This study using recent, real-world data shows that treatment patterns in metastatic breast cancer patients vary to a large extent. This supports the notion that guidelines for metastatic breast cancer are generally complex and often difficult to implement in clinical practice. We found that most Luminal A/B patients received endocrine therapy followed by chemotherapy in alignment with guideline recommendations [10], while HER2+ patients mostly received combinations of anti-HER2-targeted immunotherapies, with and without chemotherapy. Interestingly, treatment patterns for HER2+/ER+ patients indicate that several patients received endocrine maintenance therapy for long periods of time, and the proportion of time on endocrine treatment was higher than that on HER2-targeted immunotherapy. During the study period there was in fact some evidence to support such a treatment approach [11]. Moreover, the ABC Guidelines suggest that endocrine maintenance therapy following chemotherapy may be a reasonable option despite a lack of randomized data [10, 12]. The recommendation was based on clinical experience and associated lower toxicity [12] and further supported by the mechanistic rationale of cross-talk between estrogen- and HER2-receptors [13].
More recently, further evidence of endocrine maintenance therapy following chemotherapy/HER2-targeted antibody therapy for HER2+/ER+ patients has emerged [14, 15]. In the RegistHER and SystHER prospective registry studies, addition of endocrine therapy to chemotherapy and HER2-targeted therapy was associated with improved progression free survival and OS compared with chemotherapy and HER2-targeted therapy alone for HER+/ER+ patients [1, 15]. In our study, TNBC patients typically received chemotherapy; given the limited available treatment options and evidence to support the benefit of Programmed Cell Death (PD-1) and PD-L1-targeting antibodies during the observation period, this is not surprising. Nevertheless, a small number of patients received bevacizumab. Patients whom we were unable to classify based on tumour subtype received endocrine therapy. Surprisingly, our analyses reveal that a high number of HER2+ patients were managed for a long time without receiving HER2-targeted treatment. Currently we cannot explain this finding, but it does suggest that the younger age of these patients may have influenced these treatment patterns.
As regards survival, our study shows that the mortality rate for TNBC patients was about three times higher than for patients with all other subtypes, the latter all being associated with a comparable risk of death. This corresponds to the study of Li et al. [16], which also demonstrated that patients with TNBC had a worse overall survival than patients with non-TNBC independent of disease stage. Furthermore, we found that age (> 80 years) and 3+ metastatic sites were also independent risk factors for mortality, whereas time since primary diagnosis, dominating site of disease and calendar time were not statistically associated with increased mortality. Five-year survival was highest for HER2+/Luminal patients and median OS was 46 months. Similarly, in a French real-world study [17], HER2+ patients had a median OS of 45 months and also corresponded to the only metastatic subtype showing improvements in survival over calendar time. In our study, however, HER2+/ER- patients had a median OS of 31 months and, in contrast, no significant improvement in survival during the full study period despite a tendency to improved survival in the most recent years. This is in line with the French study [17] and also highlights the need for new treatment options. Notably, HER2+ patients were both younger and displayed a shorter time between primary and metastatic diagnosis than other subgroups.
Luminal subtypes
Following the introduction of molecular subtyping of tumours in breast cancer [18], the Luminal B subtype has been associated with a worse prognosis than Luminal A breast cancer [19, 20]. Our data, however, suggest no difference in OS between Luminal A and Luminal B subgroups from the time of metastatic diagnosis, even when adjusting for prognostic factors. Since most previous reports on the prognostic impact of molecular subtypes contrary to our study analyse survival from time of diagnosis, the associated difference in survival outcomes we see may be associated primarily with a faster and higher prevalence of recurrence. Our study indicates that Luminal B patients were treated more often with chemotherapy and less often with endocrine therapy compared with Luminal A patients. This treatment approach is in line with suggested evidence that Luminal B breast cancer is more sensitive to chemotherapy, and less so to endocrine therapy than Luminal A breast cancer [21]. This is not, however, supported by guidelines for advanced breast cancer [6, 10, 12]. Conflicting results on the difference in survival of metastatic breast cancer between Luminal A and B patients have been reported previously. Two retrospective studies from Italy showed that patients with Luminal B breast cancer had a shorter time to progression when treated either with endocrine therapy and a CDK4/6 inhibitor [22] or with first-line endocrine therapy alone [23]. Another retrospective study from Japan showed that ER+ patients treated with first-line endocrine therapy showed no significant difference in survival from time of metastatic diagnosis whatever their Ki67 expression, whereas PgR expression was associated with improved survival [24].
Only a small proportion (< 10%) of patients were expected to be premenopausal, but unfortunately data on menopausal status was not available. Likely, menopausal status does not affect the differences observed between the Luminal A and B groups.
Strengths and limitations
The major strength of our study is the detailed information on the diagnosis, treatment and follow-up of patients with metastatic breast cancer stratified by tumour subtype in a real-world setting with limited risk of selection bias. The completeness of the registry per se is high (approx. 95%) when validated with medical records. As this study was based on local data, however, the findings may not be directly generalizable to the entire advanced and/or metastatic breast cancer population in Sweden. Moreover, a number of limitations common to all observational studies apply here. Firstly, potential confounders have not been included, which may affect both internal and external validity of the results. This relates primarily to socio-economic factors that are known to be associated with breast cancer diagnosis [25], although access to healthcare is tax-financed in Sweden. Furthermore, lack of statistical power prevented us from describing specific treatment patterns within patient subgroups and investigating, for example, whether survival improved over time for HER2+ patients, as was shown by Gobbini et al. [17]. Our study reports on OS and treatment patterns. The focus for metastatic breast cancer remains prolonging survival and improving quality of life; however, the important quality of life evaluation was not possible using these data. Also, information on treatment side-effects, which may impact treatment patterns, could not be included.