Talazoparib in Patients With Solid Tumors With BRCA1/2 Mutation: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA-mutated human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α = .10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P < .001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non-small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration-approved.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.

BACKGROUND: PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures. METHODS: A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels. RESULTS: Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma. CONCLUSIONS: Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.

Concordance between Immunohistochemistry and Microarray Gene Expression Profiling for Estrogen Receptor, Progesterone Receptor, and HER2 Receptor Statuses in Breast Cancer Patients in Lebanon.

INTRODUCTION: Accurate evaluation of estrogen and progesterone receptors and HER2 is critical when diagnosing invasive breast cancer for optimal treatment. The current evaluation method is via immunohistochemistry (IHC). In this paper, we compared results of ER, PR, and HER2 from microarray gene expression to IHC in 81 fresh breast cancer specimens. METHODS: Gene expression profiling was performed using the GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix Inc). Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 status was performed using standard methods at a CAP-accredited pathology laboratory. Concordance rates, agreement measures, and kappa scores were calculated for both methods. RESULTS: For ER, Kappa score was 0.918 (95% CI, 0.77.3-1.000) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). For PR, Kappa score was 0.652 (95% CI, 0.405-0.849) and concordance rate was 86.4% (95% CI, 77%-93%). For HER2, Kappa score was 0.709 (95% CI, 0.428-0.916) and concordance rate was 97.5% (95% CI, 91.4%-99.7%). CONCLUSION: Our results are in line with the available evidence with the concordance rate being the lowest for the progesterone receptor. In general, microarray gene expression and IHC proved to have high concordance rates. Several factors can increase the discordance rate such as differences in sample processing.

Prevalence of EGFR and ALK Mutations in Lung Adenocarcinomas in the Levant Area - a Prospective Analysis

Background: A significant percentage of lung adenocarcinomas have a driver mutation. To date, there has been no assessment of the prevalence of such mutations in a Middle Eastern population. The present multicenter prospective study of formalin fixed paraffin embedded (FFPE) tissues from patients diagnosed with lung adenocarcinoma was performed to assess the prevalence of EGFR and ALK mutations in the Levant. Methods: Patients of Middle Eastern origin with lung adenocarcinomas at 10 sites in Lebanon, Jordan and Iraq were prospectively enrolled. Tumors were tested for EGFR by PCR and for EML4-ALK translocation by fluorescence in situ hybridization (FISH). Results: A total of 210 patients were enrolled, 139 (66.2%) males and 71 females (33.8%), with a mean age of 63.4 years. EGFR testing of 205 (97.6%) demonstrated the wild type in 173 (84.4%) and mutated forms in 32 (15.6%). Some 46.9% of EGFR positive patients were non-smokers and 62.5% were females as opposed to 22.4% and 33.8%, respectively, in the general population. As for the EML4-ALK translocation, testing in 157 (74.8%) cases gave negative results in 154 (98.1%) , only 3 being positive (1.9%), 2 being females and 2 non-smokers.Conclusion: Our study established a 15.6% EGFR mutation rate in lung adenocarcinomas with ALK translocation mutations in only 1.9%, as compared to a 15-20% and 5%, respectively, in the Western literature.

Nurse-Led Competency Model for Emergency Physicians: A Qualitative Study.

STUDY OBJECTIVE: To develop a competency model for emergency physicians from the perspective of nurses, juxtapose this model with the widely adopted Accreditation Council for Graduate Medical Education (ACGME) model, and identify competencies that might be unique to the nurses' perspective. METHODS: The study relied on secondary data originally collected as part of nurses' assessment of emergency physicians' nonclinical skills in the emergency department (ED) of an academic medical center in the Middle East. Participants were 36 registered nurses who had worked in the ED for at least 2 years and had worked for at least 2 shifts per month with the physician being evaluated. RESULTS: Through content analysis, a nurse-led competency model was identified, including 8 core competencies encompassing 33 subcompetencies. The 8 core competencies were emotional intelligence; problem-solving and decisionmaking skills; operations management; patient focus; patient care, procedural skills, and medical knowledge; professionalism; communication skills; and team leadership and management. When the developed model was compared with the ACGME model, the 2 models diverged more than they converged. CONCLUSION: The nurses' perspective offered distinctive insight into the competencies needed for physicians in an emergency medicine environment, indicating the value of nurses' perspective and shedding light on the need for more systematic and more methodologically sound studies to examine the issue further. The differences between the models highlighted the competencies that were unique to the nurse perspective, and the similarities were indicative of the influence of different perspectives and organizational context on how competencies manifest.

