Abstract Background Continued HER2 suppression in metastatic breast cancer (MBC) has been demonstrated to improve progression free survival (PFS) and overall survival (OS) in many randomized studies to date. Current funding policy in British Columbia (BC) restricts to two lines of HER2 directed therapy (HER2Rx) in MBC. With the development of novel HER2Rx agents, accessing continued HER2 suppression in the MBC has become complex. The financial implications of adapting future funding policies to reflect increasing lines of proven HER2Rx is unknown. Purpose The purpose of this study is to assess the proportion of patients with HER2 positive MBC eligible to receive systemic therapy beyond 2 lines of HER2Rx. We also wished to assess the proportion of eligible patients who accessed continued HER2Rx despite lack of public funding, and how their treatment beyond second line was funded. Methods The BC outcomes unit collects clinical and outcome information on 85% of all patients diagnosed with in the province of BC. In addition, all anti-neoplastic therapy delivered in the province is recorded in the BC Cancer pharmacy database. These two databases with queried and cross referenced to identify patients who received any HER2Rx for MBC dispensed by BC Cancer between 2013 and 2018, in the era where trastuzumab plus pertuzumab and TDM-1 were standard options and publically available. The number of lines of therapy received, specific treatments, and fitness to continue therapy beyond two lines were analyzed through targeted chart review. PFS and OS data were also analyzed. Expected financial implications were calculated based on current cost of most commonly used therapies in the third line. Results We identified 230 patients who met inclusion criteria with detailed information about treatment at the time of analysis. 51% (117) of these patients were eligible to continue therapy beyond second line. Of these, 86 (37% of the whole cohort) did access continued HER2-directed therapy, while 26 (11% of the whole cohort) were eligible but unable to access continued HER2Rx. The remaining 49% of were not eligible for consideration of further HER2Rx due to either stable disease on current treatment or deterioration precluding further treatment. The median lines of therapy in the entire study population was 3. Minimum lines of therapy was 1, maximum number of lines of therapy delivered was 12. Median number of cycles of therapy received beyond second line for those eligible to continue treatment was 22 cycles. Median OS for those who continued HER2Rx was 58.6 months compared to 38.0 months for those who were eligible but did not continue therapy, but this was not statistically significant (p = 0.13). The vast majority of these patients are receiving continued HER2Rx through either exceptional access or clinical trial, and very rarely through private pay or insurance. Conservative estimated cost per cycle of HER2Rx was based on currently available biosimilars to Trastuzumab. If these trends in survival continue we would expect an additional cost of $44000 per patient over current costs. Conclusion 51% of patients with HER2 positive MBC are eligible to receive more than two lines of HER2 directed systemic therapy. Of these eligible patients, the majority of patients (77%) are accessing treatment despite prohibitive funding policies, based on clinical trial or compassionate access programs. As funding policies adapt to the evolving treatment landscape for patients with HER2 positive MBC, we can expect a significant increase in cost per patient in this setting with conservative estimates of $44000 per patient above current costs. As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems. Citation Format: Emily B Jackson, Lauren Corke, Hyejee Ohm, Christine Simmons. Predicted financial impact of continued HER2-directed therapy in metastatic breast cancer: What is the financial toxicity in a public payer healthcare system? [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 PD8-09.
Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality, with liver transplantation as the sole curative treatment. For advanced disease, first-line systemic therapies including immune checkpoint inhibitors (ICIs) have shown a survival benefit, but there is scarce data on clinical outcomes when used prior to transplantation.
393 Background: First-line treatment for mRCC includes I/N and A/P. These two regimens have not been compared in a randomized clinical trial as both CM-214 and KN-426 used single-agent tyrosine kinase inhibitors (TKIs) as the comparator. Meta-analyses suggest improved efficacy outcomes with A/P, but increased likelihood of complete response with I/N. We compared these treatments in the real-world. Methods: Data of consented mRCC patients with clear cell histology from the Canadian Kidney Cancer information system (CKCis) was obtained from January 2013 to December 2021. Treatment outcomes adjusting for age including overall survival (OS), progression free survival (PFS), and response rate (RR) for all patients and intermediate-poor risk patients were completed. Chi-square tests compared the frequency of side effects. Results: Among 547 patients, 360 received I/N and 187 received A/P. Median follow-up was 30.0 (0.1-112.1) months. Median duration of treatment was 6.9 (0.0-68.4) months for I/N and 20.2 (0.1-72.4) months for A/P. Intermediate-poor risk patients were higher in the I/N compared to A/P cohort (91.9% vs. 66.2%; p<0.0001). Cox regression for OS showed no difference between I/N compared to A/P (aHR 1.1, 95% CI [0.77-1.58], p=0.61). PFS showed no statistical difference but a trend for worse with I/N at 12.1 months compared to 22.3 months for A/P (aHR=1.2, 95% CI [0.95-1.62], p=0.11). RR was 40.9% with I/N compared to 56.0% in A/P (aOR 0.52, 95%CI [0.33-0.83], p=0.005). Subgroup analyses for the intermediate-poor risk mRCC patients showed no differences in OS (aHR 0.95, 95%CI [0.65-1.38], p=0.79) and PFS (aHR 1.21, 95%CI [0.90-1.62], p=0.21) between treatment groups but improved RR (aOR 0.58, 95%CI [0.35-0.96], p=0.06) with A/P. 61.7% of I/N patients compared to 79.1% of A/P suffered adverse events that led to a dose or schedule change (p<0.001). Most common toxicities for both groups include diarrhea, fatigue, transaminitis, rash, and anorexia. Conclusions: There was no difference in OS between mRCC patients treated with I/N compared to A/P. A/P demonstrates improved RR and a trend towards longer PFS at the expense of increased frequency of side effects. Despite a median follow-up of 30 months, the data is limited by a high amount of censoring.[Table: see text]
OBJECTIVES: Severe acute respiratory syndrome–related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2–binding viruses from viruses that do not bind to angiotensin-converting enzyme-2. DATA SOURCES: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE. STUDY SELECTION: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram. DATA EXTRACTION: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome–related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B. DATA SYNTHESIS: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44–57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18–26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26–49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 ( p = 0.061) and 12% (95% CI, 7–22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 ( p < 0.001) experienced a cardiac injury. CONCLUSIONS: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2.
