Antibody Drug Conjugates in Bladder Cancer: Current Milestones and Future Perspectives.

OPINION STATEMENT: Over the last several years, the treatment landscape of urothelial carcinoma has witnessed an unprecedented expansion of therapeutic options including checkpoint inhibitors, tyrosine kinase inhibitors, and antibody drug conjugates (ADC). Early trial data has shown that ADCs are safer and potentially effective treatment options in advanced bladder cancer as well as in the early disease. In particular, enfortumab-vedotin (EV) has shown promising results with a recent cohort of a clinical trial demonstrating that EV is effective as neoadjuvant monotherapy as well as in combination with pembrolizumab in metastatic setting. Similar promising results have been shown by other classes of ADC in other trials including sacituzumab-govitecan (SG) and oportuzumab monatox (OM). ADCs are likely to become a mainstay treatment option in the urothelial carcinoma playbook as either a monotherapy or combination therapy. The cost of the drug presents a real challenge, but further trial data may justify the use of the drug as mainstay treatment.

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion.

Alterations in c-MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non-small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14-mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET-selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41-year-old woman with advanced NSCLC harboring an HLA-DRB1-MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. KEY POINTS: To our knowledge, this is the first report of a patient with non-small cell lung cancer harboring an HLA-DRB1-MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

BRCA mutation screening and patterns among high-risk Lebanese subjects.

BACKGROUND: Previous studies have suggested that the prevalence of BRCA1 and 2 mutations in the Lebanese population is low despite the observation that the median age of breast cancer diagnosis is significantly lower than European and North American populations. We aimed at reviewing the rates and patterns of BRCA1/2 mutations found in individuals referred to the medical genetics unit at the American University of Beirut. We also evaluated the performance of clinical prediction tools. METHODS: We retrospectively reviewed the cases of all individuals undergoing BRCA mutation testing from April 2011 to May 2016. To put our findings in to context, we conducted a literature review of the most recently published data from the region. RESULTS: Two-hundred eighty one individuals were referred for testing. The prevalence of mutated BRCA1 or 2 genes were 6 and 1.4% respectively. Three mutations accounted for 54% of the pathogenic mutations found. The BRCA1 c.131G > T mutation was found among 5/17 (29%) unrelated subjects with BRCA1 mutation and is unique to the Lebanese and Palestinian populations. For patients tested between 2014 and 2016, all patients positive for mutations fit the NCCN guidelines for BRCA mutation screening. The Manchester Score failed to predict pathogenic mutations. CONCLUSION: The BRCA1 c.131G > T mutation can be considered a founder mutation in the Lebanese population detected among 5/17 (29%) of individuals diagnosed with a mutation in BRCA1 and among 7/269 families in this cohort. On review of recently published data regarding the landscape of BRCA mutations in the Middle East and North Africa, each region appears to have a unique spectrum of mutations.

Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon.

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients' reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.

B-type proto-oncogene-mutated tumors of colon cancer: promising therapeutic approaches.

PURPOSE OF REVIEW: B-type proto-oncogene (BRAF) mutations have been observed in about 10.8% of patients with colorectal cancer (CRC). These patients do not respond to standard therapy with anti-epidermal growth factor receptor kinase (EGFR). Here we review novel BRAF inhibitors that are currently being investigated in these tumors. RECENT FINDINGS: Clinical experience with the BRAF inhibitor vemurafenib in CRC suggests significant differences in response compared with melanoma. Based on preclinical data, resistance to BRAF inhibitors employs alternative signaling pathways that in turn induce cell proliferation and survival. Therapeutic strategies that combine BRAF inhibitors in addition to targeted therapy with anti-EGFR monoclonal antibodies and phosphoinositide 3-kinase pathway inhibitors or standard therapy have yielded promising results in preclinical models and some reported cases. SUMMARY: Results from current clinical trials that are exploring novel BRAF inhibitors and others that employ combined therapy are eagerly awaited for the treatment of BRAF-mutated CRC. VIDEO ABSTRACT: http://links.lww.com/COON/A13.

Crosstalk between HER2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges.

