Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer.

BACKGROUND: Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed. PATIENTS AND METHODS: This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined. RESULTS: In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes. CONCLUSIONS: Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.

ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Potential histological discordance revealed by second review in the national rare gynecological cancer network (TMRG).

INTRODUCTION: Since 2010, the network of rare malignant tumors of the ovary (TMRG) was developed to optimize the management of patients, also allowing a histological second opinion of rare ovarian tumors. The aim of this work was to study the contribution of second opinion to improve histological diagnostic accuracy on ovarian rare malignant tumors included in the TMRG database. MATERIAL AND METHODS: Histological data of patients diagnosed with a rare ovarian tumor included in TMRG network over a one-year period (2018) were collected. Initial diagnoses were compared with second opinion from national gynecological pathologist experts. The modalities of histological second opinion requests were studied, as well as the histological characteristics of the tumors. The discordances were classified as minor (if the modification of histological diagnosis did not change patient management) and major (if the patient management can be modified). RESULTS: Of 1185 included patients, 937 matched the inclusion criteria. Full concordance between primary diagnosis and expert second opinion was reached in 611 cases (65,3%), minor discordance was seen in 114 (12,2%) and major discordance in 209 (22,3%) of cases. In systematic review requested by the network, 26% (n = 137) of cases were reported with a change in histological diagnosis, while the change concerned 44% (n = 186) of cases for a second opinion spontaneously requested by the initial pathologist. The discrepancies concerned all categories of ovarian tumors, with a majority of mucinous tumors (43% of major discordances), followed by stromal and sex-cord tumors (13.8% of major discordances) and clear cell tumors (12,4% of major discordances). CONCLUSION: This analysis confirms the diagnostic difficulty of ovarian tumors, due to their rarity and morphological heterogeneity. French pathologists are aware of these difficulties and spontaneously refer ovarian tumors with unusual histology for a second opinion and collaborate with rare tumor networks for systematic review.

Refining patient selection for breast cancer immunotherapy: beyond PD-L1.

Therapies that modulate immune response to cancer, such as immune checkpoint inhibitors, began an intense development a few years ago; however, in breast cancer (BC), the results have been relatively disappointing so far. Finding biomarkers for better selection of BC patients for various immunotherapies remains a significant unmet medical need. At present, only tumour tissue programmed death-ligand 1 (PD-L1) and mismatch repair deficiency status are approved as theranostic biomarkers for programmed cell death-1 (PD-1)/PD-L1 inhibitors in BC. However, due to the complexity of tumour microenvironment (TME) and cancer response to immunomodulators, none of them is a perfect selector. Therefore, an intense quest is ongoing for complementary tumour- or host-related predictive biomarkers in breast immuno-oncology. Among the upcoming biomarkers, quantity, immunophenotype and spatial distribution of tumour-infiltrating lymphocytes and other TME cells as well as immune gene signatures emerge as most promising and are being increasingly tested in clinical trials. Biomarkers or strategies allowing dynamic assessment of BC response to immunotherapy, such as circulating/exosomal PD-L1, quantity of white/immune blood cell subpopulations and molecular imaging are particularly suitable for immunotreatment monitoring. Finally, host-related factors, such as microbiome and lifestyle, should also be taken into account when planning integration of immunomodulating therapies into BC management. As none of the biomarkers taken separately is accurate enough, the solution could come from composite biomarkers, which would combine clinical, molecular and immunological features of the disease, possibly powered by artificial intelligence.

Delayed care for patients with newly diagnosed cancer due to COVID-19 and estimated impact on cancer mortality in France.

BACKGROUND: The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France. PATIENTS AND METHODS: The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses. RESULTS: A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years. CONCLUSIONS: In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years.

ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research.

Aberrant activation of RET is a critical driver of growth and proliferation in diverse solid tumours. Multikinase inhibitors (MKIs) showing anti-RET activities have been tested in RET-altered tumours with variable results. The low target specificity with consequent increase in side-effects and off-target toxicities resulting in dose reduction and drug discontinuation are some of the major issues with MKIs. To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The results of these trials showed marked and durable antitumour activity and manageable toxicity profiles in patients with RET-altered tumours. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Information About Donation and Organ Transplantation Among Spanish Medical Students.

