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 June 16 - 30.
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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Annals of Oncology
SACI-IO HR+: A Randomized Phase II Trial of Sacituzumab Govitecan with or without Pembrolizumab in Patients with Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer
Garrido-Castro AC, Kim SE, Li T, Desrosiers J, O'Connor T, Sinclair N, Augdahl G, Wrabel E, DiLullo M, Rahman T, Patel A, Hughes ME, Baginska J, Lange PB, O'Meara T, Keenan TE, Koca B, Kurnia PT, Perry AN, Tejeda Zanudo JG, Dillon DA, Lin NU, Burstein HJ, Mittendorf EA, Jeselsohn R, Tayob N, Tolaney SM
BACKGROUND: Sacituzumab govitecan (SG), a TROP2-directed topoisomerase I-inhibitor (TOP1i) antibody-drug conjugate, is approved for chemo-refractory hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). To evaluate if pembrolizumab (PD-1 inhibitor) enhances the activity of SG, we conducted a randomized phase II study comparing SG with or without pembrolizumab in HR+/HER2- MBC.
METHODS: Patients with HR+/HER2- MBC pretreated with endocrine therapy and 0-1 chemotherapy regimens for MBC (no prior TOP1i) were randomized 1:1 to receive SG+pembrolizumab or SG. Primary endpoint was progression-free survival (PFS). Key secondary endpoints included PFS in the PD-L1-positive population (pharmDx 22C3 CPS ≥1), overall survival (OS), objective response rate (ORR), and toxicity. Baseline tumor tissue and plasma samples were collected for correlative analyses.
RESULTS: Between 03/2021-01/2024, 104 patients started treatment; 47% (49) had not received chemotherapy for MBC. At 15.5-month median follow-up, SG+pembrolizumab did not significantly improve PFS compared to SG (8.4 vs 6.7 months; HR 0.76, 95% CI 0.48-1.19, p=0.12). Median OS was 20.0 vs 18.0 months (p=0.18); ORR was 28.8% vs 19.2% (p=0.36). In the PD-L1-positive population (44%; 39/88 with tissue), median PFS (11.1 vs 5.6 months; HR 0.51, 95% CI 0.24-1.12, p=0.09) and OS (18.5 vs 12.5 months; HR 0.59, 95% CI 0.18-1.98, p=0.39) numerically increased with the combination. Most frequent grade ≥2 adverse events were neutropenia, alopecia, fatigue, anemia, nausea, leukopenia, and diarrhea. Neither TROP2 expression by immunohistochemistry, immunofluorescence, or plasma epigenome-based analysis, or tumor-infiltrating lymphocytes were associated with outcomes. Higher ctDNA fraction and PIK3CA mutations were associated with worse PFS. Plasma epigenome-pathway analysis suggested that high cell-cycle or EMT activation may confer sensitivity or resistance to SG, respectively.
CONCLUSION: Addition of pembrolizumab to SG did not significantly improve outcomes in HR+/HER2- MBC unselected by PD-L1. In the PD-L1-positive population, the trend in PFS and OS favoring SG+pembrolizumab warrants further investigation in larger randomized trials.
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Cell
Genetic Variation Reveals a Homeotic Long Noncoding RNA that Modulates Human Hematopoietic Stem Cells
Lyu P, Agarwal G, Guo CJ, Sychla A, Bourgeois W, Ye T, Weng C, Antoszewski M, Joubran S, Caulier A, Poeschla M, Armstrong SA, Rouskin S, Sankaran VG
The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We found that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we named HOXA opposite-strand transcript, stem-cell regulator, antisense mid-cluster between loci (HOTSCRAMBL). The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.
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JAMA Oncology
Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab for Stage II to III, ERBB2-Positive Breast Cancer: A Secondary Analysis of the DAPHNe Trial
Tarantino P, Li T, Ogayo ER, Rahman T, DiLullo MK, Patel A, Desai NV, Spring LM, Tung NM, Sinclair N, Faggen M, Constantine M, King TA, Tayob N, Mittendorf EA, Tolaney SM, Parsons HA, Waks AG
IMPORTANCE: The neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) represents a promising abbreviated regimen for early-stage ERBB2-positive breast cancer, but long-term outcomes and the role of ultrasensitive circulating tumor DNA (ctDNA) monitoring remain incompletely defined.
OBJECTIVE: To assess 5-year outcomes and characterize ctDNA dynamics with an ultrasensitive assay in patients with ERBB2-positive breast cancer receiving neoadjuvant THP.
DESIGN, SETTING, AND PARTICIPANTS: This study was a prespecified secondary analysis of the prospective, single-arm, investigator-initiated phase 2 DAPHNe nonrandomized clinical trial. Patients were enrolled in the DAPHNe trial from November 2018 to January 2020. The trial took place at a multicenter academic cancer center and affiliated community practices. Participants included patients with stage II to III ERBB2-positive breast cancer receiving neoadjuvant THP for 12 weeks. Ultrasensitive ctDNA analyses were performed in patients with available tumor tissue and serial plasma samples. The secondary analysis was conducted between between March 2023 and April 2025.