PURPOSE OF REVIEW: Angiogenesis is an essential hallmark of cancer. Targeting angiogenesis has proven its efficacy in the modern therapeutic paradigm. HER2 positive breast cancer, in particular, is a challenging disease in which resistance to standard therapy has been attributed to parallel and downstream signaling cascades including angiogenesis. This review explores the molecular mechanisms underlying crosstalk between HER2 signaling and angiogenesis. It highlights the role of angiogenesis in the emerging resistance to anti-HER2 therapy. It surveys the current repertoire of clinical trials involving use of combination of anti-HER2 and antiangiogenic therapies. Finally, it entertains the hopes and challenges posed by this novel therapeutic approach. RECENT FINDINGS: HER2 signaling upregulates angiogenesis at different levels and by different mechanisms. A large number of clinical trials were conducted in attempt to exploit the potential benefit of the combination. Results of early phase trials were promising. However, in the late phase clinical trials, the AVEREL trial did not demonstrate a consistent benefit for bevacizumab in the HER2 positive breast cancer patient population. The BETH trial is ongoing and recruiting patients. Safety issues regarding cardiovascular toxicity of the combination have been already raised. Negative experience of dual EGFR and VEGF targeting in colon cancer cannot be overlooked. SUMMARY: Angiogenesis and HER2 signaling are closely related at the molecular level. Appraisal of efficacy of antiangiogenic therapies requires revisit of the current literature as well as following the results of ongoing trials.

Postoperative outcomes following pancreaticoduodenectomy: how should age affect clinical practice?

BACKGROUND: Pancreaticoduodenectomy is an increasingly common procedure performed for both benign and malignant disease. There are conflicting data regarding the safety of pancreatic resection in older patients. Potentially modifiable perioperative risk factors to improve outcomes in older patients have yet to be determined. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for 2008 to 2009 was used for this retrospective analysis. Patients undergoing pancreaticoduodenectomy were identified and divided into those above and below the age of 65. Preoperative risk factors and postoperative morbidity and mortality were evaluated. RESULTS: Among 2,045 patients included in this analysis, 994 patients were >65 years (48.6%) while 1,051 were (less than or equal to) 65 years (51.4%). Thirty-day mortality was higher in the older age group compared to the younger age group 3.6% vs. 1.9% respectively, P = 0.017, odds ratio 1.94. Older patients had a higher incidence of unplanned intubation, ventilator support >48 h and septic shock compared with younger patients. On multivariate logistic regression, after adjusting for other 30-day postoperative occurrences (significant at the P <0.1 level) only septic shock was independently associated with a higher odds of mortality, unplanned intubation, and ventilator support >48 h in older patients compared with younger patients. CONCLUSIONS: This report from a population-based database is the first to highlight postoperative sepsis as an independent risk factor for mortality and morbidity in older patients undergoing pancreatic resection. Careful perioperative management addressing this issue is essential for patients over the age of 65.

Volume matters and intensification is needed: emerging trends in the management of advanced prostate cancer.

Significant changes in the management of patients with de novo metastatic prostate cancer have led to the use of novel oral agents and docetaxel-based chemotherapy earlier in the natural history of their disease. Our main challenge is the lack of prospective randomized data comparing these regimens. It is clear that treatment intensification is needed. Yet, the heterogeneity of this patient population coupled with the lack of understanding of the specific biology for a given individual makes treatment selection challenging. The aim of this narrative review is to discuss the importance of defining advanced disease by volume, the necessity for treatment intensification, and the current and future landscape of metastatic hormone-sensitive prostate cancer management.

Improvement of EGFR Testing over the Last Decade and Impact of Delaying TKI Initiation.

BACKGROUND: Epidermal growth factor receptor (EGFR) is the most common oncogenic mutation in lung adenocarcinoma and tyrosine kinase inhibitors (TKIs) have been considered standard treatment for more than a decade. However, time to initiation of TKIs (TTIT) from diagnosis is often delayed and represents a challenge for clinicians. We aimed to assess the impact of TTIT on clinical outcomes and complications. METHOD: TTIT was defined as the time between confirmed advanced diagnosis and the initiation of a TKI. Complications during this pre-TKI period were retrospectively collected from all patients with EGFR-mutant non small cell lung cancer (NSCLC) in our institution. RESULTS: 102 patients were diagnosed with EGFR mutated NSCLC between 2006 and 2019. The median PFS and OS were 12.9 and 22.5 months, respectively. TTIT was 5.7 months (95% CI 3.4-8) with a significant decrease in the latter years of this cohort. During the pre-TKI period, 23 patients received chemotherapy as first line treatment, of which 5 developed severe adverse events and 3 were not fit to receive TKI thereafter. Additionally, 29 patients had rapid clinical deterioration before initiation of first line TKI and 16 had to be hospitalized. Among the patients presenting a performance status deterioration, their prognosis was markedly affected compared to the remainder of the cohort (p = 0.01). CONCLUSION: Our real-world evidence study supports the concept that a delay to treat EGFR mutant NSCLC with TKIs is associated with adverse events, patient progression, hospitalization, and decreased overall survival. Rapid molecular diagnosis, including access to ctDNA technology may circumvent these deleterious delays.

