ESMO Open

We evaluated the applicability of the scale and assessed the reasonableness of the generated scores in early breast cancer. Form 1 of the ESMO-MCBS v1.1 provided a generally robust tool for scoring of adjuvant breast cancer studies. Six shortcomings were identified including lack of information regarding acute and long-term toxicity, an inability to grade single arm de-escalation scales and limitations related to grading based on disease free survival (DFS). Read the paper on the ESMO Open website: http://dx.doi.org/10.1136/esmoopen-2020-000743

Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Form 1 provided very reasonable grading and expert field testers confirmed the reasonableness of generated scores. Exploratory toxicity evaluation and annotation was feasible but problematic given inconsistent toxicity reporting and limited results of late toxicity. Moreover, the experts identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. Future revisions of Form 1 of the ESMO-MCBS will be cognoscente of these findings. Read the paper on the ESMO Open website: http://dx.doi.org/10.1136/esmoopen-2020-000681

The therapeutic landscape in melanoma is evolving rapidly. In this podcast, Jonathan Lim (a member of the ESMO Young Oncologists Committee) interviews Dr Teresa Amaral (the current chair of the ESMO Young Oncologists Committee and an expert in melanoma) for an update on the current practice and advances in adjuvant and neoadjuvant therapies in melanoma. Dr Amaral summarises key practice-changing studies which have established the current recommendations in this field, including CheckMate 238, KEYNOTE 054, COMBI-AD, Combi-Neo, NeoCombi and opACIN-neo. We also deliberated on the toxicity profile of these therapies, and currently available evidence of neoadjuvant versus adjuvant therapies. Finally, we addressed how COVID-19 has affected the delivery of adjuvant and neoadjuvant therapies in patients with melanoma. Further reading: CheckMate 238 – https://doi.org/10.1056/NEJMoa1709030 KEYNOTE 054 – https://doi.org/10.1056/NEJMoa1802357 EORTC18071 – https://doi.org/10.1016/S1470-2045(15)70122-1 Mixture-Cure Modeling in CheckMate 238 – https://doi.org/10.1093/annonc/mdz255 COMBI-AD – https://doi.org/10.1056/NEJMoa1708539 Combi-Neo – https://doi.org/10.1016/S1470-2045(18)30015-9 NeoCombi – https://doi.org/10.1016/S1470-2045(19)30331-6 OpACIN-neo – https://doi.org/10.1016/S1470-2045(19)30151-2

The advent of cancer immunotherapy has radically changed the field of oncology by improving the way many malignancies, including several aggressive and orphan diseases, are being treated with subsequent major improvement of patients’ prognosis. The first crucial and successful step in the field was the development of agents able to inactivate inhibitory immune receptors resulting in a subsequent increased anti-tumor response. Among them, antibodies blocking CTLA-4 (ipilimumab) and PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab and durvalumab) are already widely available in clinical practice. More recently, to further improve the ability of the immune system to eradicate cancer cells, several other stimulatory or inhibitory molecules have been recognized as possible targets. ESMO Open has launched a special series of mini-reviews aiming to provide an update of the most interesting and upcoming targets in cancer immunotherapy including LAG3, TIM3, CD40, B7x, OX40, ICOS, VISTA, CD27, GITR and neoantigens. All these mini-reviews contain information on biological background (i.e. what the target is, where it is expressed and what is the physiological role as well as the expected effect when targeting it), drugs under development for targeting that specific molecule as well as current on-going clinical trials with targeted agents (including those in combination with other immune checkpoint inhibitors). In this podcast, Anna Berghof talks to Matteo Lambertini - Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy. Read the Abstract: https://esmoopen.bmj.com/content/4/Suppl_3/e000795

Anna Berghof talks to Matteo Lambertini - Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy. The year 2019 has brought relevant new biological and clinical evidence to further improve the care of breast cancer patients. Regarding biological knowledge, in addition to the many important steps forward in enhancing the understanding of several aspects related to tumor biology and treatment resistance, more predictive biomarkers have entered clinical use. In addition to knowing the status of hormone receptors and HER2, other biomarkers should now be tested in different disease subtypes and clinical situations including PD-L1, PIK3CA mutations and germline BRCA mutations. The clinical management of breast cancer patients has also significantly changed. Important evidence has become available to further personalize the choices of the best chemotherapy, endocrine treatment and targeted therapy approaches in both the advanced and early settings. Importantly, for patients with advanced breast cancer including those treated in the first-line setting, overall survival improvements have finally been observed in all disease subtypes thanks to the availability of more effective targeted agents. Many upcoming translational and clinical data are expected in 2020 with a great promise of further changing clinical practice in the breast cancer field. This is the case also for the triple-negative subtype where more effective and targeted treatment options beyond chemotherapy are expected to enter clinical use and improve patients’ outcomes and quality of life. Read the Abstract on the ESMO Open website: https://esmoopen.bmj.com/content/5/3/e000794

