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Monday, January 18, 2021

Combining Genomics & Mathematics to Personalize Radiation Therapy for Lung Cancer

Clinical trials in lung cancer over the decades have determined an optimal one-size-fits-all dosing scheme for patients treated with radiation therapy, but new research now shows this is not as biologically accurate as once believed. A new technology using tumor genomics to personalize radiation dosing demonstrates that the standard of care approach may be suboptimal for up to 75 percent of lung cancer patients.

 A paper published in the Journal of Thoracic Oncology, co-authored by Javier F. Torres-Roca, MD, a senior member in the Radiation Oncology Program at Moffitt Cancer Center, and Jacob G. Scott, MD, DPhil, a radiation oncologist and physician researcher in the Department of Translational Hematology and Oncology Research at Cleveland Clinic, demonstrates an approach to combine individual tumor genomics and mathematics to personalize the dose of radiation therapy for lung cancer patients (2020; https://doi.org/10.1016/j.jtho.2020.11.008). By applying this personalized technology, their study shows an opportunity to increase the efficacy and decrease the toxicity of radiation therapy.

 “It's standard of care to give patients the same radiation dose based on the type of cancer and its stage," Torres-Roca said. “The idea that this is optimal for every patient is in direct conflict with the fact that all cancers are different. In this study, we demonstrate that the standard dose results in the majority of patients getting either too much or too little radiation. So we developed a new technology that can personalize the dose required for a specific patient's tumor biology and quantified the clinical opportunity this provides."

 In 2017, Torres-Roca and Scott developed the Genomic Adjusted Radiation Dose (GARD), a method of dosing that accounts for biological differences and can be utilized to predict the optimal radiation therapy dose for each individual patient. The results were published in Lancet Oncology and were used as a basis for this most recent advance (2016; https://doi.org/10.1016/S1470-2045(16)30648-9).

“Here we extend our work with GARD to define a new paradigm for clinical radiotherapy dose decision-making," Scott said. “By developing a patient-specific mathematical model that factors in individual tumor biology and healthy tissue complication probabilities, we optimize clinical outcome for each individual patient."

While the study involved non-small cell lung cancer patients, Torres-Roca and Scott are confident the technology can be used in other cancers as well.

Moffitt Cancer Center expects to start a clinical trial utilizing the new technology in early 2021.​

Monday, January 18, 2021

Mouth Bacteria Linked to Lung Cancer Risk In Non-Smokers

The type and abundance of bacteria found in the mouth may be linked to lung cancer risk in non-smokers, finds the first study of its kind (BMJ Thorax 2020; doi: 10.1136/thoraxjnl-2020-215542). Fewer species and high numbers of particular types of bacteria seem to be linked to heightened risk, the findings indicate.

Around one in four cases of lung cancer occurs in non-smokers and known risk factors, such as secondhand tobacco smoke, background radon exposure, air pollution, and family history of lung cancer don't fully explain these figures, researchers noted. The type and volume of bacteria (microbiome), found in the mouth has been associated with a heightened risk of various cancers including those of the gullet, head and neck, and pancreas.

The researchers wanted to find out if this association might also hold for lung cancer, given that the mouth is the entry point for bacteria to the lungs.

They drew on participants in The Shanghai Women's Health Study and the Shanghai Men's Health Study, all of whom were lifelong non-smokers, and whose health was monitored every 2-3 years after entry to the study between 1996 and 2006.

At enrollment, participants rinsed out their mouths to provide a profile of the resident bacteria, and information was obtained on lifestyle, diet, medical history, and other environmental and workplace factors that might influence their disease risk.

In all, 90 of the women and 24 of the men developed lung cancer within around 7 years, on average. These cases were matched with 114 non-smokers of the same age and sex, who also provided a mouth rinse sample. This comparison group didn't have lung cancer but they had similar levels of education and family histories of lung cancer.

Comparison of both sets of rinse samples showed that the microbiome differed between the two groups. A wider range of bacterial species was associated with a lower risk of developing lung cancer. And a larger volume of particular types of species was also associated with lung cancer risk.

A larger volume of Bacteroidetes and Spirochaetes species was associated with lower risk, while a larger volume of Firmicutes species was associated with heightened risk.