High rates of advanced prostate cancer in the Middle East: Analysis from a tertiary care center.

OBJECTIVES: Prostate cancer incidence is increasing in the Middle East (ME); however, the data of stage at the diagnosis and treatment outcomes are lacking. In developed countries, the incidence of de novo metastatic prostate cancer ranges between 4% and 14%. We hypothesized that the rates of presentation with advanced disease are significantly higher in the ME based on clinical observation. This study aims to examine the stage at the presentation of patients with prostate cancer at a large tertiary center in the ME. METHODS: After Institutional Review Board approval, we identified the patients diagnosed with prostate adenocarcinoma and presented to a tertiary care center between January 2010 and July 2015. Clinical, demographic, and pathological characteristics were abstracted. Patients with advanced disease were stratified according to tumor volume based on definitions from practice changing clinical trials. Descriptive and Kaplan-Meier survival analysis was used. RESULTS: A total of 559 patients were identified, with a median age at the diagnosis of 65 years and an age range of 39-94 years. Median prostate-specific antigen (PSA) at the presentation was 10 ng/ml, and almost a quarter of the men (23%) presented with metastatic disease. The most common site of metastasis was the bone (34/89, 38%). High-volume metastasis was present in 30.3%, 9%, and 5.2% of the cohort based on STAMPEDE, CHAARTED, and LATITUDE trial criteria, respectively. CONCLUSION: This is the first report showing the high proportion of men from ME presenting with de novo metastasis. This could be due to many factors, including the highly variable access to specialist multidisciplinary management, lack of awareness, and lack of PSA screening in the region. There is a clear need to raise the awareness about prostate cancer screening and early detection and to address the rising burden of advanced prostate cancer affecting men in the ME region.

The role of candidate genetic polymorphisms in the interaction between voriconazole and cyclosporine in patients undergoing allogeneic hematopoietic cell transplantation: An explorative study.

PURPOSE: To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses. RESULTS: The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant. CONCLUSION: To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others.

High-Cost Cancer Treatment Across Borders in Conflict Zones: Experience of Iraqi Patients in Lebanon.

PURPOSE: Conflict-induced cross-border travel for medical treatment is commonly observed in the Middle East. There has been little research conducted on the financial impact this has on patients with cancer or on how cancer centers can adapt their services to meet the needs of this population. This study examines the experience of Iraqi patients seeking care in Lebanon, aiming to understand the social and financial contexts of conflict-related cross-border travel for cancer diagnosis and treatment. PATIENTS AND METHODS: After institutional review board approval, 60 Iraqi patients and caregivers seeking cancer care at a major tertiary referral center in Lebanon were interviewed. RESULTS: Fifty-four respondents (90%) reported high levels of financial distress. Patients relied on the sale of possessions (48%), the sale of homes (30%), and vast networks to raise funds for treatment. Thematic analysis revealed several key drivers for undergoing cross-border treatment, including the conflict-driven exodus of Iraqi oncology specialists; the destruction of hospitals or road blockages; referrals by Iraqi physicians to Lebanese hospitals; the geographic proximity of Lebanon; and the lack of diagnostic equipment, radiotherapy machines, and reliable provision of chemotherapy in Iraqi hospitals. CONCLUSION: As a phenomenon distinct from medical tourism, conflict-related deficiencies in health care at home force patients with limited financial resources to undergo cancer treatment in neighboring countries. We highlight the importance of shared decision making and consider the unique socioeconomic status of this population of patients when planning treatment.

Younger age is an independent predictor of worse prognosis among Lebanese nonmetastatic breast cancer patients: analysis of a prospective cohort.

