Background: As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression. Materials and methods: Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing. Results: ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response. Conclusion: ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.

Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy / E. Ortolan, V. Appierto, M. Silvestri, R. Miceli, S. Veneroni, S. Folli, G. Pruneri, A. Vingiani, A. Belfiore, V. Cappelletti, M. Vismara, F. Dell'Angelo, L. De Cecco, G.V. Bianchi, F.G. de Braud, M.G. Daidone, S. Di Cosimo. - In: ESMO OPEN. - ISSN 2059-7029. - 6:2(2021 Apr), pp. 100086.1-100086.10. [10.1016/j.esmoop.2021.100086]

Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy

M. Silvestri;G. Pruneri;A. Vingiani;M. Vismara;F.G. de Braud;
2021-04

Abstract

Background: As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression. Materials and methods: Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing. Results: ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response. Conclusion: ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.
circulating tumor cells; circulating tumor DNA; neoadjuvant chemotherapy; prognosis; triple-negative breast cancer; Genomics; Humans; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Circulating Tumor DNA; Triple Negative Breast Neoplasms
Settore MED/06 - Oncologia Medica
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S2059702921000429-main.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 644.15 kB
Formato Adobe PDF
644.15 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/908348
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 6
social impact