The Covid-19 pandemic is currently active all over Europe and especially in Italy. In this podcast Anna Berghof discusses with Matteo Lambertini - Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy - the difficulties of cancer treatment during this pandemic. Read the editorial: https://esmoopen.bmj.com/content/5/2/e000759

Advanced cholangiocarcinoma is associated with a particular impaired survival prognosis. So far targeted therapies with relevant clinical efficacy are missing. isocitrate dehydrogenase 1 (IDH1) mutations are observed in a fraction of patients with cholangiocarcinoma. The ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib ersus placebo in patients with advanced cholangiocarcinoma with an IDH1 mutation met its primary endpoint. Therefore, ivosidenib is a promising new treatment opportunity in patients with Advanced cholangiocarcinoma harboring an IDH1 mutation. Read the Abstract: https://esmoopen.bmj.com/content/5/2/e000699

Glioblastoma is the most frequent primary malignant brain tumor in adults. Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promotor is of prognostic as well as of predictive value, as patients with MGMT promotor methylation survive longer and have better responses to the alkylating chemotherapeutic agent temozolomid. The current first line therapy approaches after maximum safe resection include radio-chemotherapy with temozolomid, radio-chemotherapy with the combination of temozolomid and CCNU as well as tumor treating fields. Currently several early clinical studies investigate new treatment possibilists in glioblastoma. Listen to the podcast with Professor Ulrich Herrlinger, Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology, University Hospital Bonn, Germany. Read the Abstract: https://esmoopen.bmj.com/content/5/1/e000601

There has been a lot of exciting trials in lung cancer reported in 2019. In this podcast, Jonathan Lim (YOC member) speaks to Professor Sanjay Popat about how these studies are practice-changing in the context of the current treatment landscape, and highlights what is on the horizon for 2020 (including targeting KRAS). Read the Abstract: https://esmoopen.bmj.com/content/5/1/e000676

Immunotherapy approaches have revolutionized medical oncology in the last years. However, still only a fraction of patients is responding. Given the risk of side effects without efficacy, therefore, biomarkers providing reliable and reproducible prediction of response are urgently needed. In this podcast, next generation biomarkers including the challenge of branched genomic evolution of cancer are discussed by Professor Samra Turajlic, The Royal Marsden Hospital, London, UK.

Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. The phase III trial Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA) showed a significant increase in progression free survival. In the now available finale survival analysis also the overall survival showed a statistical significant increase. Expert: Suresh S. Ramalingam, Winship Cancer Institute of Emory University, Atlanta, GA

The present podcast gives a short summary of the PAOLA-1 trial investigating the addition of Olaparib to bevacizumab as maintenance therapy in patients with newly diagnosed, advanced ovarian cancer treated with platinum-based chemotherapy plus bevacizumab. Expert: Isabelle L. Ray-Coquard Affiliation: Centre Leon Bèrard, Université Claude Bernard Lyon, Groupe d'Investigateurs Nationaux pour l'Étude des Cancers de l'Ovaire (GINECO), Lyon, France

In this podcast, Marina Parry, ESMO Open Digital Editor, speaks to Amanda Herbrand, Medical Oncologist Trainee working at University Hospital Basel, Switzerland, about her team’s work on off-label use (OLU) of Drug Treatments in Cancer Care, presented at ESMO Congress 2019 and a preprint of which is available on medRxiv: https://www.medrxiv.org/content/10.1101/19003152v1 With new drug treatments for cancer patients constantly being investigated in clinical trials, ensuring access to the ones which prove to be effective in improving patient care is critical. These drugs are initially assessed by medical authorities for their efficacy and cost effectiveness, which means it can take time before they are approved. However, physicians will sometimes wish to use therapies which have been shown to be effective in clinical trials but without specific approval in the disease setting they are treating. This leads to off-label use (OLU) of cancer therapies, which, depending on the healthcare system, is not covered by patients’ health insurance. Dr Herbrand and her team set out to understand what the reasons were behind insurers’ acceptance or denial of payment for OLU of drug treatments for cancer patients within the Swiss healthcare system. They investigated the relationship between reimbursement decisions and the underlying clinical evidence by extracting patient characteristics and treatment and reimbursement details of cancer drugs from over 3,000 patients in 3 Swiss hospitals, and created an evidence overview of the requested OLU indications. Their study provides a systematic assessment of OLU and its reimbursement reality in Switzerland. This may provide a better understanding of the access to cancer care that is regulated by health insurers and identify factors that determine the level of evidence-based cancer care in a highly diverse Western healthcare system. Further work will be undertaken as a follow up to this study. These data are preliminary and further work will be undertaken as a follow up to this study.

