Background

About 25% of pancreatic cancers harbour actionable molecular alterations, defined as molecular alterations for which there is clinical or strong preclinical evidence of a predictive benefit from a specific therapy. The Know Your Tumor (KYT) programme includes US patients with pancreatic cancer and enables patients to undergo commercially available multi-omic profiling to provide molecularly tailored therapy options and clinical trial recommendations. We sought to determine whether patients with pancreatic cancer whose tumours harboured such actionable molecular alterations and who received molecularly matched therapy had a longer median overall survival than similar patients who did not receive molecularly matched therapy.

Methods

In this retrospective analysis, treatment history and longitudinal survival outcomes were analysed in patients aged 18 years or older with biopsy-confirmed pancreatic cancer of any stage, enrolled in the KYT programme and who received molecular testing results. Since the timing of KYT enrolment varied for each patient, the primary outcome measurement of median overall survival was calculated from the initial diagnosis of advanced disease until death. We compared median overall survival in patients with actionable mutations who were treated with a matched therapy versus those who were not treated with a matched therapy.

Findings

Of 1856 patients with pancreatic cancer who were referred to the KYT programme between June 16, 2014, and March 31, 2019, 1082 (58%) patients received personalised reports based on their molecular testing results. Actionable molecular alterations were identified in 282 (26%) of 1082 samples. Among 677 patients for whom outcomes were available, 189 had actionable molecular alterations. With a median follow-up of 383 days (IQR 214–588), those patients with actionable molecular alterations who received a matched therapy (n=46) had significantly longer median overall survival than did those patients who only received unmatched therapies (n=143; 2·58 years [95% CI 2·39 to not reached] vs 1·51 years [1·33–1·87]; hazard ratio 0·42 [95% CI 0·26–0·68], p=0·0004). The 46 patients who received a matched therapy also had significantly longer overall survival than the 488 patients who did not have an actionable molecular alteration (2·58 years [95% CI 2·39 to not reached] vs 1·32 years [1·25–1·47]; HR 0·34 [95% CI 0·22–0·53], p<0·0001). However, median overall survival did not differ between the patients who received unmatched therapy and those without an actionable molecular alteration (HR 0·82 [95% CI 0·64–1·04], p=0·10).

Interpretation

These real-world outcomes suggest that the adoption of precision medicine can have a substantial effect on survival in patients with pancreatic cancer, and that molecularly guided treatments targeting oncogenic drivers and the DNA damage response and repair pathway warrant further prospective evaluation.

Funding

Pancreatic Cancer Action Network and Perthera.

中文翻译：

---

在分子谱分析后接受匹配治疗的胰腺癌患者的总生存期：“了解您的肿瘤”注册研究的回顾性分析。

背景

大约25％的胰腺癌具有可操作的分子改变，定义为分子改变，对于这种分子改变，有临床或有力的临床前证据表明可从特定疗法中获益。“了解您的肿瘤”（KYT）计划包括美国胰腺癌患者，并使患者能够进行市售的多组学分析，以提供分子定制的治疗选择和临床试验建议。我们试图确定胰腺癌患者的肿瘤具有这种可操作的分子改变，并且接受分子匹配疗法的患者的中位总生存期是否比未接受分子匹配疗法的相似患者的更长。

方法

在此回顾性分析中，分析了18岁或以上患有活检证实的任何阶段胰腺癌的18岁或以上患者的治疗史和纵向生存结果，这些患者参加了KYT计划并获得了分子检测结果。由于每位患者的KYT登记时间各不相同，因此从初期诊断为晚期疾病直至死亡，计算了中位总生存期的主要结局指标。我们比较了接受配对疗法治疗的可操作突变患者与未接受配对疗法治疗的患者中位总体生存率。

发现

在2014年6月16日至2019年3月31日之间接受KYT计划治疗的1856例胰腺癌患者中，有1082例（58％）患者根据其分子检测结果收到了个性化报告。在1082个样品中的282个（26％）中发现了可行的分子变化。在可获得结果的677例患者中，有189例具有可操作的分子改变。中位随访时间为383天（IQR 214–588），那些接受了相匹配疗法（n = 46）且具有可操作分子改变的患者的中位总生存期比仅接受不匹配疗法（n = 143; 2·58年[未达到95％CI 2·39] vs1·51年[1·33–1·87]；危险比0·42 [95％CI 0·26-0·68]，p = 0·0004）。与没有进行有效分子改变的488位患者相比，接受匹配疗法的46位患者的总生存期也明显更长（2·58年[95％CI 2·39到未达到] vs 1·32年[1· [25–1·47]； HR 0·34 [95％CI 0·22-0.53]，p <0·0001）。但是，接受不匹配治疗的患者和未发生可改变的分子改变的患者的中位总体生存率无差异（HR 0·82 [95％CI 0·64-1·04]，p = 0·10）。

解释

这些现实结果表明，采用精密药物可以对胰腺癌患者的生存产生重大影响，并且针对致癌驱动程序以及DNA损伤反应和修复途径的分子指导治疗值得进一步的前瞻性评估。

资金

胰腺癌行动网络和Perthera。