e18623 Background: Continuing HER2-directed therapy in metastatic breast cancer (MBC) beyond first line has been demonstrated to improve progression free survival (PFS) and overall survival (OS) in many randomized studies. Due to cost, many publicly funded health care systems restrict public funding to 2 lines of HER2 directed therapy (HER2Rx) in MBC. The purpose of this study is to assess the proportion of patients with HER2 positive MBC who were eligible to receive systemic therapy beyond second-line and successfully accessed continued HER2Rx despite lack of public funding. We also analyzed how the ability to access continued HER2Rx impacts survival. Methods: The BC Cancer Breast Cancer Outcomes Unit collects clinical, pathological and outcome data on patients diagnosed within BC. In addition, all publically funded anti-neoplastic therapy is recorded in the BC Cancer pharmacy database. These 2 databases were cross-referenced to identify patients who received any HER2Rx for MBC between 2013 and 2018, in the era where trastuzumab plus pertuzumab and TDM-1 were standard, publically available options. The number of lines of therapy received, treatment choice, and fitness to continue therapy beyond 2 lines were analyzed by manual chart review. Survival data was analyzed. Results: 571 patients met inclusion criteria. Median follow up was 47.6 months. Overall, 267 (47%) patients were eligible to continue therapy beyond second-line. Of these, 210 (37% of the whole cohort) accessed continued HER2-directed therapy, while 57 (10%) were eligible but unable to access continued HER2Rx. Of the remaining 304 patients in the total cohort, 110 patients (19%) had stable disease on continued first- or second-line therapy and 194 patients (34%) had deteriorating status precluding further treatment beyond second-line. The median lines of therapy in the entire study population was 3 (range 1-12). Median number of cycles of HER2-directed therapy received beyond second-line for those eligible to continue was 18 cycles. Median OS for those who continued HER2Rx was 59.7 months compared to 31.4 months for those who were eligible but unable to access continued HER2Rx; HR 0.42 (95% CI 0.31-0.58, p < 0.001). The vast majority of patients who continued to access HER2Rx did so through clinical trial or patient assistance programs, very rarely through private health insurance or out-of-pocket expenditures. Conclusions: Nearly half of patients with HER2 positive MBC were eligible to receive more than 2 lines of HER2 directed therapy. The majority of eligible patients do ultimately secure access despite prohibitive public funding policies. Receiving further HER2Rx was associated with a significant and clinically meaningful OS benefit of 28 months over those who go on to receive non-HER2 directed therapy. This survival advantage provides real-world evidence in support of the urgent need for more permissive public funding of HER2 directed therapy for MBC.
The intracellular parasite Leishmania uses neutrophils and macrophages as host cells upon infection. These immune cells harbour their own intrinsic circadian clocks, known to influence many aspects of their functions. Therefore, we tested whether the host circadian clocks regulate the magnitude of Leishmania major infection in mice. The extent of parasitic infection varied over 24 h in bone marrow-derived macrophages in vitro and in two different in vivo models, footpad and peritoneal cavity infection. In vivo this was paralleled by time of day-dependent neutrophil and macrophage infiltration to the infection site and rhythmic chemokine expression. Thus, rhythmic parasitic infection observed in vivo was likely initiated by the circadian expression of chemoattractants and the subsequent rhythmic infiltration of neutrophils and macrophages. Importantly, all rhythms were abolished in clock-deficient macrophages and when mice lacking the circadian clock in immune cells were infected. Therefore we demonstrated a critical role for the circadian clocks in immune cells in modulating the magnitude of Leishmania infection. To our knowledge this is the first report showing that the circadian clock controls infection by protozoan parasites in mammals. Understanding the timed regulation of host-parasite interactions will allow developing better prophylactic and therapeutic strategies to fight off vector-borne diseases.
Gastrointestinal (GI) cancers are a group of malignancies that globally account for a significant portion of cancer incidence and cancer-related death. Survival outcomes for esophageal, gastric, pancreatic, and hepatobiliary cancers remain poor, but new treatment paradigms are emerging with the advent of immune checkpoint inhibitor (ICI) therapy. This review characterizes patient-related prognostic factors that influence the response to ICI therapy. We performed an analysis of the landmark randomized clinical trials in esophageal, gastric, colorectal, hepatocellular, pancreatic, and biliary tract cancers in terms of patient demographic factors. A literature review of smaller retrospective studies investigating patient-related factors was completed. The immunological bases for these associations were further explored. The key predictive factors identified include age, sex, performance status, geography, body mass index, sarcopenia, gut microbiome, various biochemical factors, and disease distribution.
