S1 - THE POWER OF PATHOLOGY - INFLUENCE OF MUTATIONAL STATUS IN NSCLC ON ONCOLOGICAL TREATMENT

The identification of numerous gene alterations in the past decade had a major impact on the treatment of Non Small Cell Lung Cancer (NSCLC). These driver mutations lead to specific biochemical pathways, which further promote growth and survival of cancer cells. There are several important mutations which represent well establish targets in the treatment of NSCLC. The first discovered drug-sensitive mutation in NSCLC was Epidermal Growth Factor Receptor (EGFR). The inhibition of EGFR has led the way for targeted therapy in the treatment of NSCLC. Erlotinib, the first anti-EGFR antibody was first approved in 2004. At first, the approval was referred to unselected patients after failure of chemotherapy, but was later proven to be superior in comparison with chemotherapy as first-line treatment of metastatic NSCLC with sensitizing EGFR mutations. Today, there are a variety of other anti-EGFR antibodies, such as gefitinib, afatinib, osimertinib or dacomitinib. The analyzes of phase 3 randomized trial FLAURA, showed superiority of osimertinib in first-line therapy with osimertinib in metastatic NSCLC with EGFR mutations regardless of T790M status. Antoher dirver mutation, found in approximately 5% of patients with NSCLC is ALK gene rearrangemet, also known as ALK fusion. This mutation is not routinely found in patients with squamous cell carcinoma, and therefore it is recommended to test for ALK fusions in patients with metastatic non-squamous NSCLC, based on the data showing efficacy of different kinase inhibitors, such as alectinib, brigatinib, ceritinib and crizotinib. ROS1 gene rearrangements (also known as ROS1 fusions) occur in about 1% to 2% of patients with NSCLC. There are different fusion partners that can be detected in NSCLC: CD74, SLC34A2, CCDC6 and FIG. The benefit of crizotinib, ceritinib and entrectinib for patients with ROS1 fusions was shown in different trials. Aditionally, there are others gene alterations, such as BRAF V600E mutation. These patients have a significant benefit in the treatment with combination of BRAF and MEK inhibitors dabrafenib and trametinib. Detection of RET rearrangements is predictive for the treatment with TKIs selpercatinib and pralsetinib. Furthermore, NTRK, METex14, KRAS mutations are proven to be very efficacious molecular biomarkers in the treatment of NSCLC. Testing for the expression of immune biomarker PD-L1 is crucial predictive biomarker for the treatment with immune checkpoint inhibitors. IHC testing for PD-L1 expression should be performed before first-line treatment in all patients with metastatic NSCLC. There are different checkpoint inhibitors (pembrolizumab, atezolizumab, nivolumab, ipilimumab, cemiplimab), which showed efficacy alone or in combination with other treatment regimens. Testing of lung cancer specimens for these alterations is important for identification of potentially efficacious targeted therapies, as well as avoidance of therapies unlikely to provide clinical benefit. With the invention of targeted therapies and antibodies directed against tyrosine kinases and other specific driver mutations, the treatment options in lung cancer changed from histology-based to molecular and biomarker-based treatment. These changes in the treatment of NSCLC put in spotlight the significance of the cooperation between oncology and pathology. Brain metastases occur in about 30- 50% of patients with HER2 positive and 40% of patients with triple negative breast cancer. Occurrence of CNS metastases is a marker of aggressive disease. Median overall survival of patients with brain metastases is 13 – 19 months in patients with HER2 positive disease and 4.4 months in patients with triple negative disease. Regarding radiotherapy, breast cancer brain metastases are treated the same as metastases from all other tumor sites. When setting up an indication for local treatment, crucial is to have information about the control of extracranial disease, possibility of further systemic therapy lines and patient’s performance status. Local therapy consists of surgical treatment, with or without consolidation stereotactic radiotherapy and radiotherapy as a sole modality. Preferred method of radiotherapy would be stereotactic radiotherapy (SRT), in patients with up to 10-15 metastases, limiting factor being the volume of the disease (up to 15 mL). With STR local control can be achieved in up to 60% of patients. Fractionated stereotactic radiotherapy (FSRT), delivered in 3 to 12 fractions provides 1- year local control rate in up to 80% of patients. In case stereotactic radiotherapy is not available or possible, patients with good performance status and extracranial disease control could be referred to whole brain radiotherapy (WBRT), which palliates symptoms in about 60% of patients. Both stereotactic and whole brain radiotherapy are connected with cognitive impairment, which is more often after WBRT. WBRT induced cognitive