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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

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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.

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Data availability

The datasets used for the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the patients and their families and the I-SPY 2 TRIAL Investigators for their participation in this study.

Funding

This project was funded by the “2-PREVENT” Breast Cancer Translational Center of Excellence at the University of Pennsylvania through funds provided by the University of Pennsylvania Health System. MJMM received support from the Breast Cancer Research Foundation and a fellowship from the Cancer Cell Mapping Initiative (U54 CA209891).

Author information

Authors and Affiliations

  1. University of California San Francisco, San Francisco, CA, USA

    Mark Jesus M. Magbanua, Laura van ‘t Veer, A. Jo Chien, Christina Yau, Andrea Ordonez, Tulasi I. Solanki, Feng Hsiao, Jen Chieh Lee, Amrita Basu, Lamorna Brown Swigart, Jane Perlmutter, Amy L. Delson, Laura J. Esserman & John W. Park

  2. University of Pennsylvania, Philadelphia, PA, USA

    Amy S. Clark, E. Paul Wileyto, Lauren Bayne, Shannon Deluca, Stephanie S. Yee, Erica L. Carpenter, Lewis A. Chodosh & Angela DeMichele

  3. Mayo Clinic, Rochester, MN, USA

    Judy C. Boughey & Minetta C. Liu

  4. Mofitt Cancer Center, Tampa, FL, USA

    Hyo S. Han

  5. University of California San Diego, San Diego, CA, USA

    Anne Wallace

  6. University of Minnesota, Minneapolis, MN, USA

    Heather Beckwith

Authors
  1. Mark Jesus M. Magbanua
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  2. Laura van ‘t Veer
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Contributions

Concept or design of work: MJM, ASC, MCL, CY, EPW, AB, LBS, JP, ALD, LB, SD, SSY, EC, LJE, JWP, LAC, and AD. Data collection: MJM, ASC, AJC, JCB, MCL, HSH, AW, HB, AO, TS, FH, JCL, LBS, LB, SD, SSY, EC, and AD. Data analysis and interpretation: MJM, LVV, ASC, MCL, EPW, AO, TS, FH, JCL, AB, LBS, JWP, LAC, and AD. Drafting the article: MJM and AD. Critical revision of the article: MJM, LVV, ASC, EPW, AB, LB, SD, SSY, EC, LAC, and AD.

Corresponding author

Correspondence to Mark Jesus M. Magbanua.

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Competing interests

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.

Ethical approval

The I-SPY 2 Trial sites that participated in the SURMOUNT sub-study obtained Institutional Review Board approval at each site.

Consent to participate

All patients provided written informed consent to the sub-study.

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Not Applicable.

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Magbanua, M.J.M., van ‘t Veer, L., Clark, A.S. et al. 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. Breast Cancer Res Treat 198, 383–390 (2023). https://doi.org/10.1007/s10549-022-06803-0

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