Gene expression profiling of breast cancer in Lebanese women.

Breast cancer is commonest cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. Molecular alterations in breast cancer are complex and involve cross-talk between multiple signaling pathways. The aim of this study is to extract a unique mRNA fingerprint of breast cancer in Lebanese women using microarray technologies. Gene-expression profiles of 94 fresh breast tissue samples (84 cancerous/10 non-tumor adjacent samples) were analyzed using GeneChip Human Genome U133 Plus 2.0 arrays. Quantitative real-time PCR was employed to validate candidate genes. Differentially expressed genes between breast cancer and non-tumor tissues were screened. Significant differences in gene expression were established for COL11A1/COL10A1/MMP1/COL6A6/DLK1/S100P/CXCL11/SOX11/LEP/ADIPOQ/OXTR/FOSL1/ACSBG1 and C21orf37. Pathways/diseases representing these genes were retrieved and linked using PANTHER®/Pathway Studio®. Many of the deregulated genes are associated with extracellular matrix, inflammation, angiogenesis, metastasis, differentiation, cell proliferation and tumorigenesis. Characteristics of breast cancers in Lebanese were compared to those of women from Western populations to explain why breast cancer is more aggressive and presents a decade earlier in Lebanese victims. Delineating molecular mechanisms of breast cancer in Lebanese women led to key genes which could serve as potential biomarkers and/or novel drug targets for breast cancer.

Perspective of Lebanese oncologists on the symptom burden among adult cancer patients.

Background: Proper approach to symptom control in cancer patients requires a good understanding of the prevalence of the various symptoms these patients have. Aim: This study aims at assessing the Lebanese oncologists' point of view concerning the symptom burden among cancer patients of Lebanon and comparing their opinions to the real complaints of patients themselves. Methods: A cross-sectional study was conducted among a representative sample of the Lebanese medical oncologists. Thirty-six physicians filled out a questionnaire regarding their demographics as well as the symptom profile of their patients. Those results were compared to the ones obtained from our previous study about symptom profile as reported by patients. Results: Fatigue was the symptom most our patients suffered from according to their physicians (64.167%). Also, a good percentage of physicians agreed that patients suffer from appetite loss, pain, weight loss, and nausea. When compared to the patients' reports of their own symptoms, a statistically significant difference existed between the two profiles for the majority of symptoms (14 out of 19). Also, for the majority of symptoms, physicians were found to underestimate the percentage of patients suffering from each symptom. Conclusion: This study shows that there is a statistically significant difference between the physicians' and the patients' perspectives on most of the common distressing symptoms. This entails more detailed questioning of the cancer patients about their distressing symptoms.

Complementary and alternative medicine use and its association with quality of life among Lebanese breast cancer patients: a cross-sectional study.

BACKGROUND: Breast cancer patients are increasingly seeking Complementary and Alternative Medicine (CAM) therapies with the hope of alleviating the burden of the disease and improving their quality of life (QOL). The objective of this study was to assess the prevalence, types, socio-demographic and disease-related correlates as well as characteristics of CAM use (including disclosure to treating physicians) among breast cancer patients in Beirut, Lebanon. A secondary objective was to evaluate the association between CAM use and QOL. METHODS: A cross-sectional survey was conducted on breast cancer patients recruited from two major referral centers in Beirut: a philanthropic hospital and a private academic medical center. In face-to-face interviews, participants completed a questionnaire of three sections: socio-demographic and lifestyle characteristics, breast cancer condition, and CAM use. Three to four weeks following these interviews, the secondary QOL assessment was carried out via telephone using the Arabic version of the Functional Assessment of Cancer Therapy-Breast questionnaire. The main outcome in this study, CAM use, was defined as using CAM at least once after breast cancer diagnosis. RESULTS: A total of 180 breast cancer patients completed the survey (response rate: 94.6 %). Prevalence of CAM use was 40 %. Using multivariate logistic regression, CAM use was negatively associated with age (OR: 0.96, CI: 0.92-0.99), treatment at the philanthropic hospital (OR: 0.13, CI: 0.05-0.35) and was positively associated with an advanced stage of the disease (OR: 4.20, CI: 1.65-10.69). Among study participants recruited from both sites, the most commonly used CAM was 'special food' followed by 'herbal teas', 'diet supplements' and 'Spiritual healing'. Only 4 % of CAM users cited health professionals as influencing their choice of CAM and only one in four patients disclosed CAM use to their treating physician. There was no significant association between CAM use and QOL. CONCLUSIONS: The findings of this study revealed a prevalent CAM use among Lebanese breast cancer patients. Furthermore, physicians' role in orienting CAM use was found to be marginal as patients relied mainly on family and media for their choice of CAM and were less likely to disclose CAM use to their treating physicians.

