Cancer Medicine

PurposeTumor genomic testing (TGT) is standard-of-care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact and durability of a concise 3-4 minute video for patient education prior to TGT in community versus academic sites and across cancer types. Patients and MethodsPatients undergoing standard-of-care TGT were enrolled at a tertiary academic institution in three cohorts: Cohort 1-breast cancer; Cohort 2-lung cancer; Cohort 3-other cancers. Cohort 4 consisted of patients with any cancer type similarly undergoing SOC TGT at one of three community cancer centers. Participants completed survey measures prior to video viewing (T1), immediately post-viewing (T2), and after return of TGT results (T3). Outcome measures included: 1) 10-question objective genomic knowledge/understanding (GKU); 2) 10-question video message-specific knowledge (VMSK); 3) 11-question Trust in Physician/Provider (TIPP); 4) perceptions regarding TGT. ResultsA total of 203 participants completed all survey timepoints. Higher baseline GKU and VMSK scores were significantly associated with higher income and greater years of education. For the primary objective, there was a significant and sustained improvement in VMSK from T1:T2:T3 (Poverall p<0.0001), with no significant change in GKU (p=0.41) or TIPP (p=0.73). This trend was consistent within each cohort (all p[&le;]0.0001). Results for four VMSK questions significantly improved, including impact on treatment decisions, incidental germline findings, and insurance coverage of testing. ConclusionsA concise, 3-4 minute, broadly applicable educational video administered prior to TGT significantly and sustainably improved video message-specific knowledge in diverse cancer types and in academic and community settings. This resource is publicly available at http://www.tumor-testing.com, with a goal to efficiently educate and empower patients regarding TGT while addressing guidelines within the flow of clinical practice.

BackgroundFluoropyrimidine-based adjuvant chemotherapy is globally recommended for postoperative stage III colon cancer and high-risk stage II patients. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, a recurrence-prevention biomarker of adjuvant chemotherapy for colorectal cancer is necessary for providing such treatments to appropriate patients. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between the single-nucleotide variants of autophagy-related genes and recurrence rates to identify the recurrence-prevention biomarkers of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer patient relapse rates. ResultsWe detected 560 single-nucleotide variants or insertions/deletions in the target region. The results of Fishers exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single- nucleotide variants (c.1018G>A [p < 0.005] or c.1562A>C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. ConclusionsThe two single-nucleotide variants of this mitophagy-related gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

BackgroundRemnant cholesterol (RC) is becoming an increasingly well-recognized risk factor for cardiometabolic diseases. However, no study has explored the predictive role of RC in new-onset cancer. This study aimed to examine the associations between RC and time-weighted RC with incident cancer in the general population. MethodsThis was a retrospective population-based study enrolling patients attending family medicine clinics in Hong Kong between 1st January 2000 and 31st December 2003 with at least three RC measurements during follow-up visits. The primary outcome was new-onset cancer. The secondary outcome was cancer-related mortality. Multivariable Cox regression was used to evaluate associations between baseline RC and time-weighted RC with outcomes. ResultsA total of 75,342 adults (39.7% males, mean age: 62.5 years old) were included. During a median follow-up of 16.8 years, 8335 (11.1%) incident cancer and 4349 (5.7%) cancer-related deaths were observed. After adjusting for potential confounders, one mmol/L increased of time-weighted RC was associated with 41% and 62% higher risk of incident cancer (HR, 1.41; 95%CI, 1.26-1.57; p<0.0001) and cancer-related mortality (HR, 1.62; 95%CI, 1.43-1.85; p<0.0001), respectively. However, no significant association between baseline RC with risk of new-onset cancer (HR, 1.04; 95%CI, 0.82-1.31; p=0.768) and cancer-related mortality (HR, 0.85; 95%CI, 0.61-1.17; p=0.315) in the adjusted model. The association between time-weighted RC and incident cancer was significant regardless of age, gender, and remained consistent amongst those with baseline use of most cardiometabolic agents, as well as those complicated with most comorbidities. ConclusionsHigher time-weighted RC was associated with increased risk of new-onset cancer and cancer-related mortality amongst the general population.

