publication date: Sep. 18, 2020

Clinical Roundup

Korean study examines the combined impact of aspirin, metformin, and statin’s impact on lung cancer risk

The combined use of aspirin, statins, and metformin is associated with decreased lung cancer incidence and mortality, according to a study published in the Journal of Thoracic Oncology, the journal of the International Association for the Study of Lung Cancer.

All three medications are common—approximately 35 million people take a statin to control cholesterol; more than 120 million people take metformin to control diabetes and between 6 and 10 million people take aspirin daily.

The aim of this study was to investigate the associations of aspirin, metformin, and statins with lung cancer risk and mortality using population-based nationwide cohort data from The Korean National Health Insurance Services database was used in the present study. The KNHIS is a universal health care system that covers the entire Korean population of 50 million.

“To our knowledge, no study has evaluated aspirin, statins, and metformin use and their combined impact on lung cancer incidence and mortality,” lead study author Dong Wook Shin, of the Sungkyunkwan University School of Medicine, said in a statement.

Shin and his colleagues (Jihun Kang and Su-Min Jeong) examined 732,199 Koreans from the Korean National Health Insurance Services database. The patients were followed between January 2004 and December 2013. Lung cancer incidence and mortality were identified using a registered lung cancer diagnosis code (ICD-10 code C34) and the Korean National Death Registry.

To address the combined associations of these cardiovascular drugs with lung cancer risk and mortality, the researchers categorized the cohort into eight groups, based on exposure to aspirin, statins, and metformin.

Combined use of aspirin, statins, and metformin was associated with decreased lung cancer incidence (aHR 0.83, 95% CI, 0.69–0.99) and mortality (aHR 0.83, 95% CI, 0.70–0.99) compared with non-users.

“When these cardiovascular drugs were used in combination, their protective associations with lung cancer risk and related mortality were augmented and the magnitude of effect increased with increasing duration of medication use,” Shin said in a statement.

During 2012-2013 (the most recent period in the study), study participants taking all three medications were 3.4% (23,163 out of 676,520).

“Interestingly, the inverse association of combined use of aspirin, statins, and metformin was prominent, and the longer the duration of combined use, the more protective the association.

This finding is in line with a study demonstrating that aspirin and metformin synergistically inhibit lung cancer cell proliferation by activating AMP-activated protein kinase, which plays a critical role in regulation of lipogenesis in cancer cells,” Shin wrote.

Shin theorized that concomitant use of aspirin, statins, and metformin concurrently inhibits multiple pathways related to lung cancer cell growth and proliferation resulting in favorable associations with lung cancer risk and mortality.


Cigarette smoking associated with worse outcomes for bladder cancer patients after surgery

Patients treated for bladder cancer with a surgery known as radical cystectomy have worse outcomes if they are smokers, according to a systematic review and meta-analysis by Keck Medicine of USC. The study appeared in the Journal of Urology.

“This study is important because while it is known that tobacco smoking is the leading cause of bladder cancer, this is the first study to suggest that smoking puts bladder cancer patients at risk after diagnosis,” Giovanni Cacciamani, lead author of the study and assistant professor of research urology at the Keck School of Medicine of USC, said in a statement.

More than 500,000 cases of bladder cancer are diagnosed each year worldwide. When the cancer is large or has spread beyond the bladder, patients are typically treated with chemotherapy followed by a radical cystectomy.

Cacciamani and fellow Keck Medicine researchers searched databases to select 17 studies that reported on the impact of tobacco smoking on chemotherapy response and survival outcomes of 13,777 patients following radical cystectomy. Of these patients, 40.8% were active smokers at the time of the surgery, 14.1% former smokers and 45.1% had never smoked or were not smoking at the time of the surgery.

The study showed that active smokers responded worse to chemotherapy and had higher mortality rates, both in general and specifically from bladder cancer, and a higher rate of bladder cancer recurrence than patients who never smoked or were not smoking at the time of surgery.

Former smokers also fared worse in these categories than those who had never smoked, even though the differences were less significant.

“The research suggests that as long as a person is not smoking at the time of chemotherapy and surgery, they might do better,” Cacciamani said in a statement.

He also recommends that physicians monitor smokers more carefully post-surgery than other patients because they are more at risk for complications or death.

In addition, the study authors recommend that future studies or clinical trials involving bladder cancer chart patients’ smoking status to create a more accurate picture of what factors affect cancer survival and recurrence.

Other Keck Medicine physicians who authored the study include Mihir Desai, Parkash Gill, Inderbir Gill, and Hooman Djaladat. Saum Ghodoussipour who is a former surgical oncology fellow with Keck Medicine, co-authored the study.

Researchers from medical institutions in Austria, Italy and Russia also participated in the study.


Partner Therapeutics begins phase III study of leukine + ipilumimab and nivolumab front-line melanoma

The EA61411 study conducted by ECOG-ACRIN Cancer Research Group has begun its phase III portion.

