Emerging Role of EGFR Mutations in Creating an Immune Suppressive Tumour Microenvironment

Several types of tumours overexpress the Epidermal Growth Factor Receptor (EGFR) in either wild type or mutated form. These tumours are often highly aggressive and difficult to treat. The underlying mechanisms for this phenomenon have remained largely unresolved, but recent publications suggest two independent mechanisms that may contribute. According to one line of research, tumours that overexpress the EGFR grow autonomously and become “addicted” to growth factor signalling. Inhibition of this signal using EGFR inhibitors can, therefore, induce cell death in tumour cells and lead to tumour shrinkage. The other line of research, as highlighted by recent findings, suggests that the overexpression, specifically of mutant forms of the EGFR, may create an immune-suppressive and lymphocyte depleted microenvironment within tumours. Such a lymphocyte depleted microenvironment may explain the resistance of EGFR overexpressing cancers to tumour therapies, particularly to check-point inhibitor treatments. In this article, we discuss the recent data which support an immune modulatory effect of EGFR signalling and compare these published studies with the most recent data from The Cancer Genome Atlas (TCGA), in this way, dissecting possible underlying mechanisms. We thereby focus our study on how EGFR overexpression may lead to the local activation of TGFβ, and hence to an immune suppressive environment. Consequently, we define a novel concept of how the mitogenic and immune modulatory effects of EGFR overexpression may contribute to tumour resistance to immunotherapy, and how EGFR specific inhibitors could be used best to enhance the efficacy of tumour therapy.

Current Reality of Treating Advanced Soft Tissue Sarcoma as Illustrated by Case Studies

In the first-line setting of advanced soft tissue sarcomas (STS), the treatment aim generally drives decision-making. Anthracycline combinations with ifosfamide or dacarbazine are more appropriate when the aim is tumour shrinkage, and doxorubicin monotherapy is suitable for tumour control. In patients who progress on anthracycline-based regimens, scope exists for tumour shrinkage with trabectedin and concurrent low-dose radiotherapy. Selecting systemic treatment for patients with advanced STS unsuited to receive standard anthracycline-based therapy often involves complex decision-making as clinical trial evidence comparing alternative options is lacking. Key factors to consider are patient characteristics (e.g., age, medical history, performance status), disease characteristics (e.g., stage, histology), and treatment requirements such as the drug’s safety profile, evidence of efficacy by subtype, and approved indication as an alternative first-line treatment option. Real-world data for elderly STS patients derived from retrospective studies and post hoc analyses of clinical trials have particular value in guiding treatment selection and improving the management of this populous but undertreated segment of the STS population.

Real-world outcomes of patients with intrahepatic cholangiocarcinoma treated with trans-arterial radioembolization: Results from the CIRSE Registry for SIR-Spheres Therapy (CIRT), a large European prospective multi-center observational study.

308 Background: Trans-arterial radioembolization (TARE) is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). The CIRSE Registry for SIR-Spheres Therapy (CIRT) is the first European prospective multi-centre observational study designed to evaluate the clinical outcomes of patients treated with TARE with SIR-Spheres Y90 resin microspheres for ICC in the multi-institutional real-life clinical setting. The study was conducted by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE). Methods: Patients were enrolled prospectively between Jan 2015 and 31 Dec 2017. Eligible patients were adults treated with TARE with Y90 resin microspheres for ICC. Data on baseline characteristics and treatment intention/clinical context and dosimetry were collected, as well as follow-up data (every 3 months; for 24 months after treatment), including overall survival (OS), (hepatic) progression-free survival [(h)PFS], safety and Global Health Status (GHS, using the European Organisation for the Research and Treatment of Cancer QLQ-C30). Results: 120 patients were included from 18 sites in 8 European countries. Median age was 63 years (range: 29-86) and 54.2% were male. Median tumour to liver percentage was 12.8%. Median prescribed activity was 1.32 GBq for whole liver treatments (n = 49), 1.20 GBq for right lobe treatments (n = 56) and 0.82 GBq for left lobe treatments (n = 51). 97.5% of the delivered activity was within 90% of the prescribed activity. TARE treatment as a first line (L1) global strategy was applied in 39.1%, 27.4% as second line (after systemic therapy). Treatment intention was predominantly palliative (69.2%) or tumour shrinkage (20.8%). Median OS was 14.7 months (95% confidence interval (CI) 10.9 – 17.9). Median PFS was 5.7 months (95% CI 3.9 – 7.5), whereas hPFS was 6.2 months (95% CI 4.1 – 8.5). Mean GHS was 59.3 at baseline, 61.0 after 3 months, 56.0 at 6 months, 54.4 at 9 months and 63.0 after 1 year. Severe adverse events (grade 3 and 4) were found in 13 (10.8%) patients: (abdominal pain 3.3%, fatigue 1.7%, gastrointestinal ulceration 0.8%, gastritis 0.8%, radiation cholecystitis 0.8%, radiation-induced liver disease 1.7%, other 5.8%). Detailed subgroup analyses are currently being performed. Updated data describing OS, PFS and hPFS for L1 TARE vs TARE after systemic chemotherapy, as well as prognostic factors for OS, PFS and hPFS will be shown. Conclusions: The results from this large prospective multi-centre observational study shows that in the real-world context, TARE is applied early and successfully in the treatment pathway. TARE is shown to be an effective and safe treatment with no meaningful deterioration of quality of life. Clinical trial information: NCT02305459.