Despite all the efforts done so far, access to essential drugs in Oncology is still asymmetric. In this podcast, Teresa Amaral, member of the ESMO YOC, interviews Professor Martine Piccart (Scientific Director of the Institut Jules Bordet, Universite Libre de Bruxelles, Belgium) that shares valuable insights on the work that has been done on this field by the ESMO Magnitude of Clinical Benefit Scale (ESMO – MCBS) group. You can find more information about the ESMO-MCBS group in the following publications: https://doi.org/10.1093/annonc/mdv249 http://dx.doi.org/10.1136/esmoopen-2017-000216 More information on the ESMO Magnitude of Clinical Benefit Scale: Scale Evaluation Forms v1.0 & v1.1 can be found here: https://www.esmo.org/Guidelines/ESMO-MCBS/Scale-Evaluation-Forms-v1.0-v1.1 You can read the complete Abstract relating to this podcast on the ESMO Open website: https://esmoopen.bmj.com/content/4/5/e000594.

Professor Kim Margolin (Department of Medical Oncology, City of Hope National Medical Center, Duarte, California) discusses in this podcast the different treatment strategies as well as the clinical challenge of handling melanoma patients with brain metastases. Brain metastases are a particular problem of melanoma patients, as this complication occurs early and frequently. Further, brain metastases are associated with a high symptom burden. Recently, systemic treatment approaches including immunotherapy and tyrosine kinase inhibitors have become increasingly important in the management of melanoma brain metastases patients. Indeed, some patients with small, asymptomatic brain metastases without edema and need for steroid treatment might be candidates for a primarily systemic treatment. https://esmoopen.bmj.com/content/4/5/e000579

The IMpassion130 trial was a global, randomized, double-blind, Phase III study of Atezolizumab + nab-paclitaxel vs. placebo + nab-paclitaxel in treatment naïve locally advanced or metastatic triple negative breast cancer patients. Here, progression free survival was statistically significantly longer in patients treated with the combination of Atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel. The side effect profile was favorable as no unexpected toxicities were observed in the intervention compared to the control arm. In this podcast, Prof. Schmid provides insight on the response rate as well as the preliminary survival analysis of IMpassion130. Further possible biomarkers and the impact of the results on the treatment standard in breast cancer are discussed. Read the full Abstract on the ESMO Open website: https://esmoopen.bmj.com.

Radiotherapy to the primary tumor has been a controversially discussed intervention in patients with newly diagnosed metastatic prostate cancer. Results of the STAMPEDE trial indicate that overall no survival advantage can be achieved by the addition of radiotherapy however subgroups might actually have a benefit. Here, patients with low volume, oligometastatic disease were shown to benefit in a predefined subgroup analysis. In this podcast, Dr. Parker provides insight on the practice changing impact of the STAMPE trial and gives an outlook what is next on the horizon in metastatic prostate cancer therapy. Read the full Abstract on the ESMO Open website: https://esmoopen.bmj.com/

In this podcast, Marina Parry, ESMO Open Digital Editor, speaks to Elana Anastasio, Partnership Outreach Manager, and Brett Tomson, Scientific Outreach Manager, both from the Metastatic Breast Cancer (MBC) Project team at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, USA. The MBCproject is a novel model of a patient-partnered initiative whose aim is to accelerate the understanding of metastatic breast cancer by generating a massive open database of genomic information from patients’ tumour samples, alongside abstracted clinical information, and patient-reported data. In the podcast, we discuss the challenges faced by the team, the enthusiasm they were met with from patients, the logistical and operational hurdles they have overcome, the importance of finding a common language and building trust between participants and researchers, the role of social media and patient advocates, as well as the other patient-partnered projects this team has since initiated. The MBCproject organisers want to hear back from scientists and researchers about ideas or questions they have on how to use the existing data or new data you think would be good to try and generate. They encourage listeners to get in touch! Their website is https://www.mbcproject.org.

Biosimilars will soon become broadly available in the oncology field, raising important questions from both patients and healthcare providers. These questions need to be clarified upfront, in order to increase confidence in using these therapies. In this podcast, Teresa Amaral (YOC member) talks to Professor Josep Tabernero (ESMO President and Director of the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona about this timely topic – Biosimilars in Oncology. Read the full Abstract on the ESMO Open website: https://esmoopen.bmj.com/content/3/6/e000456

In this podcast, Marina Parry, ESMO Open Digital Editor, speaks to Nicholas McGranahan, Junior Group Leader of the Cancer Genome Evolution Group at University College London’s Cancer Institute about the role of bioinformatics in translating genomics research into the clinic and his most recent paper “Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution”, Cell, 2017 https://www.cell.com/cell/pdf/S0092-8674(17)31185-6.pdf. Read the full Abstract on the ESMO Open website.

