Trastuzumab-Deruxtecan: Redefining HER2 as a Tumor Agnostic Biomarker.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.

Liquid biopsy as a tool for KRAS/NRAS/BRAF baseline testing in metastatic colorectal cancer.

BACKGROUND: The absence of KRAS and NRAS gene mutations (RAS wild type) in metastatic colorectal cancer (mCRC), is associated with a good response to targeted therapy with anti-EGFR receptor antibodies. The current gold standard for RAS mutational status identification is genetic testing on tissue biopsy samples. OBJECTIVE: This study aimed to assess the relevance of liquid biopsy as a less invasive alternative to tissue biopsy for detecting KRAS/NRAS and BRAF mutations in patients with metastatic colorectal cancer (mCRC). The study also aimed to determine the concordance between liquid biopsy and tissue biopsy. METHODS: This is a phase IV, observational, uncontrolled, non-comparative, non-randomized, open label study. RAS/BRAF status will be tested at baseline using tissue and liquid biopsy using the Idylla/Biocartis PCR-based device. The primary endpoint is the comparison of the RAS status based on liquid biopsy with the RAS status based on tissue biopsy. RESULTS: 100 patients with mCRC were included in the study. 75% of patients showed concordant results between liquid biopsy and tissue biopsy, while 25% had discordant results. Liquid biopsy demonstrated a sensitivity of 62% and a specificity of 93%. The accuracy of liquid biopsy was 75%, with a moderate agreement between the two tests. The most frequent mutations in concordant cases were in KRAS (41%), followed by NRAS (4%) and BRAF (3%). Mutations were not detected in 42% of tissue biopsy samples and 60% of liquid biopsy samples. The presence of hepatic metastases did not significantly affect the concordance between the biopsy methods. CONCLUSION: Liquid biopsy using the Idylla™ system showed a relatively low sensitivity but high specificity for detecting KRAS/NRAS and BRAF mutations in mCRC patients. Despite some discordant cases, liquid biopsy remains a promising alternative to tissue biopsy due to its non-invasiveness, ability to provide multiple samples, and better representation of tumor heterogeneity.

Genetic Polymorphisms Involved in Bladder Cancer: A Global Review.

Bladder cancer (BC) has been associated with genetic susceptibility. Single peptide polymorphisms (SNPs) can modulate BC susceptibility. A literature search was performed covering the period between January 2000 and October 2020. Overall, 334 articles were selected, reporting 455 SNPs located in 244 genes. The selected 455 SNPs were further investigated. All SNPs that were associated with smoking and environmental exposure were excluded from this study. A total of 197 genes and 343 SNPs were found to be associated with BC, among which 177 genes and 291 SNPs had congruent results across all available studies. These genes and SNPs were classified into eight different categories according to their function.

The first Middle East and North Africa expert consensus recommendations for management of advanced gastric cancer.

Gastric cancer (GC) ranks as the fifth most prevalent cancer and the fourth deadliest cancer worldwide. In the Middle East and North Africa (MENA) region, GC represents about 4.8% of cancer cases with more than 35,000 new cases in 2020. To strengthen and improve the management of this cancer in the region, a group of MENA experts in the field of GC developed the first MENA consensus recommendations for the management of advanced GC. A total of 28 statements were drafted, discussed and voted on, using a modified Delphi process, during a virtual consensus meeting. The statements addressed the areas of epidemiology, biomarkers and treatment.

Simultaneous inhibition of PD-1 and LAG-3: the future of immunotherapy?

Immunotherapy has improved the prognosis of many cancers, yet a large number of patients have demonstrated resistance to current immune checkpoint inhibitors. LAG-3 is an immune checkpoint expressed on tumor-infiltrating lymphocytes CD4+ and CD8+, Tregs and other immune cells. Coexpression of PD-1 and LAG-3 in solid or hematological cancers is generally associated with a poor prognosis and may be responsible for immunotherapy resistance. Dual inhibition therapy in the RELATIVITY-047 trial significantly improved progression-free survival in metastatic melanoma. This article discusses the presence of a possible synergistic interaction between LAG-3 and PD-1 in the tumor microenvironment and the utility of targeting both immune checkpoint inhibitors as an effective way to bypass resistance and increase treatment efficacy.

