Systemic Therapy For Metastatic Cancer Research Articles

Abstract 4132: Low-dose carbon monoxide therapies suppress cancer metastasis

Abstract Metastasis is the primary cause of cancer-related deaths. Novel systemic therapies for metastatic cancer are urgently needed. Carbon monoxide (CO) is an endogenously produced signaling molecule in the human body with demonstrated pharmacological activities, including organ protection and anti-inflammation. We determined the therapeutic effect of low-dose CO and CO prodrugs on cancer progression in this study. We found that low-dose CO inhibits the migration of cancer cell lines including breast, pancreatic, colon, prostate, liver, and lung cancer. We showed that low-dose CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer in preclinical mouse models. Further, to provide safer and more reliable CO delivery, we developed metal-free, organic CO prodrugs and showed that CO prodrugs inhibit tumor growth and metastasis. We demonstrated that low-dose CO blocks the transcription of heme importers, leading to diminished intracellular heme levels. Altogether, our work lays a strong foundation for the development of CO-based systemic cancer therapies. Citation Format: Tiantian Zhang, Cheryl Zhang, Xiang Chen, Xiaoxiao Yang, Qiyue Mao, George Zhang, Zhengming Chen, Adrian Tan, Jenny Zhaoying Xiang, Erika Hissong, Yao-Tseng Chen, Binghe Wang, Nancy Du. Low-dose carbon monoxide therapies suppress cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4132.

The anti-metastasis effect of low-dose carbon monoxide

: Metastasis is the primary cause of cancer-related deaths. Because of the anatomically diffused localizations in different organs, treating metastatic cancer with conventional surgery or radiotherapy is challenging. Systemic therapies, including chemotherapy, immunotherapy, and targeted therapy, are used for metastatic cancer treatment. However, resistance to chemotherapy often develops over time, and immunotherapy or targeted therapy is not available for every cancer type. Improved systemic therapies for metastatic cancer are urgently needed. Among all forms of cancer, pancreatic ductal adenocarcinoma (PDAC) is a lethal type due to the following characteristics: early distant metastasis, abundant desmoplastic stroma, insufficient therapeutics, and frequent chemoresistance. Carbon monoxide (CO) is produced endogenously in humans and has been established as an important, biologically active signaling molecule. Accumulating evidence suggests the therapeutic applications of safe, low-dose CO for various diseases. Recently, low-dose CO was shown to suppress metastasis of PDAC in an orthotopic mouse model of liver metastasis and a spontaneous PDAC metastasis mouse model after the removal of primary tumor xenograft tumors. In this mini-review, we discuss the findings and the potential development of CO-based systemic therapies for metastatic cancer. Specifically, many non-inhalation CO delivery modalities with easy control of dosages have been developed and can be further studied for their anti-metastatic properties.

A randomized controlled trial of routine financial toxicity screening via electronic patient-reported outcomes (AFT-39).

180 Background: Financial toxicity affects 20% of cancer survivors and is associated with decreased treatment adherence and poor clinical outcomes. No large-scale programs have been implemented to mitigate financial toxicity among patients undergoing cancer treatment. We evaluated the effect of monthly patient-reported financial toxicity screening as part of a larger digital monitoring intervention. Methods: PRO-TECT (AFT-39) is a cluster-randomized trial of patients undergoing systemic therapy for metastatic cancer. Practices were randomized 1:1 to digital symptom monitoring with patient-reported outcomes (“PRO practices”) or usual care (“control practices”). Digital monitoring consisted of between-visit online or automated telephone patient surveys containing symptom, functioning, and financial toxicity screening questions for up to one year, with automated alerts sent to practice nurses for concerning survey scores. Clinical team actions in response to alerts were not mandated. The primary outcome of this analysis was development or worsening of financial difficulties, assessed via the EORTC QLQ-C30 (“Has your physical condition or medical treatment caused you financial difficulties?”), at any time compared to baseline. A randomly selected subset of patients and nurses were interviewed about their experiences with the intervention. Results: 1,191 patients were enrolled (593 PRO; 598 control) at 52 US community oncology practices. Overall, 30.2% of patients treated at practices that received the intervention developed, or experienced worsening of, financial difficulties, compared to 39.0% of patients treated at control practices (p = 0.01). Patients and nurses interviewed stated that financial toxicity screening identified patients for financial counseling who otherwise would be reluctant to seek, or unaware of the availability of, assistance. Conclusions: Screening for financial toxicity as part of routine digital patient monitoring with PROs reduces the development, or worsening, of financial difficulties among patients undergoing systemic cancer therapy. Clinical trial information: NCT03249090.

