Chemotherapy effectiveness in trial-underrepresented groups with early breast cancer: A retrospective cohort study

Background Adjuvant chemotherapy in early stage breast cancer has been shown to reduce mortality in a large meta-analysis of over 100 randomised trials. However, these trials largely excluded patients aged 70 years and over or with higher levels of comorbidity. There is therefore uncertainty about whether the effectiveness of adjuvant chemotherapy generalises to these groups, hindering patient and clinician decision-making. This study utilises administrative healthcare data-real world data (RWD)-and econometric methods for causal analysis to estimate treatment effectiveness in these trial-underrepresented groups. Methods and findings Women with early breast cancer aged 70 years and over and those under 70 years with a high level of comorbidity were identified and their records extracted from Scottish Cancer Registry (2001-2015) data linked to other routine health records. A high level of comorbidity was defined as scoring 1 or more on the Charlson comorbidity index, being in the top decile of inpatient stays, and/or having 5 or more visits to specific outpatient clinics, all within the 5 years preceding breast cancer diagnosis. Propensity score matching (PSM) and instrumental variable (IV) analysis, previously identified as feasible and valid in this setting, were used in conjunction with Cox regression to estimate hazard ratios for death from breast cancer and death from all causes. The analysis adjusts for age, clinical prognostic factors, and socioeconomic deprivation; the IV method may also adjust for unmeasured confounding factors. Cohorts of 9,653 and 7,965 were identified for women aged 70 years and over and those with high comorbidity, respectively. In the >= 70/high comorbidity cohorts, median follow-up was 5.17/6.53 years and there were 1,935/740 deaths from breast cancer. For women aged 70 years and over, the PSM-estimated HR was 0.73 (95% CI 0.64-0.95), while for women with high comorbidity it was 0.67 (95% CI 0.51-0.86). This translates to a mean predicted benefit in terms of overall survival at 10 years of approximately3% (percentage points) and 4%, respectively. A limitation of this analysis is that use of observational data means uncertainty remains both from sampling uncertainty and from potential bias from residual confounding. Conclusions The results of this study, as RWD, should be interpreted with caution and in the context of existing and emerging randomised data. The relative effectiveness of adjuvant chemotherapy in reducing mortality in patients with early stage breast cancer appears to be generalisable to the selected trial-underrepresented groups. Author summaryWhy was this study done? Women aged 70 years and over and with other health conditions were largely excluded from participating in the clinical trials that established the efficacy of adjuvant chemotherapy in early breast cancer. An attempted trial for women aged 70 years and over was abandoned due to failure to recruit participants, and observational data are therefore the best available option to investigate the generalisability of chemotherapy effectiveness to trial-underrepresented groups. What did the researchers do and find? A retrospective cohort study was conducted using a population-based cancer registry with linkage to other routinely collected health data in Scotland. Propensity score matching and instrumental variable methods were used to estimate the effect of chemotherapy on breast cancer mortality and all-cause mortality, adjusting for differences in prognosis between those who received chemotherapy and those who did not. The average predicted benefit of chemotherapy was an additional 3 out of every 100 women surviving for 10 years for those aged 70 years and over, and an additional 4 out of every 100 for those with other health conditions. What do these findings mean? These results support the generalisability of treatment effectiveness estimates for adjuvant chemotherapy for early breast cancer to women aged 70 years and over and those with other health conditions. These results should be interpreted with appropriate caution as they are estimated from observational data and may be biased by residual confounding.