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Low-grade gliomas enjoy better survival when chemotherapy is added to radiation
Radiotherapy as single modality was considered the standard of care for low-grade gliomas, a mixed population of low proliferative tumours including oligodendrogliomas, oligoastrocytomas and grade 2 astrocytomas. However, a recently reported trial in the New England Journal of Medicine indicates1 that the addition of procarbacine, lomustine (CCNU) and vincristine, a combination known by its acronym, PCV, significantly prolongs survival in patients with low-grade glioma. When this trial was initially reported in 2012, after a median follow-up of almost 6 years, according to the estimated number of events needed to analyse the results, a significant difference in progression-free survival (PFS) was found. However, only 38% of patients had died at that time and overall survival (OS) did not differ among patients randomised to receive radiotherapy or those allocated to get six courses of PCV after completing radiation. In the current report, the median follow-up was 11.9 months and 55% of patients had already died. Median OS is prolonged by 5.5 years, moving from 7.8 years for radiotherapy to 13.3 for multimodality treatment, with a reduction of the risk of death by 41% with a HR of 0.59 (p=0.003). The absolute increase in OS at 10 years is 20% in favour of those receiving adjuvant chemotherapy (60% vs 40%). More toxic events occurred more frequently in patients with adjuvant PCV. However, the magnitude of the benefit is substantial. If we consider this approach as potentially curative, and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale2 is applied, the maximum score A has to be given. This trial should be taken as practice changing and adopted by clinicians treating patients with low-grade glioma. On the other hand, some questions remain unanswered in this area, such as the identification of patients who may not need any adjuvant therapy; but this is a task to be addressed in future prospective studies.
Dual *HER2 blockade: a step forward in personalised treatment in colon cancer
A very elegant proof-of-concept, multicentre, open-label phase II trial in KRAS exon 2 wild-type colon cancer shows the antitumour effect of the combination of lapatinib and trastuzumab in a very selected population of tumours where HER2 is amplified. This study, also known as the HERACLES trial, was carried out in four academic Italian institutions and recently published in Lancet Oncology.3 The concept for this clinical trial came from observations in patient-derived xenografts (PDX) of metastatic colon cancer with the amplified HER2 oncogene. In these PDX models, the combination of lapatinib and trastuzumab showed significant antitumour activity, which could not be proven, when each drug was given as a single agent. To accrue subsequently 27 HER2-positive and eligible patients, the investigators had to screen 904 patients with KRAS exon 2 wild type. Only 5% of the screened population showed tumours with strong 3+ immunostaining or fluorescence in situ hybridisation positive for HER2. All were primarily refractory to anti-epidermal growth factor receptor (EGFR) antibodies. Toxicity was mild and only one patient (4%) presented grade 3 skin rash, one presented grade 3 bilirubin elevation (4%) and four developed grade 3 asthaenia (16%) on therapy. Response rate was seen in 30% of patients with an additional 29% having stable disease. Median duration of response was 28 weeks and ranged from 24 to >94 weeks. A relation between PFS and the HER2 copy numbers above the cut-off was found, indicating a larger benefit for those with higher levels of amplification. The authors suggest that HER2 amplification should also be considered as a potential mechanism of primary resistance to anti-EGFR antibodies. A new therapeutic option is provided for HER2-dependent metastatic colon cancer, expanding the field of personalised medicine in this disease. Might patients with HER2 or HER3 mutations also benefit from this strategy? What is the optimal selection for this therapeutic approach? Should all patients with rat sarcoma wild-type tumours be tested for HER2 to avoid ineffective anti-EGFR therapies? More research to improve our understanding is needed, but this observation is an important step forward.
Neoantigen-specific lymphocytes isolated in peripheral blood from patients with melanoma: a liquid biopsy to predict the effect of immunotherapy?
There is an important need to define predictive biomarkers to improve on the use of immune checkpoint inhibitors. Overall, tumour mutational load, tumour programmed cell death ligand 1 (PDL1) expression and the intensity of intratumoural CD8+ T cell infiltrates are frequently proposed as predictors of efficacy for anti-programmed cell death protein 1(PD1) or PDL1 therapies. However, the detection of CD8+ and CD4+ lymphocytes that target neoantigens is limited to T cells isolated from tumour biopsies, which are often not available. A recent article published in Nature Medicine by investigators of the Surgical Branch of the US National Cancer Institute in Bethesda, led by Steven Rosenberg, shows that CD8+ PD1+ T lymphocytes could be found in the peripheral blood of patients with melanoma, accounting for about 5% of all circulating lymphocytes.4 Moreover, they investigated whether PD1 could be used as a biomarker to identify circulating neoantigen-specific lymphocytes in these patients with melanoma. They also show that the tumour antigen-specificity of PD1 expressing T cells in the blood very much mimics that of tumour resident PD1 expressing T cells. This work supports a novel and non-invasive strategy to study and develop these reactivities therapeutically. Isolating circulating CD8+ PD1+ T-specific or neoantigen-specific T cell receptors from this population could be very useful for the development of personalised T cell-based therapies.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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