As the deadliest cancer in the United States, lung cancer is expected to account for approximately 125,070 deaths in 2024 alone. Fortunately, researchers continue to make strides in developing and testing therapeutics, and these efforts have led to 11 new approvals by the U.S. Food and Drug Administration (FDA) for lung cancer so far this year. 

Among the new approvals were several for therapies targeting the epidermal growth factor receptor (EGFR), a cell surface protein that promotes cell division and is mutated in about 20% to 50% of non-small cell lung cancers (NSCLC), the most common type of lung cancer. EGFR mutations, including the prevalent exon 19 deletion and exon 21 L858R substitution, put the protein into overdrive and cause dysregulated cell division and cancer development.  

The first-generation EGFR inhibitors were approved in the early 2000s for patients with late-stage NSCLC. However, most patients’ tumors eventually became resistant to these inhibitors, so second- and third-generation EGFR inhibitors were developed to overcome some of the common mechanisms of resistance, as summarized in a previous blog post. 

In recent years, researchers and regulatory agencies have expanded the reach of EGFR inhibitors, making them available to additional patients including those with early-stage or newly diagnosed lung cancers.  

Osimertinib for Early-stage NSCLC 

Osimertinib (Tagrisso) is a third-generation EGFR inhibitor that targets common EGFR mutants as well as T790M, an acquired EGFR mutation that confers resistance to earlier-generation EGFR inhibitors. Originally approved for metastatic NSCLC, the therapeutic has been available to patients with nonmetastatic EGFR-mutated NSCLC since 2020—first as adjuvant therapy for patients with resectable stage 1, 2, or 3 tumors and more recently for patients with stage 3 tumors that cannot be surgically removed. 

The expanded indications for osimertinib have benefited many patients with early-stage disease, including Daniel West, who received adjuvant osimertinib to treat his stage 2B NSCLC. West, whose cancer is now in remission, shared his story in the American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024. 

Inhibition of a Less Common EGFR Mutant in Lung Cancers 

Most FDA-approved EGFR inhibitors target EGFR with the exon 19 deletion or exon 21 L858R mutations, but approximately 9% of EGFR mutations occur in exon 20. For many years, patients whose NSCLC harbored this less common EGFR mutation were not eligible for EGFR inhibitor therapy. That changed in 2021, when two EGFR inhibitors, amivantamab (Rybrevant) and mobocertinib (Exkivity), received approval to treat locally advanced or metastatic tumors with EGFR exon 20 mutations after progression on chemotherapy.  

Unlike most approved EGFR inhibitors, which are small molecule inhibitors or monoclonal antibodies, amivantamab is a bispecific antibody that works by simultaneously binding and blocking the activity of EGFR and the MET protein. Since MET activation is one way cancer cells circumvent EGFR inhibition, the combined block is meant to delay or prevent treatment resistance. 

New Combinations for Treatment of Advanced NSCLC 

Researchers have also made advances in delaying treatment resistance or improving responses by combining EGFR inhibitors with other therapeutics. This has led to the approval of several new combinations for the treatment of locally advanced or metastatic NSCLC, including in the first-line setting. 

This includes a regimen combining the EGFR inhibitor erlotinib (Tarceva) with the angiogenesis inhibitor ramucirumab (Cyramza) for newly diagnosed NSCLCs harboring exon 19 deletion or exon 21 L858R EGFR mutations. Ramucirumab inhibits the vascular endothelial growth factor receptor 2 (VEGFR2), whose activity has been shown to drive resistance to EGFR inhibition; by inhibiting both proteins, the combination suppresses this resistance mechanism. 

Combinations involving amivantamab have also been approved to treat locally advanced or metastatic NSCLC. One approved regimen combines amivantamab with another EGFR inhibitor, lazertinib (Lazcluze), for newly diagnosed tumors with the exon 19 deletion or exon 21 L858R mutations. The combined inhibition of EGFR (intracellularly by lazertinib and extracellularly by amivantamab) and MET (by amivantamab) is intended to overcome MET-dependent treatment resistance. Two other recent approvals greenlit amivantamab in combination with chemotherapy for either newly diagnosed NSCLC harboring exon 20 insertion mutations or NSCLC with exon 19 deletion or exon 21 L858R mutations that progressed after prior EGFR inhibition.  

In addition, the FDA approved osimertinib in combination with platinum-based chemotherapy as first-line therapy for certain locally advanced or metastatic tumors. The approval was based on clinical trial results that showed greater outcomes with the combination than with osimertinib alone. 

Together, these advances illustrate how cancer research is driving progress and making effective treatments available to even more patients. As researchers continue to uncover new insights into EGFR-driven cancers and their resistance mechanisms, we will hopefully see improved outcomes and longer survival for all patients with EGFR-mutated lung cancer. 

In 1977, Sir Richard Peto, FRS, FAACR, postulated that larger animals with longer lifespans should develop cancer more readily than their smaller, shorter-lived companions. Since cancer is driven largely by errors in DNA replication, animals with more cells and more time to accumulate mutations should also develop more cancer, he argued. 

He observed, however, that this does not appear to be the case. Why, then, do most elephants, whales, and bears get less cancer than humans? 

The finding became known as “Peto’s paradox,” a challenge to comparative oncologists to learn more about cancer in vertebrates and understand why cancer incidence doesn’t correlate directly with mass and longevity. Researchers speculated that perhaps understanding the evolutionary processes that prevent cancer in other animals could help us learn how to prevent or treat it in humans. 

Work on that front has produced some intriguing findings. In 2015, for instance, researchers found that elephants have 19 extra copies of the tumor suppressor gene TP53 to help them ward off cancer. 

But there’s more to cancer risk than genetics, explained Zachary Compton, PhD, a postdoctoral fellow in the University of Arizona Cancer Center’s NCI T32 fellowship program and first author of a recent study in Cancer Discovery, a journal of the American Association for Cancer Research (AACR). “Evolution has all of these crazy stochastic ways it can deal with the same problem,” Compton said. “You don’t expect there to be just one way of handling cancer across the diversity of life.” 

In the study, Compton and colleagues analyzed cancer incidence in nearly 300 vertebrate species to identify characteristics associated with cancer prevalence in animals. In addition to finding more species with incredibly high or low cancer rates to study further, the researchers demonstrated a smidge of support for Peto’s original hypothesis and hinted at an explanation for the apparent paradox. 

The Pressures of Natural Selection 

Compton is particularly interested in the evolutionary underpinnings of cancer. The constraints of natural selection suggest that cancer would be selected against during the evolutionary development of a species. 

“Somatic dysfunction is going to decrease the fitness of an individual,” Compton said. “If you have to pump energy into cells that are not working correctly … you would expect natural selection to prune that.” 

But traits like body mass, longevity, and gestation time are also subject to selection pressure, Compton explained. With all of these traits intertwined, it can be difficult to tease apart the push and pull of different selective advantages and how they may drive or suppress cancer. 

Such an endeavor requires a large sample size, for starters. Compton and colleagues collected 16,049 necropsy records from 292 different animal species at 99 animal care institutions in the United States and London. The records were derived from institutions bound by accreditation requirements to perform a necropsy on every animal that dies in their care, whether from known causes or simply old age. 

“All of these deceased animals have had a really thorough investigation by a veterinary pathologist to determine … not only what they died from but what they died with,” Compton explained. 

The researchers assessed whether neoplasia (uncontrolled cell growth) was present and in what tissue, and they developed a terminology dictionary based on the neoplasia descriptions to predict whether neoplasms were benign or malignant. Across all species, each of which had a minimum of 20 necropsy records, the median neoplasia prevalence was 4.89%, and the median malignancy prevalence was 3.2%. 