Partner Therapeutics Inc. sponsors the study.

EA6141 (NCT02339571) is a randomized controlled study of Leukine (sargramostim, yeast derived rhu-GM-CSF) in combination with ipilimumab and nivolumab for the front line treatment of melanoma.

The restart was based on results of ECOG-ACRIN’s planned interim efficacy and safety analysis of survival data from the first 250 patients enrolled in the study. FDA granted orphan drug status to Leukine in Sept. 2019, for the potential treatment of stage IIb-IV melanoma.

EA61411 is led by study chair F. Stephen Hodi, director of the Center for Immuno-Oncology at Dana-Farber Cancer Institute and study Co-Chair Ahmad Tarhini, professor of oncologic sciences and director of Cutaneous and Clinical Translational Research at H. Lee Moffitt Cancer Center and Research Institute.

“GM-CSF has unique immunomodulatory properties that have the potential to substantially benefit patients with cancer,” Hodi said in a statement. He added “This study in the front line setting is intended to confirm and broaden the findings in the randomized phase II trial EA1608, which demonstrated improved efficacy and toxicity when sargramostim was added to ipilimumab.”

ECOG-ACRIN launched the phase II/III EA6141 study in Sept. 2015. In the study, patients with stage III/IV unresectable melanoma are randomized to receive standard of care treatment with nivolumab and ipilimumab with or without sargramostim. The primary endpoint is overall survival. ECOG-ACRIN planned for the interim trial pause after 240 patients were enrolled, to assess efficacy.

The group paused enrollment in June 2017 and the interim analysis is now complete. Based on the findings of the interim analysis, the ECOG-ACRIN Data Safety Monitoring Committee has given the go ahead to start the enrollment into the phase III portion of the study. The total planned enrollment is 600 patients. The study remains blinded and no data will be released until completion.

“The prior data with sargramostim supporting improvement in survival and reduction in immune-related toxicity, as observed in the E1608 study, highlights the importance of further clinical evaluation in combination with checkpoint inhibitors,” Tarhini said in a statement.

ECOG-ACRIN previously reported results of Study E1608, a phase II study in which patients with advanced stage melanoma received a combination of sargramostim and ipilimumab or ipilimumab alone2. Among 245 patients, the addition of sargramostim led to longer survival (median 17.5 vs 12.7 months, HR 0.64).

Leukine is not approved for the treatment of melanoma.


Despite progress, adolescents and young adults face substantial cancer disparities by race/ethnicity

A new report examining cancer in adolescents and young adults defined as diagnoses occurring during ages 15 to 39, provides updated estimates of the contemporary cancer burden in this age group, predicting that 89,500 cases and 9,270 deaths will occur in 2020 in the United States. The report appears in CA: A Cancer Journal for Clinicians.

AYAs with cancer are frequently grouped with older or younger patient populations and/or presented in aggregate, masking the wide heterogeneity in cancer occurrence within this population. To address this issue, American Cancer Society investigators also examined cancer incidence, survival, and mortality among AYAs by race/ethnicity and for smaller age groups (15-19, 20-29, and 30-39).

Cancer incidence rates among AYAs are highest in those who are non-Hispanic white (83 per 100,000 population during 2012-2016) and lowest in those who are Asian/Pacific Islander (54 per 100,000 population) for both sexes. This reflects higher rates in non-Hispanic white AYAs for thyroid cancer, testicular tumors, and melanoma compared to other major racial/ethnic groups. Unlike adults ages 40 and older, however, female breast cancer incidence rates in non-Hispanic Black AYAs are 14% higher than those in non-Hispanic white AYAs (25.9 vs 22.3 per 100,000 population).

The authors also note that despite patterns in overall incidence, cancer mortality rates are highest in non-Hispanic Black AYAs, particularly females (12.6 per 100,000 vs 9.2 in non-Hispanic white persons), reflecting substantial survival disparities compared to those who are non-Hispanic white. The largest 5-year cancer-specific survival disparities occur among those who are non-Hispanic Black compared with non-Hispanic whites for acute lymphocytic leukemia (57% vs 71%, respectively) and female breast cancer (78% vs 89%, respectively).

By age group, the cancer incidence rate in AYAs increased during the most recent decade (2007-2016) overall but showed signs of stabilizing among men in their 20s. The rise is largely driven by thyroid cancer incidence rates, which rose by approximately 3% annually among those aged 20 to 39 and 4% among those aged 15 to 19 years. Incidence increased for several cancers linked to obesity, including kidney (3% across all age groups), uterine corpus (3% in group aged 20-39 years), and colorectum (0.9%-1.5% in the group aged 20-39 years).

