al. Intraoperative frozen section analysis for breast-conserving therapy in 1016 patients with breast cancer. Eur J Surg Oncol. 2009. https://doi.org/10.1016/j.ejso.2008.05.007.CrossRefPubMed

11.

Cabioglu N, Hunt KK, Sahin AA, et al. Role for intraoperative margin assessment in patients undergoing breast-conserving surgery. Ann Surg Oncol. 2007. https://doi.org/10.1245/s10434-00609236-0.CrossRefPubMed

12.

Brachtel EF, Johnson NB, Huck AE, et al. Spectrally encoded confocal microscopy for diagnosing breast cancer in excision and margin specimens. Lab Invest. 2016. https://doi.org/10.1038/labinvest.2015.158.CrossRefPubMedPubMedCentral

13.

Ngyuyen FT, Zysk AM, Chaney EJ, et al. Intraoperative evaluation of breast tumor margins with optical coherence tomography. Cancer Res. 2009. https://doi.org/10.1158/0008-5472.CAN-08-4340.CrossRef

14.

Schnabel F, Boolbol SK, Gittleman M, et al. A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies. Ann Surg Oncol. 2014. https://doi.org/10.1245/s10434-014-3602-0.CrossRefPubMedPubMedCentral

15.

Allweis TM, Kaufman Z, Lelcuk S, et al. A prospective, randomized, controlled, multicenter study of a real-time, intraoperative probe for positive margin detection in breast-conserving surgery. Am J Surg. 2008. https://doi.org/10.1016/j.amjsurg.2008.06.024.CrossRefPubMed

16.

O’Kelly Priddy CM, Forte VA, Lang JE. The importance of surgical margins in breast cancer. J Surg Oncol. 2016. https://doi.org/10.10002/jso.24047.

17.

Tang R, Coopey SB, Specht MC, et al. Lumpectomy specimen margins are not reliable in predicting residual disease in patients undergoing breast conserving surgery. Am J Surg. 2015. https://doi.org/10.1016/j.amjsurg.2014.09.029.CrossRefPubMed

18.

Harness JK, Guiliano AE, Pockaj BA, et al. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Ann Surg Oncol. 2014. https://doi.org/10.1245/s10434-014-3957-2.CrossRefPubMedPubMedCentral

19.

Whitley MJ, Cardona DM, Lazarides AL, et al. A mouse-human Phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med. 2016. https://doi.org/10.1126/scitranslmed.aad0293.CrossRefPubMedPubMedCentral

20.

Mito JK, Ferrer JM, Brigman BE, et al. Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging. Cancer. 2012. https://doi.org/10.10002/cncr.27458.

21.

Smith BL, Gadd MA, Lanahan CR, et al. Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity walls using a novel cathepsin-activated fluorescent imaging system. Breast Cancer Res Treat. 2018. https://doi.org/10.1007/s10549-018-4845-4.CrossRefPubMedPubMedCentral

22.

Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. World Health Organization classification of tumours of the breast, 4th ed. Lyon: International Agency for Research on Cancer; 2012.

23.

Demos SG, Gandour-Edwards R, Ramsamooj R, White RD. Near-infrared autofluorescence imaging for detection of cancer. J Biomed Opt. 2004. https://doi.org/10.1117/1.1688812.CrossRefPubMed

24.

Sharma V, Shivalingaiah S, Peng Y, Euhus D, Gryczynski Z, Liu H. Auto-fluorescence lifetime and light reflectance spectroscopy for breast cancer diagnosis: potential tools for intraoperative margin detection. Biomed Opt Express. 2012. https://doi.org/10.1364/BOE.3.001825.CrossRefPubMedPubMedCentral

25.

Merrill AL, Coopey SB, Tang R, et al. Implications of new lumpectomy margin guidelines for breast-conserving surgery: changes in re-excision rates and predicted rates of residual tumor. Ann Surg Oncol. 2016. https://doi.org/10.1245/s10434-015-4916-2.CrossRefPubMed

26.

Lanahan CR, Specht MC, Gadd MA, et al. Use of a cathepsin-activatable fluorescent agent to rapidly distinguish tumor versus normal tissue in multiple tumor types. Poster presented at: Society of Surgical Oncology; March 21–24, 2018; Chicago, IL.

27.

Chan CH, Liesenfeld LF, Ferreiro-Neira I, Cusack JC Jr. Preclinical evaluation of cathepsin-based fluorescent imaging system for cytoreductive surgery. Ann Surg Oncol. 2017. https://doi.org/10.1245/s10434-016-5690-5.CrossRefPubMed

Title: Feasibility Study of a Novel Protease-Activated Fluorescent Imaging System for Real-Time, Intraoperative Detection of Residual Breast Cancer in Breast Conserving Surgery
Authors: Barbara L. Smith, MD, PhD
Conor R. Lanahan, BS
Michelle C. Specht, MD
Bridget N. Kelly, BA
Carson Brown, BA, MS
David B. Strasfeld, PhD
Jorge M. Ferrer, PhD
Upahvan Rai, BS
Rong Tang, MD
Travis Rice-Stitt, MD
Anna Biernacka, MD
Elena F. Brachtel, MD
Michele A. Gadd, MD
Publication date: 01-06-2020
Publisher: Springer International Publishing
Keywords: Breast Cancer
Breast Cancer
Published in: Annals of Surgical Oncology / Issue 6/2020
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-019-08158-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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