Therapy In Cancer Patients Research Articles

Cancer therapy in patients with reduced kidney function.

Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.

Impact of cancer treatment in patients with inflammatory bowel disease: A systematic review and meta analysis.

e23084 Background: The association between cancer treatments and impact of inflammatory bowel diseases (IBD) remains uncertain. Given the growing prevalence of IBD globally, it is crucial to understand the impact of various cancer treatments in this patient population to make informed decisions and optimize outcomes. Thus, the objective of our systematic review is to assess how cancer treatments impact the activity of underlying IBD. Methods: We performed a systematic review of the literature on cancer therapy in patients with pre-existing IBD. Various databases like PubMed, Cochrane, Embase and Google Scholar were searched for studies reporting effects of cancer treatment in patients with IBD, till February 1, 2024. Studies without relevant data were excluded. The outcomes studied were the flares of IBD following cancer treatment and initiation of systemic steroids or biologics for management of IBD flares. Results: In total, 36 studies were included which comprised 1,443 patients with IBD who received cancer treatment. The overall occurrence of IBD flares in patients with IBD receiving cancer treatment was 28% (CI 22.9%-33.8%, I2= 68%) out of which 35.9% (CI 27.5% - 45.3%, I2= 40) had received immune checkpoint inhibitor therapy. The flares resulted in the utilization of systemic steroids and biologics in 27% and 10% respectively. Conclusions: While the data suggests a high proportion of patients with IBD experience flares during cancer treatment, all of the reported episodes were manageable with steroids and/or biologics. However, the population studied only included 1443 patients, and larger population studies are required to optimize individual outcomes, and to explore methods to minimize severity and frequency of flares, when possible.

An international expert consensus on improving the quality of care in patients with cancer by optimal central vascular access device selection.

e23233 Background: In cancer patients (CPs), selection of an appropriate venous access is critical not only for delivering effective treatment, but also for enhancing patient comfort and quality of life to ensure treatment continuity. This consensus provides recommendations on the selection of the most appropriate central venous access device (CVAD) and its management in CPs. Methods: Eleven experts from three continents, including oncologists and healthcare professionals (HCPs) skilled in CVAD placement & maintenance, convened electronically and face-to-face at a 2-day meeting. A comprehensive review of clinical trials & guidelines on CVADs published between January 2013 and December 2023 from PubMed & Cochrane Library was conducted. Preliminarily drafted statements were discussed by the panel and voted on. Evidence and panelists' expertise was employed in an anonymous polling for consensus. The final recommendations were approved by all panelists. Results: A summary of the panel’s consensus (ten statements) is shown in Table 1. Conclusions: The present consensus provides a robust clinical framework for HCPs to select the most suitable CVAD to facilitate therapy for CPs. [Table: see text]

Bridge to cancer therapy in patients with chronic heart failure: implantation of a left ventricular assist device before surgical treatment of gastric cancer

The co-occurrence of chronic heart failure (CHF) and cancer is becoming more and more common as people live longer. The lack of a structured approach to the treatment of cancer patients with severe cardiovascular conditions is an essential issue. Up to 25% of cancer patients cannot be operated on for their main disease profile due to the presence of cardiovascular disease. This article describes a clinical case of successful treatment of a patient with two competing (prognosis-determining) diseases: end-stage heart failure and stomach cancer within the framework of a bridge-to-cancer strategy.

Effectiveness and economic evaluation of rhTPO and rhIL-11 in the treatment of cancer therapy induced thrombocytopenia based on real-world research.

