Profilo molecolare ed outcome clinico dei pazienti con recidiva precoce di carcinoma mammario triplo negativo

Abstract

La mTNBC a recidiva precoce, definita come recidiva metastatica entro 12 mesi dal termine dei trattamenti a intento curativo, è associata a prognosi sfavorevole, mentre i determinanti biologici restano poco chiari. Abbiamo esplorato le differenze molecolari in base al tempo di recidiva mediante biopsia liquida.

Abbiamo analizzato il ctDNA plasmatico di pazienti con mTNBC arruolate presso Gustave Roussy nello studio STING (NCT04932525), stratificate in recidiva precoce (<12 mesi), recidiva tardiva (≥12 mesi) o malattia metastatica de novo (entro 3 mesi dalla diagnosi). I campioni sono stati analizzati con FoundationOne® Liquid CDx. L’obiettivo primario era definire il panorama molecolare in base al tempo di recidiva; gli obiettivi secondari esploravano gli outcome clinici.

Tra il 2020 e il 2025, sono state incluse 243 pazienti: 92 (38%) con recidiva precoce, 93 (38%) tardiva e 58 (24%) de novo. Le recidive precoci presentavano più frequentemente alterazioni di TP53 (86% vs 61% vs 81%, p = 0.0003), MYC (18% vs 4% vs 8%, p = 0.009) e RB1 (17% vs 5% vs 3%, p = 0.007). PIK3CA è risultata l’unica alterazione ESCAT I/II differente tra i gruppi, più frequente nei gruppi tardivo e de novo (16%, 15%, 4%; p = 0.01). Nel gruppo precoce, le alterazioni ESCAT I/II più frequenti erano BRCA1 (6.5%) e PTEN (5.4%). La OS mediana era più breve nelle pazienti con recidiva precoce (20.4 mesi vs 41 e 29 mesi nei gruppi tardivo e de novo).

La mTNBC a recidiva precoce è caratterizzata da un aumento delle alterazioni di TP53, MYC e RB1, riflettendo una biologia tumorale più aggressiva, senza arricchimento di alterazioni ESCAT I/II azionabili, evidenziando un persistente bisogno clinico insoddisfatto.

Early recurring mTNBC, defined as metastatic relapse within 12 months after the end of curative treatments, is associated with poor outcomes, while its biological determinants remain unclear. We explored molecular differences by recurrence timing through liquid biopsy. We analysed plasma ctDNA of patients with mTNBC enrolled at Gustave Roussy in STING trial (NCT04932525) by time to first recurrence: early recurrence (<12 months from end of neoadjuvant/adjuvant treatments), late recurrence (≥12 months), or de novo metastatic (within 3 months of diagnosis). Samples were analysed using FoundationOne® Liquid CDx. Primary objective was to define the molecular landscape by recurrence timing; secondary objectives explored clinical outcomes. Variables were compared using chi-square/Fisher’s exact and Kruskal-Wallis tests; survival was assessed with Kaplan-Meier and log-rank tests (HR, 95% CI). Between 2020 and 2025, 243 mTNBC patients were included: 92 (38%) had early recurrence, 93 (38%) late recurrence and 58 (24%) de novo metastatic disease. Early recurrences had more alterations in TP53 (86% vs 61% vs 81%, p = 0.0003), MYC (18% vs 4% vs 8%, p = 0.009), and RB1 (17% vs 5% vs 3%, p = 0.007) as compared to late or de novo group. PIK3CA was the only ESCAT tier I/II alteration differing between groups, being more frequent in late and de novo group (16%, 15%, 4%; p=0.01). In early recurrence group, the most frequent ESCAT I/II alterations were BRCA1 (6.5%) and PTEN (5.4%). Median overall survival (OS) was shorter in patients with early relapse (20.4 months vs 41 and 29 months in late and de novo group [HR early vs late = 0.42, 95% CI 0.29-0.60, p < 0.001; HR early vs de novo = 0.72, 95% CI 0.48-1.07, p = 0.10)].

Early recurring mTNBC is characterized by increased TP53, MYC, and RB1 alterations, reflecting a more proliferative and aggressive tumour biology, without enrichment in actionable ESCAT tier I/II alterations, highlighting a persistent unmet clinical need.