In this large population-based study, we compared clinicopathological features, treatment and OS between all patients with de novo MBC diagnosed in the Netherlands between 2008 and 2018 to a group of patients with metachronous MBC diagnosed in that same period. Our study shows that these are not only two very distinct groups but also that patients with de novo MBC survive longer.
A number of differences in characteristics between the groups are notable. Our data corroborate earlier reports of frequent bone and lymph node metastases and less involvement of viscera and brain in patients with de novo MBC [4, 30, 31]. However, in our comparison of both groups, we did not observe more ER positive tumours in de novo patients [28], most likely caused by the 43% of metachronous patients with a MFI > 60 months, who are more often ER positive. Stage T3 and T4 and multifocal tumours were more often encountered in patients with de novo MBC, possibly reflecting delay in time to diagnosis. In de novo MBC, metastases limited to the bone were more common than in metachronous MBC resulting in increased use of endocrine treatment in this group, as was local radiotherapy on painful bone metastases [5]. The higher prevalence of triple negative tumours, liver and CNS metastases reflect unfavourable tumour characteristics and biology in metachronous patients.
Regarding outcome, our data support a better OS in de novo MBC compared to patients with metachronous MBC, partly explained by differences in disease characteristics. Even after correction for known confounding characteristics, improved survival persists in patients with de novo MBC. This finding is consistent with previous literature [4, 21, 28, 30, 33–35] showing that absolute differences in median OS range from 1.5 months (when comparing de novo to MFI > 24 months) to 20.3 months (comparing to MFI < 24 months)[31]. Without selection for MFI the reported median OS differences are similar to the 10.4 months found in our study [28, 30, 32, 33]. In our sensitivity analysis we found a similar effect of MFI on OS compared to the literature: longer MFI was associated with longer OS after diagnosis of metastases. However, even MFI > 60 months did not have better survival than de novo MBC, which is not a consistent observation [21, 31, 34].
There are a number of possible explanations for the longer survival observed in de novo MBC. The most likely hypothesis is that shorter survival of patients with metachronous MBC is related to previous (neo)adjuvant systemic therapies. Recurrence despite previous therapy could reflect 1) disadvantageous tumour-characteristics, 2) patient comorbidity / fitness and 3) primary or acquired therapy resistance. In our study, we could not quantify to what extent these factors played a role because we did not have data on the exact regimens and duration of systemic therapy nor could we account for fitness because data on performance score was only assessed at primary breast cancer diagnosis and contained too many missing values to include in the model. Nevertheless, the difference in use of systemic therapy in the metastatic setting (any systemic therapy in 89% of de novo and 79% of metachronous MBC and specifically targeted therapy in 75% of de novo and 41% of metachronous HER2 positive patients) may indicate that metachronous patients were less fit or had less treatment options for other reasons. As mentioned before, previous therapy can decrease treatment options in the metastatic setting due to acquired resistance to a drug, reaching a maximum tolerated cumulative dose or lasting side effects such as peripheral neuropathy or cardiotoxicity. Of note, due to the method of registration our data on systemic therapy could be an underestimation, as therapies administered not directly after metastasis diagnosis, but for example when symptoms did arise, may have been missed. In addition, the difference in targeted therapy among HER2 positive patients could be an overestimation because HER2 status was determined on the primary tumour and (a small percentage of) metachronous patients may have converted to HER2 negative.
Still, we did find some evidence to corroborate the hypothesis that previous systemic therapy plays a role in the survival difference between de novo and metachronous MBC. In a supplementary exploratory analysis we observed a longer OS among patients with metachronous MBC who were not systemically treated for their primary tumour. While this metachronous group had favourable characteristics at primary tumour diagnosis, the difference remained after correcting for baseline characteristics.
We also hypothesize that differences in metastatic burden could contribute to the observed differences in survival. Possibly, clinicians are inclined to perform more (and perhaps more sensitive) diagnostic imaging in a patient presenting with de novo MBC than in those diagnosed with recurrent disease. This would lead to detection of smaller, asymptomatic or oligo metastases in de novo MBC, associated with longer survival and possibly even curative treatment options. Although we have no data on number or volume of metastases, our data do support this hypothesis (Supplementary table 2) as we saw an increase in patients with de novo distant metastases limited to lymph nodes and increased use of anthracycline and taxane treatment (first choice in the neoadjuvant curative setting [5] and used for curative treatment of oligometastases).
In this study we extensively studied OS of patients with de novo and metachronous MBC using Kaplan Meier curves and Cox PH analysis. In the literature it is seldom reported whether the PH assumption was met and time-varying effects are often overlooked[51]. In our study, the variable of interest (de novo versus metachronous MBC) did not meet the PH assumption and therefore we additionally estimated the time-varying effects on OS. Overall, it appeared that the OS difference between de novo and metachronous MBC persisted over the years. The relatively small difference in OS between de novo and metachronous MBC in the first year could mean that a group of patients progress and die quickly despite any beneficial characteristic. Apparently, differences between de novo and metachronous MBC start to count after surviving longer than a year.
This study is unique as it presents a complete overview of patients with de novo MBC diagnosed in 2008–2018 in the Netherlands and the comparison to patients with metachronous MBC. The data convincingly shows that patients with de novo and metachronous MBC are distinct patient groups.
However, there are some limitations of our data. It would be relevant to also study metachronous patients in more detail using nationwide data. The MFI of our patients was probably not an accurate representation of all patients with metachronous MBC in 2008–2018 because the majority of metachronous patients in our cohort had their initial diagnosis in 2003 or 2005 (thus MFI at least 5 or 3 years respectively) (Fig. 1). Another limitation is that for patients with an initial diagnosis in 2008, distant metastases were only registered if they did not have a local or regional recurrence preceding the occurrence of metastases. Due to this registration difference, we probably missed approximately 20% of patients with metachronous MBC and an initial diagnosis in 2008 (i.e. of patients with a primary tumour in 2003/2005/Q1 2012, about 20% had a local or regional preceding their distant metastases). Additional patients were missed because recurrences from 2008 had only been registered in half of the hospitals. Nationwide data including all patients with metachronous metastases in a given period would have allowed a more accurate comparison of the two groups. Ideally, such data would also include information on metastatic burden (e.g. oligometastases) and information about treatment administered in the metastatic setting in more detail and beyond those given as initial therapy.