Objective: Based on real-world research, we aimed to evaluate the effectiveness and economy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin 11 (rhIL-11) in the treatment of cancer therapy induced thrombocytopenia (CTIT). Methods: We retrospectively collected clinical data of patients with CTIT who were treated with rhTPO or rhIL-11 in a single cancer hospital from January 2020 to December 2021. Propensity score matching (PSM) was applied to eliminate confounding factors. The measurements of effectiveness analysis were the platelet compliance rate, days of medication, days of compliance, highest platelet count after medication, platelet count elevation before and after medication, and the lowest platelet count after next-cycle cancer therapy. The economic evaluation was performed according to the results of the effectiveness evaluation. At the same time, patients were stratified according to type of tumor and grade of thrombocytopenia for subgroup analysis. Results: A total of 262 patients were collected and 174 patients were enrolled after PSM, 87 in the rhTPO group and 87 in the rhIL-11 group. In all patients, there were no significant differences in the platelet compliance rate, mean days of medication, median days of compliance, median highest platelet count after medication, and the median platelet count elevation before and after medication between the two groups (p > 0.05), but the median lowest platelet count after next-cycle cancer therapy in the rhTPO group was lower than that in the rhIL-11 group (p = 0.014). The subgroup analysis showed that the rhTPO group had longer mean days of medication than the rhIL-11 group in patients with hematological malignancies (p = 0.042), and a lower median lowest platelet count after next-cycle cancer therapy in patients with grade I/II thrombocytopenia than rhIL-11 group (p = 0.022), with no significant difference in other outcome indicators (p > 0.05). As there was no statistically significant difference in platelet compliance rate between the two groups, the cost-minimization analysis showed that the rhIL-11 group had lower treatment costs than the rhTPO group. Conclusion: RhTPO and rhIL-11 showed similar effectiveness in the treatment of CTIT, but rhIL-11 was more advantageous in economic cost.

Candidiasis in breast cancer: Tumor progression or not?

Candida albicans is an "opportunistic fungal agent" in cancer patients that can become colonized in both mucosal and deep tissues and cause severe infections. Most evidence has shown that C. albicans can enhance the progress of different cancers by several mechanisms such as generating virulence factors, participation in endogenous production of pro-inflammatory mediators, and stimulating a wide range of immune cells in the host. The main idea of this review is to describe a range of Candida-used mechanisms that are important in candidiasis-associated malignant processes and cancer development, particularly breast cancer. This review intends to provide a detailed discussion on different regulatory mechanisms of C. albicans that undoubtedly help to open new therapeutic horizons of cancer therapy in patients with fungal infection. The current therapeutic approach is not fully effective in immunocompromised and cancer patients, and further studies are required to find new products with effective antifungal properties and minimal side effects to increase the susceptibility of opportunistic fungal infections to conventional antifungal agents. So, in this situation, a special therapy should be considered to control the infection and simultaneously have the most therapeutic index on tumor patients.

The utility of the HFA-ICOS cardiotoxicity risk assessment tool for HER2-targeted cancer therapies in patients with metastatic breast cancer: from theory to clinical practice

Abstract Background Breast cancer is the most common cancer in women. In developing countries, a considerable proportion of breast cancer diagnoses are made in advanced stages. Nevertheless, the development of targeted therapies, such as trastuzumab and other HER2 targeted agents, has revolutionized the care of these patients, leading to large improvements in disease-free and overall survival. In the other hand, these therapies are associated with cardiac dysfunction. As such, a comprehensive assessment of cardiovascular health before initiation of cancer treatment is fundamental. The HFA-ICOS´s proforma for HER2 targeted therapies is a proposed tool to evaluate the baseline risk of cardiotoxicity in these patients. Purpose To evaluate if the HFA-ICOS´s cardiotoxicity risk assessment tool for HER2-targeted cancer therapies allows to properly identify patients with HER2-positive metastatic breast cancer treated with trastuzumab at high risk for cardiotoxicity. Methods We performed an electronic chart review of patients with HER2-positive metastatic breast cancer treated with trastuzumab seen at the outpatient oncology clinic from January 2018 to December 2022. We collected the necessary data to apply the HFA-ICOS´s cardiotoxicity risk assessment tool for HER2-targeted cancer therapies, except for cardiac biomarkers. Cardiotoxicity was defined as 10% drop of left ventricular ejection fraction (LVEF) to a value of less than 50%. Results Seventy patients were included in our analysis. Mean age was 54.6+12.5 years. Cardiotoxicity was found in twenty-three patients (32%), of which, nine (39.1%) were classified at high risk for cardiotoxicity, twelve patients (52.1%) at medium risk, and two patients (8.6%) at low risk. Among the group with cardiotoxicity there was a higher proportion of older patients, obesity, borderline LVEF at baseline, prior treatment with anthracyclines, and prior exposure to radiotherapy. A high-risk score was more frequent among patients with cardiotoxicity than in those without cardiotoxicity. Most patients were classified with medium risk in both groups. The proportion of patients with low risk was not different in patients with and without cardiotoxicity. None of the variables evaluated was statistically significant. Conclusions There was a higher proportion of patients at high risk according to the HFA-ICO´s proforma for HER2 targeted therapies who developed cardiotoxicity in comparison to patients without cardiotoxicity. However, there were no significant differences in patients classified as medium or low risk. Future studies are needed to precise the most adequate method to stratify cardiotoxicity risk in patients with breast cancer exposed to anti-HER2 therapies, in order to establish effective surveillance and a suitable treatment.Table 1.

