Introduction: Receptor tyrosine kinases (RTKs) and their signaling pathways, control normal cellular processes; however, their deregulation play important roles in malignant transformation. In ...advanced non-small cell lung cancer (NSCLC), the recognition of oncogenic activation of specific RTKs, has led to the development of molecularly targeted agents that only benefit roughly 20% of patients. Entrectinib is a pan-TRK, ROS1 and ALK inhibitor that has shown potent anti-neoplastic activity and tolerability in various neoplastic conditions, particularly NSCLC.
Areas covered: This review outlines the pharmacokinetics, pharmacodynamics, mechanism of action, safety, tolerability, pre-clinical studies and clinical trials of entrectinib, a promising novel agent for the treatment of advanced solid tumors with molecular alterations of Trk-A, B and C, ROS1 or ALK.
Expert opinion: Among the several experimental drugs under clinical development, entrectinib is emerging as an innovative and promising targeted agent. The encouraging antitumor activity reported in the Phase 1 studies, together with the acceptable toxicity profile, suggest that entrectinib, thanks to its peculiar mechanism of action, could play an important role in the treatment-strategies of multiple TRK-A, B, C, ROS1, and ALK- dependent solid tumors, including NSCLC and colorectal cancer. That being said, further evidence for its clinical use is still needed.
Legend
•IHC: Immunohistochemistry
•FISH: In situ hybridization with fluorescence
•CISH: Chromogenic in situ hybridization
•RT-PCR. Reverse transcription polymerase chain reaction
•NGS: ...Next-generation sequencing
Display omitted
The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2–7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment.
The interactions between pregnancy and breast cancer (BC) are complex. Overall, parity is associated with long-term protective effects against BC, however in a small group of susceptible patients, ...pregnancy can lead to the development of a form of BC with a particularly poor prognosis. Pregnancy-associated breast cancer (PABC) remains an under-studied but important and growing clinical problem worldwide. Several aspects of PABC, including risk factors and mechanisms involved in its occurrence and aggressiveness, are incompletely understood. This review aims to summarize the epidemiology, biology, patho-physiology and clinical characteristics of PABC. We emphasize that age at first pregnancy, absence of breastfeeding and family history stand out as possible risk factors for developing PABC that ought to be incorporated into clinical tools for assessing a woman's risk of developing PABC. Also, improved methods for identifying women at risk of developing PABC in the general population are needed.
•Pregnancy exerts a dual effect on the subsequent risk of developing breast cancer (BC).•Pregnancy-associated breast cancer (PABC) is a BC case that occurs during pregnancy or within 1 year following birth.•Mechanisms causing PABC are unclear due to hormonal and immune changes that occur during pregnancy and breast involution.•Older age- first pregnancy, no breastfeeding, and family history of BC are possible clinical biomarkers for developing PABC.•A higher awareness and improved methods for identifying women at risk in the general population are needed.
The introduction of immunotherapy has brought about a paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). It has not only significantly improved the prognosis of patients ...but has also become a cornerstone of treatment, particularly in those without oncogenic driver mutations. Immune checkpoint inhibitors (ICIs) play a crucial role in the treatment of lung cancer and can be classified into two main groups: Anti-cytotoxic T lymphocyte antigen-4 (Anti-CTLA-4) and anti-T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti-PD-L1). Certainly, the landscape of approved first line immunotherapeutic approaches has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The complexity of decision-making in this realm arises due to the absence of direct prospective comparisons. However, a thorough analysis of the long-term efficacy and safety data derived from pivotal clinical trials can offer valuable insights into optimizing treatment for different patient subsets. Moreover, ongoing research is investigating emerging biomarkers and innovative therapeutic strategies that could potentially refine the current treatment approach even further. In this comprehensive review, our aim is to highlight the latest advances in immunotherapy for advanced NSCLC, including the mechanisms of action, efficacy, safety profiles, and clinical significance of ICI.
Pneumococcal pneumonia (PP) is a serious infection caused by Streptococcus pneumoniae (pneumococcus), with a wide spectrum of clinical manifestations. The aim of this study was to analyze the ...comorbidity factors that influenced the mortality in patients with asplenia according to PP. Discharge reports from the Spanish Minimum Basic Data Set (MBDS) was used to retrospectively analyze patients with asplenia and PP, from 1997 to 2021. Elixhauser Comorbidity Index (ECI) was calculated to predict in-hospital mortality (IHM). 97,922 patients with asplenia were included and 381 cases of PP were identified. The average age for men was 63.87 years and for women 65.99 years. In all years, ECI was larger for splenectomized than for non-splenectomized patients, with men having a higher mean ECI than women. An association was found between risk factors ECI, splenectomy, age group, sex, pneumococcal pneumonia, and increased mortality (OR = 0.98; 95% CI: 0.97-0.99; p < 0.001). The IHM increased steadily with the number of comorbidities and index scores in 1997-2021. Asplenia remain a relevant cause of hospitalization in Spain. Comorbidities reflected a great impact in patients with asplenia and PP, which would mean higher risk of mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Despite the advances in the management of advanced non–small cell lung cancer (NSCLC), the access to genetic profiling and target therapies remains a challenge in Latin America, even in ...countries with a higher rate of targetable mutations. The aim of this study is to evaluate the clinical outcomes of anti‐epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) treatment in a Peruvian real‐world setting.