Role of baseline echocardiography prior to initiation of anthracycline-based chemotherapy in breast cancer patients.

BACKGROUND: Anthracycline adjuvant therapy has taken a particular role in the treatment of early stage breast cancer with an associated decrease in rates of both relapse and death. Their success however has been limited by their myelosuppression and their well-established risk of cardiac dysfunction. Guidelines have emerged that would limit the maximum lifetime dose of anthracyclines and make a baseline assessment and periodic monitoring of cardiac function part of the routine practice, which could be cumbersome, and may condemn the patient to an unwarranted modification of his/her regimen. Our study aimed at assessing the incidence of abnormal baseline echocardiography in asymptomatic women with breast cancer prior to anthracycline therapy and establishing risk criteria associated with abnormal echocardiograms at baseline. METHODS: 220 Patients seen at AUBMC (American University of Beirut Medical Center) who had non- metastatic breast cancer, and had an echocardiography performed before starting anthracycline chemotherapy were chosen. Data about demographic characteristics, tumor characteristics, baseline echocardiography results, and change in clinical decision was collected. Patients with suboptimal (less than 50%) ejection fraction (EF) on baseline echocardiography were analyzed for the prevalence of cardiac risk factors. Results were compared to those among the overall study group using Fisher's Exact test. A p- value of = < 0.05 was used as reference for statistical significance. RESULTS: All 220 of our patients had received a baseline echo prior to initiation of anthracycline therapy. 6.7% of these patients had already some abnormality in wall motion but only 2.7% had a suboptimal ejection fraction. 1.3% had a change in chemotherapy regimen based on ejection fraction. The patients with depressed EF had higher rates of CAD (coronary artery disease), diabetes, hypertension and dyslipidemia than the overall study group but without statistical significance. CONCLUSIONS: Our study, as well as the previous contingent studies raise the question about routine echocardiography prior to anthracycline therapy and might eventually lead to a modification of current practice guidelines.

Use of herbal medications and their perceived effects among adults in the Greater Beirut area.

OBJECTIVES: To measure the magnitude of use of so-called "herbal medications" with or without prescribed drugs and to assess the benefits and adverse effects perceived by herbal users in the Greater Beirut area. METHODS: A sample survey of 480 adults (18-65) in the Greater Beirut (GB) area was conducted over a one-month period in 2009. RESULTS: The estimated weighted prevalence of herbal use in the previous 12 months in GB was 58.9% (56.7-61.2). Most of the 293 users (72.4%) believed that their use had been of no benefit, but 70% thought use was relatively safe. Of users, 53% were concomitantly using conventional drugs for a chronic condition yet only 45% had thought of informing their physician about herbal use. Among the "concomitant users" 60% had suffered some form of adverse effects. CONCLUSIONS: There is a relatively high prevalence of herbal medicine use in Greater Beirut, with an important rate of self-reported adverse effects, especially among those who suffer chronic conditions, and little exchange of information on this between patients and doctors. Data indicate the need to educate patients about realities associated with abusive use, expected benefits and potential drug-herb interaction. Patients on chronic medications should not be left to actually experience adverse effects in order to discover that herbal medicines are not always effective or innocuous.