Cost-Effectiveness of SABR in Oligometastatic Cancer: An Economic Analysis Based on Long-Term Results of the SABR-COMET Trial

<h3>Purpose/Objective(s)</h3> Our published economic analysis of the SABR-COMET randomized trial determined that SABR is cost-effective for patients with 1-5 oligometastases, with incremental cost-effectiveness ratios (ICERs) of $37,157 (2018 CAD$) and $54,564 (2018 USD$) for the Canadian and American health care systems, respectively. Long-term outcomes from SABR-COMET, with a median follow-up of 51 months, are now available. The aim of this study is to re-evaluate the cost-utility of SABR for oligometastatic cancers in the context of these new results. <h3>Materials/Methods</h3> The published Markov model was updated to perform a cost-utility analysis based on the long-term results of the SABR-COMET trial from the Canadian and American payer perspectives. Utility values and probabilities were derived from individual patient-level trial data. Costs were extracted from the published literature and adjusted to 2018 Canadian dollars and 2018 US dollars. Deterministic sensitivity analyses were performed to obtain thresholds at which each strategy would be preferred. Probabilistic sensitivity analysis was performed to assess the robustness of this model. A lifetime horizon was used with a cycle length of 3 months. A willingness-to-pay threshold of $100,000 in each respective currency, per quality-adjusted life year (QALY) was used. QALYs and costs were discounted at a rate of 1.5% and 3% for Canadian and American analyses, respectively. <h3>Results</h3> In the base case scenario, SABR was cost-effective at an ICER of $30,793 (CAD) and $48,370 (USD) per QALY gained. This finding was most sensitive to the difference in systemic therapy use (ICER: $25,051-48,021[CAD]; $36,319-69,096 [USD]), number of metastatic lesions treated with SABR (ICER: $22,702-44,709 [CAD]; $40,868-70,874 [USD]), and variation in general cancer care cost (ICER: $24,780-36,807 [CAD]; $38,377-58,362 [USD]). Probabilistic sensitivity analysis revealed that SABR was a cost-effective strategy in 99.9% of tested iterations. <h3>Conclusion</h3> This updated decision-analytic model suggests that SABR for patients with 1-5 metastatic lesions is more cost-effective than was initially estimated in both Canadian and the American health care systems. As systemic therapies for metastatic cancer are rapidly evolving, the efficacy and value of SABR with novel agents are currently undergoing further prospective evaluation.

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue-Going Beyond Apoptosis Induction.

The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or “normalizing” such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.

EFFECTIVENESS OF MAINTENANCE THERAPY AFTER THE END OF THE FIRST LINE OF TREATMENT FOR PATIENTS WITH METASTATIC COLORECTAL CANCER – THE RESULTS OF A POPULATION-BASED STUDY

Aim.To evaluate the effectiveness of different regimens of maintenance chemotherapy after the first line of treatment for patients with metastatic colorectal cancer.Materials and methods.We performed retrospective analyses of the data from 432 patients from 17 clinics in 14 regions of the Russian Federation who started systemic therapy for metastatic cancer in 2013. The main inclusion criterion was objective response or stabilization after the first 16 weeks of first-line therapy. Four groups of patients were compared, depending on the nature of maintenance therapy: those receiving fluoropyrimidines, a combination of fluoropyrimidines with bevacizumab, monotherapy of bevacizumab and monotherapy of anti-EGFR antibodies. The main criteria for assesment of the effectiveness of treatment were progression-free survival and overall survival. The statistical analysis was performed with the SPSS 20.0 sof tware package.Results.Maintenance therapy after completion of the first 16 weeks of the 1st line of chemotherapy was administered in 126 patients, most of them were treated with fluoropyrimidines (53.1 %). The median overall survival in the maintenance group was 27 versus 21 months in the observation group, p=0.01, HR=0.78 (95 % CI 0.6–1.02) Median progression-free survival in the maintenance group was 11 vs 7 months in the observation group (p&lt;0.001, HR=0.6, 95 % CI 0.5–0.8). The worst results of progression-free survival were observed in the group with monotherapy of bevacizumab – median was 10 months versus 12 months in the fluoropyrimidine monotherapy group, 10 months for the combination of fluoropyrimidine with bevacizumab and 14 months for monotherapy of the anti-EGFR (p=0,9, HR=1.0, 95 % CI 0.9–1.2).Conclusions.There were no statistical differences in survival with different regimens of maintenance therapy. Monotherapy of bevacizumab in maintenance treatment was associated with the worst sur vival rates.

The impending financial healthcare burden and ethical dilemma of systemic therapy in metastatic cancer.

Metastatic cancer remains a devastating disease that threatens to disrupt entire family structures creating economic and psychosocial stress. Fortunately, great strides have resulted in improved therapies over the years but at a huge social-economic cost. The economic burden has risen greatly and carries with it new ethical concerns when deciding treatment. Here, we discuss the financial and ethical challenges that oncologists and their patients face in the era of novel treatment strategies. J. Surg. Oncol. 2016;114:323-328. © 2016 Wiley Periodicals, Inc.

Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.

Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.

Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites.

Systemic therapy for metastatic cancer is currently determined exclusively by the site of tumor origin. Yet, there is increasing evidence that the molecular characteristics of metastases significantly differ from the primary tumor. We define the evolutionary dynamics of metastases that govern this molecular divergence and examine their potential contribution to variations in response to targeted therapies. Darwinian interactions of transformed cells with the tissue microenvironments at primary and metastatic sites are analyzed using evolutionary game theory. Computational models simulate responses to targeted therapies in different organs within the same patient. Tumor cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases usually exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence. Thus, metastases in the liver from different primary tumors and even in different hosts will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. The results suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ.