OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

 is honored to recognize oncology leaders whose innovations have contributed to immeasurable improvements in outcomes for countless patients with cancer. The 13 winners of the 2025 Giants of Cancer Care awards have made their mark with novel therapies and protocols across the spectrum of care.

Carey's work is devoted to the understanding and characterization of molecular subtypes of breast cancer to further prevention and treatment advances.

Through collaboration with Charles M. Perot, PhD, and Robert C. Millikan, PhD, Carey discovered that young African American women are at a higher risk of developing the poor-prognosis basal-like breast cancer subtype.

Carey is a global expert in triple-negative breast cancer, having led the first trial evaluating a new treatment regimen in this patient population.

She led a National Cancer Institute (NCI)–sponsored trial in HER2-positive breast cancer that illustrated that tumor characteristics, including immune cell activation and subtype, were critical to outcomes with dual HER2-targeted therapy.

Carey is a member of the NCI Breast Cancer Steering Committee, cochair of the NCI-sponsored Alliance Breast Committee, cochair of the Translational Breast Cancer Research Consortium Steering Committee, and member of the board of directors of the American Society of Clinical Oncology.

Tefferi has been a faculty member for several national board review courses, including those sponsored by Harvard Medical School, The University of Texas MD Anderson Cancer Center, and George Washington University.

Tefferi has published more than 1000 articles, reviews, abstracts, and book chapters across several peer-reviewed journals.

He received the Henry M. Stratton Medal for Clinical/Translational Science, American Society of Hematology in 2016.

He was a member of the World Health Organization classification committee for myeloid neoplasms, which has helped revise diagnostic criteria. He also was the lead study author on a paper outlining proposals for revised International Working Group–European LeukemiaNet criteria for anemia response in myelofibrosis.

, as well as an associate editor for the 

In 2024, he coauthored a paper on the challenges associated with establishing end points for myelofibrosis clinical trials and the importance of selecting a standardized set of primary end points for studies in this disease. The paper was published in 

Wolpin is the coprimary investigator for the Pancreatic Cancer Cohort Consortium (PanScan), a National Cancer Institute (NCI)–based, multi-institutional collective that studies the inherited genetic causes of pancreatic ductal adenocarcinoma (PDAC). PanScan performed the first genomewide study of the correlations between genetic variation and PDAC risk and identified the first genome regions associated with sporadic PDAC risk.

He is chair of the NCI Pancreatic Cancer Detection Consortium Steering Committee.

Wolpin leads a PDAC biospecimen bank at Dana-Farber Cancer Institute that collects patient blood specimens,
tumor samples, and data to provide information for early detection and predictive biomarker research.

Wolpin received a grant from the Lustgarten Foundation to support his research on personalized medicine for PDAC.

The Wolpin Lab has demonstrated connections between metabolism alterations and pancreatic cancer development. Wolpin led a 2013 study that was the first to show that insulin resistance is a classical risk factor
of subclinical PDAC, as well as a paraneoplastic syndrome that can be caused by subclinical PDAC. Additionally, in 2014, a study from the Wolpin Lab showed that pancreatic tumors cause amino acid elevations several years before diagnosis.

Lara’s research is dedicated to the development of new strategies to treat patients with cancer of the genitourinary tract and lungs. He has seen several clinical trials through from phase 1 to phase 3 completion.
He received the Faculty Research Award from UC Davis School of Medicine’s Department of Internal Medicine in 2018.

Lara is a coauthor on several trials evaluating novel targeted inhibition strategies in patients with advanced prostate and urothelial cancer, including strategies aimed at PARP, AKR1C3, EphrinB2, and ATR.

Much of Lara’s research extends to renal cell carcinoma (RCC). He has been an investigator on work in clear cell and non–clear cell subtypes, including the phase 3 EVEREST (SWOG S0931; NCT01120249) and KEYNOTE-679(NCT03260894) trials, which evaluated adjuvant everolimus (Afinitor) in patients with completely resected, very high-risk clear cell RCC, and the combination of pembrolizumab (Keytruda) and epacadostat as first-line therapy for patients with metastatic clear cell RCC, respectively. He was involved in the phase 2 PAPMET trial (NCT02761057), which evaluated sunitinib (Sutent), cabozantinib (Cabometyx), crizotinib (Xalkori), and savolitinib in patients with papillary histology.

In addition to his work in novel drug development, Lara has been an early advocate for eradicating barriers to cancer clinical trial enrollment. He published a study in 2008 looking at the effects of a mass media campaign in overcoming existing accrual challenges.

Lara is a member of multiple professional societies, including the American Association for Cancer Research, the American Society of Clinical Oncology, the European Society for Medical Oncology, and the International Association for the Study of Lung Cancer.

Pfister was the first author of a study that examined predictive biomarkers of response to pembrolizumab (Keytruda) in head and neck cancer. The study’s findings indicated that PD-L1 status and T-cell inflamed gene expression profile could be useful for characterizing response to pembrolizumab in this patient population.