IntroductionIn the United States, colorectal cancer (CRC) remains a substantial public health challenge, with approximately 150,000 new cases diagnosed annually. Guidelines from organizations such as the United States Preventive Services Task Force (USPSTF) recommend several screening strategies, including endoscopic, radiologic, and stool-based options such as the multi-target stool DNA (mt-sDNA) test. In this analysis, we analyzed the estimated clinical, social, and economic impacts of mt-sDNA screening over the inaugural 10-year period for test availability. MethodsTo assess the effectiveness of CRC screenings with the mt-sDNA test, published rates of advanced precancerous lesions (APL) and cancer prevalence by stage, as well as the transition rate of APL to CRC for the average-risk population in the US were used for a simulated population. The mt-sDNA tests sensitivity and specificity for APL and CRC were derived from previously published data. To assess the economic impact of screening with mt-sDNA compared to colonoscopy, we utilized data from literature regarding the time and resources required to prepare and complete each test. Furthermore, the costs of treatment according to the stage of colorectal cancer are considered, to show the value of CRC prevention and early detection. ResultsOur analysis indicates that mt-sDNA screening detected an estimated 98,000 cases of CRC and 525,000 individuals were found to have APLs, precursors to CRC. When using 10-year survival rate from CRC, it is estimated that the mt-sDNA test led to more than 34,000 patients surviving due to earlier intervention compared to no screening. Furthermore, the mt-sDNA test demonstrated approximately $22.3 billion cost savings compared to no screening, including an estimated $9.7 billion in cancer treatment costs through early CRC detection and an additional $12.6 billion resulting from cancer prevention through APL detection and management. ConclusionClinical availability, adoption, and growth of stool-based CRC screening have significantly increased overall screening rates in the US. It is estimated that mt-sDNA utilization will continue to grow, providing a home-based CRC screening solution for millions of screen-eligible US adults over the next decade and beyond.

Circulating tumor DNA (ctDNA) panels hold high promise of accurately predicting the therapeutic response of tumors while being minimally invasive and cost-efficient. However, their use has been limited to a small number of tumor types and patients. Here, we developed individualized ctDNA fingerprints suitable for most patients with multiple cancer types. The panels were designed based on individual whole-exome sequencing data in 521 Chinese patients and targeting high clonal population clusters of somatic mutations. Together, these patients represent 12 types of cancers and seven different treatments. The customized ctDNA panels have a median somatic mutation number of 19, most of which are patient-specific rather than cancer hotspot mutations; 66.8% of the patients were ctDNA-positive. We further evaluated the ctDNA content fraction (CCF) of the mutations, and analyzed the association between the change of ctDNA concentration and therapeutic response. We followed up 106 patients for clinical evaluation, demonstrating a significant correlation of changes in ctDNA with clinical outcomes, with a consistency rate of 93.4%. In particular, the median CCF increased by 204.6% in patients with progressive disease, decreased by 82.5% in patients with remission, and was relatively stable in patients with stable disease. Overall, 85% of the patients with a ctDNA-positive status experienced metastasis or relapse long before imaging detection, except for two patients who developed recurrence and metastasis almost simultaneously. The average lead time between the first ctDNA-positive finding and radiological diagnosis was 76 days in three patients that changed from a ctDNA-negative to -positive status. Our individualized ctDNA analysis can effectively monitor the treatment response, metastasis, and recurrence in multiple cancer types in patients with multiple treatment options, therefore offering great clinical applicability for improving personalized treatment in cancer.\n\nOne Sentence SummaryctDNA fingerprint panels were customized to predict the treatment response for multiple cancer types from individual whole-exome sequencing data.

