Patient characteristics
A total of 386 patients diagnosed with MBC between 8-January-2010 and 27-June-2012 were enrolled in the study from 12-March-2013 to 31-March-2015, by oncologists practicing in 16 hospital-based sites distributed in 4 regions of Greece. The 12 sites located in Attica enrolled 77.5% of the patients. Of the enrolled patients, 7 did not meet all inclusion criteria. The median study look-back period of the eligible population was 29.1 [interquartile range (IQR): 19.2–37.7] months.
Eligible patients (N = 379) had been diagnosed with MBC at a mean ± SD age of 60.4 ± 12.8 years. At MBC diagnosis, 77.6% (256/330) were postmenopausal, 81.4% (206/253) had at least one term pregnancy and 54.8% (119/217) had a positive nursing history, while 92.0% (344/374) had an ECOG PS of 0 or 1. The primary tumor was histologically classified as invasive ductal carcinoma (IDC) in 76.0% of patients, as invasive lobular carcinoma in 7.9%, and for the remaining patients the tumor had characteristics of IDC with other histological features. The primary tumor differentiation was grade I or I/II in 3.4%, grade II or III or II/III in 81.5%, while for 15.0% the grade was unknown. Τhe most common metastatic sites were the bones (207/369; 56.1%), lungs (138/369; 37.4%;) and liver (28.7%; 106/369) (Table 1).
Table 1 Clinical and primary tumor characteristics of the overall population at MBC diagnosis (N = 379) Patient disposition based on HR/HER2 status and on de novo diagnosis or progression from an earlier stage
At the time of MBC diagnosis, nearly half of the patients (49.9%; 189/379) were HR+/HER2−, while 14.8% (56/379) were HR+/HER2+, 12.9% (49/379) triple negative, and 11.3% (43/379) HR−/HER2+. Classification could not be performed in the remaining patients (11.1%; 42/379). Additionally, 59.9% (227/379) of the eligible population had been first diagnosed at an earlier breast cancer stage (a mean ± SD of 5.2 ± 5.3 years prior to MBC diagnosis), while the remaining 40.1% (152/379) presented with de novo metastatic disease.
MBC management patterns
Of the eligible patients (n = 379), 99.5% had been exposed to systemic therapy, 32.2% had received radiotherapy and 13.2% had undergone surgery for MBC management. Of the patients exposed to systemic treatment (n = 377), 374 had received first line therapy [median exposure 5.5 (IQR: 3.7–11.0) months], 254 proceeded to second line [median 4.4 (IQR: 2.7–7.9) months], 175 to third line [median 3.5 (IQR: 1.9–5.7) months] and 105 to fourth line treatment. Information for patients of each subpopulation per HR/HER2 status that received first line treatment and those that advanced to the second, third and beyond the third line is indicated in Table 2.
Table 2 Systemic treatment management patterns per HR/HER2 status The median time elapsed from MBC diagnosis to first line treatment onset was 0.6 (IQR: 0.2–1.4) months (373 patients with available data). Chemotherapy was administered in 76.7% (287/374) of the overall population in the first line setting; TT (i.e. anti-HER2 agents, antiangiogenic agents and mTOR inhibitor) in 52.4% (196/374) and ET in 28.3% (106/374); additionally, chemotherapy, TT and ET were administered in 65.0% (165/254), 46.5% (118/254) and 36.6% (93/254) of patients in the second line; in 73.1% (128/175), 42.3% (74/175) and 28.6% (50/175) of patients in the third line setting; and in 87.6% (92/105), 42.9% (45/105), 36.2% (38/105) of patients receiving systemic fourth line treatment and beyond.
Systemic treatment patterns in terms of therapeutic drug classes administered in the first, second and third line setting of the overall population and subpopulations per HR/HER2 status are displayed in Fig. 1. Similarly, first, second, third and beyond the third line treatment patterns per therapeutic agent(s) subgroup administered in at least 10% of any of the subpopulations per HR/HER2 status are displayed in Table 2.