Pfister’s research interests include the link between the human papillomavirus (HPV) and head and neck cancers. He has advocated for the importance of HPV vaccination in order to reduce cancer risk.

In 2011, he was honored with Memorial Sloan Kettering Cancer Center’s Willet F. Whitmore Award for Clinical Excellence.

He is a pioneer in organ preservation treatment approaches, which aim to maintain patients’ organ function without sacrificing treatment efficacy.

He was named to Castle Connolly’s list of America’s Top Doctors from 2023 to 2025.

Pfister is on the NCCN board of directors, chairs the NCCN Head and Neck Cancers Panel, is on the editorial board for the 

Journal of the National Comprehensive Cancer Network

, and is a member of the NCCN Guidelines Steering Committee.

Stock is cochair of the Leukemia Committee for the National Cancer Institute–supported Alliance, a Clinical Trials Cooperative Group developed with the goal of leading practice-changing trials across oncology.

She was an investigator on the phase 3 INO-VATE trial (NCT01564784), findings from which supported the 2017 FDA approval of inotuzumab ozogamicin (Besponsa) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Stock led the phase 2 CALGB 10403 trial (NCT00558519). Its results showed that the induction regimen used in pediatric patients with newly diagnosed ALL during the phase 3 AALL0232 trial (NCT00075725) was feasible and effective in adolescent and adult patients aged up to 40 years with newly diagnosed ALL.

She directs the Adolescent & Young Adult (AYA) Oncology Program at University of Chicago Medicine. The group’s mission is to provide access to innovative clinical trials and clinical care to AYA patients with cancer.

Stock is an associate editor for Blood Advances, and she is a councillor for the American Society of Hematology.

Cavalli is the founder and was the scientific director of the Oncology Institute of Southern Switzerland until 2017.

He received the 2024 American Association for Cancer Research Distinguished Public Service Award for Lifetime Achievement in Cancer Research.

Cavalli played a key role in the clinical investigations of etoposide (VP-16), and he contributed to the research that helped develop other chemotherapy agents such as cisplatin, carboplatin, and paclitaxel.

 Textbook of Medical Oncology, Fourth Edition, 

While serving as president of the Union for International Cancer Control, Cavalli helped launch My Child Matters, an initiative that originated in 2005 to improve survival rates for children with cancer from low—and middle-income countries. He also helped create the World Cancer Declaration, designed to promote equal access to cancer treatment.

He has published more than 600 articles in peer-reviewed journals and contributed to other oncology books. Cavalli was the founding editor and editor in chief of Annals of Oncology, and he is on the editorial boards of several other journals.

Cavalli helped establish the International Extranodal Lymphoma Study Group, the European School of Oncology, the Institute for Research in Biomedicine, the Bellinzona Institutes of Sciences, and the European Organisation for Research and Treatment of Cancer Early Clinical Trials Group.

Usmani has won multiple awards, including the LLS Scholar in Clinical Research Award, the 2018 Celgene Young Investigator Award for Clinical Research in Hematology, the Multiple Myeloma Excellence in Clinical Research Award at the 2020 COMy Congress, the Bart Barlogie Young Investigator Award in Clinical and Translational Research at the 18th International Myeloma Workshop, and the 2022 Career Development Achievement Award from the Leukemia & Lymphoma Society.

Usmani’s research interests include high-risk multiple myeloma and other plasma cell disorders.

He is the chair of the Alliance Myeloma Committee, a fellow at the Royal College of Physicians, a board member of
the International Myeloma Society, and a fellow at the American Society of Clinical Oncology.

Usmani has authored more than 260 peer-reviewed papers.

He was the lead author for the phase 3 CEPHEUS trial (NCT03652064), which was published in 2025. The trial used MRD-negativity rate as the primary end point and showed that daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) improved outcomes vs VRd alone in patients with newly diagnosed multiple myeloma who were ineligible for or deferred transplant.

Offit and his team published the first prospective series describing the outcome of preventive ovarian surgery and screening in women at hereditary risk for breast/ovarian cancer, and his research team identified the most common mutation associated with an increased risk of breast and ovarian cancer among those of Ashkenazi Jewish ancestry.

Offit received the 2023 Basser Global Prize from the Basser Center for BRCA, the American Cancer Society Career Research Recognition Award, and the ASCO (American Society of Clinical Oncology)–American Cancer Society Prevention Award for research in cancer prevention.

He led the first ASCO policy statement after the identification of BRCA1 and BRCA2 and founded one of the first clinical cancer genetics services in 1992.

Offit serves on the Genetic Counseling Advisory Board of Weill Cornell Medicine and the Scientific Advisory Committee of the BRCA Research & Cure Alliance.

Clinical Cancer Genetics: Risk Counseling & Management

Genetic Predisposition to Cancer, An Issue of Hematology/Oncology Clinics of North America (Volume 24-5)

, which details a patient’s journey through bone marrow transplantation.