Several phase III trials on immune checkpoint inhibitor therapy in non-small cell lung cancer were recently published and changed the clinical practice Here, non-small cell lung cancer has to be categorized first according to the presence of activating mutations and second according to the programmed cell death ligand 1 (PDL1) expression. Approximately 25% of patients present with a driver mutation and should be treated with tyrosine kinase inhibitors as the first line treatment strategy for metastatic non-small cell lung cancer. Approximately 75% of patients do not present with a driver mutation and should be treated according to the presence of PDL1 expression. Patients with high PDL1 (≥ 50% of tumor cells) expression are candidates for immune checkpoint inhibitor monotherapy, although a combination with chemotherapy can be suggested in patients with high tumor load and fast progressing disease. Patients with intermediate (1-49% of tumor cells) PDL1 expression are on the other hand candidates for the combination of chemotherapy with immune checkpoint inhibitor therapy according to the recently published data. Further, combination of immune checkpoint inhibitor-based therapy with chemotherapy and bevacizumab could be an option in patients with a driver mutation after the failure of available tyrosine kinase inhibitors. Listen to the podcast with Professor Johan Vansteenkiste, MD (Respiratory Oncology Unit and Trial Unit; Department of Respiratory Diseases University Hospitals KU Leuven; Catholic University Leuven, Belgium) and read the full Abstract on the ESMO Open website.

Epigenetic biomarkers are emerging across tumor types in cancer research. Aberrant DNA methylation in tumors results in silencing of distinct genes. This modification is very stable and therefore can reliably be assessed and used as a diagnostic but also prognostic biomarker. Recently, DNA methylation was validated as an additional diagnostic biomarker in brain tumors. Here, the methylation profile allowed precise clinical diagnosis associated with the survival prognosis. Therefore, the addition of DNA methylation profiles to routine diagnostic assessment in cancer diagnosis might be promising to ensure accurate diagnosis and support treatment decisions. Further, predictive epigenetic biomarkers were identified as MGMT methylation was repeatably shown to associate with response to alkylating chemotherapy. Several current research efforts are concentrating on the identification of new diagnostic as well as predictive biomarkers in various types of cancer. This podcast with Professor Gerda Egger (Department of Pathology, Medical University of Vienna and Ludwig Boltzmann Institute Applied Diagnostics) provides an overview of the current routinely used biomarkers as well as an outlook on what is on the horizon in epigenetic biomarkers. Read the Abstract on the ESMo Open website: https://esmoopen.bmj.com/content/3/5/e000416.

Immunotherapy has been approved for several indications in Oncology, resulting in an increasing number of physicians that use it to treat their patients. In this podcast, Teresa Amaral, member of the ESMO YOC, interviews Professor John Haanen (Head of the Division of Medical Oncology and Staff Scientist in the Division of Immunology; Professor of Translational Immunotherapy of Cancer at Leiden University Medical Centre, the Netherlands) on the topic: “Questions asked in everyday practice: Immune Checkpoint Inhibitors”. Currently, there is no consensus about how long should we treat patients with immunotherapy and the optimal duration might also be different considering the tumor type (e.g. melanoma, NSCLC). In some patients, stopping early due to adverse events doesn’t seem to be detrimental, but the follow-up time is still short to make definitive assumptions. When treating a patient with a previous autoimmune disease, several aspects need to be considered, namely, which type of immunosuppression is the patient receiving now, in which dosage and how long has the autoimmune disease been stable. Patients that received a solid organ transplant pose an extra challenge. For patients that develop grade 4 autoimmune adverse events, re-treatment with immunotherapy should be extensively discussed. In case of severe autoimmune toxicity that does not respond to the treatments referred in the guidelines, and if the treating physician is not experienced with escalating immunosuppressive therapy, consultation with other centers with more familiarity and expertise on this topic should be considered. Read the abstract on the ESMO Open website: http://dx.doi.org/10.1136/esmoopen-2018-000395.

Although highly successful in other entities, immune checkpoint inhibition has so far only shown limited efficacy in an unselected population of colorectal cancer patients. The particular composition of the inflammatory microenvironment of colorectal cancer, characterized by a low density of tumor-infiltrating-lymphocytes and no PDL1 expression on the tumor cells, might explain this resistance. Indeed, colorectal cancer with microsatellite instability responds much better to immune checkpoint inhibitors and present with a much higher infiltration with T-cells. Dense infiltration with tumor-associated macrophages at the invasion margin is a further characteristic of the inflammatory microenvironment in colorectal cancer potentially causing the limited response to immune checkpoint inhibitors. Interestingly, PDL1 expression can be frequently observed on these tumor-associated macrophages at the invasion margin, which potentially reduce the infiltration with T cells. Interfering with this population of myeloid cells is a possible new immune modulating treatment approach, although more insight on the exact underlying mechanisms causing tumor supportive or suppressive behavior of the myeloid cells is needed. Here, therapeutic approaches combining immune checkpoint inhibitor modulating the T cells function and specific modulators of the tumor-associated macrophages might be successful and should be investigated in future clinical trials. Listen to the podcast with Professor Niels Halama, MD (Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany) and read the Abstract on the ESMO Open website: https://esmoopen.bmj.com/content/3/5/e000426.