Safety and efficacy of immune checkpoint inhibitor cancer therapy in patients with preexisting type 1 diabetes mellitus.

Immune checkpoint inhibitors (ICI) produce dramatic tumor shrinkage and durable responses in many advanced malignancies, but their use is limited by the development of immune-related adverse events (IRAEs) that occur in up to 60% of patients and often affect endocrine organs. Concern for more severe IRAEs in patients with preexisting autoimmune diseases, including type 1 diabetes mellitus (T1DM), has led to the exclusion of such individuals from clinical trials of ICI therapy. As a result, little is known about the safety and efficacy of ICI in this population. Here, we report safety and treatments outcomes in ICI-treated patients with preexisting T1DM. This retrospective case-controlled study evaluated adult patients with T1DM who received ICI therapy for solid malignancies from 2015 to 2021 at four academic medical centers. Patients with prior ICI therapy, bone marrow transplantation, or pregnancy were excluded. We collected data on demographics, cancer diagnosis and treatment, IRAE incidence and severity, and diabetes management. Controls were matched 2:1 by age, sex, cancer diagnosis, and ICI therapy class. Of 12,142 cancer patients treated with ICI therapy, we identified 11 with a preexisting confirmed diagnosis of T1DM prior to starting ICI therapy. Mean age was 50.6 years, 63.6% were women, and most received anti-PD1/PDL1 monotherapy (10/11) compared with combination therapy (1/11). Grade 3/4 IRAEs were seen in 3/11 subjects with preexisting T1DM and were hepatitis, myositis, and myasthenia gravis. All three cases had interruption of ICI therapy and administration of adjunct therapies, including steroids, IVIG, or mycophenolate mofetil with resolution of the IRAE. The odds of all-grade IRAEs and of severe IRAEs were comparable between cases and controls matched for age, sex, cancer type, and ICI therapy [OR 0.83 (95% CI 0.2-3.56), p = 0.81, and OR 1.69 (0.31-9.36), p = 0.55, respectively]. Overall survival was not different between patients with T1DM and controls (p = 0.54). No patients had hospitalizations for diabetes-related complications during therapy. These data suggest that ICI monotherapy can successfully be used in patients with preexisting T1DM, with IRAE rates comparable with individuals without preexisting T1DM. Larger, prospective studies of these potentially life-saving ICI therapies that include patients with preexisting autoimmunity are warranted.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

ABSTRACT Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35–3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95–5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Emergencies in cancer therapy: surgical indications under systemic therapy

Emergency surgery due to side-effects of cancer therapy in patients with metastatic disease of the genitourinary tract is rare. Nevertheless, there are a number of emergencies that require rapid intervention and should be recognized by every uro-oncologist. The following review will work out important side-effects requiring surgical treatment, highlighting the main symptoms and the initial management.

INSIGHT-HER2BC: Real-world evidence of TCHP regimen to describe the best patient profile and open up questions—The interim results.

