Impact of multi-gene mutational profiling on clinical trial outcomes in metastatic breast cancer.

PURPOSE: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes. METHODS: MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada. Molecular profiling on DNA extracted from FFPE archival tissues was performed on the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel (TSACP) on the MiSeq platform. Clinical trial outcomes by RECIST 1.1 and time on treatment were reviewed retrospectively. RESULTS: From January 2012 to November 2015, 483 MBC patients were enrolled and 440 were genotyped. At least one somatic mutation was identified in 46% of patients, most commonly in PIK3CA (28%) or TP53 (13%). Of 203 patients with ≥ 1 mutation(s), 15% were treated on genotype-matched and 9% on non-matched trials. There was no significant difference for median time on treatment for patients treated on matched vs. non-matched therapies (3.6 vs. 3.8 months; p = 0.89). CONCLUSIONS: This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings. Few patients were matched to clinical trials with targeted therapies. More comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations. Further studies are needed to evaluate if this approach leads to improved clinical outcomes.

Proteomic features of soft tissue tumours in adolescents and young adults.

BACKGROUND: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes. METHODS: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8). RESULTS: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. CONCLUSIONS: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.

Soft tissue tumours are cancers that develop in the connective and supporting tissues of the body, such as muscle or fat. These tumours arise in patients across the entire age range. However, improvements in survival outcomes in adolescent and young adult (AYA) patients have lagged behind outcomes in older adults (OA) and children. To better understand the biology of AYA patients with soft tissue tumours, we analysed protein profiles across 10 different types. We identified biological differences between AYA and OA patients and report an age-specific signature that can potentially be used to help predict which AYA patients are more likely to have aggressive cancers that will spread to other parts of the body. Our study highlights the importance of performing age-specific studies to identify new tools to predict patient outcomes and potentially find more suitable treatments.

The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma.

Soft tissue sarcomas (STS) account for less than 1% of adult cancers with a median overall survival of 12 months in the metastatic setting. Although chemotherapy remains the standard of treatment for advanced disease, molecular targeted agents (MTAs) and immunotherapies are under intensive investigation in STS. The success of MTAs comes mainly from antiangiogenic agents in various STS subtypes, from colony-stimulating factor-1 receptor inhibitor in tenosynovial giant cell tumor and neurotrophic tropomyocin receptor kinase (NTRK) inhibitors while others, such as cyclin-dependent kinase (CDK)-4 inhibitors, remain under evaluation. In advanced STS the activity of single-agent immunotherapy was not paradigm-changing as in other tumor types. A better understanding of tumor microenvironment, the immunogenic properties of MTAs, and finding an optimal treatment combination to improve patients outcomes became a central topic of research and discussion. Furthermore, the development and incorporation of transcriptomic profiling-based classification will allow identification, refined patient selection, and guided-treatment assignment. This article reviewed recent advances in STS treatment in MTAs and immunotherapy, strategies to overcome resistance, and outcomes of combination treatments in different STS subtypes. Promising preliminary results from combination strategies have shed light on STS treatment. The increasing understanding of this heterogeneous group of tumors and its microenvironment biology may help develop and guide treatment strategies with MTA and immunotherapies, alone or in combination, in a tailored way based on predictive and validated biomarkers and tumor molecular profiling in this new coming era.

A comparison of weekly versus 3-weekly cisplatin during adjuvant radiotherapy for high-risk head and neck cancer.

OBJECTIVES: To compare cumulative cisplatin dose and toxicity between patients who received 3-weekly versus weekly cisplatin during adjuvant radiotherapy for high-risk head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Consecutive HNSCC patients with involved resection margins and/or extra-capsular extension in two tertiary cancer centers with different institutional practices were identified. Cumulative cisplatin dose was calculated and information on toxicity reviewed and compared between patients who received 3-weekly versus weekly cisplatin. RESULTS: Of 270 high risk patients, 60 received 3-weekly 100mg/m(2) and 48 received weekly 50mg/m(2) cisplatin during adjuvant radiotherapy (60-66Gy in 30-33 fractions). Fourteen patients received other chemotherapy schedules and 148 received no chemotherapy. Mean cumulative cisplatin dose was 199.4mg/m(2) (standard error (SE) 5.4) in 3-weekly versus 239.8mg/m(2) (SE 11.0, P=0.001) in weekly treated patients. Cumulative cisplatin ⩾200mg/m(2) was given to 67.7% of patients in the 3-weekly cohort and 85.2% (P=0.039) in the weekly cohort. The rate of feeding tube dependency 6months after treatment, osteoradionecrosis, neutropenic fever, and persistent renal function decline were not statistically different. CONCLUSIONS: About one half of high-risk HNSCC patients are not eligible for cisplatin during postoperative radiotherapy. Patients treated with weekly 50mg/m(2) cisplatin received a higher cumulative dose with comparable toxicity as patients who received 3-weekly 100mg/m(2) cisplatin. Efficacy and applicability to the frequently used weekly 40mg/m(2) schedule remains to be evaluated.