Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 4/6 inhibitor therapy

Abstract

Background There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). Methods A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. Results The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0–14.0) months in the ET arm of group A, and 5.3 (3.9–6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8–7.7) months in the ET arm of group B, and 5.7 (4.6–6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5–8.0) months in the ET arm of group C and 4.0 (3.5–4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months. Conclusion Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.

Resistance to abemaciclib is associated with increased metastatic potential and lysosomal protein deregulation in breast cancer cells

“…CDK4/6i are used in combination with antiestrogens as the first-line treatment of ER+ metastatic breast cancer, and abemaciclib in particular is used in the adjuvant setting for patients with early, high-risk disease (4). Although CDK4/6i successfully extend progression-free survival, resistance is a common problem, and currently, there are no FDA approved drugs to specifically treat CDK4/6i resistant breast cancer (41). To this point, research into resistance had focused on implicating growth factors or cell cycle proteins (42), however, efficacy of these agents remain clinically unconfirmed.…”

Resistance to abemaciclib is associated with increased metastatic potential and lysosomal protein deregulation in breast cancer cells

“…4 Although CDK4/6i successfully extend progressionfree survival, resistance is a common problem, and currently, there are no FDA approved drugs to specifically treat CDK4/6i resistant breast cancer. 40 To this point, research into resistance had focused on implicating growth factors or cell cycle proteins, 41 however, efficacy of these agents remain clinically unconfirmed. Recently, lysosomes have been implicated in a non-apoptotic mode of cell death in response to abemaciclib and as a mode of inherent resistance to palbociclib in TNBC.…”

“…CDK4/6i are used in combination with antiestrogens as the first‐line treatment of ER+ metastatic breast cancer, and abemaciclib in particular is used in the adjuvant setting for patients with early, high‐risk disease 4 . Although CDK4/6i successfully extend progression‐free survival, resistance is a common problem, and currently, there are no FDA approved drugs to specifically treat CDK4/6i resistant breast cancer 40 . To this point, research into resistance had focused on implicating growth factors or cell cycle proteins, 41 however, efficacy of these agents remain clinically unconfirmed.…”

Cyclin-dependent kinase 4/6 inhibitors in the treatment of advanced or metastatic breast cancer

“…20 Nevertheless, in patients who progress early (< 12 months) on CDK inhibitor therapy, chemotherapy may be indicated, especially with younger patients or when managing visceral disease. 21,22 There are also data suggesting further treatment with CDK4/6 inhibitor therapy after progression, 23 targeted therapy in patients for whom an aberrant mutation has been identified or the use of an AKT inhibitor to reverse resistance to CDK and PI3Kα inhibitors. 24,25…”