Colorectal cancer has a strong interaction with the immune system as underlined by the high prognostic impact of tumor infiltrating lymphocytes in the tumor core as well as the infiltration margin in the localized setting. However in the metastatic scenario the vast majority of these tumors - the 95% lacking deficiencies in the missmatch repair sustem- demonstrated to be immune-elusive. The new therapeutic bispecific anti-CEA anti CD3 antidobody CEA-TCB is therefore a new, promising immune modulating therapy currently evaluated in clinical studies in colorectal cancer. The CEA-TCB has a 2-to-1 binding ratio, with one domain of the antibody binding directly to CD3 on T cells while the remaining two binding domains simultaneously bind to CEA molecules on the tumor cells. The CEA-TCB induces T-cell­ engagement and activation, with T-cell proliferation at the site of activation. Two phase 1 trials with CEA-TCB have been presented this year, one as a single-drug trial, the other in combination with the PD-L1 inhibitor Azetolizumab, with promising results. The two studies are debated regarding inclusion, results and toxicity. Finally, the future of CEA-TCB and its impact on Colorectal Cancer treatment are discussed in this podcast. The interview to Guillem Argilés (Gastrointestinal Malignancies Program, Vall d’Hebron University Hospital, Barcelona, Spain) is conducted by the ESMO Open Editor of multimedia and social media Laurids Poulsen. Read the abstract on the ESMO Open website: http://dx.doi.org/10.1136/esmoopen-2018-000377.

In the last decade, we have seen a significant change in the therapeutic landscape for advanced melanoma. Recently, results from two trials evaluating immunotherapy and targeted therapy in the adjuvant setting (completely resected stage III/IV) were published. In this podcast, Teresa Amaral, member of the ESMO YOC, talks with Professor Jeffrey Weber, Professor of Oncology and Deputy Director of the Laura and Isaac Perlmutter Cancer Center, about the recent developments in adjuvant therapies for patients with melanoma. Professor Weber also gives some insight on this data's impact on the treatment of real-world patients. Currently, there is enough evidence to support adjuvant treatment in patients with resected Stage IIIB/C-IV melanoma. As for Stage II patients, this option should be considered in some selected cases (e.g. T ≥ 4mm with the presence of ulceration). In both of the above-mentioned trials, patients were treated for a maximum of 12 months. Although a shorter treatment duration (e.g. 6 months) might result in the same benefit, it is unclear that a trial comparing 12 months to 6 months of therapy will be conducted to show equivalence, since it would be a very large trial requiring prolonged follow-up. So, for now, 12 months of adjuvant therapy is the standard. It is difficult to compare the results from both trials in patients with BRAF mutated melanoma since the populations treated were different but overlapping. Nonetheless, both therapies showed good results in the population of BRAF mutated stage III patients. What is clearly different is the safety profile and type of administration. Choosing one treatment over the other must also consider patient and physicians’ preferences. For patients that have a recurrence while receiving adjuvant therapy, changing from targeted therapy to immunotherapy and vice versa is probably the best approach." You can hear the full interview also on the ESMO Open homepage: http://esmoopen.bmj.com/. The related papers here: http://www.nejm.org/doi/full/10.1056/NEJMoa1708539 and http://www.nejm.org/doi/full/10.1056/NEJMoa1708539 http://www.nejm.org/doi/full/10.1056/NEJMoa1709030.

In this podcast, Editor Anna Berghoff speaks to Professor Eric Tartour (Department of Immunology; Hôpital Européen Georges Pompidou) about new therapeutic targets in the inflammatory microenvironment. The introduction of immune checkpoint inhibitors introduced a new era of oncology. The CTLA4 or PD1/PDL1 axis targeting immune checkpoint inhibitors have shown remarkable and long lasting responses in a variety of tumor types, Here, the biology of immune checkpoint inhibitors is outlined including the main site of action for the different immune checkpoint inhibitor types. Further, other possible immune checkpoints like LAG3 and other cells types including macrophages and NK cells as future directions for immune modulating therapies are discussed. Combination approaches including immune checkpoint inhibitors and chemotherapy or radiotherapy are currently investigated for their synergistic efficacy and preliminary data has shown promising results. Read the Abstract on the ESMO Open website: http://esmoopen.bmj.com/content/3/1/e000310.

Immune Checkpoint inhibitors have become an important treatment option in patients with metastatic lung cancer. This podcast gives an overview on the current evidence of immune checkpoint inhibitors in patients with non-small cell lung cancer. Based on the phase III data, patients with PDL1 expression >50% are candidates for 1st line pembrolizumab if there are no contraindications. Currently, PDL1 expression as assessed by immunohistochemistry is the most validated biomarker although other biomarkers including mutational load, neo-antigen presence or tumor infiltrating lymphocytes are currently under investigation. Importantly, the side effect profile of immune checkpoint inhibitors does not differ in lung cancer patients. Studies are currently investigating the value of immune checkpoint inhibitors for patients with small cell lung cancer. Several currently on-going studies are investigating the combination of chemo-/radiotherapy and immune checkpoint inhibitors in patients with lung cancer. Read the abstract on the ESMO Open website: http://esmoopen.bmj.com/content/3/1/e000311.

