To design the services for adolescents and young adults (AYAs) with cancer, we need to understand the patterns of disease and the other clinical and managerial challenges of the patient group. Cancer occurring between the ages of 15 and 39 years is 4 times less rare than cancer occurring during the first 15 years of life and consists of 2% of all invasive cancer in Europe, about 66,000 patients in Europe each year. AYAs have a unique distribution of cancer types, including the peak in incidence of Hodgkin lymphoma (HL) or germ cell tumors. The relative improvement in the survival rate in AYAs has not kept pace with that achieved in younger children, especially for acute leukemia, non-HLs, Ewing tumors and rhabdomyosarcoma. Etiological factors are under-researched and remain largely hypothetical. In this unique group of illnesses, improving AYA cancer management involves bridging interfaces. Since this has begun, outcomes have also begun to improve. The local nature of these interfaces determines the age group considered as AYA. Specific skills are necessary in the clinical, biological and psychosocial domains. Services need support from policy, clinical and administrative professionals. National policy and supranational groups such as SIOPE and ESMO are in constructive collaboration to develop this further.

Awareness of the need for collaboration across pediatric and adult cancer to care for adolescents and young adults (AYAs) arose from the recognition of the unique characteristics of AYAs with cancer. Neither pediatric nor adult oncology hospital departments are able to provide age-appropriate care single handedly. The best way to bridge the gap in care of AYA cancer patients is to centralize aspects of their care within dedicated AYA care programs, including the following essential components: provision of developmentally appropriate and multidisciplinary (supportive) care, availability of AYA inpatient and outpatient facilities and healthcare professional AYA expertise as collaboration between adult and pediatric departments. Barriers are related to the slowly emerging evidence of benefit, cultural differences (collaboration between pediatric and adult oncology professionals), administrative and logistic challenges (small number of AYAs makes it difficult to create an AYA program in every hospital) and financial aspects (dependency on philanthropic funds). The sustainable development of an AYA program requires acceptance as a standard of care at the clinical and patient community and at government level. To improve the quality, equity and quantity of research and innovation in AYA cancer care across the world, it is necessary to join forces and collaborate in international networks to study issues such as the features of quality care, collaboration between pediatric and adult clinical teams, trial groups and professional societies, and AYA-specific groups such as Critical Mass, Canteen or European Network for Teenagers and Young Adults with Cancer.

Breast cancer is not a single disease. Specific biological processes and distinct genetic pathways are associated with prognosis and sensitivity to chemotherapy and targeted agents in different subtypes of breast cancers. As a consequence, breast cancer can be classified by molecular events. A primary challenge for future drug development in breast cancer will be to distinguish genes and pathways that 'drive' cancer proliferation (drivers) from genes and pathways that have no role in the development of cancer (passengers). The identification of functional pathways that are enriched for mutated genes will select subpopulation of patients likely to be sensitive to biology-driven targeted agents. The selection of driver pathways in resistant tumors will permit to discover a biology-driven platform for new drug development to overcome resistance. We are moving in the era of stratified and personalized therapy. Personalized cancer therapy is based on the precept that detailed molecular characterization of the patient's tumor and its microenvironment will enable tailored therapies to improve outcomes and decrease toxicity. However, there are numerous challenges we need to overcome before delivering on the promise of personalized cancer therapy. These include tumor heterogeneity and molecular evolution, costs and potential morbidity of biopsies, lack of effective drugs against most genomic aberrations, technical limitations of molecular tests, and reimbursement and regulatory hurdles. Critically, successes and limitations surrounding personalized cancer therapy must be tempered with realistic expectations, which, today, encompass increased survival times for only a portion of patients.

Constant development of chemotherapy and more recently the introduction of VEGF- and epidermal growth factor receptor (EGFR)-directed agents have improved significantly the treatment of patients with colorectal cancer. In the adjuvant setting, especially for UICC stage III colon cancer patients, fluoropyrimidine in combination with oxaliplatin is usually the standard of care. With some surprise, both VEGF inhibitors (for all patients) and EGFR (for patients with KRAS exon 2 mutant tumors) have failed to improve adjuvant chemotherapy. Also, adding an EGFR antibody to FOLFOX as perioperative treatment in patients with resectable exon 2 KRAS wild-type liver metastases was not successful. However, patients with metastatic disease harboring a RAS wild-type tumor are with no doubt candidates for combination chemotherapy plus an EGFR antibody. In patients with liver-limited disease, metastases may become resectable following intensive chemotherapy (including an EGFR antibody for RAS wild-type disease), which may result in cure or significantly prolonged survival. In the case of RAS wild-type tumors, median survival in patients with unresectable metastases approaches now 3 years if EGFR antibodies are used in the first line. There is little evidence for VEGF inhibitors in patients with RAS wild-type or mutant disease in first-line chemotherapy if combination chemotherapy is considered. VEGF inhibitors, however, are very potent drugs to be combined with chemotherapy for second-line treatment.

In gastrointestinal stromal tumors (GIST), molecularly targeted therapies, starting with imatinib, are directed against an activating mutation of KIT or PDGFRA, which drives the disease. Their efficacy has brought the median survival from one to at least 5 years in the metastatic setting. Tumor response patterns may include tumor shrinkage or not, but are marked by pathologic and radiological changes in tumor tissue. Tumor sensitivity to imatinib can be precisely predicted by the mutational status. However, the metastatic disease has not been truly converted into a chronic condition since secondary resistance to imatinib remains a major limiting factor occurring after a median of 2 years at least in most patients. Further-line therapies are available, i.e. with sunitinib and regorafenib, which can prolong progression-free survival for limited time intervals. Resistance is due to secondary mutations. These give rise to a molecular heterogeneity, which represents a formidable therapeutic challenge. However, the scenario has aspects of a 'liquid resistance'. In fact, resistance may spread in a stepwise fashion throughout the tumor: focal progression may be one possible clinical presentation, and tyrosine kinase inhibitors may impact tumor growth even beyond conventional progression. In addition, sensitive and resistant clones may expand and shrink depending on the selective pressure of tyrosine kinase inhibitors, with be possible responses on rechallenge with drugs. In the adjuvant treatment of high-risk molecularly sensitive GIST, imatinib is able to substantially delay relapses, if due to occur, with a limited survival benefit, though, apparently, without impacting the cure rate.