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.

中文翻译：

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早期乳腺癌的临床代表性不足人群的化学疗法有效性：一项回顾性队列研究。

背景技术在超过100个随机试验的大型荟萃分析中，已显示早期乳腺癌的辅助化疗可降低死亡率。但是，这些试验在很大程度上排除了70岁以上，合并症或更高合并症的患者。因此，关于辅助化疗的有效性是否能推广到这些人群尚不确定，从而阻碍了患者和临床医生的决策。这项研究利用行政医疗数据-现实世界数据（RWD）和计量经济方法进行因果分析，以评估这些试验所代表的人群中的治疗效果。方法和研究结果发现年龄在70岁及以上的早期乳腺癌妇女和70岁以下的合并症高发女性，并从苏格兰癌症登记处（2001-2015）的数据中提取了他们的记录，并将其与其他常规健康记录相关联。合并症的高水平定义为：在Charlson合并症指数中得分最高1分，住院天数最高，和/或在特定的门诊诊所就诊5次或以上，所有这些均在乳腺癌诊断之前的5年内进行。倾向评分匹配（PSM）和工具变量（IV）分析（先前在这种情况下被认为是可行和有效的）与Cox回归结合使用，可以估算出乳腺癌死亡和各种原因死亡的危险比。该分析会根据年龄，临床预后因素进行调整，和社会经济剥夺；IV方法也可以针对无法测量的混杂因素进行调整。70岁及以上的妇女和合并症高的妇女分别得到9,653和7,965的队列。在≥70/高合并症人群中，中位随访时间为5.17 / 6.53年，乳腺癌死亡1,935 / 740。对于70岁以上的女性，PSM估计的HR为0.73（95％CI 0.64-0.95），而合并症高的女性为0.67（95％CI 0.51-0.86）。这意味着在10年总生存率方面的平均预期收益分别约为3％（百分点）和4％。该分析的局限性在于，使用观测数据意味着不确定性既来自采样不确定性，又来自残留混杂的潜在偏差。结论本研究的结果，对于RWD，应谨慎考虑并在现有和新兴随机数据的背景下进行解释。辅助化疗在降低早期乳腺癌患者死亡率中的相对有效性似乎可以推广到所选的临床试验不足的人群。