Several alumni of the European Society for Medical Oncology (ESMO) Leaders Generation Programme introduce the scope, aims and goals of the program. The ESMO Leaders Generation Programme was designed to shape the future of the oncology profession as well as the future of ESMO. This exciting and intensive course has been specifically created for young oncologists to provide them a specific training needed for future leadership. Covered topics include ESMO and the world of oncology as well as the development of personal skills especially in the areas of communication, leadership and career development. All qualified medical or clinical oncologists working in Europe who are ESMO members and aged between 31 and 45 years are invited to apply for the program. The course is divided into two parts and provides a variety of interactive training as well as mentoring by experts in the field of oncology. Applications can be filled out on the ESMO homepage. The alumni give detailed insights on their most valuable ESMO Leaders Generation Programme experience and encourage applying to the program. Participants in this podcast conducted by Editor Anna Berghoff: - Guillem Argiles and Leticia De Mattos Arruda (Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology , Barcelona , Spain); - Carmen Criscitiello (Division of Early Drug Development, European Institute of Oncology, Milano, Italy); - Matteo Lambertini (Department of Medicine, Institut Jules Bordet and Université Libre de Bruxelles (ULB), Brussels, Belgium). Read the Abstract on the ESMO Open website: http://esmoopen.bmj.com/content/3/1/e000312.

Professor Marco Merlano, Oncology Department Santa Croce e Carle, General Hospital, Italy, is the leading author of the ESMO Open article ‘Heterogeneity of colon cancer: from bench to bedside’, summarised in this podcast. Abstract The large bowel shows biomolecular, anatomical and bacterial changes that proceed from the proximal to the distal tract. These changes account for the different behaviour of colon cancers arising from the diverse sides of the colon–rectum as well as for the sensitivity to the therapy, including immunotherapy. The gut microbiota plays an important role in the modulation of the immune response and differs between the right colon cancer and the left colorectal cancer. The qualitative and quantitative difference of the commensal bacteria between the right side and the left side induces epigenetic changes in the intestinal epithelial cells as well as in the resident immune population. The second player in the pathological homeostasis of colorectal cancer is the differences of the genetic features of cancer cells and the different effects that microsatellite instability, chromosomal instability and the CpG island methylator phenotype induce on the immunological organisation of the tumour microenvironment. The third player is the immunological composition of the tumour microenvironment, which changes under the influence of both genetic structures and gut microbiota. All these three players influence each other. This review describes these three aspects, highlights their interactions and discusses data from reported clinical trials. Read the full article on the ESMO Open website: http://esmoopen.bmj.com/content/2/3/e000218.

In this podcast new, practice-changing research in gastrointestinal (GI) cancer is considered. Clinical trials focusing on immunotherapies presented at the recent ASCO Gastrointestinal Cancers Symposium in San Francisco are discussed. Highlights include reports of the ONO-4538 study, in which pretreated gastric cancer patients were randomized to receive either nivolumab or best supportive care, and of the CheckMate 040 study in which pretreated patients with hepatocellular carcinoma received nivolumab. Nivolumab is also assessed in the CheckMate 142 which considered patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer. Other new treatment options and combinations with immunotherapy are briefly considered, but the author suggests that it is too early to draw conclusions from these preliminary data. Emergent side effects from immunotherapy trials in GI cancer are also discussed. In closing the author considers developments in immunotherapy of GI cancers in the adjuvant setting but notes that trial results are still awaited. These highlights are presented by Professor Gerald Prager, Medizinische Universitat Wien, Department of Medicine, Vienna, Austria (gerald.prager@gmx.eu) and the interview is conducted by Anna Berghoff, Medical University of Vienna. http://esmoopen.bmj.com/ Read the abstract on the ESMO Open website: http://esmoopen.bmj.com/content/2/3/e000228.

Elżbieta Senkus, Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdańsk, Poland, (elsenkus@gumed.edu.pl) presents an overview of new therapies on the horizon for breast cancer in terms of data presented at the ESMO Congress, ASCO, and the San Antonio Breast Cancer Symposium. In the adjuvant setting, results from the MINDACT trial, which evaluated genomic versus clinical assessment for risk stratification, are described. Data on the role of anthracyclines in adjuvant chemotherapy is also discussed. In HER2-positive patients, dual HER2-targeted therapy was investigated in the KRISTINE study, and studies on the duration of adjuvant endocrine therapy in advanced breast cancer are also considered. Other ongoing studies in this population and the luminal population are also briefly mentioned. In the metastatic setting, the PALOMA-2 and MONALEESA-2 studies assessed the addition of CDK4/6 inhibitors to standard treatments. Results of the MONARCH 1 trial, evaluating a CDK4/6 inhibitor as a single agent, are also described, along with data on endocrine therapy in the luminal setting. Recent data on drugs interacting with the mTOR/PI3K/AKT pathway are considered. Studies in advanced HER-2 positive patients, considering HER-2 duel blockade plus either chemotherapy or endocrine therapy, are discussed. The situation in triple-negative breast cancer and advances and future directions in precision medicine and immunotherapy in breast cancer are briefly discussed. Read the abstract on the ESMO Open website: http://esmoopen.bmj.com/content/2/2/e000204.