e12607 Background: Neoadjuvant therapy (NAT) of TCHP regimen is approved for standard therapy for early and locally advanced HER2-positive breast cancer (eHER2+ BC) based on encourage TRYPHAENA and KRISTINE trials results. There are limited data regarding patients (pts) treatment outcomes after NAT TCHP in the routine clinical practice. Here we presented the 1st results of ambispective observational program to assess the efficacy and safety of cancer therapy in patients with solid tumors. Early HER2+ breast cancer group: INSIGHT-HER2BC. Methods: We ambispectively reviewed medical records of pts with eHER2+ BC who underwent NAT 6xTCHP (6 docetaxel/carboplatin + trastuzumab/pertuzumab) at three Moscow oncology centers since Jan’2017. This ongoing trial has launched in Feb’22. Here is presented descriptive analyses of pCR (ypT0/is, ypN0) rate for pts who completed NAT and 1-3 yrs. disease-free survival (DFS). Results: At the data cut-off (Jan’2023) 934 pts with HER2+ eBC underwent ≥ 1 cycle of NAТ. The median age is 54.3 y.o. (range: 22-78) where 36% pts were older 60 y.o.; 14% pts - younger than 40 y.o. 75% (571) pts had surgery results. pCR rate is related to KRISTINE trial: 58% (330) pts in the ITT (intention-to-treat) population vs 56% pts, respectively. pCR rate for pts with locally advanced BC is 55% vs 59% for operable BC (114/208 and 215/363 pts, respectively). There is difference in pCR rate achievement according to hormone status (HR+ vs HR-) and HER2 status (3+ vs 2+/ISH +). 1-yr. DFS for pCR group is 97% vs 94% for non-pCR; 2-yr. DFS is 83% vs 83%, respectively, and 3-yr. DFS 64% for pCR group vs 58% for non-pCR. In HR-HER2+ BC the biggest drop between pCR and non-pCR is registered at the 3-yr. DFS: 56% vs 22% while in HR+HER2+ there is almost equal decrease was observed every yr.: 97% vs 93% - 1st yr.; 90% vs 85% - 2nd yr.; 72% vs 68% - 3d yr. Conclusions: NAT TCHP is the effective regimen for HER2+ eBC in the real-world population. The efficiency is observed regardless of disease stage and age. However, there is clear unmet need to find new therapeutic options for HER2 (2+/ISH+) BC. Preliminary results of DFS is markedly lower than in TRYPHAENA and KRISTINE trials but in conjunction with another real-world evidence data. DFS in HR+HER2+ and HR-HER2+ pts likely reflects distinct tumor biology. The mature data for long-term outcomes are awaited. [Table: see text]

Abstract CT184: Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors

Abstract Background: SHP2 is an oncogenic tyrosine phosphatase that transduces receptor tyrosine kinase signaling to the RAS/MAPK pathway via its phosphatase-mediated regulation of guanine nucleotide exchange factors. ERAS-601 is a potent, selective, and orally bioavailable allosteric inhibitor of SHP2. In combination with cetuximab, an antibody that targets epidermal growth factor receptor (EGFR), ERAS-601 has demonstrated robust nonclinical activity in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) and RAS/RAF wild-type colorectal cancer (CRC) tumors. Method: FLAGSHP-1 is the first-in-human trial of ERAS-601 administered as monotherapy and in combination with other cancer therapies in patients with advanced or metastatic solid tumors. The primary objectives are to characterize the safety profile, determine the maximum tolerated dose (MTD)/recommended dose (RD), and characterize the pharmacokinetics (PK) profile of ERAS-601 as a monotherapy and in combination with other cancer therapies. Secondary objectives include tolerability and antitumor activity in solid tumors. Presented here are results from the combination dose escalation cohorts in which patients received ERAS-601 twice a day for three weeks followed by a one-week break (BID 3/1) in combination with cetuximab (500mg/m2) administered every 2 weeks (Q2W) on a 28-day cycle. Results: As of October 31, 2022, a total of 15 patients with previously treated advanced or metastatic solid tumors received ERAS-601 BID 3/1 at the following dose levels: 20 mg BID 3/1 (n=4), 40 mg BID 3/1 (n=8), or 60 mg BID 3/1 (n=3) in combination with cetuximab. Combination therapy MTD was determined​ to be 40 mg BID 3/1. ERAS-601 Treatment Related Adverse Events (TRAEs) at or below the MTD were all Grade 1 and 2. TRAEs occurring in ≥20% of patients included diarrhea (27%), AST increase (27%), ALT increase (20%), dermatitis acneiform (20%). Grade ≥3 TRAEs included Grade 4 hypokalaemia, Grade 3 diarrhea, platelet count decreased anemia (each 7%); high grade TRAEs were only observed at 60 mg BID 3/1 (above the MTD). Dose limiting toxicities (DLTs) were only observed at the 60mg BID 3/1 dose levels and included Grade 3 platelet count decreased (n=1) and Grade 4 hypokalemia (n=1). Pharmacokinetics of ERAS-601 and cetuximab in combination were generally comparable to historical monotherapy PK values, suggesting lack of drug-drug interaction. The evaluation of clinical activity is still ongoing. Conclusions: ERAS-601 in combination with cetuximab in patients with previously treated advanced or metastatic solid tumors shows promising preliminary safety and tolerability with reversible and manageable TRAEs. Further evaluation in relevant tumor types are ongoing. Citation Format: Meredith McKean, Ezra Rosen, Minal Barve, Tarek Meniawy, Judy Wang, David S. Hong, Jennifer Yang, Zhengrong Li, Roxana Picard, Les Brail, Daniela Vecchio, Thomas John, Ezra Cohen, Gregory Obara, Aparna Parikh. Preliminary dose escalation results of ERAS-601 in combination with cetuximab in FLAGSHP-1: a phase I study of ERAS-601, a potent and selective SHP2 inhibitor, in patients with previously treated advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT184.

