Data_Sheet_2_Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer.docx

Background: PI3K/AKT signaling pathway is activated in breast cancer and associated with cell survival. We explored the prevalence of PI3K pathway alterations and co-expression with other markers in breast cancer subtypes.Methods: Samples of non-matched primary and metastatic breast cancer submitted to a CLIA-certified genomics laboratory were molecularly profiled to identify pathogenic or presumed pathogenic mutations in the PIK3CA-AKT1-PTEN pathway using next generation sequencing. Cases with loss of PTEN by IHC were also included. The frequency of co-alterations was examined, including DNA damage response pathways and markers of response to immuno-oncology agents.Results: Of 4,895 tumors profiled, 3,558 (72.7%) had at least one alteration in the PIK3CA-AKT1-PTEN pathway: 1,472 (30.1%) harbored a PIK3CA mutation, 174 (3.6%) an AKT1 mutation, 2,682 (54.8%) had PTEN alterations (PTEN mutation in 7.0% and/or PTEN loss by IHC in 51.4% of cases), 81 (1.7%) harbored a PIK3R1 mutation, and 4 (0.08%) a PIK3R2 mutation. Most of the cohort consisted of metastatic sites (n = 2974, 60.8%), with PIK3CA mutation frequency increased in metastatic (32.1%) compared to primary sites (26.9%), p < 0.001. Other PIK3CA mutations were identified in 388 (7.9%) specimens, classified as “off-label,” as they were not included in the FDA-approved companion test for PIK3CA mutations. Notable co-alterations included increased PD-L1 expression and high tumor mutational burden in PIK3CA-AKT1-PTEN mutated cohorts. Novel concurrent mutations were identified including CDH1 mutations.Conclusions: Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for “off-label” PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.

背景：PI3K/AKT信号通路在乳腺癌中被激活，并与细胞存活相关。本研究旨在探讨PI3K通路变异及其与其他标记物在乳腺癌亚型中的共表达情况。方法：对提交至CLIA认证的基因组学实验室的非匹配原发性乳腺癌和转移性乳腺癌样本进行分子分析，以利用下一代测序技术识别PIK3CA-AKT1-PTEN通路中的致病性或疑似致病性突变。同时，还包括通过免疫组化丧失PTEN的病例。研究了包括DNA损伤反应通路和免疫肿瘤学药物反应标记物在内的共变异频率。结果：在4,895个肿瘤样本中，3,558个（72.7%）至少存在PIK3CA-AKT1-PTEN通路中的一个变异：其中1,472个（30.1%）携带PIK3CA突变，174个（3.6%）携带AKT1突变，2,682个（54.8%）存在PTEN变异（7.0%的病例中存在PTEN突变，以及51.4%的病例通过免疫组化丧失PTEN），81个（1.7%）携带PIK3R1突变，4个（0.08%）携带PIK3R2突变。大多数样本为转移性病灶（n = 2974，60.8%），其中PIK3CA突变的频率在转移性病灶（32.1%）中高于原发灶（26.9%），p < 0.001。在其他388个（7.9%）样本中发现了PIK3CA突变，这些样本被归类为“非标签”，因为它们未包含在FDA批准的PIK3CA突变伴随检测中。值得注意的是，在PIK3CA-AKT1-PTEN突变队列中，发现了PD-L1表达增加和肿瘤突变负荷高的情况。同时，还发现了包括CDH1突变在内的新型共突变。结论：本研究队列的结果支持进一步探索PI3K抑制剂对“非标签”PIK3CA突变的临床益处，以及与潜在临床益处的联合策略，以期为乳腺癌患者提供治疗选择。