In this podcast a new biological insight in brain tumors is discussed by Frank Winkler, DKFZ, CCU Neurooncology, Heidelberg, Germany (f.winkler@dkfz.de). The author’s group has identified the existence of a tumor cell network in incurable gliomas which facilitates multicellular communication and exchange of small molecules between single tumor cells. The tumor cells that are integrated in this network, around 50% of cells according to studies in mouse models and patient samples, appear to be protected from the effects of radiotherapy and possibly also chemotherapy, which may explain how such tumors develop resistance to therapies and why patients relapse after treatment. An overview of ideas that are being investigated preclinically to therapeutically target this network of tumor cells is given. These include approaches to disrupt the network, such as obstructing cellular communication with gap junction blockers and targeting the neurodevelopmental pathways required to form the networks. Conversely, methods to exploit the network through the local application of gap-permeable drugs which specifically target the integrated tumor cells could also be studied. This new discovery may result in the development of therapeutic strategies which the author hopes will reach the clinic in the next few years. Visit the ESMO Open website: http://esmoopen.bmj.com/content/1/6/e000133.

A critical review of the highlights in breast cancer research from the American Society of Clinical Oncology (ASCO) meeting 2016, held in June 2016 in Chicago, is presented in this podcast by Fatima Cardoso, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal (fatimacardoso@fundacaochampalimaud.pt). Considering the most interesting and practice-changing studies reported at the meeting, in the advanced breast cancer setting several important confirmatory studies on the use of CDK inhibitors, and studies on using data on estrogen receptor mutations to guide choices of endocrine therapy are discussed. The PHEREXA trial, in which a combination trastuzumab and pertuzumab was studied in the advanced setting is also considered. In the early breast cancer setting, the KRISTINE and ADAPT studies evaluated the potential of dual blockade in HER2-positive tumors. In HER2-negative early breast cancer several trials are also discussed with respect to types of adjuvant chemotherapy. The results of the MA.17R trial, which considered extending the duration of adjuvant endocrine therapy, are also discussed. The potential role of immunotherapy in breast cancer therapy is briefly mentioned. The podcast is conducted by Anna Berghoff, Medical University of Vienna, Austria.

These highlights are presented by Marco Merlano, Department of Medical Oncology, Santa Croce General Hospital, Cuneo, Italy,(mcmerlano@gmail.com). A critical review of the head and neck cancer research highlights of the American Society of Clinical Oncology (ASCO) meeting 2016, held in June 2016 in Chicago, is presented in this podcast. Considering the most interesting and practice-changing trials reported at the meeting, the key trial comparing gemcitabine plus cisplatin against 5-FU plus cisplatin in the treatment of nasopharyngeal carcinoma is highlighted. The GORTEC2007-02 trial comparing induction docetaxel/platinum/ 5-FU followed by cetuximab-radiotherapy against concurrent chemo-radiotherapy for N2b/c-N3 non operated stage III-IV squamous cell cancer of the head and neck is also discussed. An overview of the research reported using immunotherapy in head and neck cancer is also given, considering maturing data and particularly in relapsing patients, where response rates, though low, are better than with current therapies, and the responses are long lasting. Future developments are also considered, again with a focus on immunotherapy, but also considering combination with radiotherapy and chemoradiation. The podcast is conducted by Anna Berghoff, Medical University of Vienna Vienna, Austria, and is also available on the ESMO Open website: http://esmoopen.bmj.com/content/1/5/e000099.

The highlights are presented by Rolf A. Stahel, Universitätsspital Zürich, Onkologie, Zürich, Switzerland (rolf.stahel@usz.ch). A critical review of the highlights of the European Lung Cancer Conference (ELCC) 2016, held in April 2016 in Geneva, is presented in this podcast. Considering the most interesting and practice-changing trials reported at the meeting, the key trial on the use of osimertinib in patients with non-small cell lung cancer (NSCLC) with EGFR harbouring the T790M mutation who had progressed on first line tyrosine-kinase inhibitors (TKIs) was highlighted. The meeting also featured interesting studies on testing for the T790M mutation and highlighted the potential of liquid biopsies. Two areas of potentially valuable biomarker development were stressed: biomarkers in oncogenic-driven NSCLC, and, more controversially, immunotherapy-related biomarkers. New treatment strategies were highlighted by the presentation of the Heine H. Hansen Award to Professor Suresh Senan (Amsterdam) whose work on stereotactic radiotherapy of lung cancer has led to significant changes in practice. Further, immunotherapy of lung cancer, through the use of immune-checkpoint inhibitors is already in clinical practice, and the results of ongoing trials considering whether immunotherapy can replace chemotherapy in these settings are now eagerly waited. The podcast is conducted by Anna Berghoff, Medical University of Vienna Vienna, Austria.

