Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications.

DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation is strongly implicated in cancer development. Cancers possess an extensively hypomethylated genome with focal regions of hypermethylation at CPG islands. Due to the highly conserved nature of cancer-specific methylation, its detection in cell-free DNA in plasma using liquid biopsies constitutes an area of interest in biomarker research. The advent of next-generation sequencing and newer computational technologies have allowed for the development of diagnostic and prognostic biomarkers that utilize methylation profiling to diagnose disease and stratify risk. Methylome-based predictive biomarkers can determine the response to anti-cancer therapy. An additional emerging application of these biomarkers is in minimal residual disease monitoring. Several key challenges need to be addressed before cfDNA-based methylation biomarkers become fully integrated into practice. The first relates to the biology and stability of cfDNA. The second concerns the clinical validity and generalizability of methylation-based assays, many of which are cancer type-specific. The third involves their practicability, which is a stumbling block for translating technologies from bench to clinic. Future work on developing pan-cancer assays with their respective validities confirmed using well-designed, prospective clinical trials is crucial in pushing for the greater use of these tools in oncology.

Choosing Wisely Philippines: ten low-value or harmful practices that should be avoided in cancer care.

The Choosing Wisely Philippines campaign is an initiative that identifies low-value or potentially harmful practices that are relevant to patients with cancer in the Philippines. The main purpose of these initiatives is to facilitate quality improvement systems and maximise patient outcomes. Of the ten practices identified, four are new recommendations, and six are modified adaptations from previous Choosing Wisely initiatives in the USA and Africa. Recommendations in the final list include interventions involving diagnosis (two practices), treatment (five practices), palliative and supportive care (two practices) and surveillance (1 practice).

Cell-free DNA methylation-defined prognostic subgroups in small-cell lung cancer identified by leukocyte methylation subtraction.

Small-cell lung cancer (SCLC) methylome is understudied. Here, we comprehensively profile SCLC using cell-free methylated DNA immunoprecipitation followed by sequencing (cfMeDIP-seq). Cell-free DNA (cfDNA) from plasma of 74 patients with SCLC pre-treatment and from 20 non-cancer participants, genomic DNA (gDNA) from peripheral blood leukocytes from the same 74 patients, and 7 accompanying circulating tumor cell-derived xenografts (CDXs) underwent cfMeDIP-seq. Peripheral blood leukocyte methylation (PRIME) subtraction to improve tumor specificity. SCLC cfDNA methylation is distinct from non-cancer but correlates with CDX tumor methylation. PRIME and k-means consensus identified two methylome clusters with prognostic associations that related to axon guidance, neuroactive ligand-receptor interaction, pluripotency of stem cells, and differentially methylated at long noncoding RNA and other repeats features. We comprehensively profiled the SCLC methylome in a large patient cohort and identified methylome clusters with prognostic associations. Our work demonstrates the potential of liquid biopsies in examining SCLC biology encoded in the methylome.

Revisiting a lower starting dose of alectinib in ALK-Positive non-small cell lung cancer.

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses - 300 mg and 600 mg twice daily - across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations-particularly those with a lower body weight.

The Association Between Inflammation and Immunosuppression: Implications for ICI Biomarker Development.

Evasion of immune destruction is considered one of the hallmarks of cancer. Chronic inflammation can enable immune escape by suppressing immune surveillance and permitting the development of tumors and creating a tumor microenvironment that sustains cancer. This includes generating mechanisms that prevent the effectiveness of anti-tumor treatment including immune checkpoint inhibitor therapy. In this review, we explore the interplay of inflammation and immunosuppression, their effects on the tumor microenvironment, and their implications for immune checkpoint inhibitor therapy particularly in the context of predictive biomarkers for their use.