INTRODUCTION: Health professionals are asked to promote health, especially organ transplantation; however, they do not always have specific training. OBJECTIVE: To analyze information about donation and organ transplantation among Spanish medical students. METHOD: The population under study is medical students in Spanish universities using the database of the International Donor Collaborative Project, stratified by geographic area and academic year (n = 9275). The instrument used is the attitude questionnaire for organ donation for "PCID-DTO-Ríos" transplantation, validated with an explained variance of 63.203% and α = 0.834. The Student t test was applied together with the χ2 test, complemented by an analysis of the remainders, and Fisher's exact test was applied. RESULTS: Of the students, 74% indicate that they have received information from university professors about organ transplant. Concerning specific issues with the donation, it is notable that only 66.7% (n = 6190) know and accept the concept of brain death as the death of a person. However, only 22% consider themselves as having good information, and 35.3% indicate that their information is scarce or void. Students indicate having received information about transplant from other extra-university sources, such as television and Internet (80.9%), books and magazines (73.2%), and the press (66.9%). From the information obtained in the sociofamilial field, 60.7% have obtained information from the family and 58.1% from friends. Of this information, 9% has been negative from friends, 7.5% from family, 6% from the Internet and television, and 4% from university professors. CONCLUSION: Spanish medical students believe they have little information about organ transplantation and have received negative information.

Are Medical Students of Non-Spanish Nationality Studying in Spain as Sensitized to Transplantation as Those of Spanish Nationality?

INTRODUCTION: Awareness of organ donation among Spanish doctors and medical students is very positive. However, the emerging group of professionals of non-Spanish nationality studying in Spain has not been analyzed. OBJECTIVE: To analyze the differences in the attitudes toward the different types of donation among medical students, according to their nationality. METHODS: The population under study is medical students in Spanish universities using the database of the International Collaborative Donor Project, stratified by geographic area and academic year. Groups under study include students of non-Spanish nationality as group 1 (n = 1570) and students of Spanish nationality as Group 2 (n = 7705). Instruments are validated questionnaires of attitude toward donation "PCID-DTO-Ríos," "PCID-DVR-Ríos," "PCID-DVH-Ríos," and "PCID-XenoTx-Ríos." RESULTS: The attitude toward the donation of own organs after death is similar in both groups (P = .703). Non-Spaniards are 79.2% in favor compared to 79.6% of Spaniards. Living kidney donation, both unrelated (33.3% vs 29.3% in favor; P = .001) and related (91.2% vs 89, 6% in favor; P = .047), is more favorable among non-Spanish students. There are no differences regarding non-related living liver donation (29.7% vs 29.3% in favor; P = .063), but there are differences in the results for related living liver donation (94.1% vs 88%; P < .001). The attitude toward xenotransplantation of organs is similar (80.8% vs 80.8%; P = .999). CONCLUSIONS: Awareness of the donation of organs among Spanish medical students is similar to non-Spanish students studying in Spain, except the attitude toward living donation.

What Reasons Lead Spanish Medical Students Not to Be in Favor of Organ Donation?

INTRODUCTION: Despite sensitization of medical students toward the donation of organs, a non-negligible percentage of students are not in favor of donation. OBJECTIVE: To analyze the reasons of Spanish medical students who do not have a favorable attitude toward the donation of their own organs after death. METHOD: The population under study is medical students in Spanish universities, using the database of the International Donor Collaborative Project, stratified by geographic area and academic year. The questionnaire completion was anonymous and self-administered. The study group is medical students with an unfavorable attitude toward organ donation. The assessment instrument used is a validated questionnaire of attitude toward the donation of organs for transplant, "PCID-DTO-Ríos." The reasons against the donation are valued in the questionnaire through a question. RESULTS: Of the participants included in the PCID, students who are not in favor of organ donation were selected (n = 1899). Of them, 8.1% (n = 154) are against and 91.1% (n = 1745) are doubtful. The main reasons indicated are the fear of apparent death in 11.4% of respondents, fear of possible mutilation after donation in 11.1%, and religious reasons in 2.6%. Of those, 6.9% indicate other reasons but do not clearly specify the reasons, using words such as "fear" (2.5%) or "doubts about the process" (4.1%); 66.2% (n = 1257) indicated an "assertive refusal" ("I don't want to express my reasons"). CONCLUSION: Twenty percent of Spanish medical students are not in favor of donating their organs and are not in favor of showing their reasons.

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

Do Religious Factors Influence the Attitude Toward Organ Donation Among Medical Students? A Spanish Multicenter Study.

