Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas.
乳腺浸润性大汗腺癌: 18 例纯三阴性大汗腺癌的临床病理特征和综合基因组谱。
- 作者列表："Sun X","Zuo K","Yao Q","Zhou S","Shui R","Xu X","Bi R","Yu B","Cheng Y","Tu X","Lu H","Yang W
:Pure invasive apocrine carcinoma is a rare type of primary breast cancer, constituting ~1% of all breast cancers. Since most pure invasive apocrine carcinomas are triple negative, the lack of targeted therapies for triple-negative breast cancer has fostered efforts to discover actionable molecular targets in these tumors. In this study, we analyzed the clinicopathologic characteristics and comprehensive genomic profiling of 18 patients with pure triple-negative apocrine carcinomas (TNACs) using a 324-gene panel assay (FoundationOne CDx). The median age of these patients was 55.5 years, and the postmenopausal status rate was 77.8%. In total, 83.3% of patients were diagnosed with histological grade II, and 16.7% were diagnosed with grade III. The majority of patients presented at an early tumor-node-metastasis (TNM) stage (I: 38.9%; II: 50.0%; and III: 11.1%). The mean Ki-67 index was 9.7%, and the percent of PD-L1 positivity was 11.7%. With a median follow-up period of 76.5 months, one patient died, and two experienced distant metastases. There were 61 clinically relevant genomic alterations among all 18 pure TNACs, and the mean tumor mutation burden (TMB) was 3 Mut/Mb. The top ranked altered genes were PIK3CA (72.2%), PTEN (33.3%) and TP53 (27.8%). There were four novel mutations found in PTEN and an actionable rearrangement involving FGFR2-TACC2 that has not been reported in breast cancer before. In total, 88.9%, 50%, 44.4%, and 16.7% of TNACs had at least one clinically relevant genomic alteration in genes involved in the PI3K/mTOR, cell cycle, RAS/RAF/MEK and growth factor receptor-related pathways, respectively. All patients had at least one clinically relevant genomic alteration, and 94.4% had at least one actionable alteration. To the best of our knowledge, this study is the largest genomic sequencing cohort of pure TNACs. Incorporation of comprehensive genomic profiling into TNACs might shed light on potential therapeutic opportunities for both targeted drugs and immune checkpoint inhibitors.
: 单纯浸润性大汗腺癌是原发性乳腺癌的一种罕见类型，约占所有乳腺癌的 1%。由于大多数纯侵袭性大汗腺癌是三阴性的，三阴性乳腺癌靶向治疗的缺乏促进了在这些肿瘤中发现可操作的分子靶点的努力。在本研究中，我们使用 324 基因 panel 检测 (FoundationOne CDx) 分析了 18 例纯三阴性大汗腺癌 (TNACs) 患者的临床病理特征和全面的基因组谱。这些患者的中位年龄为 55.5 岁，绝经后状态率为 77.8%。总的来说，83.3% 的患者被诊断为组织学 ⅱ 级，16.7% 的患者被诊断为 ⅲ 级。大多数患者表现为早期肿瘤-淋巴结-转移 (TNM) 分期 (I: 38.9%; II: 50.0%; 和 III: 11.1%)。平均 Ki-67 指数为 9.7%，PD-L1 阳性率为 11.7%。中位随访期为 76.5 个月，1 例患者死亡，2 例发生远处转移。在所有 18 个纯 TNACs 中有 61 个临床相关的基因组改变，平均肿瘤突变负荷 (TMB) 为 3 Mut/Mb。排名靠前的改变基因为 PIK3CA (72.2%) 、 PTEN (33.3%) 和 TP53 (27.8%)。在 PTEN 中发现了四个新的突变和一个涉及 FGFR2-TACC2 的可操作的重排，这在乳腺癌中以前没有报道过。总共有 88.9% 、 50% 、 44.4% 和 16.7% 的 TNACs 在参与 PI3K/mTOR 、细胞周期的基因中至少有一个临床相关的基因组改变,分别为 RAS/RAF/MEK 和生长因子受体相关通路。所有患者至少有一个临床相关的基因组改变，94.4% 至少有一个可操作的改变。据我们所知，这项研究是纯 TNACs 最大的基因组测序队列。将全面的基因组谱纳入 TNACs 可能揭示靶向药物和免疫检查点抑制剂的潜在治疗机会。
METHODS::The emerging significance of the bitter taste receptors (T2Rs) role in the extraoral tissues alludes to their potential role in many pathophysiological conditions. The dysregulation of T2R expression and function in disease conditions has now been demonstrated in airways diseases, neurological disorders, and in some cancers. However, the role of T2Rs in the pathophysiology of breast cancer is unexplored thus far. Previously, we demonstrated differential expression of the 25 T2Rs in breast cancer (BC) cells. Based on our previous findings we selected two T2Rs, T2R4 and T2R14 for this work. The objective of the current study is to investigate the expression of T2R4 and T2R14 in BC clinical samples and to examine their physiological role using highly metastatic BC and non-cancerous cell lines. Using approaches, which involve receptor knockdown, pharmacological activation and biochemical assays we report that (i) T2R4 and T2R14 expression patterns are dissimilar, with decreased levels of T2R4 and increased levels of T2R14 in BC clinical samples compared to non-cancerous controls. (ii) Activation of T2Rs with their respective agonist elicited physiological responses in metastatic breast cancer cells, and no responses were seen in non-tumorigenic breast epithelial cells. (iii) Agonist activation of T2Rs (irrespective of T2R subtype) induced anti-proliferative, pro-apoptotic, and anti-migratory responses in highly metastatic breast cancer cells. Taken together, our findings demonstrate that the chemosensory T2R signaling network is involved in evoking physiological responses in the metastatic breast cancer cell line.
METHODS::RAD50 is commonly depleted in basal-like breast cancer with concomitant absence of INPP4B and several tumor suppressors such as BRCA1 and TP53. Our previous study revealed that INPP4B and RAD50 interact and such an interaction is associated with breast cancer survival at the transcriptional, translational and genomic levels. In the present study, we explored single nucleotide polymorphisms (SNPs) of these two genes that have synergistic effects on breast cancer survival to decipher mechanisms driving their interactions at the genetic level. The Cox's proportional hazards model was used to test whether SNPs of these two genes are interactively associated with breast cancer survival, following expression quantitative trait loci (eQTL) analysis and functional investigations. Our study revealed two disease-associating blocks, each encompassing five and two non-linkage disequilibrium linked SNPs of INPP4B and RAD50, respectively. Concomitant presence of any rare homozygote from each disease-associating block is synergistically prognostic of poor breast cancer survival. Such synergy is mediated via bypassing pathways controlling cell proliferation and DNA damage repair, which are represented by INPP4B and RAD50. Our study provided genetic evidence of interactions between INPP4B and RAD50, and deepened our understandings on the orchestrated genetic machinery governing tumor progression.
METHODS:BACKGROUND:Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS:IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS:The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS:The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION:"Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.