Offit cofounded the BRCA Founder Outreach Study, which offers targeted BRCA testing free to participants and seeks to pioneer new ways to integrate genetic testing into medical care

Gorlick is the principal investigator of the Gorlick Laboratory at The University of Texas MD Anderson Cancer Center. His laboratory research is dedicated to the translational study of osteosarcoma, using proteomic and genomic research methods to detect therapeutic targets in this disease that may be further investigated in preclinical and clinical trials. The Gorlick Laboratory has evaluated more than 80 novel anticancer drugs in xenograft models derived from patients with osteosarcoma, which influenced the inception of osteosarcoma clinical trials within the Children’s Oncology Group.

He is the lead study author of the PIVOT program in osteosarcoma, which is evaluating the in vivo efficacy of the
B7-H3–directed antibody-drug conjugate ifinatamab deruxtecan (I-DXd; DS-7300). This research has demonstrated that I-DXd induced tumor-regressing anticancer activity across several pediatric solid tumor models, including osteosarcoma models.

Gorlick’s involvement with the Children’s Oncology Group led to the development of one of the largest osteosarcoma biorepositories in the world, the Osteosarcoma Explorer.

Gorlick was an investigator in the preclinical trial that revealed the role of the ezrin protein in osteosarcoma metastasis and disease outcomes in pediatric patients.

He has received numerous awards, including the 2015 Sarcoma Foundation of America Nobility in Science Award, the 2016 Albert Einstein College of Medicine Saul R. Korey Award in Translational Science and Medicine, and was among America’s Most Honored Professionals Top 1% in 2016. Gorlick also received the 2024 American Society of
Clinical Oncology Pediatric Oncology Award for his work in childhood cancers and osteosarcoma.

Gorlick has participated in research that demonstrated the basis of resistance to antifolates in osteosarcoma and acute lymphocytic leukemia.

Supportive, Palliative, and/or Geriatric Care

Known as one of the founders/pioneers of the geriatric oncology field, Balducci published the first major medical textbook on the subject, Geriatric Oncology, in 1992.

He cofounded the International Society of Geriatric Oncology in 2000.

Balducci received the first B.J. Kennedy Award for Scientific Excellence in Geriatric Oncology from the American Society of Clinical Oncology.

He established a special interest group on aging and cancer within the American Geriatric Society in 1991, cochaired the first subcommittee on aging in Eastern Cooperative Oncology Group in 1992, and cochaired the first NCCN committee on cancer and aging in 1998—the same year the first guidelines on the management of cancer in older patients were published.

Comprehensive Geriatric Oncology, 1st Edition

 with William B. Ershler and Gary H. Lyman, “Anemia in the Elderly” with William B. Ershler and John M. Bennett, 

Geriatric Oncology: Treatment, Assessment and Management with Arti Hurria, Biological Basis of Geriatric Oncology (Cancer Treatment and Research Book 124)

 with William B. Ershler and Giovanni de Gaetano.

Balducci penned a poignant article in the Journal of the American Geriatrics Society following the unexpected passing of his wife, noting missteps that occurred in her care and highlighting how instruments to diagnose frailty and vulnerability in older patients are inadequate. He concluded the piece with 3 important recommendations for care in older patients.

Kris was at the helm of chemotherapy and targeted therapy drug discovery for lung cancer and contributed to the development of antiemetics, which have helped countless individuals avoid the adverse effects of nausea and vomiting.

He was the senior study author of research that found evidence of 

mutations in lung adenocarcinomas as well as 

 exon 19 deletions and L858R mutations, which helped establish a blueprint for precision medicine in lung cancer.

In 2009, Kris founded the Lung Cancer Mutation Consortium, which continues to foster the integration of precision medicine into routine care.

Kris received the American Society of Clinical Oncology’s inaugural Humanitarian Award in 2011. The award honors an oncologist who exceeds expectations and provides exceptional patient care.

He is the former chief of the thoracic oncology service at Memorial Sloan Kettering Cancer Center.

Kris was the honoree at the 2024 Annual Evening of Innovation gala hosted by the Lung Cancer Research Foundation.

Andreeff received the 2016 Waun Ki Hong Award for Excellence in Team Science from the American Association for Cancer Research.

He is the head and director of the Section of Molecular Hematology and Therapy at The University of Texas MD Anderson Cancer Center, which conducts translational research in cancer and leukemia.

His 2006 research with BH3 mimetics led to the clinical development of venetoclax (Venclexta) as monotherapy and in combination with hypomethylating agents. Based on these findings, venetoclax-based combination regimens have gained FDA approval for patients with chronic lymphocytic leukemia and acute myeloid leukemia (AML).

In both preclinical and clinical studies, Andreeff’s team was the first to identify that the tyrosine kinase inhibitor sorafenib (Nexavar) inhibits 

 ITD in AML, inspiring the further development of other FLT3 inhibitors.

Andreeff led research that discovered that BAD, a proapoptotic member of the BCL-2 family, functions as an antiapoptotic protein and is invariably phosphorylated in all patients with AML. This finding has led to the global initiation of clinical trials investigating molecular therapies targeted toward these apoptosis regulators.

