Improved systemic treatment for early breast cancer improves cure rates, modifies metastatic pattern and shortens post-metastatic survival: 35-year results from the Munich Cancer Registry

Abstract

Purpose: Systemic therapies (ATHs) in early breast cancer have improved the survival of breast cancer (BC) patients in recent decades. The magnitude of the changes in overall, metastasis-free (MFS) and post-metastatic (PMS) survival and in the metastasis (MET) pattern will be described.

Patient and methods: We analysed 60,227 patients with a diagnosis of T-N-M0 BC between 1978 and 2013 and 11,983 patients with metastases (MET) in the Munich Cancer Registry. Patients will be divided into four time periods to identify relationships between BC and METs. Survival was estimated using Kaplan-Meier curves, and Cox proportional hazards models were used to explore the impact of the BC subtype and MET status on survival with the time periods as surrogate markers for ATH evolution.

Results: During the observation period, 5-year relative survival has improved from 80.3 to 93.6% with an adjusted hazard ratio of 0.54 (P < 0.0001). Successful implementation of ATH has changed the MET pattern. The percentage of liver and CNS METs has more than doubled, the rate of lung METs remains stable, and the rate of bone METs has been reduced by approximately 50%. MFS has been prolonged with a hazard ratio 0.75 (P < 0.0001), but PMS has declined (hazard ratio 1.36; P < 0.0001); however, effects of adjuvant and palliative treatments cannot be separated. These results do not contradict improvements in advanced BC and do not suggest alterations of MET tumour biology by ATH.

Conclusions: Over the past three decades, ATHs have dramatically improved patient survival after BC diagnosis-most likely, by eradicating prevalent micro-METs; as a result, the MET pattern has changed. Eradicating only a portion of the first METs results in delaying the onset of subsequent MET, which leads to an apparently paradoxical effect: an extension of the MET-free interval and a reduction in PMS.

Keywords: Breast cancer; Metastasis; Metastasis organs; Survival; Time trend.

Fig. 1

Overall survival after metastasis (PMS) and the relative survival of BC patients with pT1c-/pT2-N-M0 tumours. a PMS based on the period (P1–P4) of the primary tumour diagnosis (P < 0.0001) (n = 10,213) and for primary advanced BC (T-N-M1) from periods P2 and P4 (dotted curves). b PMS based on the period (M1–M4) of the first MET detected (P = 0.029) (n = 10,213). c PMS based on the combined PxMx periods for METs (n = 10,196). Dotted curves describe the P1–4 view as in a but with truncated MET-free interval. d/e: PMS based on the site of unilocular MET and the negative/positive expression status of hormone receptor in diagnosed BC (n = 887/4065). f Relative survival of pT1c-/pT2-N-M0 patients depending on the period (P1–P4) (n = 19,925/18,371); for P1, only pT1 was defined. All Kaplan–Meier curves are drawn for up to either ten patients at risk or 15 years

Fig. 2

Cumulative incidence of metastases and subsequent survival. a Distribution of the time up to first MET during P1–P4 (n = 10,213). b Cumulative incidence of the first single or multiple MET sites detected based on P1–P4 (n = 60,227, P < 0.0001). c Cumulative incidence of the first lung MET detected with or without other sites based on P1–P4 (maximum y-axis 13%) (n = 60,227, P < 0.0001). d Cumulative incidence of the first liver MET detected with or without other sites based on P1–P4 (maximum y-axis 8%) (n = 60,227, P < 0.0001). e Overall survival after first lung MET detected based on P1–P4 (n = 2878, P < 0.0001). f Overall survival after first liver MET detected based on P1–P4 (n = 1971, P = 0.082)

Fig. 3

The MET process and the shortening of post-metastatic survival by only partially successful therapy. a BC grows after the division of the first cell generally over 10 and more years, for example up to 10⁹ tumour cells or a diameter of approx. 10 mm. b From 10⁵ tumour cells onwards, MET can be successfully initiated up to R0-resection. Colored cells and arrows illustrate the increasing molecular aberration. c Some of the millions of disseminated tumour cells can successfully initiate MET in one or more organs over time, probably the more foci the longer the tumour disseminates. These METs are all prevalent at the time of diagnosis of the BC. d Patient X will be cured, ATH can eradicate all METs. The survival rate increases. e Patient Y only bone METs can be eradicated and increase MET-free-survival and shorten post-MET survival