A systematic review and meta-analysis on the efficacy and safety of metformin as adjunctive therapy among women with metastatic breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and is one of the leading causes of cancer-related mortalities. Metformin has been found to have direct and indirect antitumor mechanisms, and because of its availability and good safety profile, it has been investigated to be useful in various malignancies including breast cancer. OBJECTIVE: This study aims to determine the efficacy and safety of metformin administration as adjunctive therapy on mortality among females with breast cancer. METHODS: This is a systematic review and meta-analysis of randomized clinical trials (RCTs) on the use of metformin as adjunctive therapy when combined with standard chemotherapy on the outcomes of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and clinical benefit rate (CBR). RESULTS: After a comprehensive literature search, only three phase 2 RCTs on the use of metformin as adjunctive therapy for locally advanced and metastatic breast cancer were included. Clinical trials on early breast cancer are still ongoing and none were included in the present review. This study, based on the systematic review, revealed that metformin added to standard chemotherapy does not improve the PFS and OS among women with metastatic breast cancer, and likewise, has no impact on the ORR with a relative risk of 1.42 95% CI 0.45-4.55 and CBR with an RR of 0.87, 95% CI 0.55-1.37. It appears to be safe and may even be protective for the development of neutropenia based on at least one study. CONCLUSION: This study clarifies that there is insufficient evidence on the benefits of metformin on survival among women with metastatic breast cancer.

Clinicopathologic Factors Associated with Mismatch Repair Status Among Filipino Patients with Young-Onset Colorectal Cancer.

INTRODUCTION: Young-onset colorectal cancer is recognized as a distinct disease that may be sporadic or hereditary in nature. Microsatellite instability testing is recommended as a routine procedure in evaluating colorectal cancer specimens, especially in young-onset disease, because of implications in management. Immunohistochemistry of mismatch repair proteins serves as an inexpensive alternative to microsatellite instability testing with the added advantage of monitoring protein expression levels that may suggest underlying genetic or epigenetic alterations. This descriptive study aimed to determine the frequencies of proficient and deficient mismatch repair status among Filipino young-onset colorectal cancer patients, and to investigate their clinicopathologic profile. METHODS: Tumor tissues were prospectively collected from patients from two tertiary hospitals in the Philippines. Patients of age ≤45 years with resected adenocarcinoma of the colon or rectum were recruited. RESULTS: Seventy-seven out of 124 patients had tumor samples sent for immunohistochemistry. Of these, 61 samples (79%) were found to have proficient status while 16 samples (21%) had deficient status. Mismatch repair protein deficiencies, when present, more commonly involved MSH2 and MSH6 (9%) rather than MLH1 and PMS2 (5%). The deficient group had a mean age of 37.1 years and a female preponderance (56.25%), presenting as locally advanced ascending or descending colon tumors with mucinous histology in half of the population. The mismatch repair proficient group presented as locally advanced rectal and sigmoid tumors but with fewer mucinous adenocarcinomas (26.2%) compared to the deficient group. In both the mismatch repair proficient and deficient patients with family history reports, most did not have any known relative with cancer (75.4% and 68.75%, respectively). CONCLUSION: This is the first attempt to perform mismatch repair testing among young-onset colorectal cancer patients in the Philippines and to gather data on their clinicopathologic characteristics. However, the limited sample size precludes conclusive results for the associations of mismatch repair with clinicopathologic features.

The role of the medical oncologist in the holistic care of patients with cancer in the Philippines.

In the past decade, cancer care in the Philippines has advanced in response to the complex heterogeneity inherent to the disease and the constantly increasing number of patients. Central to this development is the increased awareness and universal acceptance of the multidisciplinary team (MDT) approach in providing cancer care to optimize outcomes where medical oncologists play a vital role. This position paper summarizes the unique and multifaceted roles of the medical oncologist in ensuring that the best possible care is given to patients with cancer by actively participating in the whole spectrum of the patient's journey-from diagnosis, treatment, supportive care, until providing palliative care and addressing end-of-life issues.

Giant cell tumor of soft tissue of the nasopharynx: A case report.

