This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from December 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].
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Blood
Evolution of Multiple Myeloma from a Genomic Perspective
Samur MK, Munshi NC
In this review we explore the role of complex interactions between genomic evolution, environmental and genetic predispositions, and immune surveillance in disease progression from precursor conditions smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). MM is well-described to be universally preceded by precursor states, often decades before it is even diagnosed. Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and MM-specific loci influencing risk. The reported disparities in occurrence of precursor conditions and MM among racial groups highlights the role of predisposition and the need for broader cohort studies. Early genomic events, such as translocations and hyperdiploidy, are essential in precursor initiation. However, additional factors are usually needed to transform the precursor stages into symptomatic disease, such as positive selection of subclonal populations. This process is impacted by aging, environmental factors such as exposures to Agent Orange and agrochemicals. Therefore, integrating genomic and transcriptomic data and combining them with immune profiling or other clinical features is essential for identifying patients with high risk of progressing into MM. Here, we highlight the complexity of myelomagenesis and underline the importance of state-of-the-art approaches for improved disease prediction.
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JAMA Oncology
Predictive Role of Circulating Tumor DNA in Stage III Colon Cancer Treated with Celecoxib: A Post Hoc Analysis of the CALGB (Alliance)/SWOG 80702 Phase 3 Randomized Clinical Trial
Zhang GQ, Meyerhardt JA, Twombly T, Ma C, Zhao M, Takashima Y, Giannakis M, Ogino S, Nowak JA
IMPORTANCE: Observational studies have associated use of aspirin and selective cyclooxygenase inhibitors with decreased recurrence and improved survival in patients with colon cancer. While randomized clinical trials have not shown benefit across all patients, these findings suggest that select subgroups may benefit from their use. Despite the well-established prognostic value of circulating tumor DNA (ctDNA), its role in guiding treatment remains unclear.
OBJECTIVE: To investigate the predictive value of postoperative ctDNA for survival outcomes with adjuvant celecoxib alongside conventional chemotherapy in patients with stage III colon cancer.
DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of the phase 3 Cancer and Leukemia Group B (now Alliance)/Southwest Oncology Group 80702 randomized clinical trial (2010-2015) assessing adjuvant celecoxib vs placebo and 3 vs 6 months of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin for stage III colon cancer. Patients consented to biospecimen collection and had ctDNA analysis performed. Data analysis was performed from September 2024 to June 2025.
EXPOSURES: Postoperative ctDNA positivity was determined using a clinically validated, tumor-informed 16-plex-polymerase chain reaction-next-generation sequencing assay (Signatera; Natera Inc) performed between surgery and initiation of adjuvant therapy.
MAIN OUTCOMES AND MEASURES: Disease-free survival (DFS) and overall survival (OS). Survival by ctDNA status and adjuvant celecoxib use were assessed as part of a post hoc companion study with prespecified statistical analysis plan.
RESULTS: Among 940 patients (mean [SD] age, 60.9 [10.8] years; 426 female [45.3%] and 515 male [54.7%] individuals; 222 [23.6%] with prior low-dose aspirin use; and median follow-up of 6.0 [95% CI, 6.0-6.0] years), 767 (81.6%) were ctDNA negative and 173 (18.4%) were ctDNA positive. ctDNA positivity was highly prognostic of worse DFS (reference, ctDNA negativity; adjusted hazard ratio [aHR], 6.12; 95% CI, 4.66-8.03) and OS (aHR, 5.86; 95% CI, 4.19-8.19). In patients with ctDNA positivity, celecoxib was associated with improved DFS (aHR, 0.61; 95% CI, 0.42-0.89) and OS (aHR, 0.62; 95% CI, 0.40-0.96) compared to placebo. Among patients with ctDNA negativity, celecoxib did not provide survival benefit (DFS: aHR, 0.76; 95% CI, 0.53-1.09; OS: aHR, 0.85; 95% CI, 0.54-1.36), although the interaction was not significant (P for interaction, .41 and .33 for DFS and OS, respectively). These findings persisted when stratifying patients by microsatellite instability status and PIK3CA mutational status.
CONCLUSION AND RELEVANCE: The findings of this post hoc analysis suggest that ctDNA status has the potential to inform clinical decision-making among patients with stage III colon cancer who should consider adjuvant celecoxib in addition to conventional chemotherapy.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01150045.