Although the prognostic significance of exosomal PD-L1 (exoPD-L1) has been previously reported, its value is still controversial. For the first time, we conducted a meta-analysis to systematically evaluate the prognostic value of exoPD-L1 in various types of cancer. The pooled hazard ratio (HR) and 95% confidence interval (CI) in these studies were used to explore the relationship between these indexes and overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). Utilizing the NewcastleLJOttawa Scale (NOS), the quality of the listed studies was assessed. Heterogeneity was explored by subgroup analyses. Beggs and Eggers tests assessed publication bias. This meta-analysis included 11 trials involving 964 cancer cases. The pooled results indicate that high-level pre-treatment exoPD-L1 in circulation was associated with worse OS (HR = 2.10, 95% CI 1.51-2.91, P < 0.001), RFS (HR = 1.67, 95% CI 1.18-2.37, P < 0.01) and PFS (HR = 3.49, 95% CI 2.60-4.68, P < 0.001) compared to those with low-level pre-treatment exoPD-L1. However, high fold changes in circulating exoPD-L1 after receiving immune checkpoint inhibitors (ICIs) were correlated with significantly superior OS (HR = 0.19, 95% CI 0.10-0.38, P < 0.001) and PFS (HR = 0.35, 95% CI 0.23-0.52, P < 0.001). Through this meta-analysis, we found that pre-treatment with high levels of exoPD-L1 is associated with a poor prognosis. However, a high fold change in circulating exoPD-L1 following immunotherapy was correlated with a superior prognosis. ExoPD-L1 may have important clinical significance for assessing the prognosis of cancer patients.

BackgroundGastric cancer (GC) continues to be among the most commonly identified cancers worldwide. This study integrates glycosylation and inflammation-related gene features for the first time to construct a prognostic model for gastric cancer, providing new theoretical basis for revealing immune escape mechanisms and personalized treatment strategies. MethodsTranscriptomic and clinical data derived from GC samples were meticulously examined, utilizing resources from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Through differential expression analysis, we successfully identified glycosylation and inflammatory-related differentially expressed genes (GANDIRDEGs). To construct a prognostic gene signature, we applied least absolute shrinkage and selection operator (LASSO) analysis in conjunction with Cox regression analysis. Additionally, we performed somatic mutation (SM) along with copy number variation (CNV) analyses, alongside gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Furthermore, we conducted gene set enrichment analysis (GSEA) along with a comprehensive evaluation of immune infiltration and drug sensitivity. ResultsWe identified and validated a six-gene (INHBA, OLR1, ROS1, EPHA5, TACR1, and IL6) signature, termed GANDIRDEGs, which showed excellent performance in distinguishing overall survival (OS) between high-risk (HR) and low-risk (LR) cohorts. Moreover, we developed a prognostic nomogram utilizing this six-gene signature that provides highly accurate predictions of GC patient outcomes.SM and CNV analyses revealed that MSR1 had the highest mutation rate among the GANDIRDEGs, with a mutation rate of 5%. GO, KEGG, and GSEA revealed significant associations of each pivotal gene with pathways, including cytokine signaling, the inflammatory response, and apoptosis mediated by CDKN1A through TP53, among various biological functions and signal transduction pathways. Our findings offer a novel gene signature, GANDIRDEGs, that correlated with prognosis, immune infiltration, and therapeutic sensitivity in patients with GC. ConclusionThis study establishes a prognostic signature integrating glycosylation and inflammatory pathways in GC, providing valuable insights into the mechanisms of immune evasion and potential personalized treatment approaches.

