Aspects of Adjuvant CDK4/6 Inhibitors in Older Breast Cancer Patients - Focusing on Geriatric Screening

Adjuvant systemic therapy for breast cancer incorporates many different treatment modalities. CDK4/6 inhibitors (CDK4/6i) were initially approved in the metastatic setting, but now also as adjuvant treatment, concomitant with endocrine therapy for patients with estrogen-receptor positive/human epidermal growth factor receptor 2 -negative (ER+/HER2-) disease.

Only 15% of the study population in MonarchE was aged 65 and older, and the median age of 51 years is a decade younger than in the advanced setting pivotal studies. The median age in NATALEE was similarly 52 years, including only 773 out of 5,101 aged ≥65 years. Subgroup analysis from the MonarchE trial suggests benefit also in those \>65 years old, but no statistically significant results exist so far. This might be attributed to a relatively small number of older participants, and the fact that these subgroup analyses were not pre-planned.

At present, specific guidelines regarding the use of adjuvant CDK4/6i in older patients are lacking. Given the importance of tailoring adjuvant treatment in this population, the implementation of geriatric screening in patients ≥70 years who are candidates for adjuvant CDK4/6i therapy is warranted. Furthermore, it is of clinical relevance to investigate the associations between geriatric screening assessment, quality of life, treatment-related toxicity, and discontinuation in this cohort. Outcomes such as hospitalization rates, recurrence, survival, and treatment dose intensity are also of particular interest in this patient population.

The hypothesis that the use of geriatric screening in routine clinical practice will reveal a relationship between frailty and decreased quality of life and higher risk of developing CDK4/6i toxicity. The investigators moreover anticipate a correlation between higher frailty and lower dose intensity, and poorer outcomes in terms of recurrence and survival.

The overall aim of this study is to examine different aspects of adjuvant CDK4/i in older early breast cancer patients. In more detail the aims are to investigate the association between geriatric frailty assessment (based on screening by the Geriatric 8 (G8) and Vulnerable Elders Survey-13 (VES-13) screening tools in older breast cancer patients that are to be treated with adjuvant CDK4/6i, and the risk of treatment side effects, discontinuation, patients reported quality of life, and hospitalization. Moreover, the investigators aim at exploring the correlation between frailty as assessed by geriatric screening and dose intensity and this impact on recurrence/survival. As exploratory analysis, different cut-offs for G8 and VES-13 score will be investigated in order to find stronger correlation between vulnerability/frailty and long-term outcomes in this patient cohort, and finally a comparison between the G8 and VES-13 performance.

In detail, the primary objectives are:

1. Association between frailty as assessed by G8 and VES-13 screening and CDK4/6i treatment side effects (adverse event (AE) grade ≥3) 2. Association between frailty as assessed by G8 and VES-13 screening and quality of life after initiating CDK4/6i, as reported by the patient 3. Association between frailty as assessed by G8 and VES-13 screening and hospitalization due to CDK4/6i

The secondary objectivs are: 4. Association between frailty as assessed by G8 and VES-13 screening and relative dose intensity (RDI, defined as the ratio of the drug dose administered in the actual time, over the planned dose in the planned time) by CDK4/6i and impact on breast cancer recurrence, overall and breast cancer-specific survival after 3, 5 and 10 years, respectively.

As exploratory analysis the following will be performed:

1\. Explore whether different cut-offs of G8 and VES-13 score would result in a stronger correlation between vulnerability/frailty and long-term outcomes in this patient cohort. 2. Compare which geriatric screening tool that is more associated to outcomes

• Global health status and Quality of Life (QoL) (GHS) [Срок оценки: Baseline, 6,12, 24, 36, 60 months from CDK4/6inhibitor initiation.]
• Summary score [Срок оценки: Baseline, 6,12, 24, 36, 60 months from CDK4/6inhibitor initiation]
• Ten scales [Срок оценки: Baseline, 6,12, 24, 36, 60 months from CDK4/6inhibitor initiation.]
• Adverse events [Срок оценки: At 6, 12, 18, 24, 30, 36, 42 months after CDK4/6i initation. Last timepoint is 6 months after ending CDK/6i (e.g 30 months for those treated Abemaciclib and 42 months for those treated with Ribociclib, respectively).]
• Hospitalization [Срок оценки: At 6, 12, 18, 24, 30, 36, 42 months after CDK4/6inhibitor (CDK4/6i) initation. Last timepoint is 6 months after ending CDK/6i (e.g 30 months for those treated Abemaciclib and 42 months for those treated with Ribociclib, respectively).]
• Dose adjustment [Срок оценки: At 6, 12, 18, 24, 30, 36, 42 months after CDK4/6i initation. Last timepoint is 6 months after ending CDK/6i (e.g 30 months for those treated Abemaciclib and 42 months for those treated with Ribociclib, respectively).]
• Treatment discontinuation [Срок оценки: At 6, 12, 18, 24, 30, 36, 42 months after CDK4/6i initation. Last timepoint is 6 months after ending CDK/6i (e.g 30 months for those treated Abemaciclib and 42 months for those treated with Ribociclib, respectively).]
• Relative dose intensity (RDI) [Срок оценки: At 24 and 36 months for those treated with Abemaciclib and Ribociclib, respectively]
• Berast cancer recurrence [Срок оценки: At 3, 5, 10 years]
• Survival [Срок оценки: At 3, 5, 10 years]