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Open Access 01-12-2020 | Breast Cancer | Research article

Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens

Authors: Anup Tank, Hannah M. Peterson, Vivian Pera, Syeda Tabassum, Anais Leproux, Thomas O’Sullivan, Eric Jones, Howard Cabral, Naomi Ko, Rita S. Mehta, Bruce J. Tromberg, Darren Roblyer

Published in: Breast Cancer Research | Issue 1/2020

Abstract

Background

Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. This demonstrates the need for techniques capable of providing personalized feedback about treatment response at the earliest stages of therapy to identify patients likely to benefit from changing treatment. Diffuse optical spectroscopic imaging (DOSI) has emerged as a promising functional imaging technique for NAC monitoring. DOSI uses non-ionizing near-infrared light to provide non-invasive measures of absolute concentrations of tissue chromophores such as oxyhemoglobin. In 2011, we reported a new DOSI prognostic marker, oxyhemoglobin flare: a transient increase in oxyhemoglobin capable of discriminating NAC responders within the first day of treatment. In this follow-up study, DOSI was used to confirm the presence of the flare as well as to investigate whether DOSI markers of NAC response are regimen dependent.

Methods

This dual-center study examined 54 breast tumors receiving NAC measured with DOSI before therapy and the first week following chemotherapy administration. Patients were treated with either a standard of care maximum tolerated dose (MTD) regimen or an investigational metronomic (MET) regimen. Changes in tumor chromophores were tracked throughout the first week and compared to pathologic response and treatment regimen at specific days utilizing generalized estimating equations (GEE).

Results

Within patients receiving MTD therapy, the oxyhemoglobin flare was confirmed as a prognostic DOSI marker for response appearing as soon as day 1 with post hoc GEE analysis demonstrating a difference of 48.77% between responders and non-responders (p < 0.0001). Flare was not observed in patients receiving MET therapy. Within all responding patients, the specific treatment was a significant predictor of day 1 changes in oxyhemoglobin, showing a difference of 39.45% (p = 0.0010) between patients receiving MTD and MET regimens.

Conclusions

DOSI optical biomarkers are differentially sensitive to MTD and MET regimens at early timepoints suggesting the specific treatment regimen should be considered in future DOSI studies. Additionally, DOSI may help to identify regimen-specific responses in a more personalized manner, potentially providing critical feedback necessary to implement adaptive changes to the treatment strategy.

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Asselain B, Barlow W, Bartlett J, Bergh J, Bergsten-Nordström E, Bliss J, Boccardo F, et al. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;19(1):27–39. https://doi.org/10.1016/S1470-2045(17)30777-5.CrossRef

Avril S, Muzic RF, Plecha D, Traughber BJ, Vinayak S, Avril N. 18F-FDG PET/CT for monitoring of treatment response in breast cancer. J Nucl Med. 2016;57(Supplement_1):34S–9S. https://doi.org/10.2967/jnumed.115.157875.CrossRefPubMed

Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 2003;63(15):4342–6.PubMed

Bevilacqua F, Berger AJ, Cerussi AE, Jakubowski D, Tromberg BJ. Broadband absorption spectroscopy in turbid media by combined frequency-domain and steady-state methods. Appl Opt. 2000;39(34):6498. https://doi.org/10.1364/AO.39.006498.CrossRefPubMed

Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25. https://doi.org/10.1038/cdd.2013.67.CrossRefPubMed

Cerussi AE, Tanamai VW, Hsiang D, Butler J, Mehta RS, Tromberg BJ. Diffuse optical spectroscopic imaging correlates with final pathological response in breast cancer neoadjuvant chemotherapy. Philos Trans R Soc A Math Phys Eng Sci. 2011;369(1955):4512–30. https://doi.org/10.1098/rsta.2011.0279.CrossRef

Cerussi A, Shah N, Hsiang D, Durkin A, Butler J, Tromberg BJ. In vivo absorption, scattering, and physiologic properties of 58 malignant breast tumors determined by broadband diffuse optical spectroscopy. J Biomed Opt. 2006;11(4):044005. https://doi.org/10.1117/1.2337546.CrossRefPubMed

Chen C-S, Doloff JC, Waxman DJ. Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor Xenograft regression. Neoplasia. 2015;16(1):84–W27. https://doi.org/10.1593/neo.131910.CrossRef

Cochran JM, Chung SH, Leproux A, Baker WB, Busch DR, DeMichele AM, Tchou J, Tromberg BJ, Yodh AG. Longitudinal optical monitoring of blood flow in breast tumors during neoadjuvant chemotherapy. Phys Med Biol. 2017;62(12):4637–53. https://doi.org/10.1088/1361-6560/aa6cef.CrossRefPubMedPubMedCentral

10.