PurposeIncidence and mortality rates of colorectal cancer (CRC) in South Asia are expected to rise by 70% between 2020 and 2040. Despite recent advances in the understanding of molecular alterations in CRC, the representation of South Asians in published genomic datasets is very limited. To address this gap, we performed a pilot study based on a transnational collaboration between academic centers in the US and Pakistan to characterize copy number alterations in a Pakistani cohort with CRC. MethodsWe obtained archived formalin-fixed paraffin-embedded (FFPE) tissue samples from 43 CRC patients treated at Aga Khan University (AKU) Hospital. DNA was extracted and evaluated for quality at AKU, and whole genome sequencing library preparation and shallow whole genome sequencing was performed at University of Wisconsin-Madison. Sequencing data was aligned to the human genome, and we used ichorCNA and GISTIC2 to determine relative copy number alterations. ResultsAfter removing 13 samples with insufficient DNA quality or quantity, tumor sequencing data was analyzed from 30 patients. The cohort consisted of 19 (63.3%) males with a mean age of 50.1 years and standard deviation (SD) of 17.8 years. Twenty-one (70.0%) patients had tumor stage T3 or T4, and 15 (50.0%) had tumors of the colon. A mean of 265 ng (SD, 29 ng) of DNA was extracted from each FFPE tumor sample, and each sample was sequenced to a mean depth of 0.22x (0.21x). Analysis of copy number alterations revealed recurrent gains in regions 8q and 13q, as well as losses in region 8p. ConclusionsThis transnational pilot study helped identify the challenges related to FFPE sample quality that can impede similar efforts in the future. Our results revealed similarities in the most common copy number alterations in CRC identified in native Pakistani patients and published datasets.

AbstractsO_ST_ABSBackgroundC_ST_ABSCancer patients are considered to be highly susceptible to viral infections, however, the comprehensive features of COVID-19 in these patients remained largely unknown. The present study aimed to assess the clinical characteristics and outcomes of COVID-19 in a large cohort of cancer patients. Design, Setting, and ParticipantsData of consecutive cancer patients admitted to 33 designated hospitals for COVID-19 in Hubei province, China from December 17, 2019 to March 18, 2020 were retrospectively collected. The follow-up cutoff date was April 02, 2020. The clinical course and survival status of the cancer patients with COVID-19 were measured, and the potential risk factors of severe events and death were assessed through univariable and multivariable analyses. ResultsA total of 283 laboratory confirmed COVID-19 patients (50% male; median age, 63.0 years [IQR, 55.0 to 70.0]) with more than 20 cancer types were included. The overall mortality rate was 18% (50/283), and the median hospitalization stay for the survivors was 26 days. Amongst all, 76 (27%) were former cancer patients with curative resections for over five years without recurrence. The current cancer patients exhibited worse outcomes versus former cancer patients (overall survival, HR=2.45, 95%CI 1.10 to 5.44, log-rank p=0.02; mortality rate, 21% vs 9%). Of the 207 current cancer patients, 95 (46%) have received recent anti-tumor treatment, and the highest mortality rate was observed in the patients receiving recent chemotherapy (33%), followed by surgery (26%), other anti-tumor treatments (19%), and no anti-tumor treatment (15%). In addition, a higher mortality rate was observed in patients with lymphohematopoietic malignancies (LHM) (53%, 9/17), and all seven LHM patients with recent chemotherapy died. Multivariable analysis indicated that LHM (p=0.001) was one of the independent factors associating with critical illness or death. ConclusionsThis is the first systematic study comprehensively depicting COVID-19 in a large cancer cohort. Patients with tumors, especially LHM, may have poorer prognosis of COVID-19. Additional cares are warranted and non-emergency anti-tumor treatment should be cautiously used for these patients under the pandemic.