Immunotherapy has increased survival rates for many cancer types; however, a large number of individuals experience resistance to this therapy and poor outcomes. Among the immune molecules expressed on immune cells and tumor cells, LAG-3 can favor tumor escape and progression. The coexpression of multiple immune molecules such as PD-1 and LAG-3 in multiple cancers is generally associated with a worse prognosis and might be contributing to immunotherapy failure. Dual inhibition therapy, targeting both PD-1 and LAG-3, in the RELATIVITY-047 study has shown great antitumor activity and improved survival in metastatic melanoma. This report discusses a possible synergistic interaction between LAG-3 and PD-1 within the tumor and the utility of targeting both molecules as a way to overcome resistance and improve treatment efficacy.

BRCAness in biliary tract cancer: a new prognostic and predictive biomarker?

Cholangiocarcinoma (CCA) is a rare malignancy with a very poor prognosis. Considering that most cases of CCA are diagnosed at a locally advanced stage and the standard of care for advanced CCA remains suboptimal, new prognostic and predictive biomarkers must be developed to improve the management and survival of patients diagnosed with CCA regardless of disease stage. According to recent studies, 20% of biliary tract cancers exhibit the BRCAness phenotype, meaning that these tumors do not have germline mutations in BRCA but share phenotypic traits with tumors that possess hereditary BRCA mutations. Therefore, screening for these mutations in CCA patients is beneficial to predict tumor sensitivity and response to DNA-damaging chemotherapy such as platinum agents.

Adjuvant therapy in renal cell carcinoma in the immunotherapy era: where do we stand?

Locoregional, as well as metastatic renal cell carcinoma, tends to relapse after nephrectomy or metastasectomy. Adjuvant therapy seems to be an effective strategy to reduce the risk of recurrence. All anti-VEGF tyrosine kinase inhibitors except sunitinib have failed to show any benefit in the adjuvant setting in patients with locally advanced disease and an intermediate-to-high chance of recurrence. On the other hand, immune checkpoint inhibitors, which are now used in the first-line in the metastatic setting, are being tested in the adjuvant setting. Pembrolizumab has shown benefit in the adjuvant setting in patients with a high risk of recurrence or with resected metastatic disease with no evidence of disease. Results for other checkpoint inhibitors are still awaited.

Advanced and metastatic kidney cancer often tend to relapse after surgery. Treatment maintenance after surgery could be an effective strategy to reduce the risk of recurrence. Anti-VEGF tyrosine kinase inhibitors are the standard of care in the treatment of metastatic kidney cancer. However, they have all (but one) failed to prevent the occurrence of metastases in advanced nonmetastatic kidney cancer. On the other hand, immunotherapy is now being tested as a postsurgery treatment to prevent disease recurrence. Pembrolizumab has shown efficacy in preventing recurrence and is now approved as a postsurgery drug in advanced kidney cancer.

Genetic susceptibility of bladder cancer in the Lebanese population.

BACKGROUND: Bladder cancer (BC) is the 10th most frequent tumor worldwide. Evidence shows an association between elevated risk of BC and various single nucleotide polymorphisms (SNP). BC incidence was the highest in Lebanon according to Globocan 2018 report, but little is known about the genetic susceptibility of Lebanese people to this disease. We aim to evaluate whether this prominent incidence of BC in Lebanon is attributable to known coding genetic variants. METHODS: A case-control study was conducted at Hotel-Dieu de France Hospital, Beirut. A cohort of 51 Lebanese patients with BC were recruited between 2017 and 2020. Whole Exome Sequencing (WES) was performed on peripheral blood samples to detect coding genetic variants in the patients. An in-house database including WES data from 472 Lebanese individuals served as control. Literature review of the genetic predisposition to BC was conducted to establish a database of variants known to influence the risk of BC. In-common SNPs were identified between cases and the aforecited database, and their allelic frequencies was quantified in the former and in controls. Comparative analysis of the allelic frequencies of each in-common SNP was carried out between cases, controls, and the genome aggregation database (gnomAD). Analysis was performed by applying the binomial law and setting the p-value to 10- 10. RESULTS: 484 polymorphisms associated with BC were extracted from the literature review ;151 of which were in-common with the 206 939 variations detected by WES in our cases. Statistically significant differences (p-value < 10- 10) in allelic frequencies was seen in 11 of the 151 in-common SNPs, but none of which corresponds with a higher BC risk. Moreover, rs4986782 variant in the NAT1 gene is not associated with BC in the Lebanese population. `. CONCLUSION: This is the first next-generation sequencing (NGS)- based study investigating BC risk in a Lebanese cohort of 51 patients. The majority of known exonic variants in the literature were not associated with BC in our patients. Further studies with larger sample sizes are warranted to explore the association of BC in our population with known non-coding genetic variants, and the remainder of WES-generated private Lebanese variants.