In regards to the treatment patterns (as displayed in Fig. 1) utilized from the first to the second and third line of therapy in the overall population, no single dominant pattern emerged. It shall be noted that a total of 30.2% (57/189), 25.0% (14/56), 58.1% (25/43) and 34.7% (17/49) of the HR+/HER2−, HR+/HER2+, HR−/HER2+ and HR−/HER2− patients had received radiotherapy in the MBC setting.
Clinical outcomes: Disease progression incidence rate, progression-free survival, overall survival and mortality rate
The disease progression IR in the overall population over a cumulative 256.7 years of follow-up in the first line setting, was 0.57 (95% CI: 0.48–0.67) per person-year. The IR was the lowest among HR+/HER2− (0.47; 95% CI: 0.37–0.58) patients. Additionally, the IR was higher among patients primarily diagnosed at an earlier stage (0.85; 95% CI: 0.69–1.01) rather than de novo metastatic (0.29; 95% CI: 0.20–0.38) (Table 3).
Table 3 Disease progression incidence rate, PFS time and OS time The Kaplan-Meier estimated median PFS of the overall population over the study observation period was 22.4 months (95% CI: 20.4–24.7) while the median TTP was 22.8 months (95% CI: 20.8–25.2). The estimated median PFS in the subpopulation primarily diagnosed at an earlier stage was shorter than that of patients diagnosed with de novo MBC (log-rank p-value: 0.004) (Fig. 2A and Table 3). A statistically significant difference was also detected in the median PFS of the subpopulations per HR/HER2 status (log-rank: p-value = 0.040) (Fig. 2B). Specifically, the median PFS of the HR+/HER2+ subpopulation was 19.7 months (95% CI: 12.9–25.9) and that of the HR−/HER2− 18.3 months (95% CI: 10.0–24.7), both shorter than that of the HR+/HER2− subpopulation (24.6 months, 95% CI: 21.3–27.9).
Among the factors (Table 4) examined by a multivariable Cox proportional hazards model in regards to their association with disease progression, median PFS was estimated to be higher among patients receiving ET as part of the first line treatment [HR: 0.70 (95% CI: 0.51–0.95; p = 0.024)], and lower in patients first diagnosed at an earlier breast cancer stage [HR: 1.42 (95% CI: 1.09–1.85; p = 0.009)] as well as among those with liver metastases [HR: 1.45 (95% CI: 1.10–1.93); p = 0.009].
Table 4 Multivariable Cox proportional hazard model to identify factors associated with PFS in the overall population In regards, to the all-cause mortality rate, 143 deaths (37.7% of the overall population) due to any cause were recorded over a cumulative study observation period of 905.0 years, yielding a rate of 0.16 per person-year. The respective MBC-related mortality rate was 0.15 per person-year. The Kaplan-Meier estimated median OS was 45.0 months (95% CI: 40.9–55.0) (Table 3). The relative risk of death did not significantly differ between patients first diagnosed at an earlier breast cancer stage vs. those with a diagnosis of de novo MBC (Fig. 3A and Table 3). The relative risk of death was significantly higher for HR−/HER2+ vs. HR+/HER2− and for triple negatives vs. HR+/HER2− [HR: 1.71 (95% CI: 1.05–2.78; p = 0.032); and HR: 1.79 (95% CI: 1.12–2.87; p = 0.015), respectively] (Fig. 3B and Table 3).
Healthcare resource utilization
Over a cumulative observation period of 660.5 years, the all-cause hospitalization incidence rate was 0.74 per person-year. The hospitalization incidence rate due to treatment-related toxicity and due to other reasons was 0.21 (cumulative observation period: 724.0 years) and 0.51 (cumulative observation period: 652.6 years) per person-year, respectively.
Similarly, the all-cause emergency room and hospital outpatient visit rate over a cumulative follow-up of 605.4 years was 2.67 per person-year. The emergency room and hospital outpatient visit rate for treatment-related toxicity was 0.58 (cumulative observation period: 638.1 years), while the respective rate due to other reasons was 2.02 (cumulative observation period: 618.3 years).