Specifically, within the Spirochaetes species, a greater abundance of Spirochaetia was associated with lower risk; and within the Firmicutes species, a larger volume of organisms from the Lactobacillales order of microbes was associated with a heightened risk.

The associations remained when the analysis was restricted to those participants who had not taken any antibiotics in the 7 days before sample collection and after excluding those diagnosed with lung cancer within 2 years of sample provision.

This is an observational study, and therefore can't establish cause. And the researchers acknowledge several limitations. "While our study provides evidence that variation in the oral microbiome plays a role in lung cancer risk, the interpretation of our study must be done while considering the caveat that our findings are from a single time point in a single geographical location," they write.

In a linked editorial, David Christiani, MD, MPH, of Harvard University, suggests that mouth bacteria may provoke chronic inflammation, boost cell proliferation and inhibit cell death, prompt DNA changes, and switch on cancer genes and their blood supply, which would help to explain the findings.

The study findings raise several questions, he noted. "First, how stable is the human oral microbiome over time? Second, if the human oral microbiome varies over time, what determines that variability? Third, how does the ambient environment such as exposure to air pollutants, affect the oral (and lung) microbiome?

"It remains unclear whether the oral microbiome as measured in this (and other) epidemiological studies represents a causative agent or only a marker of disease or immune activity. If it is the former, then it will be important to understand whether the oral microbiome actually seeds the lung microbiome and thus acts locally."​

Monday, January 18, 2021

Patient Disparities in Extensive-Stage Small Cell Lung Cancer Treatment

​A recent study shows that Black individuals with extensive-stage small cell lung cancer (ES-SCLC) are less likely to receive chemotherapy for their disease compared to White and other racial groups. Led by researchers at Boston Medical Center, the results indicate that individuals who are Black, elderly, uninsured, or have non-private health insurance and lower education levels, were less likely to be treated with chemotherapy for this type of lung cancer.

Published in JTO Clinical and Research Reports, the official journal of the International Association for the Study of Lung Cancer, this study is one of the largest to investigate the racial and health disparities in treating patients with ES-SCLC, and highlights the impact that race and insurance status have on cancer care in the U.S. (2020; https://doi.org/10.1016/j.jtocrr.2020.100109).

Given the tendency of this type of lung cancer to rapidly progress, current recommendations and practices favor starting treatment as soon as possible after a patient is diagnosed with ES-SCLC. Analyzing the National Cancer Database (NCDB) between the years 2004 and 2016, researchers discovered that Black patients had lower odds of receiving chemotherapy compared to White patients, but had improved survival, with the median survival of 8.3 months compared to 8 months. This is an unexpected finding given that the disease is highly sensitive to chemotherapy, and this treatment is the most important predictor of survival.

"Our study highlights the disparities that can exist in health care, and the impact that race and socioeconomic status can have on a patient's experience throughout their treatment," stated Umit Tapan, MD, a thoracic oncologist at Boston Medical Center and the study's corresponding author.

Study Details

In this large-scale analysis, racial and socioeconomic factors impacting systemic therapy delivery and survival in ES-SCLC were identified through a total of 82,592 ES-SCLC patients between 2004 and 2016, as identified through the NCDB. The analysis showed that chemotherapy was administered to 92.1 percent of patients. Insurance and income status played a large role in treatment and survival of patients. Black patients were more likely to be uninsured or have public health insurance compared to white and other race groups, and patients with non-private insurance or without insurance were less likely to receive chemotherapy treatment. Private insurance was associated with the highest survival of 9.2 months, followed by patients with Medicaid at 8.3 months. Lower income is associated with worse survival, which has been found for all lung cancer diagnoses.

"While our study looked specifically at patients with extensive-stage small cell lung cancer, our results further demonstrate the impact that socioeconomic status can have on the health of patients, whether it be access to treatment or their outcomes," said Tapan, also Assistant Professor of Medicine at Boston University School of Medicine.

Another important point highlighted in the study shows that Black patients had higher odds of receiving chemotherapy between 2010 and 2016 compared to 2004-2009, which the authors suggest is a positive impact of the Patient Protection and Affordable Care Act (ACA) in 2010.