Primary soft tissue giant cell tumors are rare. Although these tumors resemble their osseous counterparts, sequencing studies have suggested that these two may be genetically distinct. Treatment guidelines are less clear for this tumor type compared to giant cell tumor of the bone. Surgical excision is the standard of treatment; but for those with unresectable disease treatment options are less certain. For patients with unresectable tumors, the use of bisphosphonates and RANK-L directed biologic therapy have been described in the literature. We report a case of a nasopharyngeal giant cell tumor, which is an uncommon presentation of a rare soft tissue tumor. While surgery is the preferred treatment for this disease, the location of this tumor precluded resection. This has prompted the decision to employ systemic treatment with Zoledronic acid and subsequently Denosumab for the treatment of this patient.

What Will Keep Me Coming Back to the Clinic: Factors Identified by Filipino Colorectal Cancer Patients Seen at a National Academic Referral Center.

Health-care decisions in the Philippines are widely affected by various factors such as family, community, health-care access, and educational attainment. We designed a questionnaire to evaluate patient views at the University of the Philippines-Philippine General Hospital colorectal multidisciplinary clinic to identify factors that contribute to continued follow-up at the colorectal multidisciplinary clinic. A total of 128 patients, 62% of whom were being treated with curative intent participated in the study. We found that trust in their physicians, presence of family support, and affordability of treatment were factors highly valued by patients consulting at the clinic.

Patterns of Biomarker Use in Cancer Treatment Among Medical Oncologists in the Philippines.

PURPOSE: Several factors affect how medical oncologists in the Philippines use biomarkers in real-world practice. This study describes patterns of biomarker testing for the management of breast, colorectal, and lung cancers among medical oncologists in the Philippines. METHODS: A cross-sectional survey was performed among practicing medical oncologists in the Philippines from November to December 2019. The questionnaire determined the ideal and practical use of biomarkers as perceived by the respondents. Responses were summarized. Associations between biomarker use across select conditions were determined. RESULTS: A total of 127 respondents (38% of medical oncologists in the Philippines) participated in this study. In actual practice, 97% of the respondents requested estrogen receptor/progesterone receptor testing, and 93% requested human epidermal growth factor receptor 2 testing. For colorectal cancer, the respondents would use KRAS and mismatch repair/microsatellite instability, but 59.84% had never used BRAF. For lung cancer, 97.64% of respondents would test for epidermal growth factor receptor (EGFR), 88.19% would test for PD-L1, 80.31% for anaplastic lymphoma kinase, 58.27% for ROS1, and 33.07% for BRAF. In actual practice, EGFR was the most frequently ordered test (67.72%), while 44.80% of medical oncologists had never used ROS1. The most common reason for testing was adherence to international guidelines (96%). The most commonly cited barrier to biomarker use was patients' financial constraints (94.49%). Overall, the respondents' use of biomarkers was not significantly associated with institutional affiliation, the number of patients they saw monthly, and the availability of biomarker tests in their areas of practice. CONCLUSION: Medical oncologists in the Philippines would use biomarkers in treating breast, colorectal, and lung cancers if these were clinically indicated and if cost were not a factor. Financial difficulty experienced by patients was the most commonly cited barrier to biomarker use.

Updated general recommendations in cancer management during the COVID-19 pandemic in the Philippines.

In May 2020, the Philippine Society of Medical Oncology published its initial recommendations on the treatment of cancer patients during the SARS-Cov-2 pandemic. The objective of this update is to provide answers to the questions pertaining to the diagnostic testing of SARS-CoV-2 for both cancer patients and healthcare professionals caring for cancer patients, as well as the recommended protective measures and practices that may be instituted in healthcare facilities.

Treatment of cancer patients during the COVID-19 pandemic in the Philippines.

The COVID-19 pandemic has caused disruptions in cancer care around the world due to logistical and psychosocial reasons. This paper was written with the primary objective of providing a guide for medical oncologists in addressing concerns in the management of adult patients with solid tumours in the Philippines and for those working under similar circumstances. These recommendations are divided into prioritisation of cancer care, ensuring a safe work environment, organising the transition of cancer care, and maintaining cohesion in a time of isolation.

