From Cancer Prevention to Treatment: Underpinning the Advances, Challenges to Democratizing Precision Oncology

Precision oncology has long influenced the management of common and rare cancers, in which stage of disease and pathology have been used to inform treatment strategies that aim to align with respective care needs. However, only recently have advances in precision medicine and screening expanded the possibilities of treatment for patients beyond the one-size-fits-all approach of chemotherapy and into a personalized care plan where the vulnerabilities of each particular cancer are prioritized and targeted.

BRAF, EGFR, and KRAS G12C mutations, identified via genomic testing, are some of the known targets that have led to therapeutic breakthroughs for solid and hematologic malignancies. And there is hope that precision medicine can be democratized to every single patient with cancer, said Doug Johnson, MD, MSCI, associate professor of medicine and director of precision oncology at Vanderbilt-Ingram Cancer Center, but several challenges remain that continue to limit its effectiveness in oncology.

Johnson and Ben Ho Park, MD, PhD, director of Vanderbilt-Ingram Cancer Center, served as co-chairs of The American Journal of Managed Care® Institute for Value-Based Medicine® event in Nashville, Tennessee, held November 17, 2022. The event was held in partnership with Vanderbilt-Ingram Cancer Center, with Johnson and Vanderbilt-Ingram Cancer Center’s Ben Ho Park, MD, PhD, serving as co-chairs.

The event addressed several topics in precision oncology, including novel treatment options, microsatellite instability (MSI) in gastrointestinal (GI) cancers, and precision treatments for smoking cessation. Examples of precision medicine success and best practices in leveraging structured genomic data were also discussed.

Novel Treatment Options and Challenges in Precision Oncology

The introduction of genetic and genomic testing tools, such as next-generation sequencing (NGS), has helped to provide a more personalized and precise approach to treatment for patients with cancer, noted Johnson. However, as shown in the NCI-MATCH trial, not all patients who undergo sequencing show a mutation that can be targeted with immunotherapy.¹

“Many patients didn't have a [mutation] that could be targeted—somewhere in the range of 75%. The response rates on some arms were very low, and many patients that responded had short lived responses. With that being said, there were certainly some great successes, [but] I think it sort of demoralized some people who were hoping for big wins,” he said.

Nonetheless, steady progress continues to be made in the precision oncology field. Targets that were previously thought to be undruggable, such as KRAS G12C mutations, have seen therapeutic success with drugs like sotorasib.

More targets, better drugs, and better options for resistance have expanded precision oncology beyond the “1 gene, 1 drug” paradigm, noted Johnson, and clinical research efforts seek to improve the generalizability of specific success stories to entire populations of patients with these diseases.

Management of non–small cell lung cancer (NSCLC) is a field that has seen notably significant progress in the recognition of mutations involved with development and progression, as well as novel targeted drugs and immunotherapies associated with improved patient outcomes.

The DESTINY-Lung01 trial findings demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant advanced NSCLC, providing improved response rates, progression-free survival (PFS), and overall survival (OS).²

The development of newer, more rationally designed targeted therapies also translates to other tumors that express the same mutations, said Johnson. For example, significant improvement in PFS and OS is also shown with T-DXd in HER2-low metastatic breast cancer.³

“One thing that’s exciting is that as we continue to identify these targets, we're moving even beyond tumor DNA,” Johnson said. “Of course, that's a powerful tool to do the sequencing and identify these mutations, but we really need even better options.”

A major challenge facing cancer centers who are shifting their care pathways toward precision medicine is deciding which kind of tests to order, Johnson explained.

Various types of genetic abnormalities beyond driver mutations exist in solid and hematologic tumors, including chromosomal abnormalities, mutational processes, and tumor heterogeneity, and the ability to detect these abnormalities depends on the test design and validation process utilized.⁴

At Vanderbilt-Ingram Cancer Center, Johnson said tests are selected on a case-by-case basis, and the choice depends on factors such as the amount of tumor tissue available. Another challenge is interpreting the results of these tests.

“One thing that what we've done is that we've established molecular tumor boards, including an internal one where we have a panel of people who think about this a lot, and also disease specific experts and hereditary cancer experts who all can review a case, review genetic results, and then provide a recommendation.”

Ultimately, leveraging these data can lead to the selection of appropriate treatments and the advancement of precision oncology. But Johnson said that clinicians should expand their goals to also strive for precision health, which assesses immune function and status, the microbiome, and vital signs, among other clinical features.

