Real world evidence provides complementary evidence to RCT, to further describe benefits and risks to improve evidence-based patient care [19, 24]. CDK4/6i have been shown to consistently improve progression free survival in RCTs in aBC, and even OS in the case of three ribociclib and one abemaciclib phase 3 clinical trials [25–29].
Treat ER+ight provides real-world data in alignment with the use of CDK4/6i as the most effective TT to prolong treatment duration when used in combination with ET in the treatment of HR+/HER2- aBC. In this study, a 34% risk reduction of discontinuation or death was seen, in ET + TT cohort compared to ET cohort (HR = 0.66; 95% CI; 0.52, 0.85) (Table 2). The absolute numbers favored ET + TT vs ET independent of the line of therapy, with statistical significant benefit in 1st line. These results are consistent with the ones reported from other studies, suggesting that the increased understanding of endocrine resistance and its targeted approaches may positively impact the outcomes of patients with HR+/HER2- aBC [30–32]. When the TT added to ET is a CDK4/6i, the DOT increased by 59% (601 days; HR = 0.41; 95% CI; 0.32, 0.54), compared to ET alone, demonstrating a statistically and clinically meaningful benefit in a non-curative setting (Table 2). Additionally, the well known and favorable safety profile of CDK4/6i may have allowed longer treatment exposure, in comparison to other TTs [31, 33]. These findings are comparable to previous efficacy and safety data reported from pivotal RCTs, showing a consistent benefit in progression free intervals, which reassures the currently available evidence supporting CDK4/6i use [34–36].
When considering different CDK4/6i, while both ET + palbociclib and ET + ribociclib showed a superiority in terms of treatment duration over ET alone, the effect appeared even more pronounced with ET + ribociclib (an estimated relative increase in DOT of 74% for ribociclib (HR = 0.26; 95% CI; 0.17, 0.41) and 56% for palbociclib (HR = 0.44; 95% CI; 0.33, 0.58)). For OS, while no statistically significant difference was observed for patients treated with a CDK4/6i in 2nd and 3rd line, a statistically significant difference in OS was noted in patients who received ET + CDK4/6i as 1st line of therapy (p-value = 0.0024; HR = 0.30; 95% CI; 0.13, 0.69). These advantages should be interpreted with caution due to the different number of patients and unbalanced characteristics in population exposed to different CDK4/6i in the study and the possible impact of their sequence of use [37–39].
This study provided insights into the sequence and frequency of systemic anti-cancer therapies in Canadian patients with HR+/HER2 − aBC. Overall, the options taken (either before study entry, during the study or in follow-up) align with current key breast cancer treatment guidelines, with CDK4/6i combined with ET as the preferred regimen in 1L or 2L for patients with HR+/HER2 − aBC (61.9% and 38.5%, (Fig. 4)) [5]. This is relevant in view that during the conduct of this study, there was a significant change in practice due to results from pivotal clinical trials and approval of new therapies/indications (leading to protocol amendment) (Fig. 1). Consequently, most of the participants had priority access of CDK4/6i to 1st line due to local regulations in Canada (access to second line and beyond limited to clinical trials and expanded access, among others). Remarkably, in this population, CDK4/6i indication was extended beyond 1st line, leading more patients to a delayed use of palliative CT (15.1% and 43.2% in 2nd line and 3rd line respectively), as reported by others [40–42]. Use of CDK4/6i was slightly higher (20.9%) to other TTs in 3rd line (ET: 15.5%, mTORi: 16.2%, Other: 4.1%), but all clearly below CT (43.2%) (Fig. 4).
Owing to the observational nature of this study [43], and no adjustment for small patient sample numbers, the two major limitations were the unequal distribution of patients between the treatment cohorts (ET: n = 104 and ET + TT: n = 335) and the missing data for several secondary endpoints, which could lead to incomplete, inaccurate, or inconsistently measured variables between subjects. These do not allow us to draw strong conclusions on some of the study objectives.
This study provides supportive insights into the current treatment modalities for the treatment of Canadian men and pre-/peri-/postmenopausal women with HR+/HER2-negative aBC in the real-world setting. Results reinforce the current recommendation (as in current local practice guidelines) of the early introduction of CDK4/6i in the treatment of aBC [37, 44, 45].