Aromatase inhibitor (AI) and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) combination is standard first line treatment for HR+/ HER2- metastatic breast cancer (MBC), providing improved progression-free survival (PFS) over AI alone. The combination therapy may delay anti-estrogen resistance including through clonal selection, phenotypic changes and new mutations. We hypothesized that limited progressive disease (LPD) would be more common on combination therapy driven by new mutations at limited site(s), in comparison to more generalized progressive disease (GPD) which would be more common on AI alone due to phenotypic cellular changes across broader sites. Confirmation would indicate that biopsy of progressive sites should be considered for duel-therapy PD and that loco-regional treatment (LRT) options could be explored more frequently for these cases.
Disease progression (PD) patterns on combined treatment were compared in patients treated in first-line setting for HR+/HER2- MBC. Progressing duel-treated patients (n=16) were compared to historic AI-only treated controls (n=32), matched 1:2 by age and adjuvant therapy. Mode of progression was classified as general (PD in the majority of lesions) or limited (PD in up to two lesions in a single organ). All LPDs were assessed for suitability for LRT at PD.
LPDs were observed in 8 of 16 (50%) patients in the combination group and 4 of 32 (12.5%) in the AI group (p = 0.01). 10 of 12 cases (83%) with LPD were assessed as amenable for LRT. The sites of progression in these ten cases included six in bone, three affecting contralateral breast/chest wall and one in liver. Analysis of time to and mode of second relapse as well as overall survival (OS) for LPDs v GPDs await longer follow-up.
Combined CDK4/6i with AI treated patients in first line HR+/HER- MBC are more likely to develop LPD, where local therapy could be considered with no change to systemic therapy. In contrast general PD was more commonly observed in patients treated with AI alone, warranting change in systemic therapy.
A/Prof. Andrew Redfern, Dr Indunil Weerasena.
Has not received any funding.
All authors have declared no conflicts of interest.