Introduction
Metastatic breast cancer (MBC) can present as either stage IV de novo primary breast cancer with distant metastases (dnMBC) (Any T, Any N, M1) or can become metastatic after distant recurrence of initially localized invasive breast cancer (rMBC) (stage I–III) [
1]. Estimated new cases of invasive breast cancer in 2017 in the United States (US) are 252,710 of which an estimated 40,610 will die from breast cancer [
2]. Long-term evidence comparing dnMBC and rMBC is limited with distant breast cancer recurrence not documented by the US national cancer registry database, Surveillance, Epidemiology, and End Results Program (SEER) [
3]. In the US, 6% of all breast cancer cases between 2005 and 2011 or 19,557 cases were stage IV at diagnosis (dnMBC) over the 6-year time span and 5-year relative survival for dnMBC was 26% [
4]. It is estimated 80,000 women are alive with rMBC in the US every year with an estimated average life expectancy of 20 months [
5].
De novo stage IV and distant recurrent MBC may present with different biology and respond differentially to treatment. Survival differences between dnMBC and rMBC have not been adequately studied, and we hypothesize that differences exist between de novo and recurrent MBC presentation and outcomes. Understanding these differences is important given the utilization of both types of MBC as equivalent entities in some clinical trials. With documented improvement in breast cancer survival over time and ongoing debate regarding the relative impact of screening and treatment, it is also important to characterize factors related to this phenomenon [
6,
7]. Our objective is to measure survival changes over time among de novo and recurrent metastatic breast cancer and identify similarities and differences in presentation and diagnosis to model their impact on MBC survival.
Discussion
In our cohort, we observed significant improvement in dnMBC survival but a reduction in rMBC incidence with worse survival over time using cohorts coincident with major changes in treatment for invasive and de novo stage IV BC (1990–1998, 1999–2004, 2005–2010). Triple negative subtype increased and HER2+ subtype decreased over time among rMBC cases with a concurrent shortening of disease-free interval from time of initial invasive breast cancer diagnosis to incidence of distant recurrence and rMBC diagnosis. dnMBC and rMBC had similarities but statistically significant differences in both presenting characteristics and outcomes. Both types of MBC cases were more often younger than age 70 and patient/medical professional detected compared to stage I–III non-metastatic breast cancer. Both dnMBC and rMBC were primarily high histologic grade at initial diagnosis. dnMBC dominant metastatic disease site was more likely bone than rMBC which were more often visceral.
dnMBC incidence and presentation did not change over time. rMBC incidence declined from 18% in 1990–1998 to 7% in the last time period, 2005–2010. rMBC: dnMBC ratio declined over time from 5:1 to 2:1. The survival difference increased from 5% in 1990–1998 to 24% in 1999–2004 and 42% in 2005–2010. rMBC bone dominant distant recurrence declined over time with a relative increase in visceral and soft tissue dominant disease. Both dnMBC and rMBC had better survival for single site metastatic disease (oligometastatic). Time to relapse for hormone receptor negative rMBC was significantly shorter, more often less than 5 years, than for hormone receptor positive rMBC.
From our modeling study, a number of MBC presentation and disease characteristics are probable contributors to the difference in dnMBC and rMBC survival and declining rMBC incidence. De novo MBC has a number of characteristics which may confer a survival advantage over recurrent MBC. These are the following, (1) more often a single metastatic site, (2) more likely hormone receptor positive with single bone metastases which can be treated successfully with hormonal therapy, (3) no treatment limitations from chemotherapy resistance (treatment naïve), (4) trastuzumab treatment for HER2+ disease.
rMBC cases declined over time due to both better primary breast cancer treatment over time (hormone therapy, taxanes, and trastuzumab) and improved screening with detection of cancer at an earlier more treatable stage (reduction of stage II and III). The rMBC cohort changed over time to more triple negative and fewer HER2+ cases after the introduction of trastuzumab in 1999. The rMBC survival disadvantage may be due to fewer distant recurrence cases with a more difficult treatment profile and possible chemotherapy resistance from aggressive first line treatment.
In our study, 5-year breast cancer survival was significantly better overall for de novo MBC and improved continuously over time. A recent study estimates de novo MBC 5- year relative survival has improved from 18 to 36% over time among younger women [
12]. In a recent Canadian study, a similar dnMBC/rMBC survival difference was observed with dnMBC 5-year survival 24% and rMBC survival 12% in a single time period (2001–2009) [
13]. Their model found increased mortality hazard associated with older age and relapsed versus de novo MBC. In a model using only de novo MBC, Leone et al. observed increased mortality hazard with older age and triple negative status [
14]. Vaz-Luis et al. also observed dnMBC survival improvement in a shorter survival time which may skew data to triple negative patient deaths and patients ineligible for standard treatment [
15].