Studies are just beginning to scratch the surface in determining the impact of the microbiome on the efficacy of certain immunotherapies and overall human health, said Johnson. “The goal is not just to treat cancer, but to give people long, healthy, happy, flourishing lives,” he noted. “The lessons we can learn with [precision oncology] can hopefully lead to that.”

Implications of MSI on Prognosis, Therapy in GI Cancers

Focusing primarily on colorectal cancer (CRC) and the MSI mutation, Kristen K. Ciombor, MD, MSCI, an associate professor of medicine at Vanderbilt-Ingram Cancer Center, next addressed emerging data in the localized setting.

Recent advances in screening through NGS and other technologies have identified a myriad of actionable mutations in colorectal cancer. The MSI subtype, also known as mismatch repair deficiency, affects a relatively small number of patients with colorectal cancer, but it is an important biomarker across all tumor types, said Ciombor.

“We know that mutations encode proteins that can be recognized and targeted by the immune system, and average tumors actually only have a few somatic mutations, but MSI-high tumors have thousands of mutations and we actually can use that to our advantage,” she explained.

“The hypothesis many years ago was that the immune microenvironment was counterbalanced by these inhibitory signals that resisted tumor elimination. And if you could augment with programmed cell death protein 1 [PD-1] blockade, you could potentially have more success with treatment, especially with these MSI tumors,” Ciombor pointed out.

This strategy has proven successful in the advanced setting. PD-1 inhibitors such as pembrolizumab and nivolumab have achieved significantly high response rates in refractory patients with MSI-high CRC. Clinical trials investigating the use of these drugs in the first-line setting (KEYNOTE-177 and CheckMate 142) have also demonstrated significant benefit.^5,6

In the localized setting, the improvements observed in rates of radiographic and endoscopic response with neoadjuvant pembrolizumab compared favorably with, and were sometimes even superior to, the rates in the metastatic setting, noted Ciombor, and further showed the potential for the drug’s use in an organ-sparing treatment strategy.⁷

Other PD-1 inhibitors that have shown promise for MSI-high CRC include dostarlimab and adjuvant nivolumab and ipilimumab. However, several steps remain to further examine long-term outcomes of these PD-1 inhibitors as an aspect of an organ-sparing approach vs standard-of-care surgery, Ciombor noted.

“We always knew that MSI testing was very important in patients with colorectal cancer, not only to screen for Lynch syndrome, but also in cases of metastatic disease for the potential use of immunotherapy. But now we’re finding that it needs to be tested at any stage and before treatment begins, because this can drastically change how we treat patients,” said Ciombor.

A study is underway at Vanderbilt-Ingram Cancer Center to assess the impact of adjuvant nivolumab/ipilimumab and short-course radiation on complete pathologic response rates of patients with locally advanced rectal cancer who undergo total mesorectal excision.

“It’s really important to get these prospective data, so we know how to change the standard of care in the future,” concluded Ciombor.

“We can potentially spare patients from other modalities of therapy in the case of rectal cancer, maybe surgery and radiation. And we need ongoing biomarker studies to understand not only how patients respond, but how long they respond, who doesn't respond, and the optimal duration of therapy.”

Precision Treatment for Tobacco Use Cessation

Hilary Tindle, MD, MPH, the founding director of the Vanderbilt Center for Tobacco, Addiction and Lifestyle, spoke next, discussing her work regarding precision approaches to tobacco smoking cessation.

Cigarette smoking is the leading cause of early morbidity and mortality in the United States, and although progress has been made to increase awareness and reduce use of tobacco, about 13% of US adults—30 million individuals—still smoke cigarettes frequently, noted Tindle.⁸ This rate is even higher among disproportionately affected groups, such as those living below the poverty line and those residing in the 13 states that have been described as Tobacco Nation, including Alabama, Mississippi, South Carolina, and Tennessee.⁹

“If you took these states as a country, and compared the smoking rates, it would be fifth worst in the world,” emphasized Tindle. “Many counties in this Tobacco Nation are rural, and there are weaker laws and taxes on cigarettes in some of these states.”

Several effective treatments are available for smoking cessation, such as nicotine replacement, varenicline, and bupropion, but Tindle said that success rates of quitting are relatively low, despite more than half of active smokers trying to quit every year.¹⁰

“When medications are used, which is in about a third of all cases in which people try to quit, they’re using a type of one-size-fits-all [strategy]. It’s not done in an informed way that is necessarily tailored to genetics or other important factors,” she said.