INTRODUCTION: Religious factors have conditioned the attitude toward organ donation and transplantation (ODT) since the beginning of transplantation, despite the fact that most religions are in favor of transplantation. OBJECTIVE: To assess the impact of religious beliefs of medical students on their attitude toward ODT. METHOD: Population under study: Medical students in Spanish universities. STUDY SAMPLE: Stratified by geographical area and academic course. Assessment instrument: Attitude ODT questionnaire PCID-DTO-Ríos, anonymous and self-administered. RESULTS: Of all students, 42% (n = 3907) declare themselves atheists or agnostics. The remaining 58% (n = 5368) declare themselves to be religious, the majority being Catholic (55%, n = 5102). Of the rest, 0.2% are Muslims (n = 8), 0.1% Protestants (n = 1), and the remaining 2.7% (n = 257) indicate other religious doctrines but do not want to specify it. Regarding their attitude toward ODT, those who consider themselves atheists or agnostics have a more favorable attitude than those who consider themselves religious (84% versus 76%; P < .001). Among those who follow some kind of religion, Catholics are more in favor of ODT than non-Catholics (77% vs 64%, P < .001). Note that among the religious, only 57% (n = 3050) know which religion is in favor of transplantation, while 22% (n = 1,152) consider that it has not been pronounced on the matter, 13% (n = 723) think the religion is against donation, and the remaining 8% (n = 443) do not know. CONCLUSION: The religion professed by medical students conditions their attitude toward donation, with the atheists and agnostics being more in favor of donation.

Are High Rates of Deceased Donation Conditioning the Attitude Toward Liver Donation Among Medical Students?

The involvement of health professionals from their training period is important for the promotion of living liver donation. There are data that indicate that the awareness of living donation is lower in areas with high rates of deceased donation. OBJECTIVE: To analyze the attitude toward living liver donation among Spanish medical students, according to donation rates of their regions. METHOD: Population under study: Medical students in Spanish universities. Database of the Collaborative International Donor Project, stratified by geographic area and academic course. The completion was anonymous and self-administered. Groups under study: group 1 (n = 1136): students in universities of regions with >50 donors per million population (pmp); group 2 (n = 2018): students in region universities with <40 donors pmp. Assessment instrument: the attitude questionnaire for living liver donation Proyecto Colaborativo Internacional Donante sobre Donación de Vivo Hepático-Ríos (PCID-DVH Ríos). RESULTS: The attitude toward related liver donation is more favorable among the students of regions with <40 donors pmp than among those of >50 donors pmp. Thus, in group 1, a total of 88% (n = 1002) of students are in favor compared with 91% (n = 1831) of group 2 (P=.02). The psychosocial profile of each study group about their attitude toward living related liver donation is analyzed. There is a similar profile between the 2 groups, although there are differences in some variables such as age, a belief that one might need a transplant, family discussion about donation and transplantation, discussion with friends about donation and transplantation, and knowing about a donor. CONCLUSIONS: The awareness of living related donation among Spanish medical students is greater among the regions with lower organ donation rates.

Sensitization Toward Organ Donation Among Medical Students in Spanish Regions With More Than 50 Donors Per Million Population.

The awareness of organ donation among health professionals is important at the time of transplant promotion. In this sense, the training and awareness of the professionals in training is fundamental. OBJECTIVE: To analyze the differences in the attitude toward organ donation and the factors that condition it among medical students of regions with donation rates >50 donors per million population (pmp) with respect to those with rates <40 donor pmp. METHOD: Population under study: medical students in Spanish universities. Database of the Collaborative International Donor Project, stratified by geographic area and academic course. The completion was anonymous and self-administered. Groups under study: Group 1 (n = 1136): students in universities of regions with >50 donors pmp. Group 2 (n = 2018): university students in regions with <40 donors pmp. Assessment instrument: attitude questionnaire for organ donation for transplant PCID-DTO-Ríos. RESULTS: The attitude toward organ donation for transplantation is similar among students from the autonomous communities with >50 donors pmp and with <40 donors pmp. In group 1, 79% (n = 897) of students are in favor compared with 81% (n = 1625) of group 2 (P=.29). The psychosocial profile toward donation is similar in both groups relating to the following variables (P < .05): sex, having discussed transplantation with family and as a couple, considering the possibility of needing a transplant, involvement in prosocial activities, attitude toward the manipulation of corpses, knowledge of the brain death concept, and religion. CONCLUSIONS: The awareness of organ donation in Spanish medical students is quite homogeneous and is not related to the local donation rates of each region.