乳腺癌的发生和发展，部分由于基因组变异所致。乳腺癌的基因组特征表明，驱动基因变异可造成不同患者对治疗的效果不同，因此对乳腺癌患者进行基因组分析有助于精准选择有效的治疗方法。虽然基因测序已被用于指导早期乳腺癌术后治疗，但是尚不明确基因测序结果能否改变晚期乳腺癌患者结局。 2022年9月7日，全球自然科学三大旗舰期刊之首、英国《自然》正刊发表法国综合癌症中心联盟、巴黎大学古斯塔夫鲁西研究院、图卢兹第三大学克劳狄斯雷戈研究院、巴黎大学居里研究院、昂热大学西部癌症研究院、波尔多大学伯戈尼研究院、尤金马奎斯癌症中心、蒙彼利埃大学癌症研究院、蓝色海岸大学安托万拉卡萨涅中心、弗朗索瓦巴克莱斯癌症中心、让佩兰癌症中心、鲁昂医科大学亨利贝克勒尔中心、乔治弗朗索瓦勒克莱尔中心、圣凯瑟琳研究院、斯特拉斯堡欧洲癌症研究院、里昂市立医院癌症研究所、里昂第一大学、里尔大学奥斯卡兰布雷特癌症中心、里昂贝拉德中心、巴黎文理研究大学、保利卡尔梅特研究院、意大利坎迪奥洛癌症研究院的多中心随机对照二期临床研究报告，首次探讨了用基因组分析为晚期乳腺癌患者选择治疗方法，并对患者结局进行了比较。SAFIR02-BREAST (NCT02299999): Evaluation of the Efficacy of High Throughput Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer SAFIR-PI3K (NCT03386162): A Phase II Randomized Trial Comparing Alpelisib and Fulvestrant Versus Chemotherapy as Maintenance Therapy in Patients With PIK3CA Mutated Advanced Breast Cancer
该研究于2014年4月～2019年10月对1462例HER2未过表达晚期乳腺癌患者进行基因组分析，其中238例患者随机入组两项随机对照试验，比较维持化疗或根据基因组变异进行靶向治疗的效果。
结果发现，如果按欧洲肿瘤内科学会分子靶点临床可操作性量表（ESCAT）将基因组变异分类为I或II级时，根据基因组学选择靶向治疗与维持化疗相比，进展或死亡风险减少59%（校正后风险比：0.41，90%置信区间：0.27～0.61，P＜0.001），如果不按ESCAT对基因组变异进行分类，进展或死亡风险相似（校正后风险比：0.77，95%置信区间：0.56～1.06，P＝0.109）。对于ESCAT变异高于II级的患者，靶向治疗与维持化疗相比，进展或死亡风险相似（未校正风险比：1.15，95%置信区间：0.76～1.75）。
对于49例种系BRCA突变患者，奥拉帕利与维持化疗相比：
- 种系BRCA1突变：进展或死亡风险减少64%（风险比：0.36，90%置信区间：0.14～0.89）
- 种系BRCA2突变：进展或死亡风险减少63%（风险比：0.37，90%置信区间：0.17～0.78）
- 优于OlympiaD：进展或死亡风险减少42%（风险比：0.58，95%置信区间：0.43～0.80）
因此，该研究结果表明，根据基因组分析结果选择靶向治疗可改善晚期乳腺癌患者生存结局，但是仅限于既往临床试验已证实抗肿瘤活性相关基因变异者，应该根据靶点可操作性进行基因组学主导的治疗决策。 对此，英国《自然》编辑发表同期评论：精准医学可改善晚期乳腺癌结局。Nature. 2022 Sep 7. Online ahead of print.Genomics to select treatment for patients with metastatic breast cancer.Fabrice Andre, Thomas Filleron, Maud Kamal, Fernanda Mosele, Monica Arnedos, Florence Dalenc, Marie-Paule Sablin, Mario Campone, Hervé Bonnefoi, Claudia Lefeuvre-Plesse, William Jacot, Florence Coussy, Jean-Marc Ferrero, George Emile, Marie-Ange Mouret-Reynier, Jean-Christophe Thery, Nicolas Isambert, Alice Mege, Philippe Barthelemy, Benoit You, Nawale Hajjaji, Ludovic Lacroix, Etienne Rouleau, Alicia Tran-Dien, Sandrine Boyault, Valery Attignon, Pierre Gestraud, Nicolas Servant, Christophe Le Tourneau, Linda Larbi Cherif, Isabelle Soubeyran, Filippo Montemurro, Alain Morel, Amelie Lusque, Marta Jimenez, Alexandra Jacquet, Anthony Goncalves, Thomas Bachelot, Ivan Bieche.Gustave Roussy, Villejuif, France; Université Paris Saclay, Kremlin Bicetre, France; Institut Claudius-Regaud, University of Paul Sabatier, Toulouse, France; Institut Curie, Université Paris Cité, Paris, France; Institut de Cancérologie de l'Ouest - René Gauducheau, Saint Herblain, University of Angers, Angers, France; Institut de Cancérologie de l'Ouest - Centre Paul Papin, Angers, France; Institut Bergonié, Université of Bordeaux, Bordeaux, France; Centre Eugène Marquis, Rennes, France; Institut du Cancer de Montpellier, Montpellier University, Montpellier, France; Centre Antoine Lacassagne, University Cote d'Azur, Nice, France; Centre Francois Baclesse, Caen, France; Centre Jean Perrin, Clermont-Ferrand, France; Centre Hennri Becquerel, University of Medicine of Rouen, Rouen, France; Centre Georges Francois Leclerc, Dijon, France; Institut Sainte Catherine, Avignon, France; Institut de Cancérologie Strasbourg Europe, Strasbourg, France; Institut de Cancérologie des Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France; Centre Oscar Lambret, University of Lille, Lille, France; Centre Léon Bérard, Lyon, France; PSL Research University, Mines Paris Tech, Paris, France; Unicancer, Paris, France; Institut Paoli-Calmettes, Marseille, France; Candiolo Cancer Institute, Candiolo, Italy.Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.Cancer progression is driven in part by genomic alterations. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P<0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P=0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n=49) derived high benefit from olaparib (gBRCA1: HR=0.36, 90% CI: 0.14-0.89; gBRCA2: HR=0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.DOI: 10.1038/s41586-022-05068-3Nature. 2022 Sep 7. Online ahead of print.Precision medicine improves outcomes in metastatic breast cancer.For breast cancers that have spread, a randomized phase II clinical trial shows that using genomic analysis to target therapies can improve outcomes, but only in people with a genetic alteration that has previously been associated with antitumour activity in clinical trials.DOI: 10.1038/d41586-022-02276-9
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