Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy

Abstract

Background:Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time.Methods:Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length.Results:The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The ‘prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1–0.4) at 6 months to 2.2 (95% CI 1.3–3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1–2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4–1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group.Conclusion:From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

Impact of time to local recurrence on the occurrence of metastasis in breast cancer patients treated with neoadjuvant chemotherapy: A random forest survival approach

“…Time to recurrence has been shown to be an important prognostic factor in early breast cancer [8,9,18,30–32], with patients with late recurrence having better outcomes than those with early recurrence [15]. However, the precise definition of “early” and “late” recurrence remains a matter of debate, with the threshold generally set at between two and five years [8,13,15,17,31,33].…”

“…Some studies of adjuvant chemotherapy have reported better outcomes for patients with “late recurrences” than for those with “early recurrences”[13–17]. However, only two studies have investigated the impact of time to local recurrence on distant metastasis-free survival in the neoadjuvant setting [9,18]. One limitation common to all these studies is that the threshold for distinguishing between early and late recurrences is chosen by the author and often defined arbitrarily as the median time to recurrence, a time point that does not necessarily separate subgroups with good and poor prognoses.…”

“…For this reason, Baulies et al . introduced a time-dependent effect into their analysis, and showed that early local recurrence, within five years, in patients treated by conservative surgery, was a prognostic factor strongly associated with the development of distant metastases [18].…”

Reporting and methodological quality of survival analysis in articles published in Chinese oncology journals

“…Moreover, we cannot ensure whether certain data were missing due to actual failure to perform the corresponding test, or space limitations in the article. [ 33 ] The authors might feel that it was unnecessary to perform these tests or had good reasons to make exemptions. [ 34 ] Finally, a comparison study between Chinese and non-Chinese journals may be necessary to decide whether this is a global issue.…”

Survival analysis of breast cancer patients with different chronic diseases through parametric and semi-parametric approaches

“…Surgery [14,15,25,29,36] and CA 15-3 marker [15] are the other factors that can be considered in the survival analysis. Furthermore, the combination of the following factors have been suggested across different studies: familial history [24], smoking [24], affected side [20,39], place of residence [29], number of involved lymph nodes [22,24,27,31,34,35,37], stage [5,6,8,17,25,26,42], stage of surgery [25], tumor size [16, 19, 20-24, 27, 28, 31, 34, 35, 37, 38, 41], complete clinical and pathological response [41], medicine [29], type of pathology [32], type of treatment [17,21], chemotherapy [25,33,36,37], neoadjuvant chemotherapy [18], radiotherapy [25,33,36], number of metastasis [30], bone pain [30], and time interval leading to bone metastasis [42]. No study has considered chronic diseases as an effective factor of survival analysis.…”