Actionable Mutations In Breast Cancer Research Articles

Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.

Landscape of clinically actionable mutations in breast cancer 'A cohort study'.

Breast cancer (BC) is a heterogeneous disease. Numerous chemotherapeutic agents are available for early stage or advanced/metastatic breast cancer to provide maximum benefit with minimum side effects. However, the clinical outcome of patients with the same clinical and pathological characteristics and treated with similar treatments may show major differences and a vast majority of patients still develop treatment resistance and eventually succumb to disease. It remains an unmet need to identify specific molecular defects, new biomarkers to enable clinicians to adopt individualized treatment for every patient in terms of endocrine, chemotherapy or targeted therapy which will improve clinical outcomes in BC. Our study aimed to identify frequent hotspot mutation profile in BC by targeted deep sequencing in cancer-related genes using Illumina Truseq amplicon/Swift Accel-Amplicon panel and MiSeq technology in an IRB-approved prospective study in a CLIA compliant laboratory. All the cases had pathology review for stage, histological type, hormonal status and Ki-67. Data was processed using Strand NGS™. Mutations identified in the tumor were assessed for ‘actionability’ i.e. response to therapy and impact on prognosis.

Detection of actionable gene mutations in breast cancer by amplicon-based next-generation sequencing liquid biopsy.

1035 Background: The PI3K-inhibitor, alpelisib, was approved for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancers with PIK3CA mutations based on findings from the SOLAR-1 trial. PIK3CA-positivity in tumor tissue was 29% (341/1172), but was only 15% (177/1172) in plasma cell-free DNA (cfDNA). The lower mutation detection rate observed in cfDNA may limit the clinical application of liquid biopsy in breast cancer. Amplicon-based next-generation sequencing (NGS) approach may confer improved sensitivity, allowing more effective profiling. We conducted a study to evaluate the use of this technology. Methods: Plasma cfDNA from 113 breast cancer patients (82.3% metastatic) underwent real-world testing in a CAP and ISO15189 accredited central laboratory. We analysed genetic alterations in cfDNA using an amplicon-based NGS technology. The presence of PIK3CA and other mutations relevant to breast cancer were correlated to molecular subtypes and treatment histories. Results: At least one mutation was detected in 70.8% of cases. Mutations were more frequent in metastatic cases (77.4%) compared to non-metastatic cases (27.3%). Across all patients, mutations in PIK3CA (33.6%), TP53 (32.7%), ESR1 (22.1%), GATA3 (7.1%) and ERBB2 (7.1%) were most frequently detected, in accordance with tumor tissue genotyping studies. PIK3CA mutations were more common in HR+ HER2- patients (44.4% vs 28.6% of other patients). Among PIK3CA-mutant cases, multiple PIK3CA mutations were present in 18.4% of cases, and hotspot mutations H1047R (34.2%), E542K (26.3%) and E545K (15.8%) were most frequent. An association was seen between PIK3CA mutation and prior treatment with CDK4/6 inhibitors (palbociclib, ribociclib) or mTOR inhibitor (everolimus), with 58% of PIK3CA-mutant cases having received these treatment previously compared to only 20% of PIK3CA-wild type (wt) cases. In addition, 75% of previously treated ESR1-mutant cases had specifically received hormonal treatment, compared to 60 % of ESR1-wt cases that received any treatment. Conclusions: We report similar PIK3CA mutation frequencies (~30%) with amplicon-based NGS on cfDNA compared to tumor tissue testing in breast cancer. Importantly, other driver mutations were also observed at similar frequencies as external tissue studies, implying high sensitivity as the primary reason for performance. This supports the clinical utility of an amplicon-based NGS-based approach to liquid biopsy for the sensitive detection of actionable mutations in breast cancer.

Abstract P6-07-01: Multigene profiling to identify clinically relevant actionable mutations in breast cancer: An Indian study

Abstract Background: Numerous chemotherapeutic agents are available against breast cancer (BC), but a vast majority of patients diagnosed with this disease still develop treatment resistance and eventually succumb to disease. It remains an unmet need to identify specific molecular defects against which targeted therapy are available for improving clinical outcomes in BC. Our study aims to identify frequent hotspot mutations in BCs and determine their clinical impact. Methods: 200 women with BC(early diagnosed and/or metastatic) aged 26-75 yrs (median age 50.5yrs) diagnosed at HCG from April 2013-15 were consented to be profiled by targeted deep sequencing for hotspot mutations in 48 cancer-related genes using Illumina's TSCAP panel and MiSeq technology in an IRB-approved prospective study in a CLIA compliant laboratory. All the cases had pathology review for stage, histological type, hormonal status and Ki67. The average coverage across 220 hot spots was greater than 1000X. Data was processed using Strand Avadis NGS™. Mutations identified in the tumor were assessed for 'actionability' i.e. response to therapy and impact on prognosis. Results: Somatic variants were detected in 75% of cases with direct impact on therapy or prognosis. Genetic aberrations were identified in PI3K/AKT/ mTOR signalling pathway in substantial fraction (27%) of breast cancer cases, out of which 17% had PIK3CA activating mutations,13 and 5 cases had PTEN and AKT deletions or truncating mutations respectively. Aberration in this pathway was more prevalent in HR+ve (53%) and HER2-ve including TNBC (61%) than in HR+/HER2+ve tumors (10.6%) of IDC histology. However, no correlation was found with stage and Ki67 index of the tumor. Notably 80% of BC cases presented with liver metastasis at the time of diagnosis were detected with PIK3CA mutation indicating its role as a surrogate marker of organ specific metastasis. PIK3CA was found to be co mutated with p53 in 16 cases (9%) of which 4 cases showed npCR post NACT. Also disruptive and non-disruptive mutations in TP53 alone were found in 25% of BC, varying widely among different histologies. A follow up of few cases showed shorter PFS and poor outcome in resected BC treated with NACT indicating its robust prognostic value in NACT setting. Furthermore, two patients were detected with cKIT mutations indicating sensitivity to imatinib and therefore enrolled on a clinical trial. The other variants were found in RB1(n=8),Her2 (n=2),FGFR amplification(n=1), KRAS(n=2),NRAS(n=3)CDH1(n=1),FBXW7(n=2) and EGFR(n=1).All these variants detected indicated resistance to conventional therapy and suggested sensitivity to available targeted therapy, either approved or in clinical trials. The response and outcome are being monitored in about 20 (10%) patients who have been enrolled in clinical trials and receiving mutation specific targeted therapy. Conclusions: This study confirms the utility of multigene profiling in early diagnosed and advanced BC patients, to stratify them on their molecular profile who could potentially benefit from targeted therapy. Prospective studies and randomized clinical trials are ongoing to confirm the independent prognostic and therapeutic value of the mutations in a larger cohort of Indian population. Citation Format: Ghosh M, Sheela ML, Choudhury S, Bahadur U, Patil S, Satheesh CT, Murugan K, Nayak R, Sridhar PS, Rao N, Mahesh B, Shashidhara HP, Krishnamoorthy N, Gupta V, Sankaran S, Subramanian K, Ajaikumar BS. Multigene profiling to identify clinically relevant actionable mutations in breast cancer: An Indian study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-01.