Further studies are needed to address the underlying reasons for lack of chemotherapy receipt in Black patients with ES-SCLC, and to guide the appropriate interventions to mitigate these disparities.

Thursday, January 7, 2021

Should Oncology Patients Get the COVID-19 Vaccine?

By Lindsey Nolen​

Andy Sealy was diagnosed with breast cancer on January 24, 2017, and stage IV metastatic post double-mastectomy in March. Learning to navigate care and treatment, she never could have anticipated what living with breast cancer would be like during a global pandemic.

Now, on top of forced adaptations and increased isolation, she and other oncology patients, are left wondering if the emergency authorization of the COVID-19 vaccine is their ticket to resume some level of normalcy, too.

Since the onset of this pandemic, health care leaders have urged immunocompromised patients, including those with cancer, to remain vigilant in their measures to avoid potential exposure to the virus. As vaccination distribution begins globally, oncology patients are unsure when and if they should opt to be vaccinated. Immunization against COVID-19 is ideal, but health care leaders emphasize that there is not enough data to guarantee the vaccine's safety across the oncological population.

This is because oncology patients were not included in COVID-19 vaccine clinical trials. For this reason, the outcome of vaccination for this group is unknown. However, the hope is that as more individuals worldwide receive this new mRNA vaccine, scientists will have a better idea of how patients with weakened immune systems react.

“At first, I said 'No way I'm taking this,' but then I thought about it, and I was like 'Why not?' Now, if it's between getting the vaccine or staying in the house, I would 100 percent get it," shared Sealy, who is part of the Black, Indigenous and People of Color (BIPOC) community, a population the Centers for Disease Control and Prevention (CDC) states has much higher COVID-19 death rates than White, non-Hispanic individuals.

“After 3.5 years of getting used to being on a schedule with scans, blood work, and other appointments, COVID-19 isolation makes you feel like you've lost control," she noted.

While she understands that oncology patients could not be a part of clinical trials so that they could be expedited for the benefit of millions of people, having had to essentially stay home since March has taken its toll on her mental health. Isolation left her largely alone, self-medicating and spiraling into a state of deep depression—to the point where she became suicidal and ultimately sought mental health treatment.

Coming out of treatment and back into her adapted COVID-19 lifestyle, Sealy noted that she always asks herself, “Am I living safely or am I safely living?" To her, living in isolation isn't living, and if receiving the COVID-19 vaccine could alter this state, she remains very interested. In addition to weighing the risks and benefits of possible vaccination, Sealy expressed that she has also experienced tremendous guilt, having not volunteered to participate in the COVID-19 vaccine trial on behalf of breast cancer patients.

“My cancer is terminal, so I think if I volunteered I could help researchers understand how someone with my type of breast cancer would react to the vaccine," Sealy said. “I've asked my physician about when I might be able to get it, because I really want to be able to go back out and start doing things again."

“My world is full of vaccine talk right now," said Lisa Kennedy Sheldon, PhD, ANP-BC, AOCNP, FAAN, the Clinical and Scientific Affairs Liaison at the Oncology Nursing Society (ONS). “Patients want to know if they can get the vaccine and are asking their health care providers if they think the vaccine is safe. Many have questions about the vaccine being a new type of vaccine, an mRNA vaccine."

Debra Kelly, RN, BSN, OCN, ONN-CG, Oncology Nurse Navigator at the Sarah Cannon Cancer Institute within HCA Houston Healthcare, also noted that her oncology patients are asking vaccination questions. They are wondering if the coronavirus vaccines are safe and, of the two options currently available, which is the “best?"

While Kelly noted the importance of oncology patients receiving the flu and shingles vaccines, she said COVID-19 vaccination does pose questions about whether these patients will mount an adequate immune response due to cancer-related immune suppression.

Expanding on these questions, Sheldon explained that, while there is evidence that people who have cancers experience more serious side effects and a more serious disease course from COVID-19, the ONS needs much more data before making oncological vaccination recommendations.

For example, when Pfizer's data came out and was looked at by FDA officials, there were exclusion criteria—one of which was receiving chemotherapy. Therefore, oncologists and oncology navigators can be certain that there were no patients receiving chemotherapy participating in the Pfizer vaccine trial.