The first Middle East and North Africa expert consensus recommendations for the management of advanced colorectal cancer.

Colorectal cancer (CRC) is ranked as the third most prevalent and the second deadliest cancer worldwide. In the Middle East and North Africa (MENA) region, the number of CRC cases increased over the past decades and will nearly double by 2030. The lack of clear MENA guidelines for the management of patients with CRC represents a step backwards in the fight against this burden. Therefore a panel of 24 MENA experts in the field of gastrointestinal oncology developed, using a Delphi process, the first consensus recommendations for the management of patients with advanced CRC. Forty-seven different statements were formulated in the areas of epidemiology, screening, biomarkers and treatment. These recommendations will guide, standardize and unify the management of this cancer in the MENA region.

The combination of immune checkpoint inhibitors and chemotherapy in advanced non-small-cell lung cancer: the rational choice.

Lung cancer is the second most common cancer worldwide and the leading cause of death among cancers. The progressive approvals of immunotherapy as first-line treatment options have helped improve cancer prognosis. However, longer follow-up has confirmed the possibility of acquired resistance to immune checkpoint inhibitors (ICIs) which can lead to late relapses. Chemotherapy can act as a priming therapy to increase a tumor's response to immunotherapy. We aim through this review to explain the mechanism behind ICI resistance and the value of chemotherapy in escaping this resistance. Finally, all US FDA approvals regarding the management of metastatic non-small-cell lung cancer using a combination of ICIs and chemotherapy are summarized.

First advanced course on biomarkers in molecular and immuno-oncology in the Middle East.

The first 'advanced course on biomarkers in molecular and immuno-oncology' in the Middle East took place in Beirut, Lebanon, as a hybrid meeting on 11 December 2020. The aim of this seminar was to discuss biomarker development, implications and detection modalities and to highlight advances in molecular technologies as well as the clinical applicability of biomarkers in oncology. The seminar consisted of five sessions, each discussing a special topic in the biomarker field. It also included a competition in the form of a quiz following each session. This was followed by a plenary session presented by well-known national and international speakers, highlighting various aspects of biomarkers in immuno-oncology.

PD-L1 expression as a predictive biomarker for immune checkpoint inhibitors: between a dream and a nightmare.

PD-L1 is an important predictive biomarker for treatment by immune checkpoint inhibitors (ICIs). ICIs are now indicated for the treatment of various cancer depending on the level of expression of PD-L1 on tumor cells. PD-L1 testing is done using immunohistochemistry with five different assays approved as companion diagnostic for ICIs. However, these assays have different score reporting methods and do not accurately measure PD-L1 expression. Exosomal PD-L1 testing has recently emerged as an alternative for cell-surface PD-L1 testing however studies are still premature and more extensive knowledge about this new potential biomarker is needed.

Lay abstract Immunotherapy is a new strategy for cancer treatment that aims to reactivate the body's own immune system, originally disabled by the tumor, to fight the malignancy. Immune checkpoint inhibitors are compounds developed for this purpose. However, their efficacy is subject to the abundance of their target, PD-L1, on the surface of cancer cells. Conventional PD-L1 testing through tumor biopsy has multiple technical drawbacks. Another form of PD-L1 secreted by the tumor into the circulation has emerged as a potential target for assessing immune checkpoint inhibitors efficacy but studies are still in their preliminary stages and further testing is required.

HER2 in metastatic colorectal cancer: a new to target to remember.

Metastatic colorectal cancer is the second most common cause of cancer death. Standard chemotherapy in combination with targeted therapies represent the backbone for the treatment of advanced disease. However, options are limited for patients progressing on these regimens. Genetic testing can offer patients the opportunity to benefit from novel therapies, namely immune checkpoint inhibitors in microsatellite instability-positive tumors. HER2 overexpression has recently emerged as a potentially targetable tumor marker in colorectal cancer (CRC). Despite the absence of approvals for anti-HER2 therapies in CRC, many agents such as trastuzumab and pertuzumab were tested and demonstrated significant antitumor activity, even in heavily pretreated patients. Early trials are also evaluating lapatinib, T-DM1, tucatinib and other anti-HER2 agents in patients with metastatic CRC, with promising results.