BackgroundGermline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC) and pre-diagnostic testing is offered to patients with a significant family history. However, only 41% of patients in our institution obtained genetic testing. We identified associations between patient social profiles and delays in obtaining germline genetic testing from New Yorks largest healthcare system. MethodsPatients with PDAC were identified using our EMR between Mar 2016 and Feb 2022 with an IRB-approved protocol. Median income was extrapolated using zip code. Date of diagnosis (DOD) was recorded as the date of biopsy. Delays of testing was calculated as the difference between DOD and the date of germline test. Social work needs and insurance were captured by EMR review of social work notes. Results329 patients with PDAC were identified, with 135 (41%) having reports found. Availability of germline testing did not vary by median income. Pearson analysis between income and delays showed a negative correlation (r=-0.258, p=0.0025). Patients who received social security and were unemployed/disabled had significant delays (167d) in testing compared to patients receiving social security (13d) and retired or patients receiving salaries (30d). African Americans and Hispanics, classified as underserved minority, had significant delays in testing (66d) compared to not underserved patients (22.5d, p=0.021). In addition, African American patients had significant delays in testing (66d) compared to White patients (20d, p=0.0076). Patients with social work needs had significant delays in testing (104d) compared to patients without SW needs (20.5d, p=0.0002). Of the twelve patients who required SW, six required home care, three required transportation, and two required financial assistance. In addition, patients with Medicare and supplementary insurances had significant decreases in delays (10d) of germline testing compared with patients with Medicare alone (32d, p=0.0077), Medicaid (57d, p=0.020), or commercial insurances (21d, p=0.021). We identified 12 patients who had germline mutation reports before PDAC diagnosis. For patients with pre-diagnostic testing, 5 had Medicare with supplementary insurances. For the rest of patients with germline testing after the diagnosis of PDAC, 10 had supplementary insurances (p=0.0043). ConclusionThe analysis of our 329-patient cohort showed a striking and concerning negative correlation between patient income and delays in germline testing. Under-represented minority patients had significant delays in germline testing and did not obtain any pre-diagnostic testing. Social work needs and insurance may be barriers as well. Interprofessional collaborations may be required to prompt germline testing.

BackgroundMulti-target blood tests have the potential to detect a broad range of cancer types and stages. We previously trained and independently assessed the performance of four biomarker classes for cancer detection in a retrospectively assembled case-control feasibility study. The primary aim of this study was to assess the performance of a methylation and protein (MP) classifier using samples from a large, multi-center, prospectively collected case-control study. As part of the ongoing assay development process, we also performed an exploratory analysis investigating the addition of a somatic mutation reflex approach (MP-reflex) on samples with scores below the threshold for a positive MP call but above a clear negative MP call. MethodsThis study included 6,352 samples (1,438 cancer and 4,914 non-cancer) representing all stages among 21 tumor organ types divided approximately equally between a training and a test set. The sensitivity of the MP classifier was determined at a high specificity. The MP-reflex approach was investigated on MP samples at the same specificity threshold and detectable MP signals above pre-specified lower thresholds. ResultsAt 98.5% specificity, the observed overall sensitivity for MP biomarkers was 50.9%, with sensitivities of 15.4%, 26.1%, 38.0%, 67.8%, 85.5%, and 37.5% for stages I, I and II combined, II, III, IV, and unknown, respectively. When breast and prostate cancers were excluded from the analysis, overall test sensitivity was 56.8%, with sensitivities of 17.2%, 30.7%, 48.6%, 73.5%, 86.5%, and 40.0% for stages I, I and II combined, II, III, IV, and unknown, respectively. ConclusionMethylation and protein biomarkers detected all cancer organ types incorporated in the analysis, including those without standard of care (SoC) cancer screening options and aggressive cancers with poor 5-year survival. These results demonstrate the potential clinical validity of multi-biomarker testing for the detection of several cancer types.

BackgroundDespite the role of pathogenic variants (PVs) in cancer predisposition genes conferring significantly increased risk of breast cancer (BC), uptake of genetic testing (GT) remains low, especially among ethnic minorities. Our prior study identified that a patient decision aid, RealRisks, improved patient-reported outcomes relative to standard educational materials. This study examined patients GT experience and its influence on subsequent actions. We also sought to identify areas for improvement in RealRisks that would expand its focus from improved GT decision-making to understanding results. MethodsWomen enrolled in the parent randomized controlled trial were recruited and interviewed. Demographic data was collected from surveys in the parent study. Interviews were conducted, transcribed, and coded to identify recurring themes. Descriptive statistics were generated to compare the interviewed subgroup to the original study cohort of 187 women. ResultsOf the 22 women interviewed, 11 (50%) had positive GT results, 2 (9.1%) with a BRCA1/2 PV, and 9 (40.9%) with variants of uncertain significance (VUS). Median age was 40.5 years and 15 (71.4%) identified as non-Hispanic. Twenty (90.9%) reported a family history of BC, and 2 (9.1%) reported a family history of BRCA1/2 PV. The emerging themes included a preference for structured communication of GT results and the need for more actionable knowledge to mitigate BC risk, especially among patients with VUS or negative results. Few patients reported lifestyle changes following the return of their results, although they did understand that their behaviors can impact their BC risk. ConclusionsPatients preferred a structured explanation of their GT results to facilitate a more personal testing experience. While most did not change lifestyle behaviors in response to their GT results, there was a consistent call for further guidance following the initial discussion of GT results. Empowering patients, especially those with negative or VUS results, with the knowledge and context to internalize the implications of their results and form accurate risk perception represents a powerful opportunity to mediate subsequent risk management strategies. Informed by this study, future work will expand RealRisks to foster an accurate perception of GT results and include decision support to navigate concrete next steps.