Further, Compton and colleagues evaluated the associations between evolutionary traits—including maximum lifespan, adult body mass, basal metabolic rate, gestation length, litter size, time to sexual maturity, and growth rate—and the prevalence of neoplasia and malignancy.  

Larger body mass was significantly associated with a higher prevalence of neoplasia; for every tenfold increase in body mass, the risk of neoplasia increased by 2.1%. Other factors associated with malignancy and/or neoplasia included increased maximum longevity, larger litter size in mammals, and, in a subset analysis of 15 species, somatic mutation rate, or the rate at which new mutations occur in the body.  

Longer gestation time was significantly associated with a lower prevalence of both neoplasia (5.3% decrease in neoplasia risk per tenfold increase in months of gestation) and malignancy (5.65% decrease in malignancy risk per tenfold increase in months of gestation). Compton speculated that for a large animal to develop rapidly in the womb (or an egg), they must possess mechanisms to suspend natural growth restriction programs—mechanisms that could potentially be exploited later to form cancer. 

Because both longevity and gestation time are generally associated with body mass, the researchers performed additional analyses in which they normalized data based on these factors. Body mass was more strongly associated with neoplasia and malignancy prevalence when accounting for gestation time, and vice versa. 

Compton and colleagues also addressed the notion that animals in captivity may live longer than nature intended and thus be more susceptible to cancer. In this study, the vast majority of species typically developed tumors within their natural lifespan, and age at death only correlated with higher rates of malignancy in amphibians. 

“We not only controlled for natural lifespan, but we discovered that we didn’t need to control for it,” Compton said. “The rates [of neoplasia] we were seeing weren’t because animals live longer in zoos.” 

Species ‘Leaderboards’ for Future Research 

A component of the study that Compton found particularly exciting was the identification of animals with unusually high or low levels of neoplasia prevalence—a “leaderboard” of species for other researchers to explore. He hopes that animals particularly resistant to neoplasia or malignancy can provide clues to cancer prevention mechanisms that can be repurposed in humans. Similarly, species with abundant cancer may point to genetic, viral, or environmental causes that we can model to study analogous cancer drivers in humans. 

Overall, the median prevalence of neoplasia and malignancy varied among taxonomic orders, from 12% and 7%, respectively, in mammals to 1.2% and 0%, respectively, in amphibians. Still, there were outliers in each group. 

“It’s not like all of the large mammals have low cancer … or a certain group of amphibians or reptiles,” Compton said. “There are representative species from all of these clades that seem to be very good at preventing cancer.” 

Mammals with exceptionally low levels of neoplasia included the Nubian ibex, the tammar wallaby, and several species of bats. Many species of birds appeared particularly resistant to neoplasia, including the black-footed penguin and common songbirds like finches and starlings. Lizards such as the plumed basilisk and the chameleon forest dragon, plus a handful of snakes, also had no neoplasia detected. 

On the other end of the leaderboard, ferrets and opossums had the highest risks of neoplasia—63% and 56%, respectively. Rounding out the top 10 list for neoplasia prevalence were the Dominican mountain chicken frog, jaguar, four-toed hedgehog, Asian elephant, pygmy sugar glider, milk snake, common mouse, and chimpanzee. 

Where Do Humans Stack Up? 

According to federal statistics, approximately 39.3% of Americans will be diagnosed with cancer during their lifetime, but Compton warned that we may not know the exact prevalence of malignancy in humans. Most natural human deaths do not warrant autopsies, and there is currently no robust way to estimate benign neoplasia at the population level. 

But Compton hopes that the data from this study may help researchers better understand and model cancer development and cancer suppression mechanisms that may be translatable to humans. Then, perhaps, we can decrease our own species’ cancer incidence rate or make the disease less deadly. 

This study, Compton emphasized, demonstrated that the breakthrough findings about p53 in elephants was merely a starting point for comparative oncologists. “There is so much that nature has to teach us about cancer risk and what controls it,” he said. 

Research consistently points to the chronic disparities that exist for some populations in accessing cancer care. The crucial next step that follows identifying these gaps is developing intervention programs to close them.  

Evidence-based interventions—whether it be education initiatives, tobacco cessation programs, public service announcements (PSAs), or something similar—have helped more people from racial and ethnic minoritized groups and medically underserved populations get screened for cancer, address preventable risk factors like smoking, participate in medical research, and more. But even with this progress, additional intervention programs are needed to continue to address cancer health disparities. 

For the past 17 years, the American Association for Cancer Research (AACR) Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved has facilitated the exchange of innovative ideas with presentations on the latest research devoted to this field. At this year’s meeting, held September 21-24, more than 450 abstracts were presented, including intervention programs that have demonstrated results in helping address issues such as food insecurity, quitting vaping, screening and clinical trial awareness, and quality of life during survivorship. 

Cancer Research Catalyst spoke with the researchers behind a few of these interventions, who shared the progress they are making in addressing disparities and their vision for the future of these programs.  

Food Farmacy: From the Farm to the Hospital  

If they build it, will they come? Those within the Harris Health System wondered that as they dreamed of a field of fresh produce in the area surrounding Lyndon B. Johnson (LBJ) Hospital in Houston, Texas. This area is considered a food desert by the U.S. Department of Agriculture, meaning many residents lack access to healthy food options. So, they built a nearby farm to kick start a farm-to-hospital nutritional program that supplies access to tomatoes, green beans, lettuce, squash, and other produce in addition to more healthy food options secured outside of the farm.  

The farm has resulted in a number of interventions, including one for cancer patients led by Hilary Y. Ma, MD, the center medical director of the MD Anderson Cancer Center Oncology Program at LBJ Hospital. As part of the program, a two-question screener is used for all cancer patients to identify those who lack access to healthy foods. If they are identified as food insecure, clinicians can refer them to the Food Farmacy, which is located around the corner from the medication pharmacy within the hospital, where they can pick up 30 pounds of healthy food. Patients are also provided with other resources detailing how to eat healthier, including 1:1 nutrition counseling. Each referral is good for three redemptions, and referrals can be refilled by physicians.  

At the meeting, Ma shared results from the first year of the program. In total, 3,254 of the 9,809 patients screened were positive for food insecurity and 88.9% of them were referred to the Food Farmacy. Of those, 50.7% redeemed their referrals, many of whom provided positive feedback. One said, “I always struggle to get food in the house because it’s hard to make ends meet because I’m on social security and so it helps me a lot.” Another said, “I love the bananas and the carrots. Oh, the chicken, too. Oh, and they give you also dry beans.” 

Both patients and clinicians noted the ease of the program’s structure, in terms of the ability for clinicians to refer patients with one click within the electronic medical record and then for patients to pick up the food right on site. Ma said that the next step is to evaluate this intervention’s impact on clinical outcomes, both specific to cancer and more general health such as weight management, as well as explore options to expand the program. 

“It’s about scalability and sustainability,” Ma said. “Not every health care system, especially a safety net system, has the resources to build something like this or have a farm near the campus of the hospital. We have built relationships with community organizations and even with private investment to be the initial key ingredients for further growth.” 

Kick Vaping: By Latinos for Latinos 

When Rafael Orfin and his colleagues searched for vaping cessation interventions specifically geared toward Latinos, they came up empty. 

“We couldn’t find any that were even in Spanish,” said the senior human subject research specialist at the University of Rochester Medical Center. “We wanted to fill in the gap when it came to cessation services available that were created for and by Latinos.” 