Eamonn Nolan, Senior Manager of Oncology Communications at Pfizer, affirmed this, explaining that the ongoing COVID-19 vaccine study protocol “excluded immunocompromised individuals with known or suspected immunodeficiency," as determined by history and/or laboratory/physical examination. However, individuals who have a history of cancer, including breast, colon, prostate and other cancers, and who are in remission, were eligible to participate and were part of the trial population.

“A future clinical trial focused specifically on the immunocompromised population is planned for next year," Nolan said. “We recognize that this is an important topic for cancer patients. If someone is living with cancer, they should talk to their doctor about vaccination."

Sheldon added that, as an organization, the ONS will follow the recommendations of the FDA, CDC, and Infectious Diseases Society of America about how to care for people with cancer and make recommendations about vaccines for COVID-19. The organization plans to work with other organizational partners to find the best evidence before making recommendations for all vaccinations, including the COVID-19 vaccine.

“We're waiting for all of the information, just like everyone else is," said Sheldon, who has a background in both academic research and clinical practice. “We want to make sure the vaccine is safe and effective. We want to know how it actually works across special populations, such as people with cancer and people with cancer receiving treatment."

Until then, she stresses that the only answer to whether or not oncology patients should receive the COVID-19 vaccine is that the ONS does not have the information yet to make this determination. Sheldon believes that, as the vaccination clinical trial progresses over the next 2 years, scientists and medical professionals will have more information needed to better understand the vaccine's safety and efficacy.

With or without receiving vaccination in the immediate future, health professionals continue to stress that precautions like mask-wearing, handwashing, and social distancing are as important as ever—especially for immunocompromised oncology patients. By implementing these safety measures, oncology patients can best mitigate risks and maintain optimal health outcomes as the world waits for the pandemic to end.

Lindsey Nolen is a contributing writer.

If any oncology patients are interested in speaking with Andy Sealy about her journey, they can contact her on Facebook or Instagram at @justaskwithandysealy, or by email at [email protected].​

Wednesday, December 16, 2020

Disrupting the Cellular Process That Promotes Pancreatic Cancer's Deadly Growth

Researchers say they've identified a way to disrupt a process that promotes the growth of pancreatic cancers—one of the most difficult and deadly cancers to treat.

The team, led by scientists at Georgetown Lombardi Comprehensive Cancer Center and including investigators from Lawrence Livermore National Laboratories published their findings in the journal Gastroenterology (2020; doi: 10.1053/j.gastro.2020.11.044).

Pancreatic cancer is on course to be the second-leading cause of cancer-related death in the country, according to the American Cancer Society, with most people surviving less than a year after diagnosis. Therapies approved to treat the cancer are poorly effective and extend survival by only a few months.

One of the hallmarks of the disease is a build-up of scar tissue called fibrosis, in which the cancer-associated fibroblasts (CAF) that trigger fibrosis serve a tricky dual role—depletion of CAF is just as likely to promote as inhibit pancreatic cancer.

"We hypothesized that if we can alter the microenvironment where cross-talk between the fibroblasts, immune cells, and cancer cells happens, then we can cause just enough disruption to push back tumor growth," says lead author, Ivana Peran, PhD, a research instructor of oncology at Georgetown Lombardi.

To do that, the team focused on adhesion molecule cadherin 11 (CDH11), which is expressed by CAFs in the pancreatic tumor environment and has been associated with other fibrotic disorders where it is expressed by activated fibroblasts. They examined inhibiting CDH11 in tumors growing in mice.

Their hypothesis turned out correct. For the first time, the team demonstrated that CDH11 is important in the natural history of pancreatic cancer. "Knocking out" the ability of mice to produce CDH11 reduced the growth of pancreatic tumors, increased the tumor's response to a common chemotherapy called gemcitabine, reversed immunosuppression, and significantly extended the survival of mice.

"Separately, we have identified a drug that can inhibit CDH11," said Stephen Byers, PhD, Professor of Oncology at Georgetown Lombardi. "This drug also inhibited the growth of pancreatic tumors and taken together with our earlier work, this finding warrants study in human clinical trials for people with pancreatic cancer whose tumors express CDH11."​