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2016年7月7日，《美国医学会杂志肿瘤学分册》在线发表美国卡里斯生命科学公司、加利福尼亚大学圣迭戈分校、日本东京医科歯科大学的研究报告，从19784例多种实体肿瘤标本中发现磷脂酰肌醇3激酶（PI3K）通路突变率为38%，其中PIK3CA突变多见于子宫内膜癌（37%）、乳腺癌（31%）、子宫颈癌（29%）和肛门癌（27%），在HER2阳性组比HER2阴性组更多见。当激素受体（雄激素、孕激素或雌激素受体）过度表达存在时，PIK3CA、PTEN和AKT1突变发生更频繁。 JAMA Oncol. 2016 Jul 7. [Epub ahead of print] Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19,784 Diverse Solid Tumors. Sherri Z. Millis, Sadakatsu Ikeda, Sandeep Reddy, Zoran Gatalica, Razelle Kurzrock. Caris Life Sciences, Phoenix, Arizona; Tokyo Medical and Dental University, Tokyo, Japan; University of California-San Diego, La Jolla. IMPORTANCE: Molecular aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway drive tumorigenesis. Frequently co-occurring alterations in hormone receptors and/or human epidermal growth factor receptor 2 (HER2) may be relevant to mechanisms of response and resistance. OBJECTIVE: To identify patterns of aberration in the PI3K and interactive pathways that might lead to targeted therapy opportunities in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: From January 2013 through December 2014, 19,784 consecutive tumor samples (>40 cancer types) were sent from thousands of clinicians in 60 countries to a single commercial laboratory for molecular profiling, including next generation sequencing, protein expression (immunohistochemical analysis [IHC]), and gene amplification (fluorescent in situ hybridization or chromogenic in situ hybridization). MAIN OUTCOMES AND MEASURES: Patterns in targetable genomic and proteomic alterations in the PI3K pathway and coincidence with hormone receptor and HER2 alterations. EXPOSURES: Molecular profiling across solid tumors. RESULTS: Overall, 38% of patients had an alteration in 1 or more PI3K pathway components, most commonly phosphatase and tensin homologue (PTEN) loss (by IHC) (30% of all patients), followed by mutations in PIK3CA (13%), PTEN (6%), or AKT1 (1%). Seventy percent of patients with endometrial cancer and more than 50% of patients with breast, prostate, anal, hepatocellular, colorectal, and cervical cancer exhibited alterations in at least 1 PI3K pathway gene and/or gene product. Examples of frequent aberrations included PTEN loss in hepatocellular (57% of patients), colorectal (48%), gastric (36%), prostate (52%), and endometrial cancer (49%); PIK3CA mutations in endometrial (37%), breast (31%), cervical (29%), and anal cancer (27%). PIK3CA, PTEN, and AKT1 mutations occurred more frequently in the presence of hormone receptor overexpression (androgen, progesterone, or estrogen receptor). PIK3CA mutations were also more common in the HER2-positive than in the HER2-negative group; the opposite pattern was seen for PTEN mutation or PTEN loss. CONCLUSIONS AND RELEVANCE: PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types. DOI: 10.1001/jamaoncol.2016.0891 |
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