Genetic counseling and testing for germline mutations are essential for identifying individuals at increased risk for cancer. Pathogenic variants in TP53 are diagnostic of Li-Fraumeni syndrome (LFS), a highly penetrant disorder with diverse, early-onset tumors. Current clinical guidelines, such as Chompret and Classic criteria, provide frameworks for identifying individuals at risk for likely pathogenic/pathogenic TP53 variants; however, genetic counselors often encounter patients with features concerning for LFS that do not clearly meet established criteria, creating challenges for risk assessment and testing decisions. We evaluated whether LFSPRO, a Mendelian, family-history-based model that estimates the individuals probability of harboring a deleterious TP53 variant, improves carrier identification relative to guideline criteria. In a prospectively collected cohort of 182 probands who underwent clinical genetic counseling and germline TP53 testing, LFSPRO showed superior discrimination compared with Chompret criteria, with higher sensitivity (81% vs. 33%) and specificity (88% vs. 65%) and improved predictive values (PPV 0.53 vs. 0.14; NPV 0.96 vs. 0.85). Receiver operating characteristic analysis confirmed strong discriminatory performance (AUC=0.88). Calibration analysis using observed-to-expected ratios indicated good agreement between predicted and observed carrier frequencies (Observed/Expected=1.07). These findings demonstrate that LFSPRO outperforms traditional guideline-based criteria for identifying TP53 mutation carriers in real-world clinical settings. By providing quantitative, well-calibrated carrier probabilities rather than binary classifications, LFSPRO can enhance genetic counseling and support testing decisions, particularly for individuals who do not clearly meet existing criteria.

PurposeTumor mutational burden (TMB) is an approved biomarker for immunotherapy in metastatic cancer patients. While initially measured from tissue (tTMB), TMB derived from circulating tumor DNA (ctDNA) - also known as blood TMB (bTMB) - is increasingly being used in the clinic. Currently, real-world concordance between tTMB and bTMB is not well understood. Patients and methodsFrom October 2020 to March 2021, cancer patients who had both tTMB and bTMB results were selected. Patients were classified according to clinical variables and tumor burden, and correlation analyses or tests of independence were performed to explore any associations. ResultsFrom a total of 38 patients included in our study, 20 patients (52.6%) had non-small cell lung carcinoma and 18 (47.4%) had other cancers. Median bTMB of 9.6 mut/MB was higher than median tTMB of 4.0 mut/Mb, and the distributions of bTMB and tTMB differed significantly (n=38, p < 0.001). bTMB was positively correlated with tTMB in the total study population (Spearman {rho}=0.57, p < 0.001) and a tTMB of 10 mut/Mb correlated with a bTMB of 21.1 mut/Mb. Dividing patients by cancer type or site of tumor biopsy resulted in significantly differing strength and degree of correlation, but dividing patients by concordant and discordant bTMB:tTMB ratio did not reveal any significantly different distributions of clinical variables or tumor burden. ConclusionbTMB was positively correlated with tTMB, and median bTMB was higher than median tTMB. Cancer type and site of tissue biopsy may influence concordance between tTMB and bTMB. Future studies with more patients may help define the optimal bTMB threshold for receiving immunotherapy, which may be different from the tTMB threshold.