Kick Vaping is a text messaging intervention for Latinos between the ages of 18 and 25 that features four different storylines—each with 212 preplanned text messages—disseminated over the course of 12 weeks. The storylines are built around language and gender, with one for English speakers and then ones for those who speak Spanish depending on if they identify as male, female, or nonbinary. For each group, the storylines are told in four consecutive phases. The first is pre-quit, which lasts for 15 days with 55 messages. Then three messages are sent over the course of the day someone decides to quit. Next is the post-quit intensive phase, which has the highest volume of messages (87 over 28 days) considering this is the time people often need the most support. Finally, the post-quit maintenance period lasts seven weeks with 67 messages.  

These messages were further supplemented with automated responses triggered by keywords (such as crave/antojo or stress/estrés) as well as specific messages sent over 11 days if someone admitted to relapsing. Plus, participants could also engage via text with members of the research team. 

“We’d have a genuine conversation and just kind of lay out their motivations, their anxieties, their barriers,” Orfin said. “Folks really loved that component, and I think it helped a lot … having a genuine person that cared about you on the other end of the messages.” 

In a pilot program with 40 participants, Orfin said they retained 90% of study participants who then completed a follow-up assessment after three months. When asked how much this program helped them quit vaping, choosing from four options—“not at all,” “a little,” “somewhat,” and “a lot”— 86.1% of the participants responded with “a lot.”  Further, self-efficacy scores for avoiding vaping significantly increased at the three-month mark and 88.9% reported being satisfied with the program. 

The next step is to assess the efficacy of the intervention in a randomized controlled trial, with a long-term vision of disseminating this program throughout the Latino community, not just in the United States but across Latin and South America.  

Active Living After Cancer and Project CHURCH: Adaptation Equates to Participation  

The Active Living After Cancer (ALAC) program was originally adapted from a group program that encouraged physical activity in healthy but sedentary adults. Over the past 11 years, the intervention has reached over 2,000 cancer survivors and has continued to be tweaked to better serve those in medically underserved communities around Texas, according to Karen M. Basen-Engquist, PhD, MPH, a professor in the Department of Health Disparities Research at The University of Texas MD Anderson Cancer Center.  

“We recognized the need for cancer survivors to have access to programs to help them improve their quality of life through physical activity out in the community,” Basen-Engquist said. “And we’re working to tailor it now to different communities and test it in different settings.” 

One of the latest adaptations has been a partnership with Project CHURCH, an acronym for creating a higher understanding of cancer research and community health, which was created to reach African American cancer survivors and cancer patients—oftentimes at their church.  

“We find the African American community trusts the program more because it goes through the church,” explained Stacy Mitchell, program manager of the ALAC Research Project at the University of Texas MD Anderson Cancer Center. “They’re starting a class with people they’ve probably known for years. Plus, the pastor, who they trust, is going to talk about how it’s important to increase your physical activity and function to reduce cancer recurrence.” 

Mitchell said the ALAC team also works with the pastor or health ministry liaison to make any adaptations that the church feels is necessary. For example, in addition to workouts, the 12-session program includes cognitive and behavioral components such as meditation or cooking demonstrations to help learn about nutrition. But not every church is comfortable with meditation, so that can be replaced with a prayer or a spirituality discussion with a church leader.  

Ultimately, Mitchell and her colleagues found that the retention rate of African American participants was higher when ALAC worked through the Project CHURCH partnership compared to its partnership through another institution not associated with the church. In the Project CHURCH cohort, 95% stayed until the completion of the 12 sessions, compared to 85% in the other cohort.  

Part of the program also encouraged participants to be more active in their leisure time, such as parking a greater distance from the entrance to a grocery store to walk further. Weekly physical activity through actions like this were measured by the Godin Leisure-time Exercise Questionnaire. Those in the Project CHURCH cohort increased their scores by 38.8 units from before the program compared to an increase of 12.5 units in the other cohort.  

This is only one example of the types of adaptations that Mitchell and her colleagues are making to expand the reach of the ALAC program, with other versions dedicated to Hispanic communities as well as virtual classes for people who may not be able to attend in person. 

“Once a patient finishes treatment, we always get the ‘what’s next,’” Mitchell said. “We just like to let them know Active Living After Cancer is what’s next.” 

Colorectal Cancer Education: Boosting Screening and Clinical Trial Awareness  

Michelle Moseley, MA, CHES, and her colleagues within the Office of Community Engagement at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center want to eventually deliver colorectal cancer education year-round, but to start, they developed a series of educational initiatives that they felt addressed a key area of need in their community. 

“Colorectal cancer is one of the most commonly diagnosed cancers, and in our catchment area, colorectal cancer screening has been underutilized in some of the populations that we’re working with,” Moseley explained. “Clinical trials awareness, education, and participation has been low, as well, [and] we know that awareness and education play a role.” 

The Office of Community Engagement arranged educational sessions with community groups such as the Chinese Community Health Resource Center, Mujeres Unidas, Shanti Project, Chinese Newcomers Service Center, and Vietnamese American Nail Association. These sessions could be in person or virtual and often involved a PowerPoint-like presentation as well as video vignettes featuring colorectal cancer survivors who shared their stories about the benefits of screening and catching the disease early. 

While each session could include some tailored information specific to the ethnic or racial group they were engaging with, the programs largely focused on providing an overview of colorectal cancer and clearing up common misconceptions. That included explaining the location and function of the colon and rectum, providing visual aids for how screening through colonoscopies and fecal immunohistochemical tests (FIT) work, and digging into the importance of clinical trials and the role they played in bringing common treatments—such as allergy pills, pain medications, or X-rays—to patients to alleviate concerns related to participating in research. Moseley and her colleagues also shared this information at community events, like festivals or health fairs, via handouts and time spent networking with attendees.  

The sessions, which were conducted between the fall of 2019 and May 2024, were assessed via pre- and post-engagement surveys. From a total of 772 completed surveys, knowledge improved about colorectal cancer by 14% (76% before vs. 91% after) and about clinical trials by 7% (83% vs. 90%). Further, respondents either strongly agreed or agreed that they now understood the importance of people of color participating in clinical trials (78%) and would seek out clinical trial information (69%), search for clinical trials (59%), or talk to a health care provider about clinical trials (75%). Nearly one half (48%) also said they would join a clinical trial while 70% said they would talk to family/friends about joining one. As for screening, 92% indicated they would get screened and 89% said they would talk with family/friends about colorectal cancer. 

Moseley said they are also evaluating how to improve the programs in the future, which may involve creating shorter educational materials, adding information about blood-based screening tests, and including more testimonials from patients and clinical trial participants. They are also working on a year-round awareness campaign with multiple components, including attendance at health-related events not directly connected to cancer, posters in public transportation vehicles and waiting areas, and radio PSAs.  

“We would ultimately like to have an impact on saving lives,” Moseley said. “We’d like to be able to prevent colorectal cancer by having people engage in regular screening and … we would like to be able to have trials that people can actually enroll in on the spot when we’re providing the education.” 

As Halloween approaches, Cancer Research Catalyst brings you no tricks and all treats in the October edition of editors’ picks. This month, the editors of the 10 American Association for Cancer Research (AACR) journals selected a head-to-head comparison of two CAR T therapies for lymphoma, a new type of blood test for colorectal cancer detection, two phase II clinical trials, and more. 

Like your Halloween candy, these studies are freely available for a limited time. 

Journal: Blood Cancer Discovery 

A Multicenter Real-life Prospective Study of Axicabtagene Ciloleucel versus Tisagenlecleucel Toxicity and Outcomes in Large B-cell Lymphomas 

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. 

Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel’s superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies. 

Journal: Cancer Discovery 

The History of Chromosomal Instability in Genome-Doubled Tumors 

Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors. 

Significance: Complex genomic gains are associated with whole-genome duplications, which are frequent across tumors, span a large fraction of their genomes, and are linked to poorer outcomes. GRITIC infers when these gains occur during tumor development, which will help to identify the genetic events that drive tumor evolution. 

A related commentary was published in the September issue, and this article was featured on the cover. 

Journal: Cancer Epidemiology, Biomarkers & Prevention 

Blood Magnesium Level and Risk of Hepatocellular Carcinoma in a Prospective Liver Cirrhosis Cohort 

Background: Higher magnesium intake was linked to a lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among patients with liver cirrhosis who are at a higher risk for HCC. 

Methods: In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,430 patients with liver cirrhosis without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazards models to generate hazard ratios (HRs) with 95% confidence intervals (CI) for incident HCC and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection. 

Results: During a median follow-up period of 4.26 years, 109 patients developed HCC. Magnesium deficiency (<1.70 mg/dL; N = 158) was associated with a higher risk of HCC (HR = 1.93; 95% CI, 1.12–3.30) compared with magnesium sufficiency (≥1.70 mg/dL; N = 1282). This association remained robust in the 1-year lag analysis (HR = 2.18; 95% CI, 1.11–4.28) and in sensitivity analysis excluding patients with alcoholic liver disease (HR = 2.41; 95% CI, 1.23–4.74). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (β = 4.35; 95% CI, 1.06–7.63), aspartate aminotransferase (β = 6.46; 95% CI, 0.28–12.6), direct bilirubin (β = 0.18; 95% CI, 0.01–0.35), and total bilirubin (β = 0.21; 95% CI, 0.03–0.39), compared with the highest quartile. 

Conclusions: Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarker changes. 

Impact: If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis. 

This study was highlighted in the October issue. 

Journal: Cancer Immunology Research 

Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells 

Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation. Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies. We focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9⁺ T-cell population displayed reduced effector function. We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system enhanced the functionality of primary human T cells. Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation. Thus, we designed several Siglec-9–based chimeric switch receptors (CSR), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen-specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers. Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors. Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell–based cancer treatment. 

A related commentary was published in the October issue. 

Journal: Cancer Prevention Research 

Preventive Treatment with a CD73 Small Molecule Inhibitor Enhances Immune Surveillance in K-Ras Mutant Pancreatic Intraepithelial Neoplasia 

Immunoprevention is an emerging consideration for solid tumors, including pancreatic ductal adenocarcinoma (PDAC). We and others have shown that Kras mutations in genetic models of spontaneous pancreatic intraepithelial neoplasia (PanIN), which is a precursor to PDAC, results in CD73 expression in the neoplastic epithelium and some populations of infiltrating immune cells, including macrophages and CD8 T cells. CD73 is an ecto-enzyme that converts extracellular adenosine monophosphate to adenosine, a critical immune inhibitory molecule in PDAC. We hypothesized inhibition of CD73 would reduce the incidence of PanIN formation and alter the immune microenvironment. To test our hypothesis, we used the Kras^G12D; Pdx^Cre1 (KC) genetically engineered mouse model and tested the utility of AB-680, a small molecule inhibitor targeting CD73, to inhibit PanIN progression. AB-680, or vehicle control, was administered using oral gavage delivery 3 days/week at 10 mg/kg, beginning when the mice were 2 months old and lasting 3 months. We euthanized the mice at 5 months old. In the KC model, we quantified significantly less pancreatitis, early and advanced PanIN, and quantified a significant increase in M1 macrophages in AB-680-treated mice. Single-cell RNA sequencing (scRNA-seq) of pancreata of AB-680-treated mice revealed increased infiltration of CD4⁺ T cells, CD8⁺ T cells, and mature B cells. The scRNA-seq analysis showed that CD73 inhibition reduced M2 macrophages, acinar, and PanIN cell populations. CD73 inhibition enhanced immune surveillance and expanded unique clonotypes of TCR and BCR, indicating that inhibition of CD73 augments adaptive immunity early in the neoplastic microenvironment. 

Prevention Relevance: Previous studies found PanIN lesions in healthy pancreata. Not all progress to PDAC, suggesting a window for enhanced antitumor immunity through immunoprevention therapy. CD73 inhibition in our study prevents PanIN progression, reduces immune-suppressive macrophages and expands TCR and BCR unique clonotypes, highlighting an encouraging therapeutic avenue for high-risk individuals. 

This study was featured on the cover of the October issue. 

Journal: Cancer Research (October 1 issue) 

Multidimensional Fragmentomics Enables Early and Accurate Detection of Colorectal Cancer 

Colorectal cancer is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage colorectal cancer detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 patients with colorectal cancer and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish patients with colorectal cancer from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 patients with colorectal cancer and 119 controls) and a prospective cohort of 242 participants (129 patients with colorectal cancer and 113 controls). The ensemble stacked model showed remarkable discriminatory power between patients with colorectal cancer and controls, outperforming all base models and achieving a high area under the receiver operating characteristic curve of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting colorectal cancer in the validation cohort, with sensitivity increasing as the cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early colorectal cancer detection and broad patient benefit. 

Significance: The development of a minimally invasive, efficient approach for early colorectal cancer detection using advanced machine learning to analyze cfDNA fragment patterns could expedite diagnosis and improve treatment outcomes for patients. 

A related commentary about blood tests for colorectal cancer detection was published in the October 1 issue. 

Journal: Cancer Research (October 15 issue) 

A Genomics-Driven Artificial Intelligence–Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating Mechanisms 

Artificial intelligence (AI) systems can improve cancer diagnosis, yet their development often relies on subjective histologic features as ground truth for training. Herein, we developed an AI model applied to histologic whole-slide images using CDH1 biallelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted CDH1 biallelic mutations (accuracy = 0.95) and diagnosed ILC (accuracy = 0.96). A total of 74% of samples classified by the AI model as having CDH  biallelic mutations but lacking these alterations displayed alternative CDH1 inactivating mechanisms, including a deleterious CDH1 fusion gene and noncoding CDH1 genetic alterations. Analysis of internal and external validation cohorts demonstrated 0.95 and 0.89 accuracy for ILC diagnosis, respectively. The latent features of the AI model correlated with human-explainable histopathologic features. Taken together, this study reports the construction of an AI algorithm trained using a genetic rather than histologic ground truth that can robustly classify ILCs and uncover CDH1 inactivating mechanisms, providing the basis for orthogonal ground truth utilization for development of diagnostic AI models applied to whole-slide image. 

Significance: Genetic alterations linked to strong genotypic–phenotypic correlations can be utilized to develop AI systems applied to pathology that facilitate cancer diagnosis and biologic discoveries. 

Journal: Clinical Cancer Research (October 1 issue) 

First-Line Anlotinib Treatment for Soft-Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-Label, Single-Arm, Phase 2 Clinical Trial 

Purpose: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma. 

Patients and Methods: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from days 1 to 14 every 3 weeks until disease progression or intolerable adverse events (AE) occurred. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate, and disease control rate (DCR). The safety profile was also evaluated. 

Results: Forty patients were enrolled from April 2019 to June 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI), 4.17–8.71] and the median OS 27.40 months (95% CI, 16.43–not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for liposarcoma patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). 

Conclusions: The findings suggest a potential benefit in using front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the liposarcoma subgroup of patients were encouraging. 