Articles

The 2025 Giants of Cancer Care awards honor 13 oncology leaders for their groundbreaking contributions to cancer treatment and research. These experts have advanced novel therapies and protocols across various cancer types, including breast, gastrointestinal, genitourinary, head and neck, leukemia, lymphoma, myeloma, sarcomas, and thoracic malignancies. Their work spans molecular subtype characterization, clinical trials, genetic research, and translational science. They have also made significant strides in community outreach, education, and supportive care, improving patient outcomes and advancing the field of oncology.

OncLive® showcases 13 cancer care pioneers, who have won the 2025 Giants of Cancer Care award. 

2025 Giants of Cancer Care: OncLive® Honors 13 Cancer Care Pioneers

Although allogeneic hematopoietic cell transplantation (allo-HCT) remains an important part of the therapeutic paradigm of myelofibrosis as the only curative option for the disease, the emergence of new treatment options and risk assessment considerations often make deciding which patients are ideal candidates for transplant complex. In response to these barriers, a team of investigators from the European Society for Blood and Marrow Transplantation (EBMT) have developed a machine learning model designed to identify and stratify transplant risk for patients with myelofibrosis.

On March 27, 2025, the EBMT announced the launch of the machine learning model. It can predict overall survival (OS) for patients with myelofibrosis following allo-HCT based on patient characteristics including age, performance status, and comorbidity index. The open-access tool is now available for use free of charge online.

“I’ve worked in transplantation for myelofibrosis for almost 2 decades, and, despite that experience, choosing the right time and patient to bring forward for transplant is still challenging,” Donal McLornan, MBBCh, MRCP, PhD, FRCPath, said in an interview with OncologyLive. “This is even more [true] in the current year because we have many clinical trials that patients are interested in and a whole host of new drugs that we don’t fully understand how to integrate into the transplantation algorithm. This tool will help us decide on the right patient to bring forward to transplant, alongside many other factors that we need to consider.”

During the 51st Annual Meeting of the EBMT, OncologyLive spoke with McLornan; Juan Carlos Hernández-Boluda, MD, PhD; and Adrián Mosquera Orgueira, MD, PhD, who were part of the EBMT team that developed the machine learning tool, to learn more about how the model was developed and its utility in predicting transplant risk in myelofibrosis.

Designing and Training the Machine Learning Model

To create the machine learning tool, investigators gathered data from adult patients with primary or secondary myelofibrosis who underwent their first allo-HCT between 2005 and 2020 in EBMT centers.2 A random survival forests model was then created using 10 variables: age, comorbidity index, performance status, blood blasts, hemoglobin, leukocytes, platelets, donor type, conditioning intensity, and graft-vs-host disease prophylaxis.

In total, data from 5183 patients from 288 centers were included to inform the machine learning model. The training cohort included 3887 patients, and the validation cohort included 1296 patients. Once the model was created, investigators performed a retrospective study to compare the performance of the new machine learning approach with a 4-level Cox regression-based score, other machine learning–based models derived from the same data set, and Center for International Blood and Marrow Transplant Research (CIBMTR) score.

“The study was conducted to explore the visibility and impact of machine learning tools in risk stratification for patients with myelofibrosis before allo-HCT because this is a very complex decision-making process and we wanted to develop a tool that could enhance the capacities of clinicians through datadriven approaches,” Orgueira said in an interview with OncologyLive. “We took advantage of the baseline data that [were] included in the registry to train a model that could predict the outcomes of these patients, both in terms of OS and relapse-free survival, to better understand whether these patients are [experiencing] worse outcomes due not only to disease-related factors but also due to toxicity.”

In the overall cohort, the median age at the time of allo-HCT was 58.3 years (range, 52.0-63.5). Most patients were male (62.6%), had primary myelofibrosis (72.2%), had constitutional symptoms at the time of allo-HCT (59.6%), had low-risk disease at the time of allo-HCT per the Dynamic International Prognostic Scoring System (2.4%), and had a low CIBMTR risk score at the time of allo-HCT (40.1%). Allo-HCT donor types were composed of identical sibling (29.6%), matched related donor other than a sibling (0.9%), mismatched related donor (6.5%), matched unrelated donor (42.0%), mismatched unrelated donor (13.0%), or unrelated with an unknown number of mismatches (8.0%).

EBMT Model Identifies High-Risk Patients for Transplant

At a median follow-up of 58.2 months (95% CI, 55.6-59.8) in the training set and 60.0 months (95% CI, 55.7-63.2) in the test set, the median OS was 79.4 months (95% CI, 69.2-89.6) and 73.7 months (95% CI, 54.7-92.7), respectively. No significant differences were reported between the 2 cohorts beyond a higher platelet count at the time of allo-HCT and a lower rate of antithymocyte globulin use in the test cohort.