BackgroundResearch on the link between hematological characteristics and cancer risk has gained significant attention. Traditional epidemiological and cell biology studies, have identified correlations between blood traits and cancer risks. These findings are important as they suggest potential risk factors and biological mechanisms. However, these studies often cant confirm causality, pointing to the need for further investigation to understand these relationships better. MethodsMendelian randomization (MR), utilizing single-nucleotide polymorphisms as instrumental variables, was employed to investigate hematological trait causal effects on cancer risk. Thirty-six hematological traits were analyzed, and their impact on 28 major cancer outcomes was assessed using data from the FinnGen cohort, with eight major cancer outcomes and 22 cancer subsets. Furthermore, 1,008 MR analyses were conducted, incorporating sensitivity analyses (weighted median, MR-Egger, and MR-PRESSO) to address potential pleiotropy and heterogeneity. FindingsThe analysis (data from 173,480 individuals primarily of European descent) revealed significant results. A decrease in eosinophil count was associated with a reduced risk of colorectal malignancies (OR 0.7702, 95% CI 0.6852, 0.8658; p = 1.22E-05). Similarly, an increase in total eosinophil and basophil count was linked to a decreased risk of colorectal malignancies (OR 0.7798, 95% CI 0.6904, 0.8808;p = 6.30E-05). Elevated hematocrit (HCT) levels were associated with a reduced risk of ovarian cancer (OR 0.5857, 95% CI 0.4443, 0.7721;p =1.47E-04). No significant heterogeneity or horizontal pleiotropy was observed. InterpretationSpecific hematological traits may serve as valuable indicators and biomarkers for cancer monitoring. FundingNone. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSPreclinical and conventional epidemiological studies have identified correlations between hematological characteristics and cancer risks. For instance, elevated eosinophil levels have been linked to improved prognosis in colorectal cancer (CRC) patients, and a high basophil-to-lymphocyte ratio (BLR) has been associated with adverse outcomes in prostate cancer. Additionally, increased red cell distribution width (RDW) has been correlated with poorer survival outcomes in metastatic penile and muscle-invasive bladder cancers. These findings suggest potential roles for hematological traits in cancer risk assessment and treatment strategies. However, traditional research methods, including randomized controlled trials (RCTs), face ethical and practical limitations, while observational studies suffer from biases and confounding variables, complicating the establishment of causal relationships. Added value of this studyThis study represents the first comprehensive application of Mendelian randomization (MR) to evaluate causal relationships between hematological characteristics and cancer risk. MR uses genetic variations as instrumental variables to minimize confounding, providing more reliable causal insights. Thirty-six hematological traits were analyzed, and their impact on 28 major cancer outcomes was assessed using data from the FinnGen cohort. Significant findings include the negative association between eosinophil count and CRC risk, supporting previous research on eosinophils antitumor role. Increased total eosinophil and basophil counts were linked to decreased CRC risk. Elevated hematocrit (HCT) levels were associated with a reduced risk of ovarian cancer, suggesting these traits could be potential targets for cancer treatment. Implications of all the available evidenceOur findings provide new insights into the role of hematological traits in cancer risk, emphasizing their potential in cancer treatment and as prognostic biomarkers.

Most studies examining the causes of cancer-related deaths have primarily focused on specific cancer types, often neglecting the evolving spectrum of death causes among cancer patients in the 21st century. This study, utilizing data from the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) Program, analyzed the causes of death in patients diagnosed with 36 types of cancer between 2000 and 2021. By categorizing these causes into deaths from index cancers, non-index cancers, and non-cancer causes, this study provides a comprehensive analysis of cause-of-death patterns and emerging trends, stratified by year of death, age at diagnosis, and survival duration. The findings reveal that while relative mortality rates from index cancers remain elevated for brain, pancreatic, and gallbladder cancers, significant declines were observed for lung, liver, nasopharyngeal, and esophageal cancers, as well as multiple myeloma cancers, reflecting advancements in cancer treatment. Besides, relative mortality rates from non-index cancers surpassed those from index cancers in oral cavity, oropharyngeal, vaginal, and small intestine cancers, indicating a potential benefit from enhanced surveillance and early detection of non-index cancers in these patient populations. Importantly, non-cancer-related causes of death, such as heart disease, chronic liver disease and cirrhosis, also emerged as prominent contributors to mortality among cancer patients. The results of this study offer critical and current data to inform public health policy, optimize healthcare resource allocation, and facilitate international collaboration in cancer research and control. Meanwhile, this study is of great reference value for developing countries to formulate medium- and long-term public health policies.