Cochran JM, Busch DR, Leproux A, Zheng Z, O’Sullivan TD, Cerussi AE, Carpenter PM, et al. Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment. J Biomed Opt. 2018;24(02):1. https://doi.org/10.1117/1.JBO.24.2.021202.CrossRefPubMed

11.

Danishada KKA, Sharmaa U, Saha RG, Seenub V, Parshadb R, Jagannathan NR. Assessment of therapeutic response of locally advanced breast cancer (LABC) patients undergoing neoadjuvant chemotherapy (NACT) monitored using sequential magnetic resonance spectroscopic imaging (MRSI). NMR Biomed. 2010;23(3):233–41. https://doi.org/10.1002/nbm.1436.CrossRef

12.

Dehdashti F, Mortimer JE, Trinkaus K, Naughton MJ, Ellis M, Katzenellenbogen JA, Welch MJ, Siegel BA. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat. 2009;113(3):509–17. https://doi.org/10.1007/s10549-008-9953-0.CrossRefPubMed

13.

Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, et al. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess tils in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Bre. Semin Cancer Biol. 2018;52(September 2017):16–25. https://doi.org/10.1016/j.semcancer.2017.10.003.CrossRefPubMed

14.

Doloff JC, Waxman DJ. VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res. 2012;72(5):1103–15. https://doi.org/10.1158/0008-5472.CAN-11-3380.CrossRefPubMedPubMedCentral

15.

Esserman LJ, DeMichele A. Accelerated approval for pertuzumab in the neoadjuvant setting: winds of change? Clin Cancer Res. 2014;20(14):3632–6. https://doi.org/10.1158/1078-0432.CCR-13-3131.CrossRefPubMed

16.

Falou O, Soliman H, Sadeghi-Naini A, Iradji S, Lemon-Wong S, Zubovits J, Spayne J, et al. Diffuse optical spectroscopy evaluation of treatment response in women with locally advanced breast cancer receiving neoadjuvant chemotherapy. Transl Oncol. 2014;5(4):238–46. https://doi.org/10.1593/tlo.11346.CrossRef

17.

FDA. 2014. “Guidance for industry: pathologic complete response in early-stage breast cancer: use as an endpoint to support accelerated approval.” https://www.fda.gov/media/83507/download. Accessed 27 June 2019.

18.

Gibson A, Dehghani H. Diffuse optical imaging. Philos Trans R Soc A Math Phys Eng Sci. 2009;367(1900):3055–72. https://doi.org/10.1098/rsta.2009.0080.CrossRef

19.

Graham LJ, Shupe MP, Schneble EJ, Flynt FL, Clemenshaw MN, Kirkpatrick AD, Gallagher C, et al. Current approaches and challenges in monitoring treatment responses in breast cancer. J Cancer. 2014;5(1):58–68. https://doi.org/10.7150/jca.7047.CrossRefPubMedPubMedCentral

20.

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and Cancer. Cell. 2010;140(6):883–99. https://doi.org/10.1016/j.cell.2010.01.025.CrossRefPubMedPubMedCentral

21.

Gunther, Jacqueline E., Emerson A. Lim, Hyun K. Kim, Molly Flexman, Mirella Altoé, Jessica A. Campbell, Hanina Hibshoosh, et al. 2018. “Dynamic diffuse optical tomography for monitoring neoadjuvant chemotherapy in patients with breast cancer.” Radiology 000 (0): 161041. doi: https://doi.org/10.1148/radiol.2018161041.

22.

Hanahan D, Bergers G, Bergsland E. Less is, more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Investig. 2000; https://doi.org/10.1172/JCI9872.

23.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013.CrossRefPubMed

24.

Haskell RC, Svaasand LO, Tsay T-T, Feng T-C, Tromberg BJ, McAdams MS. Boundary conditions for the diffusion equation in radiative transfer. J Opt Soc Am A. 1994;11(10):2727. https://doi.org/10.1364/JOSAA.11.002727.CrossRef

25.

