Unmet needs in EGFR exon 20 insertion mutations in Central and Eastern Europe: reimbursement, diagnostic procedures, and treatment availability.

Lung cancer remains the leading cause of cancer-related deaths in Europe, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. NSCLC is a heterogeneous disease encompassing various oncogenic alterations. Among them, EGFR exon 20 insertion mutations, constituting 0.3-2.2% of NSCLC cases, rank as the third most common EGFR alteration after exon 19 deletions and the L858R point mutation in exon 21, also known as "typical" EGFR alterations. Recent advancements in understanding the molecular pathogenesis of NSCLC have led to significant breakthroughs in targeted therapies, revolutionizing treatment options for patients with specific genetic alterations.This article presents the outcomes of a Virtual Meeting conducted on the online platform (provided Within3©) from September 19 to October 30, 2022. The meeting focused on addressing the challenges in the diagnosis and treatment of NSCLC patients with EGFR exon 20 insertion mutations. The participants consisted of healthcare professionals from ten Central and Eastern European countries who shared their experiences and opinions on various aspects, including epidemiology, treatment options, and diagnostic approaches employed in their respective healthcare institutions. The discussions were facilitated through open-ended and multiple-choice questions.The primary objective of this article is to provide an overview of the identified challenges associated with the diagnosis and treatment of this heterogeneous disease, based on the assessments of the meeting participants. Among the major emerging challenges discussed, the reimbursement issues concerning next-generation sequencing (NGS), a recommended method in NSCLC molecular diagnosis, and the availability of approved targeted treatments to enhance patient outcomes were of paramount importance. Furthermore, fostering community awareness of lung cancer and promoting harmonized lung cancer care were identified as areas deserving greater attention. Notably, the rapidly evolving treatment landscape, particularly with NGS for NSCLC patients with genomic alterations like EGFR, ALK, RET, MET, NTRK, and ROS1, necessitates prioritizing the development of new drugs, even for the relatively smaller subgroup with exon 20 insertion mutations.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

How do international gastric cancer prevention guidelines influence clinical practice globally?

Clinical guidelines recommend particular approaches, including 'screen-and-treat' strategy for Helicobacter pylori, to prevent gastric cancer. However, little of this is implemented in clinical practice. The aim of the study was to identify barriers to implementation of international guidelines. A web-based questionnaire distributed globally to specialists in the field. Altogether 886 responses from 75 countries were received. Of the responders, 570 (64%) were men of mean age 47 years. There were 606 gastroenterologists and 65 epidemiologists among the responders. Altogether, 79.8% of the responders disagreed that the burden of gastric cancer is a diminishing problem. 'Screen-and-treat' strategy for H. pylori in the responder's country was considered appropriate by 44.4%, inappropriate by 24.3%, with 31.3% being uncertain. Population-based screening for gastric cancer was considered appropriate in the respective home-country by 62.2%, in other areas - but not the home country - by 27.6%, and inappropriate by 10.2%. As a screening tool, upper endoscopy was acceptable by 35.6%, upper X-ray series by 55.3%, pepsinogens by 26.2% and breath-tests by 23.4%; accuracy, cost-effectiveness and feasibility among the tests varied widely. The attitude towards H. pylori vaccination was that 4.6% of the responders were eager to start vaccination immediately, 55.9% were supporting vaccination but considered that more data are required 12% were negative, and 27.6% did not have an opinion. In general, the attitude of the specialists was in line with guidelines, but was not always translated into clinical practice, particularly in the case of 'screen-and-treat' strategy.

Duration of previous treatment as a prognostic factor in metastatic colorectal cancer treated with trifluridine/tipiracil.

We herein describe the findings from the trifluridine/tipiracil (TAS-102) Compassionate Use program in Latvia, set up prior to marketing authorization for the management of pretreated patients with metastatic colorectal cancer (mCRC). The efficacy and safety of TAS-102 in patients with refractory mCRC were evaluated in the phase III trial RECOURSE. A previous report confirmed neutropenia and duration of previous treatment for mCRC as prognostic factors in TAS-102 users. The aim of the present study was to analyze possible prognostic factors, such as neutropenia, in TAS-102 responders. A retrospective analysis of 14 patients who received TAS-102 chemotherapy in two institutions in Latvia (Clinic of Oncology of Pauls Stradins Clinical University Hospital and Oncology Centre of Riga East University Hospital) was performed. Grade 3-4 neutropenia was observed in 28% of the patients. In patients with grade 3-4 neutropenia the median progression-free survival (mPFS) was 7 months, whereas in those without neutropenia the mPFS was 5 months [hazard ratio (HR)=0.24, P=0.033]. In 64% of the patients, the duration of previous treatment was >18 months. In patients treated for >18 months from the start of first-line mCRC treatment the mPFS was 7 months, whereas in those treated for ≤18 months from the start of first-line mCRC treatment the mPFS was 5 months (HR=0.15, P=0.029). Therefore, a longer time from mCRC diagnosis until disease progression may be used to select chemotherapy-refractory mCRC patients for TAS-102 treatment. Furthermore, severe neutropenia may be considered as a surrogate marker for predicting TAS-102 treatment outcomes.

Prognostic relevance of carbonic anhydrase IX expression is distinct in various subtypes of breast cancer and its silencing suppresses self-renewal capacity of breast cancer cells.

PURPOSE: Carbonic anhydrase IX (CAIX) is a hypoxia-inducible enzyme with extracellular catalytic domain that is overexpressed in a variety of cancers including breast cancer and plays a crucial role in maintaining favourable intracellular pH and reducing extracellular pH. The purpose of the current study was to elucidate the prognostic significance of CAIX in the intrinsic subtypes of breast cancer and to characterise CAIX as a drug target in breast cancer. METHODS: The prognostic significance of CAIX mRNA expression was interrogated in a cohort of 3,455 breast tumours by using an online tool, Kaplan-Meier plotter. The functional effects of stable CAIX depletion by shRNA in three breast cancer cell lines­MDA-MB-231, MCF7 and SKBR-3, representing basal-like, luminal A and HER2+ subtypes, respectively­were studied by proliferation, invasion, clonal spheroid formation and chemosensitivity assays under normoxia and hypoxia. Finally, the effect of pharmacological CA inhibition alone or in the combination with doxorubicin on self-renewal was assessed by spheroid-forming assay. RESULTS: High CAIX mRNA expression was significantly associated with poor survival in patients with basal-like, luminal B and triple-negative breast cancer, but not luminal A and HER+ subtypes. Silencing of CAIX expression had no significant effect on the cell proliferation or viability upon treatment with doxorubicin in any of the cell lines studied, while it inhibited spheroid formation in hypoxic conditions. Furthermore, pharmacological inhibition of CAs using acetazolamide had a synergistic effect with doxorubicin on decreasing the spheroid-forming efficiency in MDA-MB-231 cells. CONCLUSIONS: Inhibition of CAIX reduces the self-renewal capacity of breast cancer cells, and the combination of doxorubicin and CAIX inhibition is an attractive therapeutic strategy in basal-like and triple-negative breast cancer, which warrants further investigations.