Tindle’s work centers around the promise of precision medicine to address these limitations, particularly how nicotine dependence can inform what treatment for smoking cessation is best for each patient. Nicotine dependence, like many other conditions and addictions, is heritable from initiation all the way through cessation, she explained. Hundreds of genetic variants help determine smoking persistence, how much one smokes, and how well smoking-cessation medications fare.

Two chromosomes that influence ​​nicotinic acetylcholine receptors in the brain and nicotine metabolism in the liver have risen to the top in terms of importance, noted Tindle. Right now, nicotine metabolism, a process that can be captured by running a genome-wide association studies analysis, has the most evidence in terms of actionability.

“We can capture nicotine metabolism with just a simple blood, urine, or saliva test, and we can measure the nicotine-metabolite ratio [NMR],” Tindle explained. “That ratio can help us predict how much trouble an individual will have in quitting smoking, and there’s also evidence that it can predict how well a person will do in relation to a certain drug.”

NMR stratifies patients into those with high (fast) or low (slow) nicotine metabolism, she continued. Those with high nicotine metabolism are at greater risk for smoking persistence and intensity and for having more difficulty in quitting smoking, even with treatment.

A clinical trial conducted 7 years ago further showed the utility of the NMR in predicting treatment success. Participating smokers seeking treatment were randomly assigned by baseline NMR status to 11 weeks of placebo, nicotine patch, or varenicline, plus behavioral counseling.¹¹

After 6 to 12 months, patients who metabolized nicotine faster were found to be approximately twice as likely to quit smoking with varenicline vs nicotine patch, whereas those with slow metabolism showed no difference between the modalities in terms of quitting success. Slow metabolizers, however, experienced significantly more adverse effects with varenicline than with the nicotine patch.

A subsequent clinical trial conducted by Tindle and colleagues demonstrated that most patients seeking smoking cessation treatment would be interested in doing the NMR-based blood test and would follow the recommended strategies based on the results.¹² However, a patient’s age, education level, and race could affect their willingness to embrace precision approaches.

“When people are counseled about quitting smoking, sometimes it’s helpful to actually bring in other information, such as what’s your risk of heart disease and lung cancer, and that can actually potentially enhance the conversation and get people motivated or at least help them understand why this is really important,” Tindle added. “Precision medicine is only as good as the foundation of medicine under it.”

Leveraging Genomic Data and Democratizing Precision Oncology

As Vanderbilt-Ingram Cancer Center’sdirector of cancer clinical informatics, Travis Osterman, DO, MS, plays a key role in interpreting and translating genomic data as they relate to cancer care delivery. He discussed how clinical informatics can optimally support precise diagnosis and individualized treatments.

Although advances in pharmacogenetics have created novel possibilities for personalized care management, Osterman said that these data can prove very complex for clinical teams nationwide. As such, the next step to leverage structured genomic data requires the establishment of data standards to integrate these data into the electronic medical record (EMR) and have clinical decision support.

“I’m going to take the very provocative view that I’m against faxing medical records to me for patient care. I want to receive those records [electronically], just like any other test I order,” he said.

“We had the first group convened to work on a national open-source standard to transmit genomic data in late 2018. At that time, there was one institution in the country that had made a connection to a reference laboratory doing these complex tests receiving that data in a structured format.”

As of 2022, nearly 30 health care systems had adopted the second version of the data standard, the Minimal Common Data Elements initiative, that was released earlier this year. These health systems now receive genomic data from reference laboratories.

The shift away from the PDFs, faxes, and outside records that proved detrimental to the clinical decision-making process allows for the streamlining of effective care delivery to not only 1 patient, but the entire population of patients cared for at a given cancer center, Osterman said. And over time, the knowledge gained by the expanded use of genomic data can advance precision medicine further on a national and international scale.

“One of the best ways to look at this is as a pipeline….We enter this test in our normal EMR like we normally do. It goes out to a third-party laboratory, which is able to [keep] up with the science benefit and economies of scale. They send us the results back not as a fax, but like any other result internally to our lab that lands in this data set. Then, it’s immediately available to our patients in our patient portal,” explained Osterman.

The availability of these data can allow patients to access findings from their phones and receive second opinions if needed, he said. The data can also help clinicians place patients in groups based on their respective mutations, to match these individuals with clinical trials or effective drugs that best fit their care needs.

Osterman has called for federal guidance over the next decade to address the ethical considerations of genomic data sharing, particularly whether to rerun data from these tests when knowledge about further actionable mutations and targeted treatments enters the oncology pipeline.