In terms of overall transplantation outcomes, the estimated 1-, 5-, and 10-year OS rates were 70% (95% CI, 69%-71%), 53% (95% CI, 51%-54%), and 43% (95% CI, 41%-45%), respectively. These respective estimated progression- free survival rates were 62% (95% CI, 60%-63%), 44% (95% CI, 43%-46%), and 35% (95% CI, 33%-37%). The estimated nonrelapse mortality (NRM) rates were 23% (95% CI, 22%-24%), 32% (95% CI, 31%-33%), and 36% (95% CI, 35%-38%), respectively.

The EBMT model displayed higher concordance indices for OS and NRM in both the training and test sets compared with 3 other machine learning approaches. The EBMT model showed a significant rate of reassignment to other risk groups from the intermediate-2 risk group in terms of Cox score.

Notably, the EBMT machine learning model assigned 25% of patients as high risk with a poor outcome following transplantation (approximately 35% NRM and 40% overall mortality 1-year rates) compared with 10.1% using the Cox-derived score and 8.2% using the CIBMTR model. The 12- and 24-month OS rates in the training set (n = 471) of the machine learning high-risk group were 58.9% and 51.5%, respectively, compared with 58.3% and 52.7%, respectively, in the high-risk group identified by Cox-derived scores (n = 180). In the test set, these respective rates were 61.0% and 48.1% using the machine learning approach (n = 164) and 61.8% and 50.1%, respectively, using the Cox model (n = 55).

“CIBMTR scores identify 8% to 10% of patients as being high risk, but reality tells us [this number] is closer to 30%,” Orgueira noted. “When we identified the optimal threshold, our tool identified a [group of] 25% [of patients] who are performing very poorly [after allo-HCT]. That more than doubles the amount of high-risk patients that you can predict with other tools, and it is better aligned with what we see in the clinic.” Additionally, the machine learning model identified a larger high-risk group in terms of NRM compared with the Cox-derived score. In the test set, the 12- and 24-month NRM rates in the machine learning high-risk group were 36.4% and 42.6%, respectively. In the test set of the high-risk group via Cox-derived score, these respective rates were 36.0% and 42.8%.

The EBMT model also features an interactive web-based calculator that visualizes the risk score for a patient who is a candidate for allo-HCT. The calculator features inputs for the 10 variables used by the machine learning tool and produces OS and NRM curves, 1- and 2-year NRM and mortality rates, and a text and percentile display of the patient’s risk group. 

“We currently have good [transplant risk projection] scoring systems, but you [also] have to consider the toxicity and the results of transplant, and we don’t have very good tools at this time [for that],” Hernández-Boluda said in an interview with OncologyLive. “With this [machine learning] tool, we will have information on the disease and transplantation risk, and we can share this information with the patient. We also have a web application that is visual, and we can share this image with the patient if they are interested. [Using this tool], we can make a more informed decision, which is critical because transplantation is a curative treatment, but also it poses a lot of danger [in terms of] the life of the patient. I believe combining what we had before with this tool will help us to make that decision.”

1. Machine learning program enhances transplant risk assessment in myelofibrosis patients better than current models. News release. American Society of Hematology. March 27, 2025. Accessed April 8, 2025. bit.ly/3RKIOPa 

2. Hernandez-Boluda JC, Mosquera Orgueira A, Gras L, et al. Use of machine learning techniques to predict poor survival after hematopoietic cell transplantation for myelofibrosis. Blood. Published online March 27, 2025. doi:10.1182/blood.2024027287

A new machine learning model developed by the European Society for Blood and Marrow Transplantation (EBMT) aims to improve risk stratification for myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This model, based on data from 5183 patients, predicts overall survival and nonrelapse mortality using ten variables, including age and comorbidity index. It outperforms existing models by identifying a larger high-risk patient group, aligning more closely with clinical observations. The model is accessible online, featuring an interactive calculator for personalized risk assessment and decision-making support.

The EBMT have developed a machine learning model designed to identify and stratify transplant risk for patients with myelofibrosis.

New EBMT Machine Learning Model Outperforms Available Tools in Predicting Transplant Risk in Myelofibrosis

A rapidly expanding arsenal of molecularly targeted therapeutic approaches has improved breast cancer outcomes in both early-stage and advanced disease and supported the development of treatment approaches that tailor treatment intensity to individual patient risk to minimize exposure to unnecessary treatment-related toxicity. The resulting complexity of the breast cancer treatment landscape relies on tumor molecular profiling both to identify precision treatment approaches and to tailor treatment intensity across breast cancer subtypes and stages. This includes tumor mutation–directed small molecule targeted therapies for tumors with somatic mutations in PI3K pathway genes such as 

, and select additional DNA damage repair genes, as well as emerging data for therapies targeting 

Beyond small molecule targeted therapies, cell surface targeted therapies, including antibody-drug conjugates targeting HER2 and TROP2 proteins, are FDA approved for an expanding subset of metastatic breast cancers, with ongoing clinical trials in early-stage disease as well as with other types of cell surface targeted therapies such as radioligands and bispecific T-cell engagers.