toxicity can be lowered by using hippocampal sparing radiation techniques. WBRT after SRT or neurosurgical procedure improves local control but has no effect on overall survival and can also lead to cognitive impairment. Therefore, WBRT is not indicated after these procedures. Upon neurosurgical operation, SRT of resection cavity should be performed, as it lowers the risk if intracranial relapse of the disease. There are several ongoing trials exploring different radiotherapy techniques (SRT or WBRT), and their timing and combination with various systemic agents in breast cancer patients with brain metastases, such as lapatinib, trastuzumab emtansine, pembrolizumab. In patients with low performance status, loss of extracranial disease control and short life expectancy, it would be reasonable to omit whole brain radiotherapy since it has no effect on survival or quality of life and the same palliative effect can be achieved with corticosteroids use only. Immunotherapy has evolved recently as very promising and possibly effective treatment of several tumor types. Immunotherapy has dramatically changed treatment landscape of some entities, but benefit in colorectal cancer was so far very modest due to fact that only up to 5% of patients with mCRC have high microsatelite instability and mismatch-repair deficient genes. These features are considered as biologic markers for tumors which we expect to respond to immunotherapy. According to data obtained from early clinical studies (phase II) and last year presented phase III study, KEYNOTE-177, led to FDA-approval of pembrolizumab in first line treatment of metastatic colorectal cancer in June 2020. KEY-NOTE-177 was a randomized, open-label study enrolling 307 treatment-naive patients with microsatelite instability-high/mismatch repair-deficient (MSI-H/dMMR) mCRC. Randomization was 1:1 to treatment with pembrolizumab or investigator’s choice of doublet chemotherapy (n=154) meaning standard of care. Dual primary endpoint were PFS and OS, and crossover was permitted at disease progression. This is very important trial, since it was the first randomized- trial evaluating first-line pembrolizumab in patients with metastatic colorectal cancer. This was especially critical for Europe, because pembrolizumab was not approved. It is worth to mention that about 25% of patients had BRAF V600E-mutant tumor sin the trial. Median PFS2 was not reached in the pembrolizumab group and was 23.5 months in the chemotherapy group (HR:0.63)(ASCO GI 2021). The 12-month rate was PFS2 76% for pembrolizumab and 67% for chemotherapy. The same tendency was at 24-month PFS2. The rate of adverse events (AEs) and treatment-related AEs was similar in both treatment arms. Grade ≥ 3 treatment-related AEs were much more common in the chemotherapy group, affecting 66% of the patients compared with 22% of the patients receiving pembrolizumab. Grade ≥ 3 diarrhea, fatigue, and neutropenia also were significantly higher in the chemotherapy group. These results were expected, as pembrolizumab is generally well-tolerated. Generally, quality of life did not decrease in pembrolizumab group (QoL scores), and pain and appetite loss also improved with pembrolizum vs chemotherapy. So, there was a clear benefit in both PFS and QoL for the use of pembrolizumab over chemotherapy. The rate of adverse events (AEs) and treatment-related AEs was similar in both treatment arms. Grade ≥ 3 treatment-related AEs were much more common in the chemotherapy group, affecting 66% of the patients compared with 22% of the patients receiving pembrolizumab. Grade ≥ 3 diarrhea, fatigue, and neutropenia also were significantly higher in the chemotherapy group. These results were expected, as pembrolizumab is generally well-tolerated. Although this results put immunotherapy as very attractive treatment modality, there are many questions still to be answered in the future. We still don’t know the relationship between KRAS-mutant phenotype and immunotherapy, as well as the meaning of other biomarkers. After all, some patients do not respond to immunotherapy, so in the near future we should define which patients would be optimal for immunotherapy in first line setting and which would benefit from chemotherapy, nevertheless. Bacground : Hepatocellular carcinoma is fourth leading cause of death among cancer patients. This cancer is four to eight times more common in the male population and is usually associated with chronic liver damage (hepatitis B (HBV), hepatitis C (HCV) and alcoholic cirrhosis). Cirrhosis, regardless of the cause, is present in 70-80% of HCC cases. Chronic infection with HBV and cirrhosis increases the possibility of HCC up to 100 times. 5-30% of patients with HCV infection develop chronic liver disease, > 30% progress to cirrhosis, and in that population, 1-2% of them develop HCC annually. Co-infection with HBV further increases the risk of developing the disease. Other risk factors are: alcohol abuse, autoimmune diseases (autoimmune hepatitis and primary biliary cirrhos