BACKGROUND: Several retrospective studies have reported that younger age at presentation is associated with a worse prognosis for nonmetastatic breast cancer patients. In this study, we prospectively assessed the association between different baseline characteristics (age, tumor characteristics, mode of treatment, etc) and outcomes among newly diagnosed nonmetastatic Lebanese breast cancer patients. METHODS: We recruited a sample of 123 women newly diagnosed with nonmetastatic breast cancer presenting to American University of Beirut Medical Center. Immunohistochemical, molecular (vitamin D receptor, methylene tetrahydrofolate reductase polymorphisms), and genetic assays were performed. Patient characteristics were compared by age group (<40 and ≥40 years). A Cox regression analysis was performed to evaluate the variables affecting the disease-free survival (DFS). Outcome data were obtained, and DFS was estimated. RESULTS: Among the 123 patients, 47 were 40 years of age or younger, and 76 were older than 40 years. Median follow-up duration was 58 months. Nine out of 47 patients <40 years (19.1%) experienced disease relapse in contrast to four out of 76 patients >40 years (5.2%). A wide immunohistochemical panel included Ki-67, cyclin B1, p53, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor, and did not reveal any significant difference in these markers between the two age groups. Older patients had a larger percentage of Luminal A than younger patients. On multivariate analysis including age, stage, grade, and subtype, only age <40 and stage were significantly associated with shorter DFS with hazard ratios of 4 (p=0.03, 95% confidence interval [CI]: 1.1-13.5) and 3 (p=0.03, 95% CI: 0.8-14.9), respectively. The estimated 5-year DFS for patients >40 years was 90%, and for patients <40 years was 37%. CONCLUSION: Being <40 years old was an independent risk factor for recurrence in this cohort of patients.

Thymoma with Concomitant Pure Red Cell Aplasia, Good's Syndrome and Myasthenia Gravis Responding to Rituximab.

Thymomas are often associated with a variety of autoimmune diseases, mostly myasthenia gravis. The association of thymomas with both pure red cell aplasia (PRCA) and Good's syndrome is exceedingly rare. To the best of our knowledge, the combination of a thymoma with manifestations of myasthenia gravis, PRCA, and Good's syndrome, as in our case herein, has not been described before in the medical literature. We present a 90-year-old man initially diagnosed with an asymptomatic thymoma. Later, he developed generalized muscle weakness and was found to have severe anemia. He was diagnosed with PRCA, myasthenia gravis and Good's syndrome. He responded to rituximab with restoration of bone marrow erythroid maturation and stabilization of red blood cell counts.

Cardiac and vascular toxicities of angiogenesis inhibitors: The other side of the coin.

Angiogenesis is one of the best-described tumor hallmarks. Targeting angiogenesis is becoming a successful strategy to suppress cancer growth. Vascular endothelial growth factor (VEGF), the fulcrum of angiogenesis, contributes to vascular and cardiac homeostasis. Angiogenesis inhibitors classically associated with vascular side effects are increasingly recognized for cardiac adverse effects as reflected by several meta-analyses. A global approach to these findings is a pressing need, and future strategies involving collaboration among different medical specialties are highly encouraged.

Methods of overcoming treatment resistance in colorectal cancer.

Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.

From sprouting angiogenesis to erythrocytes generation by cancer stem cells: evolving concepts in tumor microcirculation.

Angiogenesis is essential for tumor growth and metastasis. Over the last decades, a substantial progress has been achieved in defining different patterns of tumor microcirculation. Sprouting angiogenesis, the oldest model of microcirculation, is the de novo vessel formation from preexisting blood vessels. Vessel splitting and hijacking, also known, respectively, as intussusception and cooption, are alternative models that account for tumor resistance to antiangiogenic therapy. In addition to remodeling the microenvironment, the tumor cell can undergo intrinsic changes and survive hypoxic conditions by acquiring stem cell properties. In line with the concept of pluripotency, tumor cells can form vascular mimicry structures creating their own microcirculation despite a latent vessel growth. The recent identification of the polyploid giant cancer cells and tumor-derived erythrocytes is the most innovative survival mechanism in hypoxia and provides a potential target for more effective therapies.

Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer.

Despite major advances in cancer therapeutics, the prognosis for lung cancer patients is still poor and the median survival for patients presenting with advanced non-small cell lung cancer (NSCLC) is only 8-10 months. Angiogenesis is an important biological process and a relatively early event during lung cancer pathogenesis. Anti-angiogenic agents are used in treating patients with NSCLC, and their molecular biomarkers are also being assessed to predict response. A better understanding of the biology of angiogenesis in NSCLC may reveal new targets for treating this malignancy. In this article, we review the expression and prognostic impact of the angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in NSCLC.