Abstract 4451: Developing a PROTAC-based NR4A1 degrader for melanoma cancer therapy

Abstract Introduction: Melanoma originates from melanocytes within the epidermis and is one of the most common cancers, with nearly 100000, new cases yearly. Despite numerous advancements in therapies to treat melanoma, a prevalent population of patients still do not respond to currently approved therapies. Recent studies have highlighted the role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in melanoma for cancer survival, invasion, and metastasis. NR4A1 is also involved in glucose metabolism. Our project aims to identify an effective degrader of NR4A1 using a PROTAC strategy and then validate its effectiveness in reducing the growth of melanoma. PROTACs consists of three domains: a warhead that binds to the protein of interest, a ligand to an E3 ligase, and a linker that brings both domains in proximity to one another. The PROTAC can recruit an E3 ligase to ubiquitinate NR4A1 and degrade it via the ubiquitin-proteasome system (UPS). Results: Our first goal was to identify valid PROTAC candidates that can effectively degrade NR4A1. We identified NR-V04, which demonstrated a dose-dependent degradation of NR4A1 in various melanoma cell lines. We further investigated time-dependent degradation, and NR-V04 was able to achieve in vitro degradation of NR4A1 16 hours after treatment. Additionally, we validated the mechanism of degradation via the UPS through various models. NR-V04 treatment of cells with a VHL knockout, which removes the E3 ligase recruited, experienced no degradation of NR4A1, and treatment of cells treated with MG132, a proteasome inhibitor, also showed no degradation. We observed degradation in vitro of numerous mouse and human cell lines. To investigate the cancer-killing effects of NR-V04, we completed MTS assays on the human melanoma cell lines CHL1 and A375, which showed an EC50 of 0.723 μM and 1.025 μM, respectively. When comparing NR-V04 treated and untreated CHL1 cells, NR-V04 was able to significantly decrease melanoma cell viability. NR4A1 knockout in CHL1 also showed decreased melanoma cell viability, and when comparing NR-V04 treated and untreated in NR4A1 knockout, there was no further decrease in melanoma cell viability. As for in vivo models, NR4A1 knockout in CHL1 and A375 exhibited slower tumor growth compared to the wild type. Furthermore, NR-V04 showed suppression of CHL1 and A375 tumor-bearing NSG mice melanoma growth at low dose concentrations of 1 mg/kg after seven days compared to vehicle and warhead treatment. Western blot analysis of tumor tissue provides support for the ability of NR-V04 to degrade tumor-intrinsic NR4A1. Conclusion: NR-V04 can selectively degrade NR4A1, in vitro and in vivo, to decrease melanoma cancer cell viability via the UPS. NR-V04 holds promising therapeutic potential as a cancer therapy for patients with melanoma. Citation Format: Rohan Master, Yuewan Luo, Yufeng Xiao, Daohong Zhou, Lei Wang, Guangrong Zheng, Weizhou Zhang. Developing a PROTAC-based NR4A1 degrader for melanoma cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4451.

PI3K/AKT/mTOR inhibitors as potential extracellular matrix modulators for targeting EMT subtype gastric tumors.

Targeting the extracellular matrix (ECM) is considered as a promising strategy in cancer therapeutics. This study was designed to identify the potential ECM modulators for gastric cancer therapeutics. Exploration of the expression profiles of gastric tumors revealed the elevated expression of ECM genes in gastric tumor tissues compared to the adjacent normal tissues with increased expression in diffuse subtype gastric tumors and specifically in epithelial to mesenchymal transition (EMT) molecular subtype tumors. Consensus ECM gene set was derived from the expression profiles of gastric tumors. The correlative analysis was performed between the expression pattern of the ECM gene set and the drug sensitivity pattern of a panel of drugs across gastric cancer cell lines. Negative correlation between the expression of ECM genes and sensitivity of a number of drugs targeting PI3K/mTOR signaling, chromatin histone acetylation and ABL signaling was observed. These pathways are known for their role in cell-mediated adhesion, differentiation and epithelial to mesenchymal transition. The current results reveal the possibility of using PI3K/AKT/mTOR modulators for targeted gastric cancer therapy in patients with dysregulated ECM.