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Journal of Clinical Oncology
BRUIN 313 and 314 Trials Open the Door for Noncovalent Bruton Tyrosine Kinase Inhibition as Initial Therapy for Chronic Lymphocytic Leukemia
Davids MS
Over the past decade, the treatment landscape for chronic lymphocytic leukemia (CLL) has evolved rapidly with the approval of three oral, covalent Bruton tyrosine kinase inhibitors (cBTKi)—ibrutinib, acalabrutinib, and zanubrutinib—which were all previously shown to lead to superior progression-free survival (PFS; and in some cases overall survival [OS]) compared with chemoimmunotherapy when given as continuous therapies in the treatment-naïve (TN) setting. Time-limited targeted regimens incorporating the oral B-cell leukemia/lymphoma-2 inhibitor (BCL-2i) venetoclax as a backbone, combined with anti-CD20 monoclonal antibodies such as obinutuzumab, cBTKi, or all three mechanisms together, have also now become standard frontline treatment options.
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Journal of Clinical Oncology
Genomically Smoldering Multiple Myeloma Is Not a Distinct Entity but a Collection of Monoclonal Gammopathy of Undetermined Significance or Multiple Myeloma
Aktas Samur A, Talluri S, Rivera J, Fan Y, Dakiki Korucu B, Fulciniti M, Anderson KC, Sperling A, Parmigiani G, Munshi NC, Samur MK
PURPOSE: The diagnosis of smoldering multiple myeloma (SMM) primarily relies on clinical features such as plasma cell involvement, immunoglobulin protein levels, and end-organ damage. However, as early intervention becomes a priority, the role of genomic features in differentiating risk is gaining attention.
METHODS: This study analyzed next-generation sequencing data from 224 precursor condition samples with 51 patients having paired SMM and multiple myeloma (MM) and 1,779 samples from newly diagnosed MM to identify genomic features linked to progression in SMM and those with a low-risk nonprogressor precursor condition.
RESULTS: Our findings from paired samples revealed no significant differences in somatic alterations and clonal structures between SMM and MM samples from the same patient. This indicates that plasma cells in progressor SMM are genomically pre-equipped with changes that define myeloma. Over 80% of driver mutations were present at both time points, and more than 66% of progressor samples showed only minor clonal changes. We further compared genomic changes between nonprogressor and progressor SMM. Nonprogressor plasma cells showed significantly lower mutational load and the absence of copy number alterations on chromosome 8. They reduced focal genomic loss compared with progressor plasma cells. A scoring system using genomic features predictively identified patients with low-risk SMM unlikely to progress, validated on 101 additional independent samples, and additive clinical value of genomic classification was further shown in combination with 20/2/20.
CONCLUSION: In summary, the genomic distinctions now suggest that a proportion of SMMs with progressor phenotype are akin to MM, whereas nonprogressor SMM has monoclonal gammopathy of undetermined significance-like characteristics. The results should influence further investigation in larger studies to inform future diagnostic criteria and trial designs.
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Journal of Clinical Oncology
Management of Cancer During Pregnancy: ASCO Guideline
Partridge AH
PURPOSE: To provide guidance on the recommended management of cancer in pregnant patients.
METHODS: A multidisciplinary Expert Panel convened and conducted a systematic review of the literature.
RESULTS: The systematic review identified 450 eligible studies. Much of the evidence consisted of observational data, case series, and case reports.
RECOMMENDATIONS: Management of cancer during pregnancy should be grounded in a values-based informed-consent process outlining maternal and fetal risks and anticipated benefits. Diagnostic evaluation should follow the as low as reasonably achievable (ALARA) principle, with timing of diagnostic studies individualized based on urgency of cancer detection, potential dangers of delay, and the balance of risks to both the pregnant patient and her embryo or fetus. Due to significant risk of harm to the developing embryo and/or fetus, systemic therapy should be deferred until the second trimester. Methotrexate, hormonal therapies, human epidermal growth factor receptor 2-targeted agents, vascular endothelial growth factor and poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and all cellular therapies are contraindicated during pregnancy, regardless of gestational age. For patients who wish to continue their pregnancy, delivery should be planned at or after 37 weeks, with the final chemotherapy dose scheduled 2-4 weeks before birth. Referral to psychosocial support services is essential to address emotional and practical challenges, reduce distress, and support shared decision making. Additional information is available at www.asco.org/survivorship-guidelines.
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Journal of Clinical Oncology
Molecular Characterization Informs Prognosis in Patients with Localized Ewing Sarcoma: A Report from the Children's Oncology Group
Gillani R, Shulman DS, Klega K, Tanhaemami M, Ward A, Bainer V, Ricker C, DuBois SG, Church AJ, Crompton BD, Janeway KA
PURPOSE: Identifying discrete subgroups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children's Oncology Group (COG) biology study AEWS18B1-Q was to molecularly characterize patients with localized EWS on prospective modern-day trials.