A related commentary was published in the October 1 issue. 

Journal: Clinical Cancer Research (October 15 issue) 

Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial 

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1–3, in patients with solid tumors harboring a functional FGFR1–3 fusion. 

Patients and Methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events. 

Results: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events. 

Conclusions: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. 

A related commentary was published in the October 15 issue. 

Journal: Molecular Cancer Research 

NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion 

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten–eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with the silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss–Handler pathway of NAD⁺ biosynthesis, in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi). NAPRT silencing was also associated with synergistic tumor cell killing with PARP inhibitors and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite-associated hypermethylation can impact diverse cellular processes and lead to therapeutically relevant vulnerabilities in cancer cells. 

Implications: NAPRT is a novel biomarker for targeting NAD⁺ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARP inhibitors. 

This study was highlighted in the October issue. 

Journal: Molecular Cancer Therapeutics 

FZ-AD005, a Novel DLL3-Targeted Antibody–Drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models  

Delta-like ligand 3 (DLL3) is overexpressed in small cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine was the first DLL3-targeted antibody–drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with rovalpituzumab tesirine. In this study, we developed a novel DLL3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody, FZ-A038, and a valine–alanine (Val–Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line–derived xenograft and patient-derived xenograft models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable, and the highest nonseverely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of patients with SCLC. 

This study was highlighted and featured on the cover of the October issue. 

Journal: Cancer Research Communications 

Synergistic Effects of PARP Inhibition and Cholesterol Biosynthesis Pathway Modulation 

An in-depth multiomic molecular characterization of PARP inhibitors revealed a distinct poly-pharmacology of niraparib (Zejula) mediated by its interaction with lanosterol synthase (LSS), which is not observed with other PARP inhibitors. Niraparib, in a similar way to the LSS inhibitor Ro-48-8071, induced activation of the 24,25-epoxysterol shunt pathway, which is a regulatory signaling branch of the cholesterol biosynthesis pathway. Interestingly, the combination of an LSS inhibitor with a PARP inhibitor that does not bind to LSS, such as olaparib, had an additive effect on killing cancer cells to levels comparable with niraparib as a single agent. In addition, the combination of PARP inhibitors and statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme catalyzing the rate-limiting step in the mevalonate pathway, had a synergistic effect on tumor cell killing in cell lines and patient-derived ovarian tumor organoids. These observations suggest that concomitant inhibition of the cholesterol biosynthesis pathway and PARP activity might result in stronger efficacy of these inhibitors against tumor types highly dependent on cholesterol metabolism. 

Significance: The presented data indicate, to our knowledge, for the first time, the potential benefit of concomitant modulation of cholesterol biosynthesis pathway and PARP inhibition and highlight the need for further investigation to assess its translational relevance. 

In Ancient Greek legends, Sybil was a name bestowed upon prophetesses who were thought capable of predicting the future. Today, can artificial intelligence help create a modern-day Sybil capable of predicting future cases of lung cancer? That was just one of the questions raised at the American Association for Cancer Research (AACR) Industry Roundtable 2024, held October 8-9 in Philadelphia.  

This principal event of the AACR Sustaining Membership Program has helped connect corporate partners aligned with the AACR’s mission to prevent and cure cancer with the larger cancer research community. This year, more than 30 attendees from biopharmaceutical companies that are sustaining members were brought together with cancer researchers, AACR leaders, officials from the U.S. Food and Drug Administration (FDA), and patient advocates. 

“At the AACR, our Industry Roundtable serves a critical role in advancing our mission by fostering collaboration and opening doors to new partnerships,” said Mitch Stoller, chief philanthropic officer of the AACR Foundation and vice president of development. “These events are where ideas are shared, connections are made, and alliances are forged—all of which drive our ability to advance groundbreaking research.” 

The topic at the heart of this year’s event was “Tracking and Treating Early Cancers to Increase Cures,” which included discussions on the latest advancements in early cancer detection, how to design clinical trials for early cancer treatments, the use of therapeutic cancer vaccines in early stages, and more.  

“We identified this topic with our industry partners earlier in the year, with consensus that this is a high-priority area in cancer research,” said Lillian L. Siu, MD, FAACR, AACR 2024-2025 president-elect, chair of the Industry Roundtable, and director of the Phase I Clinical Trials Program at Princess Margaret Cancer Centre. “Various formats, including debates, panel discussions, and breakout groups created a highly interactive program for our participants.”  

Can AI-powered Cancer Detection See into the Future? 

The program kicked off with an AI algorithm called Sybil. Lecia Sequist, MD, MPH, the program director of the Cancer Early Detection and Diagnostics Clinic at Massachusetts General Hospital and the Landry Family Professor of Medicine at Harvard Medical School, delivered the opening keynote centered around her work to modernize lung cancer screening. 

Sequist said she saw the need to develop a different approach due to two huge gaps with lung cancer screening. Currently, the U.S. Preventive Services Task Force recommends lung cancer screening for individuals who are 50 to 80 years old, have a 20 pack-year smoking history, and still smoke or quit within the past 15 years, but this has been found to exclude over half of Black patients with lung cancer. It also does not include people who could be getting lung cancer from other risk factors besides tobacco, as 10% to 20% of cases in the United States are now in people who have never smoked or smoked fewer than 100 cigarettes in their life. The other big gap is that less than 10% of those eligible even participate in lung cancer screening.  

Sequist partnered with Regina Barzilay, PhD, the School of Engineering distinguished professor for AI and health at the Massachusetts Institute of Technology, and Florian Fintelmann, MD, the head of thoracic imaging percutaneous thermal ablation at Massachusetts General Hospital, to develop a deep learning model capable of predicting lung cancer risk without the need for demographic or clinical data. Unlike similar models that may require radiologists to circle a region of interest to examine, Sybil was built to look at the entire thoracic volume from a CT scan, including variables within the whole body that are picked up by the scan.  

The model was trained on data from three cohorts, including the National Lung Screening Trial and low-dose computed tomography (LDCT) imaging from Massachusetts General Hospital, which mostly consisted of white patients with a history of tobacco exposure. Meanwhile, LDCTs from Chang Gung Memorial Hospital in Taiwan included individuals with a range of tobacco history, including nonsmokers.  

Sybil showed high accuracy in predicting lung cancer one year prior to diagnosis in all three cohorts, with the highest accuracy found in the Chang Gung Memorial Hospital cohort. Sequist said that this indicated the model’s performance is not dependent on the patient having tobacco exposure. She added that while the model definitely performed better in the short term, they still saw “decent” results in its predictions six years prior to diagnosis. 

“I have gone to way too many funerals of young people under the age of 50 dying from lung cancer who never smoked and are not eligible for screening,” Sequist said. “My dream is to be able to use Sybil or another tool like it that helps figure out who’s at risk for lung cancer to bring screening to the general population.” 

Sequist is continuing to explore other uses for Sybil, including in predicting lung cancer in firefighters, and added that this open-source model is available on the web and is currently being tested by researchers around the world.  

Examining the Short-term Prognosis for AI in Health Care 

While Sybil has shown promising results, a later session focused on whether AI-driven technologies would become standard of practice and lead to increased cancer cure rates by 2034. Alexander T. Pearson, MD, PhD, an associate professor of medicine and director of data sciences at the University of Chicago Section of Hematology/Oncology, served as the “realist” tasked with downplaying the immediate impact of AI in what was called a “dialogue.” Vivek Subbiah, MD, the chief of early-phase drug development at the Sarah Cannon Research Institute, served as the “optimist,” highlighting the promise AI has shown so far, including the 2024 Nobel Prize in Physics for discoveries in machine learning and AI. 