Methods
This is a retrospective study of recurrent or advanced NSCLC EGFR mutated patients diagnosed and treated with anti‐EGFR TKI at Instituto Nacional de Enfermedades Neoplásicas (INEN) between January 1, 2015 to December 31, 2020. The outcomes were objective response rate (ORR), progression free survival (PFS), and overall survival (OS).
Results
We identify 613 stage IV or recurrent NSCLC patients who were tested for EGFR mutations and found a pathogenic mutation in 39.5% of patients. Only 51.2% of them received anti‐EGFR TKI as institutional treatment. ORR was 58%, after median follow‐up of 32 months, the estimated median PFS was 13.9 months (11.1–16.7 months), and the estimated median OS was 21.7 months (18.5–24.9 months). No differences were found in PFS according to line of treatment or brain metastases at diagnosis (p = 0.46 and p = 0.07, respectively), respect to OS there were no differences line of treatment (p = 0.12), significant difference were found in presence of brain metastases (p = 0.006).
Conclusion
Our study demonstrates that erlotinib for advanced NSCLC harboring EGFR‐activating mutations is effective even in patients usually excluded from clinical trial, like those previously exposed to one or more lines of chemotherapy or with brain metastases.
After molecular study of 613 patients with stage IV or recurrent non–small cell lung cancer, epidermal growth factor receptor (EGFR) mutation was detected in 39.5% of patients, however, only 51.2% received anti‐EGFR tyrosine kinase inhibitors as institutional treatment and 72 (0.6%) of them as first line. Despite the lack of access to target therapy and the late onset of treatment, erlotinib showed effectiveness even in patients previously exposed to one or more lines of chemotherapy or with brain metastases.
Background
Lung cancer in the young is a rare entity of great interest due to the high frequency of targetable mutations. In this study, we explored the genomic landscape of non-small cell lung ...cancer (NSCLC) in young patients and compared it with genetic alterations in older patients.
Methods
Comparative study of the genomic profile of NSCLC young (≤40 years old) vs older patients (>40 years old) from Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Archival paraffin-embedded tumor samples were profiled with FoundationOne CDx assay to identify short variants alterations (insertions and deletions), copy number variations (CNV), tumor mutational burden and microsatellite instability in 324 driver genes and rearrangements in 28 commonly rearranged genes. A targetable alteration was defined as any alteration in a driver oncogene for which an FDA approved therapy existed at the time of study enrollment.
Results
Overall, 62 tumors were profiled, 32 from young and 30 from older patients. All clinicopathological features (smoking status, clinical stage, and histology) were similar between groups, except for gender (65.6% of females in the younger group vs 40% in the older group, P=0.043). At least one actionable mutation was present in 84.4% and 83.3% in younger and older patients, respectively. Alteration rates in the main genes were: BRAF, 3.1%(n=1) vs 0%; EGFR, 46.9% (n=15) vs 43.3% (n=13); ERBB2, 12.5% (n=4) vs 16.7% (n=5); KRAS, 15.6% (n=5) vs 16.7% (n=5); ALK, 6.3% (n=2) vs 3.3% (n=1); RET, 0.0% vs 3.3% (n=1); ROS1, 3.1% (n=1) vs 3.3% (n=1); NTRK1, 0.0% vs 3.3% (n=1) and MET, 3.1% (n=1) vs 13.3% (n=4). Mean TMB was 4.04 Mut/Mb (SD ± 3.98) for young vs 8.06 Mut/Mb (SD ± 9.84) for older patients (P=0.016). There were not significant differences in CNV, frequency of gene rearrangements, or microsatellites instability.
Conclusion
NSCLC in the young in our cohort was characterized by a high frequency of actionable genetic aberrations and a low TMB, which was also true for our older patients. The enrichment of actionable mutations in young patients described in other reports might be attributed to differences in the etiology and clinicopathological characteristics between younger and older patients and therefore not be applicable to all populations.