In our model, we found bone dominant site associated with better survival which may account for a portion of the survival difference as dnMBC is more often bone dominant than rMBC. Better clinical outcomes have been observed among bone-only MBC patients [
16]. Superior long-term survival in oligometastatic disease has been observed with greater than one metastatic site identified as an adverse risk factor [
17‐
19].
In 2000, Sir Richard Peto noted a marked 25% decline in BC deaths in the UK and USA for 20–69 year old patients related to early detection by mammography and hormonal and cytotoxic adjuvant treatment changes [
6]. Meta-analysis of randomized trials has found mortality reduction related to treatment changes, primarily taxane-plus-anthracycline and higher-cumulative dose anthracycline-based regimens [
20]. In a large longitudinal study of MBC in Sweden, survival improvement was observed in a more recent time period (2000–2004) for patients 60 years or younger [
21]. A Canadian MBC survival study found population-based improvements in the most recent cohort related to the release of new systemic agents for MBC including trastuzumab and taxanes [
22].
In a previous study of invasive breast cancer at our institution, mammography detection, hormone therapy, and taxane-containing chemotherapy were associated with decreased hazard of mortality over time [
7]. In a study by Wu et al., identification of breast cancer by symptoms as opposed to a mammogram was an independent predictor of recurrence [
23]. The majority of both rMBC and dnMBC patients in the current study were symptomatically detected either clinically or by the patient in a time period when mammography screening was readily available and mammography detected breast cancer increased [
24].
The observed reduction in both HER2+ and HR+ rMBC cases over time indicates increasing success of initial targeted therapy with trastuzumab and hormone therapy [
25‐
27]. Decreased distant recurrence among HER2+ patients is consistent with reported results of improved long-term outcomes after neoadjuvant/adjuvant treatment with HER2 targeted therapy [
28‐
30]. Improvements in early disease treatment targeted at hormone receptor and HER2 positive disease has reduced overall distant relapse rates but left a remainder of rMBC cases with more aggressive disease and fewer treatment options.
A strength of our study is the meticulous patient follow up for recurrence and vital status by a dedicated registrar. Our modeling did not include time to distant recurrence as it is an intermediate outcome and would interfere with interpretation of the presenting characteristics’ relationship to survival. Differential time to recurrence by HR status may skew incidence of TNBC versus HR+ rMBC as the last time period (2005–2010) has shorter follow up than the previous time periods [
31]. Inclusion of diagnostic year interval in the Cox model adjusts for differential follow up time in later years and treatment changes over time. We are only able to analyze outcomes based on HR/HER2 status after 1998.
dnMBC is inherently treatment naive which may confer a survival advantage with better response to treatment and decreased likelihood of chemo-resistance [
32,
33]. rMBC cases may be more likely to have or develop intra-tumor heterogeneity after primary exposure to chemotherapy which fosters subsequent therapeutic failure for metastatic disease [
34]. dnMBC patients may represent a less complex disease type than breast cancer patients who present with localized disease and subsequently develop distant recurrence (rMBC) [
35]. Future studies of tumor genomics to study differential response between dnMBC and rMBC receiving the same therapy may help to understand these differences.
Our observation of a significantly greater survival improvement for de novo MBC than that seen in other studies suggests a need for demographic and treatment comparisons in other populations to explain and understand lesser outcomes. Characterization of dnMBC and rMBC with worse survival can be used to focus research on breast cancer subtypes that continue to have poor outcomes [
36]. Expansion of national registry data to capture distant recurrence to track recurrent disease survival would make these types of studies possible. MBC treatment, population, and cohort studies may need to include separate evaluation of de novo and recurrent MBC as their presentation and outcomes indicate a possible differential response to therapy.
Our study provides a community-based confirmation of HER2-directed therapy effectiveness to support expanded access to adjuvant HER2-directed treatment. Current use of targeted therapy using single tumor biopsies may be adequate for only a portion of MBC treatment planning. Research using tumor sequencing and patient-derived xenografts to study biologic evolution of breast cancer clones and complex tumor response to new treatments may help the hardest to treat achieve better outcomes [
37].
The advent of effective targeted therapy for hormone receptor positive disease, HER2 positive disease and taxane therapy in the adjuvant/neoadjuvant setting coincide with improved dnMBC survival and decline in rMBC incidence. Patients with recurrent metastatic disease who are ineligible for specialized treatment have a poor outlook. Tailored care of patients most at risk for distant disease recurrence and the expansion of up to date treatment use may be an opportunity to improve outcomes.