Alexander T. Pearson, MD, PhD and Vivek Subbiah, MD participated in a dialogue about AI at the AACR Industry Roundtable 2024.

Pearson, however, pointed to four main hurdles that AI will face over the next decade: 1) integrating AI into clinical practice will remain a challenge as medical training for AI is still sparse and patients strongly prefer human interactions for any meaningful health discussions; 2) results have displayed an algorithmic bias with inaccurate connections that can disproportionately affect a particular group; 3) a lack of transparency and inability to explain why AI makes certain connections can lead to mistrust among providers and patients; and 4) a lack of liability guidance from governments can hamper the pace of innovation. 

“AI for medicine is totally different than AI for other consumer products,” Pearson said. “We have to rigorously test all of the concepts that we put forward in order to know that they are done on behalf of our patients with the highest standard possible. So even if we have robust models that reliably progress us to a place where we can implement an algorithm on behalf of our patients, that doesn’t mean we are going to—in the next 10 years’ time—reshape the full regulatory landscape in the U.S. in order to speed these technological concepts into the real world.” 

Looking Down the Road 

Other sessions from the event touched on the impact of patient advocates on research, the challenges and potential solutions in implementing new technologies in early cancers, cancer screening in low- to middle-income countries and underrepresented populations in high-income countries, increasing diversity in clinical trials, and updates from the FDA. 

“The 2024 AACR Industry Roundtable was exceptional, featuring a well-rounded agenda focused on early cancer detection and interception,” Siu said. “Rapid advances in molecular biology, immunology, technology, and drug development are making it increasingly feasible to detect and eliminate cancers at an early stage. In collaboration with industry, academia, regulatory partners, survivors, and patient advocacy groups, the AACR will continue to drive progress in this field.”  

For next year’s event, the AACR will once again work with industry partners from the Sustaining Membership Program to craft an equally engaging agenda focused on another key area of cancer research. 

“This year’s event was particularly impactful in bringing together leaders who share our vision for defeating cancer, and I am excited to see how these relationships will shape the future,” Stoller said. “We’re already looking forward to building on this success next year.” 

By Vinay Tergaonkar, PhD, and Wai Leong Tam, PhD, cochairs of the Frontiers in Cancer Science 2024 conference

Singapore will hold its 16th Frontiers in Cancer Science (FCS) conference from November 13- 15, 2024, at the Matrix at Biopolis, Singapore. This annual conference started in 2009 as a one-day symposium dedicated to the purpose of stimulating the growth of the regional community of cancer researchers, and their links with international colleagues. Since its inception, FCS has grown into a major international cancer conference in the Asia-Pacific region, and the largest of its kind in Singapore, with over 500 participants registering annually. Since 2020, we have partnered with the American Association for Cancer Research (AACR) to concurrently hold the AACR-FCS Education Sessions, the first of their kind in Southeast Asia. Prepare for this year by viewing highlights of the previous FCS conferences.  

FCS 2024 brings together a stellar list of international and regional speakers covering many current trends in cancer research, spanning basic science and clinical research with selected thematic focus on immuno-oncology, genomics, metabolism, and AI. Young investigators will have an opportunity to showcase their work as posters, and talks selected from outstanding poster abstracts will also be presented at the Lightning Talk sessions. Prizes for the best posters will include two travel awards (each worth US$2,500) to support travel to the AACR Annual Meeting 2025. This year, we gave out 10 “Outstanding FCS Abstract Travel Awards” to selected abstracts from international participants to help cover their expenses for attendance at FCS.

The AACR-FCS Education Sessions, initiated in 2020, have enjoyed a high level of participation and positive feedback from FCS participants. These sessions aim to provide graduate students, postdoctoral researchers, and early-career basic or clinical investigators with a broader view of key topics in contemporary cancer research, presented by international opinion leaders. At FCS 2024, the AACR-FCS Education Sessions will include presentations from Zemin Zhang, PhD, (Peking University), Katy Rezvani, MD, PhD, (MD Anderson Cancer Center) and Sarah-Maria Fendt, PhD, (VIB-KU Leuven Center for Cancer Biology), recipient of the 2024 AACR Award for Outstanding Achievement in Basic Cancer Research.

FCS is jointly organized by the Cancer Science Institute of Singapore; Duke-NUS Medical School; Genome Institute of Singapore; Institute of Molecular and Cell Biology; Lee Kong Chian School of Medicine/Nanyang Technological University; National Cancer Centre Singapore; National University Cancer Institute, Singapore; and Yong Loo Lin School of Medicine, National University of Singapore.

View the program highlights for this year’s exciting international conference from Singapore, as well as information about registration and abstract submission.

We warmly welcome you to Frontiers in Cancer Science 2024 and hope to see you in Singapore!

Vinay Tergaonkar obtained his PhD through an international cancer society fellowship for collaborative research at Tufts University, Boston, Massachusetts. He has been a fellow (2001-2004) and a special fellow (2004-2006) of the Leukemia & Lymphoma Society of America and conducted his postdoctoral studies at the Salk Institute for Biological Studies, La Jolla, California. He joined the Institute of Molecular and Cell Biology, Singapore, in late 2005 as principal investigator and became a senior principal investigator in 2010 and research director in 2015. Since 2022, he is a distinguished fellow. He is also a professor, School of Medicine at National University of Singapore. Work from his laboratory has led to his inclusion (by Stanford University) in the top 2 % of the most cited scientists globally, and international recognitions including the British Council development award (2014), the Premier’s fellowship from Government of South Australia (2015), and distinguished visiting professorships at Ashoka University and University of Macau. He serves on Editorial Boards of Science Advances, Molecular and Cellular Biology (American Society for Molecular Biology), and Biochemical Journal (Portland Press).

Wai Leong Tam, PhD, is the deputy executive director of the Genome Institute of Singapore, Singapore’s flagship genome science institute spearheading the innovation of genomics for improving Singaporean lives and health, where he oversees the precision medicine effort to understand the genetic and genomic underpinnings of health and disease. Concurrently, he is a faculty member at the Cancer Science Institute of Singapore, National University of Singapore. As a cancer biologist, he develops and applies genome-scale functional genomic approaches to discover the molecular drivers and targets of cancer progression in Asian-specific (lung and liver) and Asian-prevalent (breast and colorectal) cancers. His research delves into elucidating the precise control of cellular plasticity during cancer initiation, invasion, and metastasis. This has led to key insights on how metabolic reprograming, including influences from the tumor microenvironment and diet, underpins malignant cell states, and how targeting oncogenic metabolic pathways may be exploited to restrain cellular plasticity and thwart cancer cell adaptation. He was a recipient of the prestigious National Research Foundation Fellowship, and a current recipient of the National Research Foundation Investigatorship.

In May 2022, Anibal Torres woke up with severe stomach pain that kept him from eating much over the next several days. He was eventually referred to the hospital for a CT scan that revealed a massive tumor in his liver—a hepatocellular carcinoma. 

At 11.9 cm, it was too large to be surgically removed. A referral from Marcia Cruz-Correa, MD, PhD, the then-director of University of Puerto Rico Comprehensive Cancer Center, got him into a clinical trial testing an immunotherapy-based treatment regimen in patients with tumors like his. The hope was that the drug would shrink Torres’ cancer enough that it would be safe to operate. 

Though he had some side effects, Torres gradually noticed improvements. “I’m eating better, I’m sleeping better, I’m doing everything better,” he said in the American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024, released in May. At the time, his tumor was down to 4.3 cm, and his doctors aimed to operate when it shrank below 4 cm. 