These highlights are presented by Emile Voest, The Netherlands Cancer Institute - Molecular Oncology, Amsterdam, Netherlands (e.voest@nki.nl). The author reviews the recently published article “Facilitating a Culture of Responsible and Effective Sharing of Cancer Genome Data” (Nat Med. 2016 May 5;22(5):464-71 - http://goo.gl/O3DRMf.) considering why data sharing is important and explaining the obstacles and problems involved. The need to identify common bioinformatics pipelines and resolve outstanding legal, ethical and technical issues are highlighted. Particular attention is given to emerging issues around informed consent and the handling of electronic patient records. There is a real need to address all these issues now on multiple levels in order to fulfil the promise of personalised medicine. The author further considers the work of the Global Alliance for Genomics and Health across cancer, rare diseases and in the emerging field of infectious diseases genomics. Finally, the potential impact of cancer genomic data on clinical practice is considered and the enormous potential for it to inform good decision making is underscored. The podcast is conducted by Anna Berghoff, Medical University of Vienna Vienna, Austria. Visit the ESMO Open website: http://esmoopen.bmj.com/.

A critical review of the highlights of the ESMO Symposium on Signalling Pathways in Cancer 2016, held March 2016 in partnership with the European Association of Cancer Research, is presented in this podcast. The meeting addressed developments in personalized medicine associated with the HER/EGFR family. Key subjects discussed were the bases of the mechanisms of signal transduction and primary and secondary resistance to EGFR-inhibiting drugs, and the emergence of better characterized subtypes of common tumors such as colorectal cancer, breast cancer, lung cancer and gastric cancer, and new utilities to effect these characterizations. Findings to consider include the increasing importance of tumor heterogeneity; the understanding that not all cells in a tumor have the same mutation may help develop new kinase inhibitors and new strategies. Further, data suggest that maintaining inhibition of the signaling process, even in the face of secondary resistance, can prolong clinical benefit. There is a need to develop new compounds that either bind more effectively to known EGFR mutations, or which can bind to newly identified mutations. The potential of both vertical and horizontal inhibition to achieve synergistic effects and so prolong tumor control was stressed. The highlights are presented by Josep Tabernero, of the Vall d'Hebron Institute of Oncology - Medical Oncology, Barcelona, Spain (jtabernero@vhio.net). This podcast is conducted by Anna Berghoff, Department of Medicine, Medical University of Vienna, Austria.

A critical review of key studies from the ASCO 2016 Gastrointestinal Cancers Symposium, held January 2016, is presented in this podcast. A number of tumor areas, including gastric, esophageal and colorectal cancers, are considered with an emphasis on recent developments in immunotherapy. Studies reviewed include the CheckMate-032 trial, which assessed the activity of the anti-PD-1 antibody nivolumab in patients with advanced gastric or gastroesophageal junction cancer, the KEYNOTE-028 trial, for which results of the esophageal carcinoma cohort treated with pembrolizumab were presented, and updated results of a trial considering PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers. Biomarkers are further considered in the Mavericc trial which sought to stratify metastatic colorectal cancer patients by ERCC1 in order to predict their response to platinum-based treatments. Neoadjuvant therapy was considered with the results of a study, from the Polish Colorectal Study Group, using neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancers, and the 5-year follow up results of the ACCORD 12 trial, which aimed to assess an increased radiation dose plus oxaliplatin versus standard radiotherapy of 45 Gy with concurrent capecitabine in rectal cancer. These highlights are presented by Gerald W. Prager, Medical University of Vienna, Austria (gerald.prager@meduniwien.ac.at). The podcast is conducted by Anna Berghoff, Department of Medicine, Medical University of Vienna, Austria.

A critical review on the practice changing studies presented at the San Antonio Breast Cancer Symposium, held December 2015, is presented in this podcast. A number of areas, including neoadjuvant and adjuvant treatment, treatment of metastatic disease and the emergence of new biomarkers are addressed. Trials discussed include the WSG-ADAPT HER2+/HR+ phase II trial, which assessed 12-weeks of neoadjuvant TDM1 with or without endocrine therapy vs. trastuzumab+endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer, the CREATE-X study, which assessed adjuvant capecitabine in patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy, and the TH3RESA study, which investigated trastuzumab emtansine use in patients with previously treated HER2-positive metastatic breast cancer. Further, studies on new promising biomarkers such as the prognostic value of circulating tumor cells in follow up of early breast cancer patients after adjuvant chemotherapy are highlighted. Overall, the present podcast represents a comprehensive overview on some of the most important studies presented at the San Antonio Breast Cancer Symposium. These highlights are presented by Jacek Jassem, Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland (jjassem@gumed.edu.pl). The podcast is conducted by Anna Berghoff, Department of Medicine, Medical University of Vienna, Austria. Visit the ESMO Open website: http://esmoopen.bmj.com/content/1/1/e000043.