PATIENTS AND METHODS: We analyzed clinical and molecular features from patients with localized EWS enrolled on frontline COG trials. All patients had available formalin-fixed paraffin-embedded (FFPE) tissue, frozen tissue, or whole-genome-amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations in TP53 and STAG2. Available tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses.
RESULTS: Three hundred fifty-one patients had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 patients (80.3%). Pathogenic mutations in TP53 and STAG2 were identified in 5.1% and 7.6% of patients, respectively. A total of 63.1% of patients were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients with TP53 mutation (5-year cumulative incidence of relapse 43%, 95% CI [17% to 67%] v 22%, 95% CI [17% to 27%]; Gray's test P = .039), STAG2 mutation (53%, 95% CI [29% to 73%] v 21%, 95% CI [16% to 26%]; P < .001), and recurrent CNAs (30%, 95% CI [22% to 37%] v 16%, 95% CI [9% to 24%]; P = .005). In a multivariable analysis, STAG2 mutation was the only molecular biomarker that remained prognostic.
CONCLUSION: This is a prospective validation of the molecular prognostic features of patients with localized EWS receiving standard-of-care therapy on therapeutic clinical trials. Building on previous work, patients with STAG2 mutations were at high risk of relapse.
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Journal of the National Cancer Institute
Sex Differences in Chemotherapy Completion, Toxicities, and Survival in Colon Cancer: An Analysis of 2201 Patients from CALGB/SWOG 80702 (Alliance)
Ma C, Ng K, Meyerhardt JA
BACKGROUND: Completing adjuvant chemotherapy and reducing toxicities are critical for maximizing survival after a colon cancer diagnosis. Sex, as a biological variable, may affect colon cancer chemotherapy completion, toxicities, and survival differently.
METHODS: From a National Cancer Institute-sponsored trial conducted among patients with stage III colon cancer (Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702), we included 2201 patients receiving the standard adjuvant chemotherapy regimen of fluorouracil, leucovorin, and oxaliplatin. We calculated relative dose intensity to indicate chemotherapy completion and considered reduced relative dose intensity (values <85%) as a clinically significant deviation from standard fluorouracil, leucovorin, and oxaliplatin. Using National Cancer Institute's Common Terminology Criteria for Adverse Events, we defined severe adverse events (grade ≥3) as the occurrence of any following event, including neutrophil count decrease, nausea, platelet count decrease, hypertension, peripheral neuropathy, diarrhea, fatigue, gastritis, creatinine level increase, gastric ulcer, myocardial ischemia, and cerebral ischemia. The primary survival outcome was disease-free survival (time from enrollment to colon cancer recurrence or death from any cause), and secondary survival outcomes were recurrence-free and overall survival.
RESULTS: Compared with men, women were at statistically significantly higher risks of experiencing reduced relative dose intensity (adjusted odds ratio = 1.59, 95% CI = 1.29 to 1.96; P < .001) and severe advance events (adjusted odds ratio = 1.72, 95% CI = 1.41 to 2.11; P < .001). Yet, women had statistically significantly better disease-free survival (adjusted hazard ratio = 0.72, 95% CI = 0.59 to 0.87; P < .001) as well as better recurrence-free and overall survival.
CONCLUSIONS: Our findings suggested that women with colon cancer are more likely to have worse chemotherapy completion rates and more severe adverse events, but they have better survival. Sex as a biological variable warrants further consideration in chemotherapy administration and survivorship management after colon cancer diagnosis.
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Nature Communications
Letrozole, Abemaciclib and Metformin in Endometrial Cancer: A Non-Randomized Phase 2 Trial
Konstantinopoulos PA, Zhou N, Penson RT, Campos S, Krasner C, Wright AA, Porter R, Horowitz N, Bouberhan S, Liu JF, Hindenach S, Sawyer H, Koppermann L, Hayes M, Polak M, Shea M, Widick P, Cheng SC, Castro C, Matulonis UA, Lee EK
Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty-five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9%-53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9%-84.3%) and median PFS is 19.4 months (95% CI 5.7 months-not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure.
