Prognostic factors in breast cancer with a focus on the role of tumour proliferation

Abstract

Ki67 is the most commonly used marker of proliferation in breast cancer. The general aim of the thesis was to investigate the prognostic role of Ki67 and its interplay with other prognostic factors in breast cancer cohorts.

In Paper I, the prognostic value of Ki67 as analysed in metastasis biopsies (mKi67) and the change in Ki67 from primary tumour (pKi67) to corresponding first site of relapse was studied in patients diagnosed and treated for metastatic breast cancer (MBC) at Karolinska University Hospital (Stockholm, Sweden). A significantly longer median post-relapse overall survival (OS) was demonstrated for low-mKi67 ( ≤20%) compared with high-mKi67 (>20%) group (25 vs.17 months, p 0.01 by log-rank test). mKi67 was associated with OS regardless of pKi67. Ki67 varied from primary tumour to metastasis in a significant number of patients (p 0.01 by McNemar's test) and the change from high to low was correlated to better OS in comparison with stable Ki67 levels.

In paper II, the prognostic value in terms of post-relapse OS of breast cancer subtypes and genomic signatures as assessed in primary tumour tissue was investigated, beyond classical clinical and pathological prognostic determinants, in patients diagnosed and treated for MBC at Karolinska University Hospital. Immunohistochemistry-(IHC) and PAM50-based intrinsic subtypes showed a significant but not independent prognostic value after distant relapse. Moreover, low and medium-risk categories according to PAM50 risk of relapse score (ROR-S) were independently associated with longer post-relapse OS in comparison with the high-risk category. In contrast, the 21-gene Recurrence Score and the 70-gene signature were not independently prognostic of post-relapse survival. The PAM50-derived proliferation score also independently correlated with survival and the additional clinical information deriving from combining ROR-P (ROR-S weighted for the proliferation score) with the other prognosticators was also highly significant (p < 0.001).

In paper III, the additional prognostic information deriving from the combination of genomic signatures and IHC markers, namely Ki67 alone or added to oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2) to generate IHC subtypes, compared with either classifier alone was investigated in two cohorts. Cohort 1 included patients with diagnosis of primary breast cancer from the Stockholm Breast Cancer Registry (SBCR) while cohort 2 was composed of women diagnosed with primary tumour in Uppsala county (Sweden). In cohort 1, 21-gene Recurrence Score and PAM50 added relevant prognostic information beyond Ki67/IHC subtypes. All the investigated genomic signatures provided additional prognostic information when combined with Ki67/IHC subtypes in the group of ER-positive/lymph node positive tumours while no signature reached the statistical significance when ER-negative tumours were studied. IHC subtypes, but not Ki67 alone, showed additional prognostic ability when combined with all genomic signatures except PAM50, in the overall cohort 1 and ER-negative subgroup, but not in ER-positive/lymph node negative and ER-positive/lymph node positive tumours. In cohort 2, the findings were substantially comparable but the statistical significance reduced likely due to the smaller sample size.

In Paper IV, the change in survival after local and loco-regional relapse of breast cancer over 34 years (1980-2014) was studied in a cohort of patients from the SBCR. Survival was compared between three cohorts according to years of relapse diagnosis: 1980-1989; 1990-1999; 2000-2014. In total, 1922 women were diagnosed with local and 776 with loco-regional relapse. In the group of the local recurrence, median postrelapse event-free survival (EFS) and OS significantly improved over time, regardless of age. Conversely, age-related trends in survival were demonstrated in the group of women who experienced a loco-regional relapse. Relative survival was consistent with the observed EFS and OS. In addition, a decrease in mortality over time was demonstrated only in younger patients diagnosed with a loco-regional relapse in 2000- 2014 (EMR 0.48; 95% CIs 0.42-0.72), regardless of other prognostic factors. The outcome was unchanged when the analysis was restricted to the years 1980 through 2009.