Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer
Purpose: Pathologic response after preoperative/neoadjuvant chemotherapy (NAC) is a continuum that can range from complete pathologic response (pCR) to extensive residual disease (RD). We hypothesized that post-NAC plasma circulating tumor DNA (ctDNA) fraction (TF) reflect pathologic response as con...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | The Journal of Liquid Biopsy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S295019542400033X |
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| author | Naing Lin Shan Billie Gould Xiaohong Wang Giancarlo Bonora Kim Blenman Julia Foldi Gerson Espinoza Campos Myles Walsh Pan Du Lajos Pusztai |
| author_facet | Naing Lin Shan Billie Gould Xiaohong Wang Giancarlo Bonora Kim Blenman Julia Foldi Gerson Espinoza Campos Myles Walsh Pan Du Lajos Pusztai |
| author_sort | Naing Lin Shan |
| collection | DOAJ |
| description | Purpose: Pathologic response after preoperative/neoadjuvant chemotherapy (NAC) is a continuum that can range from complete pathologic response (pCR) to extensive residual disease (RD). We hypothesized that post-NAC plasma circulating tumor DNA (ctDNA) fraction (TF) reflect pathologic response as continuum measured by the residual cancer burden (RCB) score. Methods: ctDNA was assessed using the PredicineBEACON assay, that interrogates up to 50 personalized tumor variants and 500 hot-spot mutations, in 3 mL archived plasma isolated from EDTA tubes collected post-NAC but before surgery from 44 patients with stage I/III triple negative breast cancer (TNBC) who received durvalumab and weekly nab-paclitaxel followed by doxorubicin/cyclophosphamide on a clinical trial (NCT02489448). Circulating free tumor DNA methylation profiling was performed using PredicineEPIC assay in paired pre- and post-NAC plasma (N = 30). Youden's J-statistics was used to define optimal thresholds. Results: We observed a significant positive correlation (r = 0.45, p = 0.004) between RCB scores and post-NAC TF. The median TF was significantly lower in pCR (RCB0) compared to RD patients (0.06 % vs. 0.3 %, p = 0.02). Using a TF positivity threshold of ≥0.05 %, PredicineBEACON had 58 % sensitivity at 83 % specificity for identifying RD. TF was higher in patients who experienced recurrence (n = 9) compared to those without recurrence (n = 35) (0.17 % vs. 0.05 % TF, p = 0.029). There was significant decrease in methylation signal in post-compared to pre-NAC samples, but post-treatment methylation signal was lower in cases with pCR vs RD. Conclusions: Post-NAC plasma tumor fraction and change in tumor-derived methylation signal predict the extent of RD and recurrence in TNBC patients. |
| format | Article |
| id | doaj-art-89636fc5f39e4cfeb54251e16ae1a9bc |
| institution | OA Journals |
| issn | 2950-1954 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Journal of Liquid Biopsy |
| spelling | doaj-art-89636fc5f39e4cfeb54251e16ae1a9bc2025-08-20T02:34:38ZengElsevierThe Journal of Liquid Biopsy2950-19542024-12-01610016810.1016/j.jlb.2024.100168Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancerNaing Lin Shan0Billie Gould1Xiaohong Wang2Giancarlo Bonora3Kim Blenman4Julia Foldi5Gerson Espinoza Campos6Myles Walsh7Pan Du8Lajos Pusztai9Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT, USAPredicine, Inc., Hayward, CA, USAPredicine, Inc., Hayward, CA, USAPredicine, Inc., Hayward, CA, USAYale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT, USAYale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT, USAYale Cancer Center, Yale School of Medicine, New Haven, CT, USAPredicine, Inc., Hayward, CA, USAPredicine, Inc., Hayward, CA, USAYale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Department of Internal Medicine, Section of Medical Oncology, Yale University, New Haven, CT, USA; Corresponding author. Yale Cancer Center, Yale School of Medicine, 300 George Street, Suite 120, Rm 133, New Haven, CT, 06511, USA.Purpose: Pathologic response after preoperative/neoadjuvant chemotherapy (NAC) is a continuum that can range from complete pathologic response (pCR) to extensive residual disease (RD). We hypothesized that post-NAC plasma circulating tumor DNA (ctDNA) fraction (TF) reflect pathologic response as continuum measured by the residual cancer burden (RCB) score. Methods: ctDNA was assessed using the PredicineBEACON assay, that interrogates up to 50 personalized tumor variants and 500 hot-spot mutations, in 3 mL archived plasma isolated from EDTA tubes collected post-NAC but before surgery from 44 patients with stage I/III triple negative breast cancer (TNBC) who received durvalumab and weekly nab-paclitaxel followed by doxorubicin/cyclophosphamide on a clinical trial (NCT02489448). Circulating free tumor DNA methylation profiling was performed using PredicineEPIC assay in paired pre- and post-NAC plasma (N = 30). Youden's J-statistics was used to define optimal thresholds. Results: We observed a significant positive correlation (r = 0.45, p = 0.004) between RCB scores and post-NAC TF. The median TF was significantly lower in pCR (RCB0) compared to RD patients (0.06 % vs. 0.3 %, p = 0.02). Using a TF positivity threshold of ≥0.05 %, PredicineBEACON had 58 % sensitivity at 83 % specificity for identifying RD. TF was higher in patients who experienced recurrence (n = 9) compared to those without recurrence (n = 35) (0.17 % vs. 0.05 % TF, p = 0.029). There was significant decrease in methylation signal in post-compared to pre-NAC samples, but post-treatment methylation signal was lower in cases with pCR vs RD. Conclusions: Post-NAC plasma tumor fraction and change in tumor-derived methylation signal predict the extent of RD and recurrence in TNBC patients.http://www.sciencedirect.com/science/article/pii/S295019542400033XMinimal residual disease (MRD)Circulating tumor DNA (ctDNA)Residual cancer burden (RCB) |
| spellingShingle | Naing Lin Shan Billie Gould Xiaohong Wang Giancarlo Bonora Kim Blenman Julia Foldi Gerson Espinoza Campos Myles Walsh Pan Du Lajos Pusztai Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer The Journal of Liquid Biopsy Minimal residual disease (MRD) Circulating tumor DNA (ctDNA) Residual cancer burden (RCB) |
| title | Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer |
| title_full | Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer |
| title_fullStr | Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer |
| title_full_unstemmed | Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer |
| title_short | Circulating tumor DNA fraction predicts residual cancer burden post-neoadjuvant chemotherapy in triple negative breast cancer |
| title_sort | circulating tumor dna fraction predicts residual cancer burden post neoadjuvant chemotherapy in triple negative breast cancer |
| topic | Minimal residual disease (MRD) Circulating tumor DNA (ctDNA) Residual cancer burden (RCB) |
| url | http://www.sciencedirect.com/science/article/pii/S295019542400033X |
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