Torres has since undergone a successful surgery and is doing well. His is just one success story among the many clinical trials currently evaluating neoadjuvant immunotherapy in liver cancer. 

A recent study published in the AACR journal Cancer Research Communications analyzed patient outcomes from such trials and suggested that offering immunotherapy to patients with locally advanced tumors may improve their odds of a successful surgery. 

Why Neoadjuvant Immunotherapy? 

There are several reasons a locally advanced liver cancer may not be considered resectable, according to Mark Yarchoan, MD, an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center and senior author of the study. The most common include multiple localized tumors, invasion into veins or arteries, or large tumors such as Torres’. Such high-risk features can present safety concerns and/or decrease the odds of a successful surgery. 

But neoadjuvant immunotherapy—immunotherapy given before surgery—can potentially shrink tumors so that they’re safer to remove.  

Studies have shown another important advantage to neoadjuvant immunotherapy: Giving immunotherapy when the tumor is still intact provides the immune system with a bigger repertoire of antigens to mount a response against. This has translated to more robust immune responses when patients receive immunotherapy before surgery versus after. 

The benefits of this go even further, explained Mari Nakazawa, MD, a clinical research fellow at the Johns Hopkins Kimmel Cancer Center and first author of the study. A more activated immune system trained to recognize a broader library of antigens may be better poised to attack cells that have escaped the primary tumor to seed metastases elsewhere—so-called “micrometastases.” This may decrease the odds that the cancer will come back after a successful surgery. 

“There’s a strong unmet need to expand the number of patients who may be eligible for surgery and, further, to transform more patients with early-stage liver cancer into long-term survivors of this disease,” Nakazawa said in a press release. 

Does Neoadjuvant Immunotherapy for Liver Cancer Impact on Long-term Survival? 

While other studies have shown that patients with unresectable liver cancer may respond well to neoadjuvant immunotherapy, Yarchoan, Nakazawa, and colleagues sought to characterize the long-term survival of such patients. They looked at outcomes from 92 patients who underwent curative resection—surgery intended to remove all evidence of disease—for hepatocellular carcinoma at Johns Hopkins. This included 46 patients who were treated with neoadjuvant immune checkpoint inhibitors (ICIs), most of whom were treated as part of clinical trials.  

Importantly, 61.1% of these patients would not have been eligible for curative resection at intake based on existing eligibility criteria. Consistent with this observation, patients who received neoadjuvant ICIs more commonly exhibited high-risk features that typically predispose patients to worse outcomes. 

Nevertheless, 94.4% of patients treated with neoadjuvant ICIs underwent a successful resection with negative margins. Yarchoan stressed that this was impressive in a group of patients for whom surgery would not have been advisable in the majority of cases. 

In this study, however, patients who received neoadjuvant ICIs had comparable outcomes to those treated with surgery upfront. Patients who received neoadjuvant ICIs lived a median of 44.8 months without their cancer coming back, compared with 49.3 months among patients who did not receive neoadjuvant ICIs. 

“This study shows that the criteria by which we classify patients as being candidates for curative therapy is probably too narrow for this disease,” Yarchoan said in a press release. “Systemic therapy may not only be useful for patients with advanced disease but can potentially be paradigm-changing in patients with early-stage disease.” 

Yarchoan and Nakazawa stressed that the findings are retrospective, derived from a single institution, and compiled from several different clinical trials (or upfront surgery as the standard of care), and that further studies will be necessary to confirm. “Prospective trials that are thoughtfully designed in the right populations can help us understand which patients can benefit most from this approach,” Nakazawa said. 

More clinical research in this area is certainly a notion patients like Torres can get behind. “We went through it. We’re living it. We’re seeing the results,” Torres said. “Thanks to all the research that’s coming out, I’m alive today, and I’m grateful.” 

By Bob Riter, Patient Advocate, Cornell Community Cancer Partnership 

When I was diagnosed with stage 2 breast cancer about 27 years ago, I sought out information and support from the Ithaca Breast Cancer Alliance, and quickly found the power of connection. I became increasingly involved with the organization, eventually becoming the executive director after it had expanded its scope to serve patients with all types of cancer and changed its name to the Cancer Resource Center of the Finger Lakes.  

After I retired from my role there in 2017, I have focused my advocacy on connecting cancer researchers with cancer patients and survivors. I am a graduate of the American Association for Cancer Research (AACR) ScientistSurvivor Program, which for 27 years has helped to build lasting partnerships among the scientific and patient communities. I have also had the privilege of being involved with the Cornell Community Cancer Partnership, which focuses on connecting graduate students in the basic sciences with cancer patients and other members of the local community. And I have seen how faculty members Bob Weiss, PhD, and Claudia Fischbach, PhD, have supported and nurtured this partnership program from the very beginning. 

All of this is to say, I have firsthand experience with programs focused on connecting cancer researchers with patient advocates that are built to last. While several such programs exist—with most championed by a core of individuals who propose the idea, make connections, and organize initial activities—only some take root and become ongoing and established programs. 

Bob speaking at the AACR Translational Cancer Research for Basic Scientists Workshop held October 6-11, 2024 in Cambridge, Massachusetts.

In addition to the AACR ScientistSurvivor Program and the Cornell Community Cancer Partnership, other examples of lasting programs include the Georgetown Breast Cancer Advocates, an established program that connects breast cancer researchers with patient advocates, and the Congressionally Directed Medical Research Programs, which actively engage advocates (known as consumers) throughout the research review process. 

For programs that fail to become established with ongoing activities, the challenge that often emerges is: How do programs continue to evolve and prosper once the founders—the champions—move on and reduce their involvement? Programs need to be able to regenerate both leadership and participants. This is especially true in academia.  

It’s reasonable to think that most programs at universities go through three phases: 

Emergent: The “ad hoc” events that many universities hold from time to time. These can be sessions in which cancer patients describe their experiences to young researchers, or an opportunity for students to give lab tours and explain their research. Many of these programs are initiated by students. 

Established: A program that provides ongoing opportunities to connect researchers and advocates. In a university setting, new graduate students are provided the chance to engage with advocates each year. The program is in place and available when students and researchers are ready to engage. A faculty member usually serves as the point person.  

Regenerative: In academia, a regeneration of new students each year is only natural. But over time, new patient advocates and new faculty members will also need to be brought into these partnership activities. This is because faculty involvement in community activities may not be rewarded in tenure and promotion decisions, so it’s an “extra” duty for faculty members to maintain, causing them to leave the program. Similarly, programs often begin with a cadre of committed patients/survivors, but their interest, availability, and health may change from year to year.  

The purpose of this blog post is to encourage university programs to begin thinking about a regenerative program from early in their development. 

Creating Regenerative Patient Advocate Partnership Programs  

The following suggestions are based on my experiences with programs that have proven their sustainability. While the focus is on university partnerships, these principles could be applied in other settings as well. 

For starters, committed students not only bring enthusiasm, but they can do much of the leg work. Alex McGregor, PhD, and Peter DelNero, PhD, MPH, were instrumental in getting the program at Cornell off the ground when they were graduate students in 2017, and they previously wrote about their experiences. That’s why it is important to provide incentives to committed students like this for taking leadership roles each year, including travel support to present their research, opportunities to select guest speakers, etc.  

Also, encourage faculty members to be involved on a rotating basis for time-limited terms, e.g., two years. For junior faculty, it can be part of their professional development and (hopefully) be rewarded in tenure decisions. Similarly, engage a “lead” advocate who’s well-connected in the patient community to encourage involvement from patients and survivors on an ongoing basis. Providing a stipend would be ideal, but even offering a desk and a sense of connection can go a long way. 