P555 Systematic review with meta-analysis: The impact of cancer treatments on the disease activity of inflammatory bowel diseases

Abstract Background The association between cancer treatments and exacerbation of IBD is unclear. We aimed to evaluate the effects of cancer treatments on the disease activity of IBD. Methods We performed a systematic review of the literature on cancer therapy in patients with pre-existing IBD. Electronic searches of PubMed, Cochrane Library, and Embase were combined with manual searches (September 2021). Meta-analysis was performed using the random-effects model. The primary outcome was flares of IBD following cancer therapy. Secondary outcomes were need for IBD-related hospitalization, surgery, and initiation or intensification of steroid or biological treatments to manage IBD flares. Results In total, 33 studies were included in the systematic review, comprising 1,298 patients with IBD who received cancer treatment (Figure 1). The overall occurrence of IBD flares following cancer treatment was 30% (95% confidence interval (CI) 23-37%, Figure 2). IBD flares resulted in utilization of systemic steroids and biologic therapies among 25% and 10%, respectively, and in discontinuation of cancer treatment among 8% of patients (Figures 3a and 3b). Finally, risk of gastrointestinal toxicity following immune check point inhibitor treatment (ICI) was increased in patients with IBD compared to patients without IBD (RR=3.62, 95% CI 2.89-4.78) (Figure 4). Despite this, the studies generally reported that flares were manageable. FIGURE 1. Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flow diagram summarizing study selection. FIGURE 2: Forest plot of incidence of IBD flares following cancer therapy, grouped by cancer treatment. FIGURE 3: Forest plot of incidence of need for initiation of a) systemic steroids or b) initiation or intensification of biologic therapyfor managing IBD flares following cancer treatment. FIGURE 4: Forest plot of risk ratios of GI toxicities following cancer treamtment in patients with IBD vs patients without IBD. Conclusion Current data indicate a high proportion of patients with IBD experiencing a flare following the start of cancer treatment. Patients with IBD were at increased risk of gastrointestinal toxicity following ICI treatment compared to those without IBD. However, cancer therapy-induced IBD flares were manageable and should not preclude appropriate cancer treatments.

Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data.

Quantifying the effectiveness of different cancer therapies in patients with specific tumor mutations is critical for improving patient outcomes and advancing precision medicine. Here we perform a large-scale computational analysis of 40,903 US patients with cancer who have detailed mutation profiles, treatment sequences and outcomes derived from electronic health records. We systematically identify 458 mutations that predict the survival of patients on specific immunotherapies, chemotherapy agents or targeted therapies across eight common cancer types. We further characterize mutation-mutation interactions that impact the outcomes of targeted therapies. This work demonstrates how computational analysis of large real-world data generates insights, hypotheses and resources to enable precision oncology.

Outcomes of proton therapy for non-small cell lung cancer in patients with interstitial pneumonia

BackgroundInterstitial pneumonia (IP) is a disease with a poor prognosis. In addition, IP patients are more likely to develop lung cancer. Since IP patients frequently develop toxicities during cancer treatment, minimally invasive cancer treatment is warranted for such patients to maintain their quality of life. This study retrospectively investigated the efficacy and safety of proton therapy (PT) for non-small cell lung cancer (NSCLC) in patients with IP.MethodsTwenty-nine NSCLC patients with IP were treated with PT between September 2013 and December 2019. The patients had stage IA to IIIB primary NSCLC. Ten of the 29 patients exhibited the usual interstitial pneumonia pattern. The prescribed dose was 66–74 Grays (relative biological effectiveness) in 10–37 fractions.ResultsThe median follow-up period was 21.1 months [interquartile range (IQR), 15.6–37.3] for all patients and 37.2 months (IQR, 24.0–49.9) for living patients. The median patient age was 77 years (IQR, 71–81). The median planning target volume was 112.0 ml (IQR, 56.1–246.3). The 2-year local control, progression-free survival, and overall survival rates were 85% (95% confidence interval: 57–95), 30% (15–47), and 45% (26–62), respectively. According to the Common Terminology Criteria for Adverse Events (version 4.0), grade 3 acute radiation pneumonitis (RP) was observed in 1 patient. Two patients developed grade 3 late RP, but no other patients experienced serious toxicities. The patients’ quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 and SF-36) scores had not changed after 3 months.ConclusionsPT may be a relatively safe treatment for NSCLC patients with IP, without deteriorating quality of life scores within 3 months.