 Liquid biopsies, which detect circulating tumor DNA (ctDNA) shed by tumor cells into the blood of patients with cancer, represent an approach for tumor DNA sequencing that requires only a peripheral blood draw rather than an invasive tissue biopsy. This can be particularly helpful when needed multiple times over the course of a patient’s treatment or when no accessible tissue biopsy site is available, though with the limitation that current ctDNA assays cannot estimate or predict protein biomarkers such as HER2 and PD-L1 expression, and that ctDNA approaches for tumor molecular burden assessment are much less robust than in tissue biopsies. A number of ctDNA approaches have been developed to detect minimal residual disease (MRD) in patients treated with curative intent for early-stage breast cancer. 

Current clinical ctDNA assays fall into 2 categories: tumor-informed and tumor-agnostic assays. Tumor-informed assays detect an individualized panel of mutations developed from DNA sequencing of a patient’s tumor (either a surgical specimen or tissue biopsy). Although costly and more time-consuming, this approach increases sensitivity for ctDNA detection of MRD, which is the primary use for this type of assay. Tumor-informed assays such as the Signatera assay (Natera) have been shown to be highly prognostic for metastatic recurrence in patients who have completed curative intent therapy for early-stage breast cancer with median lead times of 8 to 12 months before the development of overt metastatic disease.

However, whether the promising lead time demonstrated in the initial retrospective studies will bear out in larger prospective studies remains uncertain and may be specific to breast cancer subtype, as evidenced by recent trials attempting to risk-stratify patients with early-stage triple-negative breast cancer for additional adjuvant therapy based on ctDNA MRD positivity, which were unsuccessful due to very high rates of radiographic metastatic disease at the time of first ctDNA-positive MRD test.

 Additionally, whether interventions can be identified for patients with ctDNA-positive MRD that alter the likelihood of radiographic metastatic recurrence remains unknown and significantly limits the current clinical utility of these assays. Findings from exploratory analyses of ctDNA MRD in the phase 3 monarchE (NCT03155997) and PENELOPE-B (NCT01864746) trials of adjuvant CDK4/6 inhibitor therapy in high-risk estrogen receptor (ER)–positive breast cancer found that the adverse prognosis of patients with ctDNA-positive MRD persisted even in the CDK inhibitor arm of each study.

Multiple prospective randomized studies are ongoing to address this question, including the phase 2 DARE trial (NCT04567420), which is open nationally and at the University of Wisconsin (UW) Madison, and enrolls patients with high-risk, early-stage ER-positive/HER2-negative breast cancer for ongoing ctDNA MRD screening with random assignment to either continued endocrine therapy or fulvestrant (Faslodex) plus a CDK4/6 inhibitor if ctDNA testing becomes positive. Newer-generation ctDNA MRD assays seek to increase detection sensitivity through both computational approaches as well as evaluation of additional cell-free DNA (cfDNA) features such as cfDNA methylation to improve detection sensitivity, which may improve lead times to give a greater window for additional curative therapy to be delivered. Liquid biopsy researchers at UW Madison, including Muhammed Murtaza, MBBS, PhD; Marina Sharifi, MD, PhD; and George Zhao, MD, are currently developing ctDNA assays that leverage ctDNA structural features beyond mutation analysis, including copy number variation and fragmentation patterns, to more cost-effectively increase sensitivity for MRD detection. 

Compared with tumor-informed assays, tumor-agnostic assays detect a set panel of cancer-relevant mutations, which reduces cost and turnaround time. This type of assay is typically used to detect tumor mutations to guide treatment choice in metastatic disease, similar to tissue biopsies, and it has robust clinical utility for this indication in patients with metastatic breast cancer. However, it is important to be aware of a key limitation that sensitivity for mutation detection is dependent on the fraction of tumor DNA in the total cfDNA isolated from a peripheral blood draw, which can be quite variable. Low ctDNA fraction or content will significantly limit mutation detection, leading to the potential for false negative results, particularly for copy number alterations, and these assays are therefore most sensitive when performed at the time of disease progression when the likelihood of ctDNA shedding leading to higher ctDNA fraction/content is highest. Consequently, tumor-agnostic assays are typically insensitive for MRD detection compared with tumor-informed approaches. 

In the advanced disease setting, ongoing research is expanding the detection capabilities for breast cancer–relevant biomarkers through more advanced technical and computational approaches for ctDNA evaluation. Multiple groups, including Sharifi and Zhao at UW Madison, have shown that analysis of ctDNA modifications or fragmentation patterns can be used to accurately predict tumor protein expression, including ER- and HER2-positive/HER2-low protein expression, from analysis of ctDNA modifications or fragmentation patterns.

 Additionally, technological advances in the ability to isolate and profile circulating tumor cells allow for direct quantification of tumor cell gene and protein expression from liquid biopsies, which can be leveraged for the development of predictive and pharmacodynamic biomarkers of targeted therapy response and resistance in metastatic breast cancer.

