Abstract：
HER2-positive breast cancer is an aggressive tumor subtype and it is usually associated with worse clinical outcomes. Given the advances in HER2-targeted therapies, we hypothesized that HER2 amplification is no longer a marker of poor prognosis.
We conducted a population-based observational study employing two independent cohorts of patients with breast cancer. Samples from the METABRIC cohort were collected before clinical availability of HER2-targeted therapies, whereas samples from the SCAN-B cohort were collected afterward. The primary endpoint was overall survival (OS).
A total of 5121 patients were included in the analyses. In both cohorts, HER2-positive tumors were more likely to be node-positive (P < .05) and high grade (P < .001). Before HER2-targeted agents, HER2 patients had a significantly worse 5-year OS than hormone receptor-positive (HR+) patients (63.4% vs. 83.0%, HR = 2.49, P < .001). In contrast, after HER2-targeted agents entered clinical practice, 5-year OS no longer differed (88.3% vs. 90.4%, HR = 1.24, P = .17). Additionally, in an exploratory analysis using PAM50 subtypes, we identified that, after HER2-targeted therapies were implemented, patients clinically HER2-negative but PAM50-HER2-enriched have a lower OS (HR = 1.99, P = .009) than those who are both HER2-positive and PAM50-HER2-enriched, since they have not benefitted from HER2-targeted therapies.
HER2-targeted therapies dramatically altered the natural history of HER2-positive breast cancer, with overall survival approaching those of luminal subtype. HER2 positivity is no longer a marker of poor prognosis if access to HER2-targeted therapies is granted. Future trials should assess whether HER2-negative PAM50-HER2-enriched patients may also benefit from such therapies.
We conducted a population-based observational study employing two independent cohorts of patients with breast cancer. Samples from the METABRIC cohort were collected before clinical availability of HER2-targeted therapies, whereas samples from the SCAN-B cohort were collected afterward. The primary endpoint was overall survival (OS).
A total of 5121 patients were included in the analyses. In both cohorts, HER2-positive tumors were more likely to be node-positive (P < .05) and high grade (P < .001). Before HER2-targeted agents, HER2 patients had a significantly worse 5-year OS than hormone receptor-positive (HR+) patients (63.4% vs. 83.0%, HR = 2.49, P < .001). In contrast, after HER2-targeted agents entered clinical practice, 5-year OS no longer differed (88.3% vs. 90.4%, HR = 1.24, P = .17). Additionally, in an exploratory analysis using PAM50 subtypes, we identified that, after HER2-targeted therapies were implemented, patients clinically HER2-negative but PAM50-HER2-enriched have a lower OS (HR = 1.99, P = .009) than those who are both HER2-positive and PAM50-HER2-enriched, since they have not benefitted from HER2-targeted therapies.
HER2-targeted therapies dramatically altered the natural history of HER2-positive breast cancer, with overall survival approaching those of luminal subtype. HER2 positivity is no longer a marker of poor prognosis if access to HER2-targeted therapies is granted. Future trials should assess whether HER2-negative PAM50-HER2-enriched patients may also benefit from such therapies.
摘要：
HER2阳性乳腺癌是一种侵袭性肿瘤亚型，通常与较差的临床预后相关。鉴于HER2靶向治疗的进展，我们假设HER2扩增不再是不良预后的标志物.
我们进行了一项基于人群的观察性研究，采用了两个独立的乳腺癌患者队列。在HER2靶向治疗的临床应用之前，从METABRIC队列中收集样本，而来自SCAN-B队列的样本是随后收集的。主要终点是总生存期（OS）。
总共5121名患者被纳入分析。在这两个队列中，HER2阳性肿瘤更可能是淋巴结阳性（P<0.05）和高级别（P<0.001）。在HER2靶向药物之前，HER2患者的5年OS明显低于激素受体阳性（HR+）患者（63.4%vs.83.0%,HR=2.49,P<.001)。相比之下,HER2靶向药物进入临床实践后，5年OS不再有差异（88.3%与90.4%,HR=1.24，P=.17）。此外,在使用PAM50亚型的探索性分析中，我们确定，在实施HER2靶向治疗后，与HER2阳性和PAM50-HER2富集的患者相比，临床上HER2阴性但PAM50-HER2富集的患者具有更低的OS（HR=1.99，P=.009），因为他们没有从HER2靶向治疗中获益.
HER2靶向治疗极大地改变了HER2阳性乳腺癌的自然史，总体生存率接近管腔亚型。如果获得HER2靶向治疗，HER2阳性不再是不良预后的标志。未来的试验应评估HER2阴性PAM50-HER2富集患者是否也可从此类治疗中获益。
我们进行了一项基于人群的观察性研究，采用了两个独立的乳腺癌患者队列。在HER2靶向治疗的临床应用之前，从METABRIC队列中收集样本，而来自SCAN-B队列的样本是随后收集的。主要终点是总生存期（OS）。
总共5121名患者被纳入分析。在这两个队列中，HER2阳性肿瘤更可能是淋巴结阳性（P<0.05）和高级别（P<0.001）。在HER2靶向药物之前，HER2患者的5年OS明显低于激素受体阳性（HR+）患者（63.4%vs.83.0%,HR=2.49,P<.001)。相比之下,HER2靶向药物进入临床实践后，5年OS不再有差异（88.3%与90.4%,HR=1.24，P=.17）。此外,在使用PAM50亚型的探索性分析中，我们确定，在实施HER2靶向治疗后，与HER2阳性和PAM50-HER2富集的患者相比，临床上HER2阴性但PAM50-HER2富集的患者具有更低的OS（HR=1.99，P=.009），因为他们没有从HER2靶向治疗中获益.
HER2靶向治疗极大地改变了HER2阳性乳腺癌的自然史，总体生存率接近管腔亚型。如果获得HER2靶向治疗，HER2阳性不再是不良预后的标志。未来的试验应评估HER2阴性PAM50-HER2富集患者是否也可从此类治疗中获益。