Hendry SA, Farnsworth RH, Solomon B, Achen MG, Stacker SA, Fox SB. The role of the tumor vasculature in the host immune response: implications for therapeutic strategies targeting the tumor microenvironment. Front Immunol. 2016;7(December):1–21. https://doi.org/10.3389/fimmu.2016.00621.CrossRef

26.

Hylton NM, Blume JD, Bernreuter WK, Pisano ED, Rosen MA, Morris EA, Weatherall PT, et al. Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy—results from ACRIN 6657/I-SPY TRIAL. Radiology. 2012;263(3):663–72. https://doi.org/10.1148/radiol.12110748.CrossRefPubMedPubMedCentral

27.

Jiang S, Pogue BW, Kaufman PA, Gui J, Jermyn M, Frazee TE, Poplack SP, DiFlorio-Alexander R, Wells WA, Paulsen KD. Predicting breast tumor response to neoadjuvant chemotherapy with diffuse optical spectroscopic tomography prior to treatment. Clin Cancer Res. 2014;20(23):6006–15. https://doi.org/10.1158/1078-0432.CCR-14-1415.CrossRefPubMedPubMedCentral

28.

Kareva I, Waxman DJ, Lakka G. Metronomic chemotherapy : an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett. 2015;358(2):100–6. https://doi.org/10.1016/j.canlet.2014.12.039.CrossRefPubMed

29.

Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4(6):423–36. https://doi.org/10.1038/nrc1369.CrossRefPubMed

30.

Kümmel S, Holtschmidt J, Loibl S. Surgical treatment of primary breast cancer in the neoadjuvant setting. Br J Surg. 2014;101(8):912–24. https://doi.org/10.1002/bjs.9545.CrossRefPubMed

31.

Littell R, Freund R, Spector P. SAS System for Linear Models. 3rd ed. Cary: SAS Institute; 1991.

32.

Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: Progress, opportunities, and challenges. Annu Rev Physiol. 2019;81(1):505–34. https://doi.org/10.1146/annurev-physiol-020518-114700.CrossRefPubMedPubMedCentral

33.

Masuda N, Higaki K, Takano T, Matsunami N, Morimoto T, Ohtani S, Mizutani M, et al. A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer. Cancer Chemother Pharmacol. 2014;74(2):229–38. https://doi.org/10.1007/s00280-014-2492-y.CrossRefPubMed

34.

Mclaughlin R, Hylton N. MRI in breast cancer therapy monitoring. NMR Biomed. 2011;24(6):712–20. https://doi.org/10.1002/nbm.1739.CrossRefPubMedPubMedCentral

35.

Meisamy S, Bolan PJ, Baker EH, Bliss RL, Gulbahce E, Everson LI, Nelson MT, et al. Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo 1 H MR spectroscopy—a pilot study at 4 T. Radiology. 2004;233(2):424–31. https://doi.org/10.1148/radiol.2332031285.CrossRefPubMed

36.

Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12(11):631–44. https://doi.org/10.1038/nrclinonc.2015.131.CrossRefPubMed

37.

NCCN. 2019. “Clinical practice guidelines: breast Cancer.” National Comprehensive Cancer Network 2019. https://www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf. Accessed 18 May 2019.

38.

Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. 2012;4(3):a006049. https://doi.org/10.1101/cshperspect.a006049.CrossRefPubMedPubMedCentral

39.

No K-s, Kwong R, Chou PH, Cerussi A. Design and testing of a miniature broadband frequency domain photon migration instrument. J Biomed Opt. 2008;13(5):050509. https://doi.org/10.1117/1.2998473.CrossRefPubMed

40.

O’Sullivan TD, Cerussi AE, Cuccia DJ, Tromberg BJ. Diffuse optical imaging using spatially and temporally modulated light. J Biomed Opt. 2012;17(7):0713111. https://doi.org/10.1117/1.JBO.17.7.071311.CrossRef

41.

Partridge SC, Zheng Z, Newitt DC, Gibbs JE, Chenevert TL, Rosen MA, Bolan PJ, et al. Diffusion-weighted MRI findings predict pathologic response in neoadjuvant treatment of breast cancer: the ACRIN 6698 multicenter trial. Radiology. 2018;289(3):618–27. https://doi.org/10.1148/radiol.2018180273.CrossRefPubMed

42.

Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7(8):455–65. https://doi.org/10.1038/nrclinonc.2010.82.CrossRefPubMed

43.

Pham TH, Coquoz O, Fishkin JB, Anderson E, Tromberg BJ. Broad bandwidth frequency domain instrument for quantitative tissue optical spectroscopy. Rev Sci Instrum. 2000;71(6):2500. https://doi.org/10.1063/1.1150665.CrossRef

44.

Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26(5):778–85. https://doi.org/10.1200/JCO.2007.15.0235.CrossRefPubMed

45.

Roblyer D, Ueda S, Cerussi A, Tanamai W, Durkin A, Mehta R, Hsiang D, et al. Optical imaging of breast cancer oxyhemoglobin flare correlates with neoadjuvant chemotherapy response one day after starting treatment. Proc Natl Acad Sci U S A. 2011;108(35):14626–31. https://doi.org/10.1073/pnas.1013103108.CrossRefPubMedPubMedCentral

46.

Sajjadi AY, Isakoff SJ, Deng B, Singh B, Wanyo CM, Fang Q, Specht MC, et al. Normalization of compression-induced hemodynamics in patients responding to neoadjuvant chemotherapy monitored by dynamic tomographic optical breast imaging (DTOBI). Biomed Optics Express. 2017;8(2):555. https://doi.org/10.1364/BOE.8.000555.CrossRef

47.

Tromberg BJ, Pogue BW, Paulsen KD, Yodh AG, Boas DA, Cerussi AE. Assessing the future of diffuse optical imaging technologies for breast cancer management. Med Physics. 2008;35(6Part1):2443–51. https://doi.org/10.1118/1.2919078.CrossRef

48.

Tromberg BJ, Zheng Z, Leproux A, O’Sullivan TD, Cerussi AE, Carpenter PM, Mehta RS, et al. Predicting responses to neoadjuvant chemotherapy in breast cancer: ACRIN 6691 trial of diffuse optical spectroscopic imaging. Cancer Res. 2016;76(20):5933–44. https://doi.org/10.1158/0008-5472.CAN-16-0346.CrossRefPubMedPubMedCentral

49.

Ueda S, Roblyer D, Cerussi A, Durkin A, Leproux A, Santoro Y, Xu S, et al. Baseline tumor oxygen saturation correlates with a pathologic complete response in breast cancer patients undergoing neoadjuvant chemotherapy. Cancer Res. 2012;72(17):4318–28. https://doi.org/10.1158/0008-5472.CAN-12-0056.CrossRefPubMedPubMedCentral

50.

Ueda S, Saeki T, Osaki A, Yamane T, Kuji I. Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: multimodal functional imaging and multiplex cytokine analysis. Clin Cancer Res. 2017;23(19):5769–78. https://doi.org/10.1158/1078-0432.CCR-17-0874.CrossRefPubMed

51.

Wanderley CW, Colon DF, Luiz JPM, Oliveira FF, Viacava PR, Leite CA, Pereira JA, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1- profile in a TLR4-dependent manner. Cancer Res. 2018;78(20):canres.3480.2017. https://doi.org/10.1158/0008-5472.CAN-17-3480.CrossRef

52.

Yeh E, Slanetz P, Kopans DB, Rafferty E, Georgian-Smith D, Moy L, Halpern E, Moore R, Kuter I, Taghian A. Prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy for palpable breast cancer. Am J Roentgenol. 2005;184(3):868–77. https://doi.org/10.2214/ajr.184.3.01840868.CrossRef

53.

Zhu Q, Tannenbaum S, Kurtzman SH, DeFusco P, Ricci A, Vavadi H, Zhou F, et al. Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using Immunohistopathology and hemoglobin parameters. Breast Cancer Res. 2018;20(1):1–17. https://doi.org/10.1186/s13058-018-0975-1.CrossRef

Title: Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens
Authors: Anup Tank
Hannah M. Peterson
Vivian Pera
Syeda Tabassum
Anais Leproux
Thomas O’Sullivan
Eric Jones
Howard Cabral
Naomi Ko
Rita S. Mehta
Bruce J. Tromberg
Darren Roblyer
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Trastuzumab
Cytostatic Therapy
Published in: Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-020-01262-1

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