 At UW Madison, Sharifi has led the development of circulating tumor cell pharmacodynamic biomarkers of PI3 kinase activity undergoing prospective evaluation in a recently completed phase 2 study (NCT04762979) of alpelisib (Piqray) plus continued endocrine therapy for patients with ER-positive, 

 She also coleads an ongoing pilot study with Amy Fowler, MD, PhD, evaluating the combination of imaging- and liquid biopsy–based longitudinal assessment of estrogen signaling to predict endocrine resistance in ER-positive metastatic lobular breast cancer.

André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. 

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Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. 

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Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. 

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Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. 

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Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. 

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Tung NM, Robson ME, Ventz S, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. 

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Jhaveri K, Eli LD, Wildiers H, et al. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. 

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Ma CX, Luo J, Freedman RA, et al. The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2-mutated, non-amplified metastatic breast cancer. 

. 2022;28(7):1258-1267. doi:10.1158/1078-0432.CCR-21-3418

Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. 

. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086

Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. 

. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X

Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. 

. 2019;25(14):4255-4263. doi:10.1158/1078-0432.CCR-18-3663

Garcia-Murillas I, Chopra N, Comino-Méndez I, et al. Assessment of molecular relapse detection in early-stage breast cancer. 

. 2019;5(10):1473-1478. doi:10.1001/jamaoncol.2019.1838

Lipsyc-Sharf M, de Bruin EC, Santos K, et al. Circulating tumor DNA and late recurrence in high-risk hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. 

. 2022;40(22):2408-2419. doi:10.1200/JCO.22.00908

Turner NC, Swift C, Jenkins B, et al. Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer. 

. 2023;34(2):200-211. doi:10.1016/j.annonc.2022.11.005

Loi S, Johnston SRD, Arteaga CL, et al. Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy (ET) in HR+, HER2-, node-positive, high-risk early breast cancer (EBC). 

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Turner NC, Marmé F, Kim S-B, et al. Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: analysis from the PENELOPE-B trial. 

. 2023;41(suppl 16):502. doi:10.1200/JCO.2023.41.16_suppl.502

Helzer K, Sperger J, Shi Y, et al. Fragmentomic analysis of a circulating tumor DNA targeted cancer gene panel discriminates ER status in metastatic breast cancer liquid biopsies. 

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Parsons H, Baca S, D'Ippolito A, et al. Liquid biopsy determination of HER2 status in breast cancer: results from a novel epigenomic platform. 

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Molecularly targeted therapies have significantly advanced breast cancer treatment, allowing for personalized approaches that minimize unnecessary toxicity. Tumor molecular profiling is crucial for identifying precision treatments and tailoring therapy intensity. Small molecule therapies target mutations in genes like PIK3CA, AKT, and PTEN, while cell surface therapies, such as antibody-drug conjugates, are expanding. Liquid biopsies offer a non-invasive method for tumor DNA sequencing, though they have limitations. Tumor-informed ctDNA assays show promise in detecting minimal residual disease, but their clinical utility remains uncertain. Ongoing research aims to enhance ctDNA assay sensitivity and predictive capabilities.

Liquid biopsy approaches aid in precision therapy selection for patients with breast cancer in a noninvasive manner.

The Role of Liquid Biopsies in Precision Approaches for Breast Cancer Therapy

Following its FDA approval in December 2022 as the first adenoviral vector–based gene therapy for patients with high-risk BCG-unresponsive non–muscleinvasive bladder cancer (NMIBC), investigators are now evaluating nadofaragene firadenovecvncg (Adstiladrin) in those with intermediaterisk disease.

 The agent is being compared with observation in patients with intermediate-risk NMIBC in the ongoing phase 3b ABLE-32 trial (NCT06510374).

“In the intermediate-risk population, some oncologists have used BCG in the past, [and] some have used various intravesical chemotherapies,” Neal D. Shore, MD, FACS, said in an interview with 

. “We don’t have level 1 evidence or an FDA-approved therapy in the intermediate-risk population; therefore, [positive outcomes from ABLE-32 could] lead to a new indication for patients who have intermediate-risk disease.”

Shore is the medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Nadofaragene firadenovec is a nonreplicating and nonintegrating adenoviral vector–based gene therapy. The agent delivers the human 

, enhancing viral transduction of the urothelium. The direct cytotoxic effects of IFNa2b promote tumor apoptosis and antiangiogenesis.

“Nadofaragene firadenovec has an intravesical application,” Shore explained. “We have [many] other intravesical applications, but this therapy combines interferon alfa-2b with an adenoviral component. It’s a viral gene vector [therapy], and ultimately, the mechanism of action is to stimulate the patients’ interferon production, which [makes it an effective] apoptotic agent [against] urothelial carcinoma.”

Data from the phase 3 CS-003 study (NCT02773849) supported the 2022 FDA approval of nadofaragene firadenovec in patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors.