Cross-Reacting Material 197, a Specific Inhibitor of HB-EGF, and Its Anticancer Effects

Genetic heterogeneity and metastasis remain the most challenging aspects of cancer treatment.Recent studies have introduced a mutant of diphtheria toxin,cross-reacting material197 (CRM197), as a new promising biological anticancer drug to improve cancer therapy in patients previously resistant to chemotherapy. Weak toxicity of CRM197accounts forthe stimulation ofcell apoptosis and the antitumor effect. Increasing evidence has indicated that the expression of heparin-binding epidermal growth factor-like (HB-EGF) growth factorincreases in most cancer cells, and CRM197 is its specific inhibitor.This study has focused on the structure, properties, and anticancer activity of CRM197.

Abstract OT1-11-02: A pragmatic, randomised, multicentre trial evaluating the dose timing (morning vs evening) of endocrine therapy and its effects on tolerability and compliance (REaCT-CHRONO Study)

Abstract Background. Endocrine therapy (ET) is the mainstay treatment for hormonal receptor positive (HR+) breast cancer. ET non-compliance and non-persistence vary from 30 to 70% and are associated with reduced disease-free and overall survival. ET side effects are an important cause of non-adherence. In clinical practice, there are anecdotal reports that time of the day at which ET is taken may affect ET side effects and compliance. However, we are not aware of any high-quality studies supporting this practice. In other fields of medicine, there is evidence to suggest that the time of the day at which medication is taken can alter its effect and/or the adherence. This is known as chronotherapy. Methods. In this pragmatic, open-label, multicenter trial, eligible and consented patients with an early stage or locally advanced HR+ breast cancer will be randomized (1:1) to receive either: an ET morning dose (Arm A: within 1 hour of the patient wake up time) or an ET evening dose (Arm B: within 1 hour of patient bed time). The primary endpoint is endocrine toxicity and tolerability measured by the change in total Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) score from baseline to 12 weeks following the beginning of ET. Secondary endpoints include: endocrine toxicity/tolerability and quality of life measured respectively by the change in total score and individual items of FACT-ES and FACT-B (a validated Functional Assessment of Cancer Therapy for patients with a Breast cancer) from baseline to 4, 8, 12 and 52 weeks following the beginning of ET, rates of non-persistence or non-compliance and cost-effectiveness. A timing preference questionnaire will be filled out at the beginning and the end of the study by patients to evaluate their preferred time. As per the Rethinking Clinical Trials (REaCT) program, the integrated consent model will be used and patients will complete questionnaires in the online patient portal. For randomization, a permuted block design developed by the Ottawa Methods Centre will be used and patients will be stratified by center, type of endocrine therapy (tamoxifen yes/no) and if prior chemotherapy was received. Using a two-sided, alpha=0.05 Fisher’s exact test, and assuming a 10% of loss to follow up, the planned sample size is 235 patients. Accrual. This study opened for enrollment at The Ottawa Hospital Cancer Centre on June 30, 2021 and will open soon at the Thunder Bay Regional Health Sciences Centre. The maximum accrual period is 2 years. Conclusion. This will be world’s first prospective randomized clinical trial to evaluate ET dose timing (morning versus evening) and its effects on tolerability and adherence. Changing the time of the day at which a medication is taken is a new, simple and easy intervention that does not generate additional costs and can improve the quality of life of breast cancer patients. Funding provided by: NOAMA (Northern Ontario Academic Medicine Association) Innovation Grant (2021) Clinical Trial Registration: NCT04864405 Citation Format: Marie-France Savard, Mohammed Ibrahim, Gregory Pond, Deanna Saunders, Lisa Vandermeer, Ana-Alicia Beltran-Bless, Lesley Fallowfield, Mark Clemons. A pragmatic, randomised, multicentre trial evaluating the dose timing (morning vs evening) of endocrine therapy and its effects on tolerability and compliance (REaCT-CHRONO Study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-11-02.

Use of the ONCO-TreC electronic diary compared with a standard paper diary to improve adherence to oral cancer therapy in patients with solid and haematological tumours: protocol for a randomised controlled trial

IntroductionONCO-TreC platform consists of a mobile application delivered to patients as electronic diary and a web-based dashboard managed by healthcare professionals. We aim to compare the effectiveness of ONCO-TreC electronic...