Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Apr;198(2):383-390.
doi: 10.1007/s10549-022-06803-0. Epub 2023 Jan 23.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study

Mark Jesus M Magbanua  1 , Laura van 't Veer  2 , Amy S Clark  3 , A Jo Chien  2 , Judy C Boughey  4 , Hyo S Han  5 , Anne Wallace  6 , Heather Beckwith  7 , Minetta C Liu  4 , Christina Yau  2 , E Paul Wileyto  3 , Andrea Ordonez  2 , Tulasi I Solanki  2 , Feng Hsiao  2 , Jen Chieh Lee  2 , Amrita Basu  2 , Lamorna Brown Swigart  2 , Jane Perlmutter  2 , Amy L Delson  2 , Lauren Bayne  3 , Shannon Deluca  3 , Stephanie S Yee  3 , Erica L Carpenter  3 , Laura J Esserman  2 , John W Park  2 , Lewis A Chodosh  3 , Angela DeMichele  3
Affiliations

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study

Mark Jesus M Magbanua et al. Breast Cancer Res Treat. 2023 Apr.

Abstract

Purpose: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes.

Methods: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined.

Results: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years).

Conclusion: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Keywords: Disseminated tumor cells; Neoadjuvant chemotherapy; Pathologic complete response; Residual cancer burden.

PubMed Disclaimer

Conflict of interest statement

LV is a parttime employee of Agendia; and holds stock options from this employment. ASC reports grants and institutional research funding from Novartis and Lilly; and reports an uncompensated position on the Scientific Steering Committee for Novartis. AJC reports grants and institutional research funding from Merck, Amgen, Puma and SeaGen. ML reports grants and institutional research funding from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro; reports travel support from AstraZeneca, Genomic Health, and Ionis; reports institutional support for Advisory Boards from AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax; became an employee of Natera in 2022; and holds stock options from this employment. HH reports institutional research funding from Arvinas, Abbvie, Celcuity, GSK, G1 therapeutics, Quantum Leap Healthcare Collaborative, Pfizer, and Zymeworks; reports participation on Advisory Boards for Novartis, AstraZeneca and Gilead; and received a grant from the Department of Defense. CY reports grants and institutional research funding from the National Cancer Institute, and Quantum Leap Healthcare Collaborative; and received travel reimbursement from Quantum Leap Healthcare Collaborative. JP reports participation on a Data Safety Monitoring Board for QuantumLEAD; reports participation on an Advisory Board for VIVLI, University of Wisconsin SPORE, and a reviewer for PCORI; received travel reimbursement for ASCO and SABCS; served as an ISPY Trial Advocate Lead; and serves as a faculty member for Methods in Clinical Research. EC reports institutional research funding from Oncocyte, C2i Genomics, the Parker Institute, UHG, ChipDX, Tempus, Merck, Becton Dickinson, Menarini/Janssen, and AstraZeneca; reports honoraria from AstraZeneca, GuardantHealth, and BMS; and received research support from Personalis. LE is an unpaid member of the Board of Directors for Quantum Leap Healthcare Collaborative; reports institutional research funding from Quantum Leap Healthcare Collaborative, Merck, and the National Cancer Institute (P-01); serves on the Blue Cross Medical Advisory Panel, and receives reimbursement for travel, and honorarium for her participation. JP reports honoraria from Roche, Gilead, AstraZeneca, and Daiichi Sankyo. LAC has served as an expert consultant for Teva Pharmaceuticals, Eisai, Sanofi, Lilly, Imerys, Colgate, Whittaker, Clark and Daniels, and Sterigenics in litigation. AD reports institutional research funding from Pfizer, Genentech, Novartis, Inivata, and Calithera; reports unpaid leadership roles for American Society of Clinical Oncology, AACR San Antonio Breast Cancer Symposium, and ECOG/ACRIN Cooperative Group; received honorarium from the NCI Breast Cancer Steering Committee; and reports participation on a Data Safety Monitoring Board for QuantumLEAD; reports participation on an Advisory Board for VIVLI, University of Wisconsin SPORE, and a reviewer for PCORI.

All other participating authors have no disclosures to report. The rest of the authors declare no competing interests.

Figures

Figure 1.
Figure 1.. DTCs after neoadjuvant therapy vs. age and tumor burden at pretreatment.
A. Correlation between EPCAM+CD45- cells per mL and age at screening in DTC-positive patients. Correlation coefficient (rho) and p-value were calculated using Spearman’s rank correlation test; B. Association between DTC status and age at screening; C. Association between DTC status and longest tumor diameter by magnetic resonance imaging (MRI) at pretreatment. Means between groups (in B and C) were compared using Wilcoxon signed rank test.
See this image and copyright information in PMC

References

    1. Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ, Chodosh LA (2015) Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest 125:2484–2496. doi: 10.1172/JCI74883 - DOI - PMC - PubMed
    1. Aguirre-Ghiso JA, Sosa MS (2018) Emerging Topics on Disseminated Cancer Cell Dormancy and the Paradigm of Metastasis. Annual Review of Cancer Biology 2:377–393. doi: 10.1146/annurev-cancerbio-030617-050446 - DOI
    1. Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou A, Pant D, Grimley JS, Wandless TJ, Demichele A, ISPY Trial Investigators, Chodosh LA (2013) Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 24:30–44. doi: 10.1016/j.ccr.2013.05.007 - DOI - PMC - PubMed
    1. Bayne L, Nivar I, Goodspeed B, Deluca S, Wileyto EP, Shih N, Nayak A, Feldman MD, Edwards J, Fox K, Matro JM, Domchek S, Knollman H, Jankowitz R, Bradbury A, Shah PD, Graves J, Woodfield G, Chislock E, Wang J, Belka G, Chodosh LA, Clark AS, DeMichele A (2021) Abstract PD9–11: Identifying breast cancer survivors with dormant disseminated tumor cells: The PENN-SURMOUNT screening study. Cancer Research 81:PD9–11-PD19–11. doi: 10.1158/1538-7445.Sabcs20-pd9-11 - DOI
    1. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342:525–533. doi: 10.1056/NEJM200002243420801 - DOI - PubMed

Substances