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American Journal of Hospice and Palliative Care
Association Between Patient-Reported Engagement and Medical Record of Advance Care Planning Among Older Adults in the ED: A Cross Sectional Study
Shirai N, Hashimoto T, Fukui S, Samarakoon U, Paasche-Orlow G, Randa SN, Chang Y, Lindvall C, Sciacca KR, Joel M, Volandes A, Ouchi K
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Blood Advances
Venetoclax/FluBu2 RIC Transplant Followed by All-Oral Venetoclax/Decitabine Maintenance for Poor Risk MDS/AML
Garcia JS, Kim HT, Murdock HM, Bosch-Vilaseca A, Panaro KM, Lim F, Fiorilla J, Auriemma E, Brock J, Gooptu M, Ho VT, Cutler CS, Shapiro RM, Kelkar AH, Abel GA, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan JA, Fell G, Letai A, Ritz J, Lindsley RC, Antin JH, Soiffer RJ
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Cell Genomics
Detection of Heterogeneous Resistance Mechanisms to Tyrosine Kinase Inhibitors from Cell-Free DNA
Parsons HA, Messer C, Santos K, Weiss J, Merrell D, Danysh BP, Hughes ME, Kirkner GJ, Patel A, Hess J, Sendrick K, Stewart C, Grant E, Schlueter-Kuck K, Grinshpun A, Wagle N, Leone JP, Freedman RA, Metzger O, Tolaney SM, Getz G, Lin NU
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Clinical Cancer Research
A Phase Ib Study of Sapacitabine and Olaparib in Patients with BRCA1/2-Mutated Metastatic Breast Cancer
Lynce F, Graham N, Kochupurakkal BS, Nguyen H, Bychkovsky B, Poorvu PD, Attaya V, Davis R, DiLullo M, D'Andrea AD, Garber JE, Paweletz CP, Tayob N, Shapiro GI, Tolaney SM
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International Journal of Radiation Oncology, Biology, Physics
Associations Between G8 Geriatric Screening Score, Charlson Comorbidity Index, AI-Based Age Phenotype, and Overall Survival in Older Adults with Stage I-II Non-Small Cell Lung Cancer
Thompson LL, Amin PM, Shah S, Lipson SM, Yoon J, Lee G, Anabaraonye N, Gregg AT, Jiang S, Baxter E, Florissi C, He J, Saraf A, Bontempi D, Haugg F, Aerts HJWL, Mak RH
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JCO Precision Oncology
Presenting Features and Causes of Diagnostic Delays: A Report from the NUT Carcinoma Registry
Walton SA, Kim JJ, Paoloni F, Haradon D, Haradon J, Miller KW, Rotow JK, Jänne PA, Barbie DA, Sholl LM, DuBois SG, Hanna GJ, Shapiro GI, French CA, Luo J
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Leukemia
The Endogenous T Cell Landscape is Reshaped by CAR-T Cell Therapy and Predicts Treatment Response in Multiple Myeloma
Frede J, Poller JC, Shi K, Stuart H, Sotudeh N, Havig C, Lim K, Wiggers CRM, Cho EY, Vijaykumar T, Liu J, Waldschmidt JM, Nair MS, Anand P, Dimitrova V, Montanaro A, Yee AJ, Munshi NC, Anderson KC, Raje NS, Knoechel B, Lohr JG
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Neuro-Oncology
Prognostic Significance of MGMT Promoter Methylation Status in IDH-Mutant Glioma
Youssef G, Aquilanti E, Miller JJ, Lan Z, Lasica AB, Arrillaga-Romany I, Batchelor TT, Berger TR, Beroukhim R, Chukwueke U, Dietrich J, Forst DA, Gerstner ER, Castro LNG, Jordan JT, Lee EQ, Nayak L, Nakhate V, Ospina JP, Plotkin SR, Wang N, Rhee JY, Reardon DA, Wen PY
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OncoImmunology
Circulating Cytokine Associations with Clinical Outcomes in Melanoma Patients Treated with Combination Nivolumab Plus Ipilimumab
Chen J, Tarantino G, Severgnini M, Baginska J, Giobbie-Hurder A, Weirather JL, Manos M, Russell JD, Pfaff KL, Rodig SJ, Huang AY, Brennick R, Nazzaro M, Hathaway E, Holovatska M, Manuszak C, Ranasinghe S, Liu D, Hodi FS
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Radiotherapy and Oncology
CT Online Adaptive Radiotherapy is Associated with Dosimetric and Acute Toxicity Improvements in Prostate Cancer Treatment
Zhu LL, Bredfeldt JS, Hu YH, Hancox C, Guthier CV, Quirk S, Pursley J, Kamran SC, McClatchy D, Nguyen PL, D'Amico AV, Sayan M, Kim E, Mouw KW, King MT, Martin NE, Leeman JE
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Science Advances
Integrating Single-Cell Biophysical and Transcriptomic Features to Resolve Functional Heterogeneity in Mantle Cell Lymphoma
Debaize L, Weekes J, Vogiatzi I, Zhang M, Sumpena E, Liu H, Hackett L, Zhang J, Baghiyan S, Redd RA, Aryee M, Davids MS, Kim AI, Ryan CE, Weinstock DM, Manalis SR, Murakami MA
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