Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients’ treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10–50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice.
Aim: To investigate if the genetic information provided by sequencing of both solid and liquid biopsies can shed light on tumor heterogeneity, and to understand the clinical usefulness of adding blood profiling to standard tissue analysis in cancer care. Methods:Data from 351 patients with stage IV solid tumors for whom molecular profiling of their solid and liquid biopsies was available were studied, with a focus on the discrepant molecular information found between tissue and blood samples. Results:In 86% of patients, solid and liquid biopsies provided different molecular information. Discrepant gene mutations with a functional impact on the corresponding protein were studied in detail. In 97% of cases, these additional mutations provided clinical value, mainly predicting sensitivity or resistance to targeted therapies. Specifically, 42% of the mutations found only in the liquid biopsy were directly predictive of approved therapies (80% targeted therapies), while 54% were inclusion criteria for molecularly-matched trials. Conclusion:This study suggests that the addition of blood profiling should be considered in routine clinical oncology, especially for patients with metastatic disease where integrated analysis of solid and liquid biopsies provides a more complete characterization of tumor heterogeneity and provides valuable clinical information for patient treatment.
The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid-tumor biopsies from a broad selection of cancer types.Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1. Activating PIK3CA mutations and null PTEN mutations were identified by NGS, and for PTEN, confirmed by IHC.Overall, mTOR-pathway activation was identified in 444/538 (83%) samples representing 40 different cancer types. Functional mutations in either or both PIK3CA and PTEN genes were identified in 173/538 (32%) samples. PIK3CA mutations were identified in 60/538 (11%) samples, PTEN mutations were identified in 155/538 (29%) samples and mutations in both PIK3CA and PTEN were identified in 18/538 (3%) samples. Overall, mTOR-pathway activation was not significantly associated with the PIK3CA and PTEN genotypes. However, all 18 samples with both PIK3CA and PTEN mutations also displayed mTOR-pathway activation (χ2 p=0.0471). Also, out of a total of 95 breast cancer samples, there were 5 breast-cancer samples which did not have mTOR-pathway activation, and all 5 (100%) of these had PIK3CA and PTEN mutations compared to 51/90 (57%) in the breast-cancer samples with mTOR-pathway activation (χ2 p=0.0134). Finally, the percentages of PIK3CA mutations were higher in colorectal-cancer samples which had mTOR-pathway activation (9/27, 33%) than in colorectal-cancer samples without mTOR-pathway activation (6/44; 14%; χ2 p=0.0484).Therefore, tumor-biopsy analyses based on combined mTOR-pathway biomarkers (and combined NGS and IHC assessments) could potentially provide treatment-informative stratification for particular cancer types.
e23099 Background: Advances in the molecular profiling of tumours, together with the expanding portfolio of targeted cancer therapies have established the terrain on which personalised cancer treatment can be conducted. This expanding area of precision medicine has the potential to be offered as a routine cancer-diagnostic service. Methods: We evaluated two molecular-profiling approaches : next-generation sequencing (NGS) and a group of several assays, termed Package Plus (PP), which have been primarily designed at identifying specific clinically-relevant alterations including protein expression/activation (by immunohistochemistry), and gene-promoter methylation, gene translocations and microsatellite instability (by PCR). The molecular profiling was conducted as diagnostic service for practising oncologists, who provided formalin-fixed paraffin-embedded tumour samples (for NGS and PP) and blood samples for circulating tumour DNA (for NGS only). A subset of oncologists who received the molecular profiling results and treatment advice was then surveyed to assess whether and how the results affected their treatment plans. Results: 980 samples from 16 different cancer types were received, out of which 914 (93%) were of sufficient quality to be included in this study. Clinically-relevant (actionable) alterations that provided treatment advice were identified for the large majority (841/914; 92%) of patients using the combination of NGS and PP data, but only for a minority of (247/912; 27%) of patients using NGS data alone. Treatment advice was adhered to by the oncologist in the majority (60%) of surveyed cases, and in the cases where the advice was not followed, reasons most often cited were treatment unavailability or cost. Conclusions: Our study demonstrates the utility of a precision-medicine service based on supervised tests (protein and RNA) in combination with NGS (DNA) profiling methods for advising oncologists on appropriate cancer-treatment plans.
e23097 Background: The mTOR pathway is often activated in human cancers. In this study, a total of 538 samples representing 40 different cancer types were analysed to evaluate the relationship between mTOR pathway activity and mutations in the upstream genes PIK3CA and PTEN. Methods: FFPE samples were analysed both by NGS (PIK3CA, PTEN, mTOR, TSC1, TSC2) and IHC (PTEN, 4pEBP1). Results: Overall, mTOR-pathway activation was identified in 83% of the samples, functional mutations were found in either or both PIK3CA and PTEN genes in 32% of the samples but there was no signification association between them. However when separating samples by cancer types, potential associations were identified. One example is the combination of PIK3CA activating mutation and PTEN loss of function which was associated with mTOR-pathway activation, most notably in the breast-cancer samples. Such combination has been associated with poor outcomes to some treatments (trastuzumab). Conclusions: In conclusion, our results show that stratification of tumors using the combination of mTOR-pathway biomarkers (and combined NGS and IHC technologies in their assessment) is potentially more informative than using a single biomarker to select the best treatment.
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