Analysis of the anticancer effect of endostatin on oral squamous cell carcinoma based on results of experimental studies

При плоскоклеточном раке полости рта основной причиной летальных исходов является метастазирование в регионарные лимфатические узлы. Злокачественный рост и формирование метастазов напрямую зависят от степени кровоснабжения первичного очага новообразования. Известно, что по мере прогрессирования опухолевый процесс сопровождается нарушением сбалансированной в норме системы регуляции ангиогенеза с превалированием уровня ангиогенных стимуляторов над ингибиторами. В связи с этим, использование антиангиогенных средств является патофизиологически обоснованным методом борьбы со злокачественным ростом. В обзоре обсуждаются данные доклинических исследований участия эндостатина, природного ингибитора ангиогенеза, в процессах подавления прогрессии и метастазирования плоскоклеточного рака челюстно-лицевой области. Проанализированы патогенетические механизмы ингибирования эндостатином опухолевого роста в экспериментальных моделях рака полости рта. Эндостатин можно рассматривать в качестве потенциального противоопухолевого средства для лечения данной нозологии. The main reason for cancer-associated mortality in patients with oral squamous cell carcinoma is metastatic spread to regional lymph nodes. It is known that the processes of malignant growth and metastasis are highly dependent on blood supply to the primary cancerous focus. The development of malignancy is accompanied by failure of the normally well-balanced system of angiogenesis regulation with prevalence of proangiogenic factors over inhibitors. Therefore, the use of angiogenic inhibitors is a pathophysiologically justified method aimed at suppression of cancer progression. This review presents reports of experimental studies on the role of endostatin, a natural inhibitor of angiogenesis, in processes of tumour shrinkage in squamous cell carcinoma of the maxillofacial region. The authors analysed pathogenic mechanisms of the anticancer effects exhibited by endostatin in preclinical models of oral malignancy. Endostatin can be regarded as a potential antitumor agent for the treatment of oral squamous cell carcinoma.

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27–0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32–0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32–0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28–0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

Pegvisomant in combination or pegvisomant alone after failure of somatostatin analogs in acromegaly patients: an observational French ACROSTUDY cohort study

Objective After surgery, when somatostatin analogs (SAs) do not normalise IGF-I, pegvisomant (PEG) is indicated. Our aim was to define the medical reasons for the treatment of patients with PEG as monotherapy (M) or combined with SA, either as primary bitherapy, PB (PEG is secondarily introduced after SA) or as secondary bitherapy, SB (SAs secondarily introduced after PEG). Methods We retrospectively analysed French data from ACROSTUDY. Results 167, 88 and 57 patients were treated with M, PB or SB, respectively, during a median time of 80, 42 and 70 months. The median PEG dose was respectively 15, 10 and 20 mg. Before PEG, the mean IGF-I level did not differ between M and PB but the proportion of patients with suprasellar tumour extension was higher in PB group (67.5% vs. 44.4%, P = 0.022). SB regimen was used preferentially in patients with tumour increase and IGF-I level difficult to normalise under PEG. In both secondary regimens, the decrease of the frequency of PEG’s injections, compared to monotherapy was confirmed. However, the mean weekly dose of PEG between M and PB remained the same. Conclusions The medical rationale for continuing SAs rather than switching to PEG alone in patients who do not normalise IGF-I under SAs was a tumour concern with suprasellar extension and tumour shrinkage under SA. A potential explanation for introducing SA in association with PEG appears to be a tumour enlargement and difficulties to normalise IGF-I levels under PEG given alone. In both regimens, the prospect of lowering PEG injection frequency favoured the choice.

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

Objective: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3–4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. Methods: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity. 40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration) 30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution) The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. Results: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5–8 Gy when delivered in 2 Gy fractions. Conclusion: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. Advances in knowledge: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma

Background Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. Methods Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. Results Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. Conclusions CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.