In contrast to incidence, cancer mortality rates among AYAs for all cancers combined declined in the past decade (2008 through 2017) by 1% across sex and age groups except females aged 30 to 39, among whom rates remained stable due to a flattening of declines in breast cancer mortality. Mirroring incidence, mortality rates increased during the most recent 10 data years (2008-2017) for colorectal and uterine corpus cancers.

Other highlights from the report include:

  • Adolescents (aged 15-19 years) are more likely to be diagnosed with cancers associated with childhood, such as Hodgkin lymphoma, while those aged 20 to 39 years are more likely to be diagnosed with adult cancers, such as breast. Thyroid cancer is the only cancer predicted to rank among the three most commonly diagnosed cancers in each AYA age group in 2020.

  • Leukemia continues to be the leading cause of cancer death in ages 15 to 29 years. Among ages 30-39 years, breast (women) and colorectal (men) cancers are the leading cancer causes of death.

  • Melanoma incidence rates during 2007-2016 rapidly declined in ages 15 to 29 (4%-6% annually, on average). However, among ages 30-39 years, rates declined only slightly among men and remained flat among women.

  • Overall 5-year relative survival in AYAs for all cancers combined (83%-86% across age groups) is similar to that in children (84%), but masks lower survival for several cancer types, such as acute lymphocytic leukemia (ALL; 60% vs 91%, respectively).

The report notes an increasing body of evidence that tumors in AYAs are molecularly distinct from those in younger or older populations, suggesting differences in etiology and in treatment options. In addition, studies have shown that compared to childhood cancer survivors, AYAs have a higher risk of progression and death from their original cancer. Compared to older cancer patients, AYAs have a higher risk of long-term and late effects including infertility, sexual dysfunction, cardiovascular disease, and other future cancers. However, further research in these areas is needed.

The authors say that progress in reducing cancer morbidity and mortality among AYAs could be improved with more equitable access to health care, as AYAs are more likely than other age groups in the U.S. to be uninsured. Increased clinical trial enrollment, expanded research, and improved awareness among clinicians and patients of early symptoms and signs of cancer could also accelerate progress.


Study: Rubbery properties help RNA nanoparticles target tumors efficiently and quickly leave body

A new study by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute demonstrated that RNA nanoparticles have elastic and rubbery properties.

These properties explain why these particles target tumors so efficiently and why they possess lower toxicity in animal studies.

RNA nanoparticles show great promise for the targeted delivery of anticancer drugs. Understanding their structure and behavior is essential for their possible future use.

This study, published in the ACS Nano, reveals that RNA nanoparticles have elastic and rubbery properties that enable the molecules to stretch and return to their normal shape. Researchers say that these properties could help the particles target tumors by enabling them to slip through the poorly formed walls of tumor blood vessels and enter a tumor mass.

The researchers further proved that the same rubbery properties enable the RNA nanoparticle to slip through the kidney filters to excrete into the urine half hour after systemic injection, thereby eliminating them from the body relatively quickly. That, in turn, could reduce retention of the anticancer agent in vital organs, lowering an agent’s toxicity.

“We show that RNA nanoparticles have a flexibility that allows for the assembly of molecular structures that have stretchable angles,” study leader and corresponding author Peixuan Guo, professor in the College of Pharmacy and the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery, said in a statement. Guo also is in the OSUCCC – James Translational Therapeutics Research Program.

“These findings demonstrate the rubbery properties of RNA nanoparticles and why these molecules hold great promise for industrial and biomedical applications, especially as carriers for targeted delivery of anticancer drugs,” Guo, who directs Ohio State’s Center for RNA Nanobiotechnology and Nanomedicine, said in a statement.

For this study, Guo and colleagues tested the elasticity of nucleic acid polymers by stretching and relaxing individual RNA nanoparticle, while subjecting RNA nanoparticles to elasticity studies using dual-beam optical tweezers built in Guo lab. They used animal models to study the biodistribution, excretion and retention of RNA nanoparticles. This included measuring excretion of the particles in urine, along with the study on the effect of their shape and size. 

Key findings include:

  • RNA nanoparticles are stretchable and shrinkable, like rubber, even after repeated extension and relaxation with multiple repeats by optical tweezers.

  • In animal models, RNA nanoparticles show stronger cancer targeting and lower accumulation in healthy organs when compared to gold and iron nanoparticles of similar size.

  • Also in animal models, within half an hour after systemic injection, RNA nanoparticles that were 5, 10 and 20 nm in size were filtered by the kidneys and retained their original structure in urine, even though the upper limit of kidney pore size for filtration is generally 5.5 nm. This suggests that the larger RNA nanoparticles slipped like rubberly and amoeba through filtration pores, then returned to their original size and shape in urine.

Other researchers involved in this study were Chiran Ghimire, Hongzhi Wang, Hui Li, Mario Vieweger and Congcong Xu, The Ohio State University.

Copyright (c) 2020 The Cancer Letter Inc.