 Findings from the study showed that response-evaluable patients with BCG-unresponsive CIS (n =98) achieved a complete response (CR) rate of 51% (95% CI, 41%-61%). The median duration of response (DOR) was 9.7 months (range, 3 to 52+). Forty-six percent of patients experienced a DOR of at least 12 months.

Additionally, data from an open-label phase 3 study (NCT02773849) demonstrated that patients with BCG-unresponsive NMIBC in the CIS with or without Ta/T1 cohort who received nadofaragene firadenovec (n =103) achieved a CR rate of 53.4% (95% CI, 43.3%-63.3%).

 The median high-grade recurrence-free survival (RFS) was 5.9 months (95% CI, 3.4-8.3).

ABLE-32 Launches to Examine Nadofaragene Firadenovec in Intermediate-Risk NMIBC

ABLE-32 is enrolling adult patients with intermediate-risk NMIBC per the 2020 American Urological Association (AUA)/Society of Urologic Oncology (SUO) Guidelines, which define intermediate-risk disease as recurrence of low-grade Ta within 1 year; solitary low-grade Ta above 3 cm; multifocal low-grade Ta; high-grade Ta of 3 cm or less; and/ or low-grade T1 disease (

 Within 60 days before random assignment, all patients are required to undergo complete transurethral resection of bladder tumor with or without perioperative chemotherapy. Patients with high- or low-risk NMIBC, as well as those with evidence of muscle-invasive or metastatic disease at screening, are excluded from the trial.

Eligible patients will be randomly assigned 1:1 to receive nadofaragene firadenovec or undergo observation. In the nadofaragene firadenovec arm, patients are receiving 75 mL (3 x 10

viral particles/mL) of nadofaragene firadenovec quarterly for up to 8 intravesical instillations. Patients in the observation arm are being followed per the AUA/SUO Guidelines over the 24-month treatment period. Crossover from the observation to investigational arm is permitted if intermediate-risk NMIBC recurs within 24 months. 

Disease recurrence and progression will be monitored in all patients via cytology, cytoscopy, and for-cause biopsy for up to 5 years. An interim analysis will be performed to evaluate early stopping of therapy. In the event the trial continues, investigators will perform a sample reassessment to consider population expansion. 

"We know the unique mechanism of action [of nadofaragene firadenovec] from its approved indication," Shore explained. "[The agent] is given once every 3 months intravesically, whereas other approved intravesical therapies [have] much [more] intensive dosing schedules. [This therapy offers] a significant convenience for throughput for both the clinic and patients."

 Secondary end points consist of 12- and 24-month RFS rates as well as safety. Exploratory end points are RFS up to 5 years from randomization, changes in the expression of potential urine and blood biomarkers, and quality of life measures.

ABLE-32 was initiated in the fourth quarter of 2024 and is enrolling patients at approximately 100 centers worldwide. The estimated primary completion date is in the third quarter of 2028, and the study is anticipated to run through the first quarter of 2031. 

"Beyond] ABLE-32, which is enrolling intermediate-risk patients, an important large phase 2 study, ABLE-22 [NCT06545955], is [examining] nadofaragene firadenovec [as] monotherapy or [in combination with] pembrolizumab [Keytruda] or gemcitabine and docetaxel in patients with high-risk NMIBC,” Shore said. “Both these studies may allow for consideration [of nadofaragene firadenovec–based] options, as well as [the use of this therapy in] different stages of disease.”

FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Gu.rin unresponsive non-muscle invasive bladder cancer. FDA. Updated December 19, 2022. Accessed April 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-firstadenoviral-vector-based-gene-therapy-high-risk-bacilluscalmette-guerin

Nadofaragene firadenovec, an adenoviral vector-based gene therapy, is being evaluated in the phase 3b ABLE-32 trial for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). This trial compares the therapy with observation, aiming to establish a new indication for intermediate-risk patients. The therapy, previously approved for high-risk BCG-unresponsive NMIBC, delivers the IFNa2b gene to urothelial cells, promoting tumor apoptosis. The trial's primary endpoint is recurrence-free survival, with secondary endpoints including safety and quality of life measures. Results could expand treatment options for NMIBC.

A deep dive into the phase 3b ABLE-32 trial reveals the need for more treatments for patients with intermediate-risk NMIBC.

Vol. 26 No. 6 | Oncology Live®

2025 Giants of Cancer Care: OncLive® Honors 13 Cancer Care Pioneers

New EBMT Machine Learning Model Outperforms Available Tools in Predicting Transplant Risk in Myelofibrosis

The Role of Liquid Biopsies in Precision Approaches for Breast Cancer Therapy

ABLE-32 Looks to Expand the Use of Nadofaragene Firadenovec Into Intermediate-Risk NMIBC

Preliminary Casdozokitug Activity in HCC Supports Further Exploration of IL-27 as a Treatment Target

Multidisciplinary Collaboration Is Essential in Early-Stage NSCLC

Clinical Judgment in the Provision of Optimal Care vs Selection Bias in a Survival Analysis