But engaging with just one lead advocate is not enough. Partnering with patient support organizations in the community is the easiest way to recruit and communicate with patients and survivors. It can also help with grant funding. Writing a small proposal to support a partnership may be simpler if done under the umbrella of a small nonprofit as opposed to that of a large research university. 

Finally, collaborate with other universities in your area. This is a natural way to connect young cancer researchers with each other and with the local cancer community. It also provides an opportunity to share the benefits and burdens of a partnership program. 

It’s wonderful that many university programs that connect cancer researchers with patient advocates are maturing to the point of needing to think about the second and third generations of leadership, researchers, and advocates. Taking relatively simple and inexpensive steps can provide the renewal needed to ensure their future. 

Bob Riter is the patient advocate of the Cornell Community Cancer Partnership. Bob began his career in health services administration but became active in the cancer world after he was diagnosed with breast cancer in 1996. He was later diagnosed with prostate cancer and was found to have a CHEK2 mutation. He was previously the executive director of the Cancer Resource Center of the Finger Lakes.  

“It’s difficult for women to bring it up … You only have a small amount of time. So, you talk about other things.” 

“I was like, ‘I don’t wanna take it.’ Everything in my body is saying don’t take this pill.” 

Long before Janeane N. Anderson, PhD, MPH, began researching sexual symptoms following breast cancer treatment, she worked as a high school teacher in Texas. 

“Abstinence-only was, and still is, the law of the land,” she recalled. 

The culture of sexual silence in the U.S. South and the accompanying sexual health challenges eventually inspired her to become a researcher. As an assistant professor at the University of Tennessee Health Science Center, she’s found that the widespread discomfort of talking about sex extended into the clinic—even when it involves cancer care. 

After surgery for early-stage, hormone receptor-positive breast cancer, patients are commonly prescribed a five- to 10-year regimen of adjuvant endocrine therapy (AET), a type of breast cancer treatment that helps to prevent recurrence by blocking the effects of estrogen. While it has proven quite effective in reducing the odds of recurrence in these patients, it can cause several side effects that many patients find hard to tolerate for up to a decade; in fact, over a third of patients discontinue their AET prematurely. 

Anderson co-authored the 2023 study featuring the above quotes from women—specifically Black women—who received AET for early-stage breast cancer. But while the effects of AET on sexual health have been well documented anecdotally, comprehensive studies on their incidence and how they affect treatment adherence and survivorship remain lacking, Anderson explained. 

At the 17th American Association for Cancer Research (AACR) Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, held in Los Angeles September 21-24, Anderson presented a study showing that Black and white patients experience sexual symptoms differently, and it impacts their lives and medication adherence in different ways. 

Side Effects of Endocrine Therapy 

Even after menopause, low levels of circulating estrogen help maintain musculoskeletal integrity, vascular function, and reproductive health. Eliminating the remaining estrogen via AET can cause symptoms similar to those seen during the transition to menopause, including hot flashes, night sweats, joint pain, mood swings, and vaginal dryness. 

A variety of endocrine therapies disrupt estrogen signaling in different ways. Aromatase inhibitors, selective estrogen receptor modulators (SERMs), and selective estrogen receptor degraders (SERDs) have been approved by the FDA for certain breast cancer indications. Selective estrogen receptor covalent antagonists (SERCAs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs) remain investigational. 

In a 2023 study published in the AACR journal Cancer Prevention Research, researchers analyzed the associations between common endocrine therapy symptoms and six-month adherence to treatment in patients treated in the NSABP B-35 phase III clinical trial. Patients in the trial were randomly assigned (1:1) to receive either anastrozole (Arimidex), an aromatase inhibitor that blocks the production of estrogen in postmenopausal women, or tamoxifen, a SERM that prevents estrogen receptor signaling in the breast but stimulates it in other tissues, including the bone and endometrium. This allowed the authors of the study to comprehensively characterize symptom burden and treatment adherence in patients receiving two different classes of endocrine therapy. 

Symptoms significantly associated with time to treatment discontinuation for patients treated with anastrozole included body mass index (BMI), insomnia, joint pain, hot flashes, headaches, gynecologic symptoms, and vaginal discharge; for patients treated with tamoxifen, the symptoms included BMI, cognitive problems, joint pain, gynecologic symptoms, mood symptoms, weight problems, and pain with intercourse. 

Researchers are now beginning to tease out which symptoms are most significantly associated with treatment adherence so they can more effectively monitor patients and intervene if necessary. 

The problem, Anderson said, is that many existing studies don’t specifically address sexual symptoms for breast cancer patients. “Up to this point, we’ve mostly talked about AET symptoms as a collective,” she explained. “But in research interviews and informal conversations with more than 100 women over the last seven years, I’ve heard over and over that sexual health is one of the greatest unmet needs.”

Facing a Choice Between Quality of Life and Treatment Adherence  

In their recently presented study, Anderson and colleagues sought to characterize the landscape of sexual health symptoms in 102 Black and 173 white patients receiving AET and how those symptoms affected both quality of life and treatment adherence. 

Patients enrolled in the THRIVE clinical trial were surveyed at enrollment, six months, and 12 months about their symptoms, and their adherence was monitored via an electronic pillbox. Researchers used the 12-item Short Form Health Survey to monitor both physical and mental quality of life. 

In a post-hoc analysis, vaginal itchiness, vaginal discharge, painful intercourse, and decreased libido were associated with lower mental quality of life in both Black and white patients at all three time points. However, loss of interest in sex was also associated with a lower physical quality of life in Black patients. Further, vaginal dryness (at six months), loss of interest in sex, and sexual satisfaction (at 12 months) were associated with lower AET adherence for Black patients but not for white patients. 

Anderson emphasized that these findings not only demonstrate how bothersome these symptoms can be for women receiving AET but also that Black and white women experience them differently. Black women have a 40% higher risk of dying of breast cancer than white women, according to the AACR Cancer Disparities Progress Report 2024, and are more likely to skip or reduce prescribed AET doses that can prevent breast cancer recurrence. 

Anderson feels strongly that acknowledging and addressing sexual symptoms in Black patients can help to close the mortality gap. “If we can start to address some of these symptoms, we may start seeing parity in Black and white women’s AET adherence,” Anderson said. “What that really means is that … families will get to keep their mother, sister, auntie longer.” 

Fortunately, interventions exist to treat sexual health symptoms, Anderson explained. Vaginal moisturizers and topical estrogen may help with dryness, itching, and pain. Counseling can help boost a patient’s sexual self-image and facilitate conversations with their partner. Other hormonal therapies, including testosterone, are being evaluated as well. 

But Anderson stressed that patient-centered communication is key to ensuring that patients understand their options and that such conversations should be initiated by the oncologist. In her team’s qualitative study featuring interviews with 32 Black women receiving AET for early-stage breast cancer, some women felt they would be seen as not taking their disease seriously if they expressed concern about their sexual symptoms. 

Patients reported that they would be more comfortable discussing their sexual symptoms with a female provider and that peer support from fellow survivors—especially women of color—could help facilitate such conversations. Anderson hopes this information can help oncology practices create encouraging environments for Black women to share their experiences and receive the supportive care they deserve. 

“With their cancer diagnosis, some women are making the decision to either reclaim some sense of their sexual self or to maintain [treatment] adherence,” Anderson said. “Hopefully, we can make it so that they don’t have to make that choice anymore.”