COVID-19 in cancer patients can be challenging to screen in a resource limited setting.

During this COVID-19 pandemic, patients with symptoms such as fever, cough, sore throat, and coryza were advised to have RT-PCR testing for SARS-CoV-2 infection. We described here an elderly female with chronic lymphocytic leukemia, who presented with atypical symptoms that were not directly attributable to COVID-19. This patient was admitted to the non-COVID-19 ward for supportive care. Later, her chest x-ray revealed pneumonia that was confirmed to be COVID-19 by RT-PCR testing several days later. In resource-poor settings where molecular testing results suffered from delays or were altogether unavailable, the use of diagnostic imaging such as a chest x-ray could serve as a quick guide in the assessment and management of these patients especially if the imaging results suggest COVID-19 infection.

Beyond bevacizumab: a review of targeted agents in metastatic small bowel adenocarcinoma.

Small bowel cancers are rare tumors with an incidence 50-100-fold less than colorectal cancer. These tumors carry a poor prognosis. Owing to its rarity, treatment of this disease, particularly in its advanced stages, has not been optimized and is derived mainly from treatment regimens for colorectal cancer. Based on recent studies bevacizumab, an antibody directed against vascular endothelial growth factor and used in the management of metastatic CRC, has been added to treatment guidelines for metastatic small bowel adenocarcinoma. We investigate in this review the evidence behind other targeted treatments that may be beneficial in the treatment of metastatic small bowel adenocarcinoma. These are agents against EGFR, VEGFR-2, HER2, and NTRK as well as immune checkpoint inhibitors. The last class of drugs appears to hold the greatest promise based on the preponderance of evidence supporting its use. However, overall data remains sparse. Results of studies currently underway will be valuable in shedding more light on the management of this aggressive cancer.

Medical oncology care amidst the COVID-19 pandemic at the National University Hospital in the Philippines.

COVID-19 has abruptly and radically changed the landscape of cancer care delivery throughout the world, including the Philippines. The Philippine General Hospital is the academic hospital of the University of the Philippines. Its cancer centre is a primary referral centre that takes care of Filipinos-many resource-constrained-that are burdened by malignancy. As the global pandemic challenges healthcare delivery, centres are forced to rethink how to care for their patients. This paper discusses how a national, academic, referral cancer institute in a low-middle income country is trying to meet the challenges of COVID-19.

Treatment Outcomes of Patients With Colorectal Cancer Enrolled in a Comprehensive Benefits Program of the National Insurance System in the Philippines: Data From the Pilot Site.

PURPOSE: Cancer treatment causes significant financial burden, especially in developing countries such as the Philippines. This led the Philippine Department of Health to create the Z-Package colorectal cancer benefit program, an insurance system specifically designed to treat Filipinos with colorectal cancers with early to locally advanced-stage disease. The main goal of this program is to optimize treatment outcomes for this curable disease without causing financial toxicity. MATERIALS AND METHODS: Three-year data on patients enrolled in the Z-Package colorectal cancer benefit program from 2016 to 2018 were reviewed by the University of the Philippines, Philippine General Hospital Colorectal Polyp and Cancer Study Group. RESULTS: A total of 251 patients were enrolled in the Z-package colorectal cancer benefit program from 2016 to 2018. Mean age was 57 years old and a majority of patients (66%) were male. A majority of patients had rectal cancer (78%) and were diagnosed with stage III disease (82%). A majority (75%) were compliant to their treatment plans and clinic follow-up. Specifically, compliance to the prescribed surgery, chemotherapy, and/or radiation treatment were 90%, 77%, and 96%, respectively. Recurrence, morbidity, and mortality rates of enrolled patients in the Z-Package program from 2016 to 2018 were 17%, 22%, and 19%, respectively. Morbidities were mostly chemotherapy related (8%). Finally, patients in this program had a 2- and 3-year survival probability of 74% and 70%, respectively, which are comparable with data from more developed nations. CONCLUSION: Results of this study include real-world data that show that when the highest standards of patient care are provided through a multidisciplinary team, patients' overall survival is also maximized.