BackgroundThe therapeutic benefit of the standard combination of anti-HER2 and chemotherapy in triple-positive breast cancer (TPBC) is limited even after the addition of endocrine therapy to the regimen. Therefore, treatment optimization is required urgently. MethodsThrough the drug sensitivity test, the drug combination efficacy of anti-HER2 drug, endocrine drug and CDK4/6 inhibitor to BT474 cells were tested. The underlying molecular mechanisms were investigated using immunofluorescence, western blot analysis, immunohistochemical staining and cell cycle analysis. Potential biomarker which may indicate the responsiveness to drug treatment in triple positive breast cancer was selected out using RNA-sequence and tested using immunohistochemical staining. ResultsWe found that pyrotinib combined with dalpiciclib showed better efficacy than pyrotinib combined with tamoxifen in BT474 cells. Degradation of HER2 could enhance ER nuclear transportation, whereas cell cycle blockers could reverse this process. This may be the underlying mechanism by which the addition of dalpiciclib was more beneficial than the addition of pyrotinib plus tamoxifen. Furthermore, CALML5 was revealed to be a potential indicator of responsiveness to anti-HER2 therapy plus CDK4/6 inhibition in triple positive breast cancer. ConclusionOur study provided evidence for the introduction of CDK4/6 inhibitor in the treatment of TPBC and indicated that the combination of anti-HER2 therapy and cell cycle blockers may be a better strategy for TPBC treatment. FundingThis study was supported by the National Natural Science Foundation of China (#U20A20381, #81872159)

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially in relation to kinase fusions, remains incompletely understood. This study aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and amplifications. We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. To detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne(R) companion diagnostic (F1CDx) and FoundationOne(R) Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Of the 613 patients, 44 had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain amplifications. The number of actionable alterations in patients with kinase-domain fusion, mutation, or amplification (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and amplifications. However, those cancers with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions tended to exhibit fewer actionable alterations than those with kinase mutations and amplifications. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions are strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fishers exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitts, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.

PurposeEarly detection of cancer can improve survival following diagnosis. However, routine screening is limited to a few cancer types. Multi-cancer early detection (MCED) tests could substantially expand cancer screening by simultaneously detecting multiple cancer types. This modeling study evaluates the potential impact of an MCED test on cancer outcomes in the US general population. MethodsWe developed a microsimulation model of 14 solid tumor cancer types which account for nearly 80% of cancer incidence and mortality. The model was calibrated to reproduce annual incidence rates reported in the Surveillance, Epidemiology, and End Results database. Cancer diagnosis could arise from standard-of-care (SoC) procedures or annual MCED testing. MCED sensitivities were derived from a case-control clinical validation study. We simulated the 10-year life course of 5 million US adults aged 50-84 years. The primary outcome was cancer mortality reduction due to MCED testing. ResultsIn the best case with perfect uptake and adherence, MCED testing added to the SoC led to a 23% decrease in 10-year cancer mortality relative to the SoC alone, translating to 668,600 cancer deaths averted over 10 years. The largest mortality reductions, in absolute terms, were observed for lung (160; 802 versus 962 per 100,000), colorectal (118; 168 versus 284), and pancreatic (50; 238 versus 288) cancer. The largest relative reductions were in cervical (52%), colorectal (41%), and breast (34%) cancer. The population-level life-year gain was 7,158 years per 100,000. ConclusionMCED testing has the potential to substantially reduce cancer-related deaths, improve outcomes across multiple cancer types.