Non-small-cell lung cancer usually carries a dismal prognosis. Novel treatment approaches are clearly warranted. Immunotherapy has emerged as a promising area of research developing agents that ...manipulate the immune system to induce antitumor responses while avoiding major toxicity. New vaccines and checkpoint inhibitors are currently undergoing investigation in phase II and phase III clinical trials. In advanced non-small-cell lung cancer (NSCLC), belagenpumatucel-L, an allogeneic cell vaccine directed against transforming growth factor β in the tumor microenvironment, knocks down the immune suppression caused by the tumor and has demonstrated a dose- and time-dependent efficacy in some subgroups of patients. L-BLP25 and TG4010 are both antigenic vaccines that target mucin 1, whose encoding proto-oncogene is commonly mutated in solid tumors. The L-BLP25 vaccine achieved a significant improvement in overall survival in the subgroup of patients with stage IIIB NSCLC treated with chemoradiotherapy. TG4010 vaccination resulted in better progression-free survival when added to cisplatin–gemcitabine chemotherapy. These results are being addressed in the currently ongoing phase III TIME trial. In the adjuvant setting, MAGE-A3, an antigen-based vaccine, showed promising results in melanoma-associated antigen A3 positive lung cancer patients who underwent resection in the phase II study; however, no improvement in progression-free survival was observed in the phase III MAGRIT study. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. It has improved overall survival in patients with advanced NSCLC who achieve seroconversion. Ipilimumab, an immune checkpoint inhibitor that targets cytotoxic T-lymphocyte antigen 4, demonstrated improved progression-free survival in advanced NSCLC patients who received the drug after chemotherapy in a phased regimen. Finally, anti-programmed death receptor 1 agents have achieved durable response rates in phase I studies. This review gives an overview of the current data and the most promissory immunotherapeutic agents for NSCLC.
PURPOSE
Major progress has occurred in multiple myeloma (MM) treatment in recent years, but this is not seen in low- and middle-income countries.
MATERIALS AND METHODS
We retrospectively assessed the ...efficacy and safety of cyclophosphamide, thalidomide, and dexamethasone (cyclophosphamide 400 mg/m
2
for 5 days, thalidomide 100 mg once daily, if tolerated, and dexamethasone 40 mg once weekly; in 28-day cycles) in patients with newly diagnosed MM treated at our institution between April 2008 and December 2012. Survival outcomes were estimated by the Kaplan-Meier method.
RESULTS
Fifty-nine patients were found to meet the selection criteria. Median age was 56 years (27-78). Fifty-nine percent (n = 35) were male. International Staging System three was found in 24%. The median number of treatment cycles was 11 (range 4-12). After a median of 81-month follow-up (range 5-138 months), the overall response rate was 69.5%. The complete response and very good partial response were 5% and 32%, respectively. Median progression-free survival (PFS) was 35 months (95% CI, 18 to 41). The 3-year PFS was 47.4% (95% CI, 34.5 to 59.6) and 5-year PFS was 24.9% (95% CI, 14.4 to 36.9). The median of overall survival (OS) was 81 months (95% CI, 33 to not reached). The 3-year OS was 63.4% (95% CI, 49.2 to 74.6), and 5-year OS was 57.5% (95% CI, 43.2 to 69.4). The most common adverse event was neutropenia (grade 3 and 4, 30.5%). Out of 23 patients eligible for stem-cell transplantation, 10 (43.5%) proceeded with autologous transplantation. Treatment-related deaths occurred in four patients (6.7%).
CONCLUSION
Cyclophosphamide, thalidomide, and dexamethasone achieves good response rates with tolerable toxicity, especially in patients age 65 years or younger representing a feasible approach for patients with MM in low-income health care settings.
As the fifth international consensus on advanced breast cancer (ABC5) established guidelines for the management of this disease, the aim of this article was to present the applicability of the ...consensus recommendations and to generate knowledge to improve access.
Sixty-one recommendation statements were selected and discussed by 15 breast cancer experts from Latin America (LA). After the discussion, the level of consensus was determined through a vote. In addition to this, the level of access to each of the recommendations presented, according to the country and health system, was exposed.
Latin American experts had a high level of agreement with the ABC5 consensus recommendations (range, 83%-100%). Twelve of 61 statements are not available for all patients in LA. Among the limitations to access, the following ones are described: limited access to certain technologies (stereotactic body radiotherapy, positron emission tomography-computed tomography), the high costs of drugs that limits access to treatment with CDK4/6 inhibitors, pertuzumab, or poly(ADP-ribose) polymerase inhibitors, and the lack of molecular tests for access to therapeutic targets, as well as the difficult geography and cultural diversity of our continent.
Despite the great relevance of the recommendations of the ABC5 consensus guidelines, we highlight that we still need to improve access for all patients, regardless of the country or health system they are in, for which we call to action to policy makers and patient groups to improve clinical outcomes of patients with advanced breast cancer in our region.
PDF