Bevacizumab in metastatic small-bowel adenocarcinoma: A systematic review and meta-analysis.

Cancers of the small bowel could account for less than 5% of all gastrointestinal malignancies. Of these tumors, adenocarcinomas were the major histologic subtype and generally carried a poor prognosis. High expression of vascular epithelial growth factor (VEGF) could be seen in small bowel adenocarcinomas. A systematic review was conducted here to determine if bevacizumab, a recombinant humanized antibody against VEGF, could offer clinical benefit among patients with metastatic small bowel adenocarcinoma when combined with chemotherapy. A search for relevant published and unpublished studies was performed using PubMed, ScienceDirect, Google Scholar, the American Society of Clinical Oncology meetings library, ClinicalTrials.gov, and ISRCTN registry. Information on study design, methods, intervention, and outcomes were extracted from selected eligible studies. Methodological quality was then assessed using the Newcastle-Ottawa Scale. There was a significant improvement in mean overall survival with the addition of bevacizumab with chemotherapy versus chemotherapy alone. The use of bevacizumab with chemotherapy, likewise improved progression-free survival and objective response rate compared to chemotherapy alone. Continued use of bevacizumab beyond first progression also appeared to show benefit. The conduct of prospective controlled studies by consortia to offset the rarity of small bowel adenocarcinomas could further elucidate the efficacy of bevacizumab in the treatment of this disease.

Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis.

INTRODUCTION: Systemic inflammation is associated with prognosis in solid tumors. The neutrophil-to-lymphocyte ratio (NLR) is a marker for the general immune response to various stress stimuli. Studies have shown correlation of NLR to outcomes in immune checkpoint blockade, peripheral neutrophil count to intratumor neutrophil population, and NLR to intratumoral levels of myeloid-derived suppressor cells. Studies have shown elevated peripheral blood regulator T cells accompanied by elevated NLR are associated with poor outcomes further highlighting the importance of inflammation in the prognosis of cancer patients. METHODS: We performed a meta-analysis of published articles on the utility of baseline NLR in predicting outcomes in patients treated with immune checkpoint inhibitors (ICIs) using Review Manager, version 5.3. Seven studies on the prognostic utility of NLR in ICI treatment were included in this analysis. For outcomes of interest, the hazard ratios (HRs) were computed. Subgroup analyses were planned based on type of malignancy and type of immune checkpoint inhibitor. RESULTS/DISCUSSION: A high NLR resulted in worse overall survival (OS) (HR, 1.92; 95% CI, 1.29-2.87; p=0.001) and progression-free survival (PFS; HR, 1.66; 95% CI, 1.38-2.01; p<0.00001) across types of malignancies studied (melanoma, non-small-cell lung cancer, and genitourinary cancer). Subgroup analysis across different types of malignancies treated with ICI showed similar results for OS and PFS. The single study on genitourinary cancers also showed worse OS and PFS (OS: HR, 1.82; 95% CI, 1.29-2.87; p=0.001 and PFS: HR, 1.83; 95% CI, 0.97-3.44; p=0.06). A high NLR also showed worse OS and PFS across all ICIs (ipilimumab, nivolumab, and unspecified or pooled pembrolizumab and nivolumab; OS: HR, 1.92; 95% CI, 1.29-2.87; p=0.001 and PFS: HR, 1.66; 95% CI, 1.38-2.01; p<0.00001). Subgroup analysis by type of ICI showed similar results. CONCLUSION: A high NLR is associated with poorer outcomes across studies. This shows that NLR has the potential as a readily available prognostic indicator for patients receiving ICI based on available studies. Studies utilizing more stringent design may serve to better determine the utility of this tool.