Part 2: Genes and Tumor Biology

This blog is continued from Part 1 which can be read here. 

More Similar Than Different

All humans are about 99.5% similar genetically. Dr. Samuel Cykert, professor of Medicine at UNC Chapel Hill argues that the disparities we see in lung cancer outcomes may be slightly related to genetic differences, but the bulk of disparities are a result of widespread racism, bias, mistrust and poor communication. “The genetic differences are in the tip of the pin. The treatment and access to care differences are huge,” he says. He notes that many professionals in the field are eager to blame health disparities on income inequality, but that is only one piece of the puzzle. Most major studies on race and health outcomes control for income, comorbidities (other diseases a patient may have) and socioeconomic status (SES), and many control for other factors like age and insurance coverage. The idea that Black patients have poorer health outcomes just because many Black communities have a lower socioeconomic status than white communities is just plain wrong, according to Cykert. 

Dr. Khadijah A. Mitchell, Assistant Professor of Biology at Lafayette College notes, “Self-reported race is a social construct and genetic ancestry is a biological construct. Shared genetic ancestry in people of African descent can tie racial groups together. And this biology can influence the tumor.”1  Dr. Mitchell, amongst others are looking into what Dr. Cykert refers to as, “the tip of the pin.” Scientists have found there are differences in the tumors between Americans of African descent and Americans of European descent, and of course shared biology. But the differences they’ve identified have the potential to drive differences in outcomes, like survival rate. 

Looking Deeper into the Genome

Dr. Ann Schwartz, Deputy Director and Executive Vice President for Research and Academic Affairs at the Karmanos Cancer Institute and a Professor in the Department of Oncology at Wayne State University School of Medicine, agrees with Dr. Cykert in that we are all more alike than different, but she also notes “the trials that identify the set of actionable mutations (mutations that can be treated with a targeted therapy) include few African Americans. So, we are testing markers that may not be comprehensive for all patients.” Dr. Mitchell adds, “Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent.”

In fact,  The Cancer Genome Atlas (TCGA), a landmark cancer genomics effort between the National Cancer Institute and the National Human Genome Research Institute, sequenced the genome of close to 1,100 lung cancer patients. Of those patients, only 83 were of African descent. 

Researchers studying the tumor biology of African Americans have noted differences in genes and gene pathways that may make African Americans more susceptible to lung cancer. One study led by the National Cancer Institute’s Dr. Bríd Ryan, is looking at two genes called JAK2 and PTPRT in a certain pathway that seem to be more mutated in African American participants than in white participants. There are currently drugs to target JAK2 in other cancers and Dr. Ryan’s lab is going to test whether they would work in lung cancer, which could lead to a promising new treatment option.2,3 

Researchers like Dr. Alicia Hulbert, Assistant Professor in the Department of Surgery at the University of Illinois Cancer Center, are studying epigenetics which examines changes in genes due to external factors like air pollution and even stress. Dr. Hulbert is particularly interested in how the genes CDO1, TAC1 and SOX17 could serve as biomarkers to detect lung cancer early.4,5  She is interested in studying the Black population as they are more likely to have lung cancer diagnosed at a late stage and are underrepresented in research. Also, the Black community may experience higher levels of stress, which could contribute to changes in their genes that increase their risk of cancer.  

Moving Forward

Right now, all eligible lung cancer patients should be getting biomarker testing before beginning treatment. Dr. Cykert is amongst the many physicians committed to eliminating health disparities through proven successful tactics. At his hospital they developed a real-time registry system that alerts a patient navigator if a patient misses their appointment or treatment milestone. The patient navigator helps the patient overcome any barriers and shepherds them through the whole diagnostic and treatment processes. This solution was developed with a community partner, Greensboro Community Health Collaborative (GCHC), which was key to its success. “You need solutions of transparency where you can see who is getting treatment or not in real time and whether there’s a patient barrier or hesitancy among clinicians that needs to be addressed.  The GCHC established the concepts and the scientists built the system,” says Cykert.

Dr. Mary Pasquinelli, nurse practitioner at University of Illinois Health, knows the vital role patient navigation plays in reducing disparities and improving outcomes. Dr. Pasquinelli takes the time to develop trust and rapport with each patient, often going above and beyond to make sure her patients get what they need. Almost 60% of the population she treats are Black individuals. She remarks that when discussing treatment options with her patients, the most common question she gets is, “What would you do?” which speaks to how meaningful her relationship building is with her patients, especially since mistrust of the health system can be a common barrier cited by Black communities.

To better understand the tumor biology of Black Americans, there need to be more Black patients enrolled in clinical trials. Many of the same practices Dr. Cykert uses at his hospital to improve outcomes would work to help improve enrollment in clinical trials. At University of Illinois Health, they are addressing this issue through a clinical trials office and clinical trial coordinators. The office screens every single cancer patient to see if they are eligible for a clinical trial and then communicates with the clinicians to inform them of the result. Lastly, companies that have access to large data sets of biomarker testing results should be studying those sets and looking for how race and ethnicity may impact tumor biology.

Addressing health disparities and inequities is multifaceted and takes effort. “Systems based on communication, transparency and accountability can be applied to a wide range of things, including improving cancer care,” says Cykert. “We need to be building these systems right now for biomarker testing and lung cancer. Now is the time to put practices in place.”

And of course, keep looking into the head of the pin. 


Tremendous thanks to Dr. Samuel Cykert, Dr. Alicia Hulbert, Dr. Sushma Jonna, Dr. Khadijah A. Mitchell, Dr. Bríd Ryan, Dr. Ann Schwartz, Dr. Mary Pasquinelli and members of the American Lung Association’s Diversity Equity and Inclusion Council for their assistance with this blog.

Support provided by Amgen, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Lilly Oncology, Merck, Novartis and Pfizer.


Sources:

  1. https://pubmed.ncbi.nlm.nih.gov/32935870/
  2. J Thorac Oncol. 2019 Jul;14(7):1192-1203. doi: 10.1016/j.jtho.2019.03.014. Epub 2019 Apr 3.
  3. J Thorac Oncol. 2020 Sep 12;S1556-0864(20)30721-8. doi: 10.1016/j.jtho.2020.08.029.
  4. Hulbert A, et aJusue-Torres I, Stark A, et al. Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum. Clin Cancer Res. 2017;23(8):1998-2005. doi:10.1158/1078-0432.CCR-16-1371
  5. Liu B, Ricarte Filho J, Mallisetty A, et al. Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non-Small Cell Lung Cancer. Clin Cancer Res. 2020;26(16):4339-4348. doi:10.1158/1078-0432.CCR-19-2896
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