“We need to continue to expand genetic/genomic training in medical and nursing schools. These are complex topics,” he said. “Sometimes these get even more complicated when you're talking about germline testing, where if you have it done once at age 17, that lives with you for the rest of your life.”

Event co-chair Ben Ho Park, MD, PhD, concluded the discussion with thoughts on the advances and challenges that remain in the quest to democratize precision oncology for all patient populations.

As one of the major tools available today to sequence genomic data and interpret health information, NGS has proven effective in matching a patient’s genome sample to a reference and informing clinicians whether it is pathogenic.

However, because these references are an average only of the hundreds of thousands of genome sequences known today, Park said there is still a long way to go in figuring out what is or is not normal—and what is or is not actionable for the 8 billion people living worldwide. Germline genetics is in its infancy in precision oncology, said Park, with only a few companies and institutions incorporating these DNA into tumor sequencing.

“A big problem that many academic centers and communities have is that everyone's just picking their own favorite tests or even internal tests. And everyone's a little bit different in terms of what genes get sequenced so there's no harmonization of data,” Park said.

“Moreover, you'll get a portal on the web, and you'll get some sequences that come in this web portal, some in that portal, none of it really gets automatically integrated in electronic format until Travis and his team came along into our EMRs.”

As they’ve developed, molecular tumor boards have made progress in assisting clinicians who don’t have adequately deep knowledge of genetics to adjudicate these data in the decision-making process, said Park. Through the REDCap (Research Electronic Data Capture) database, case reports can be uploaded and referenced toward a molecular tumor board, such as the one developed at Vanderbilt-Ingram Cancer Center; results are then uploaded into the EMR.

This has proven to be important for providers, who use this reference when they submit for reimbursement for off-label therapy, said Park, because payers are more likely to approve a therapy whose pros and cons have been reviewed by a group of experts, who then provide the recommendation.

Regarding the identification of actionable mutations, Park said that RNA will play a major role in the future; it provides a new way to find more germline and somatic mutations in an unbiased manner. This will allow clinicians to find fusions that they may not be aware of, which can lead to better diagnoses as well as to new resistance mechanisms that may be druggable.

“You may not find where those genes at the DNA level have fused inappropriately because of the inability to actually get and find those sequences—you have to sequence a ton to try to make sure you get those black line sequences. On the other hand, if you’re now sequencing RNA, it gets rid of the introns, the black lines, and so now your chances of finding those are much, much greater, because you can just do a lot less sequencing.”

Advances in precision oncology must be democratized not only throughout Nashville or the United States, but globally, Park concluded.

We know, he said, that “all individuals really are different at the DNA level, and all cancers really are diseases of DNA gone bad. So why can’t we get to that next level, where we …understand the genetic underpinnings of a patient’s cancer, then try to design therapies, or best therapeutic practices, based on that?”

References

1. Targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma (The MATCH Screening Trial). ClinicalTrials.gov. Updated November 28, 2022. Accessed November 28, 2022. https://clinicaltrials.gov/ct2/show/NCT02465060

2. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431

3. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

4. Gavidia M. Recommendations, insights on use of comprehensive genomic profiling in oncology. AJMC.com. November 12, 2021. Accessed November 22, 2022. https://www.ajmc.com/view/recommendations-insights-on-use-of-comprehensive-genomic-profiling-in-oncology

5. André T, Shiu K-K, Kim TW, et al; KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability–high advanced CRC. N Engl J Med. 2020;383(23):2207-2218. doi:10.1056/NEJMoa2017699

6. Lenz H-J, Van Cutsem E, Limon ML, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol. 2022;40(2):161-170. doi:10.1200/JCO.21.01015

7. Ludford K, Raghav K, Blum Murphy MA, et al. Neoadjuvant pembrolizumab in localized/locally advanced solid tumors with mismatch repair deficiency. Ann Oncol. 2021;32(5):S1210. doi:10.1016/j.annonc.2021.08.1703

8. Smoking & tobacco use. CDC. August 22, 2022. Accessed November 22, 2022. https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm#:~:text=Smoking%20leads%20to%20disease%20and,death%20in%20the%20United%20States.

9. Tobacco Nation: an ongoing crisis. Truth Initiative. June 6, 2019. Accessed November 22, 2022. https://truthinitiative.org/tobacconation

10. What you need to know to quit smoking. Truth Initiative. November 7, 2018. Accessed November 22, 2022. https://truthinitiative.org/research-resources/quitting-smoking-vaping/what-you-need-know-quit-smoking

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