INTERVENTIONS: Neoadjuvant THP administered for 12 weeks, followed by surgery and adjuvant therapy guided by pathologic response.
MAIN OUTCOMES AND MEASURES: Main outcomes included 5-year event-free survival, recurrence-free interval (RFI), distant RFI, and overall survival. ctDNA detection and clearance were assessed using a whole-genome-based, tumor-informed ultrasensitive assay at 4 predefined time points (baseline, preoperative, postoperative, and late adjuvant).
RESULTS: The overall trial cohort included 98 patients (median [IQR] age, 49.5 years [24.0-78.0 years]; 97 female patients [99.0%]; 1 male patient [1.0%]), with mostly stage 2 disease (91 patients [92.9%]) and hormone receptor-positive tumors (65 patients [66.3%]). With a median (IQR) follow-up of 5.2 (5.0-5.4) years, the 5-year event-free survival was 99% (95% CI, 97%-100%), the 5-year RFI was 98% (95% CI, 93%-100%), the 5-year distant RFI was 100% (95% CI, 100%-100%), and the 5-year overall survival was 99% (95% CI, 97%-100%). Among 57 patients included in ctDNA analyses, baseline ctDNA was detected in 51 individuals (89.5%). After neoadjuvant therapy, ctDNA clearance occurred in 49 of 51 patients (96.1%), with only 2 individuals (3.9%) remaining ctDNA-positive preoperatively; detectability remained low (<10%) during postoperative follow-up. One single patient experienced a local recurrence, with ctDNA detected at time of recurrence and cleared following surgical resection.
CONCLUSIONS AND RELEVANCE: In this secondary analysis of the DAPHNe nonrandomized clinical trial, neoadjuvant THP was associated with excellent long-term outcomes in patients with early-stage ERBB2-positive breast cancer. Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03716180.
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Journal of Clinical Oncology
Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial
Lee EQ
PURPOSE: GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm.
METHODS: Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped.
RESULTS: When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control.
CONCLUSION: GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.
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Journal of Clinical Oncology
Ficerafusp Alfa (BCA101) With Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Two-Year Results of an Expansion Cohort of a Phase I/Ib Trial
Hanna GJ
PURPOSE: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis, particularly those with human papillomavirus (HPV)-negative disease, in which elevated epidermal growth factor receptor and transforming growth factor-β impair tumor penetration of immune cells and lessen immunotherapy responses.
METHODS: We present results from an expansion cohort of a first-in-human phase I/Ib trial (ClinicalTrials.gov identifier: NCT04429542) evaluating first-line treatment with ficerafusp alfa 1,500 mg once every week in combination with pembrolizumab 200 mg once every 3 weeks administered intravenously in patients with R/M HNSCC overexpressing PD-L1 (combined positive score ≥1). The primary end point was safety. Secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).
RESULTS: Between February 2022 and April 2023, 42 patients received ≥1 dose of study drug and 39 were included in the efficacy-evaluable set (≥1 postbaseline scan). The median follow-up was 26.3 months. Nineteen of 42 patients (45%) had a grade 3 treatment-related adverse event (TRAE), and one (2%) had a grade 4 TRAE. The most common grade ≥3 TRAEs were anemia (14%) and acneiform dermatitis (12%). In efficacy-evaluable patients with HPV-negative (n = 28) or HPV-positive (n = 11) tumors, confirmed ORRs were 54% (complete response in 21%) and 27%, respectively. In the HPV-negative subgroup, median DOR was 21.7 months (95% CI, 6.0 to not estimable [NE]), median PFS was 9.9 months (95% CI, 4.4 to 22.7), and median OS was 21.3 months (95% CI, 9.9 to NE).
CONCLUSION: Ficerafusp alfa plus pembrolizumab demonstrated favorable safety and tolerability with promising antitumor activity in the first-line treatment of R/M HNSCC, particularly in those with HPV-negative tumors.
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Journal of Clinical Oncology
Multicenter, Randomized, Phase II Trial of Olaparib Plus Radium-223 Versus Radium-223 in Men with Castration-Resistant Prostate Cancer with Bone Metastases (COMRADE)
Xie W, Manning DK, Van Allen E, Kochupurakkal B, Shapiro GI
PURPOSE: Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223.
PATIENTS AND METHODS: Men with mCRPC and ≥2 bone metastases (BM) were randomly
assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS).
RESULTS: A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%).
CONCLUSION: Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.
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Blood Advances
SAVE, Safe Accelerated Venetoclax Escalation: A Phase Ib Study of Obinutuzumab Plus Venetoclax with Daily Ramp-Up in CLL
Crombie JL, Ahn IE, Ren Y, Tyekucheva S, Carey C, Kniezewski M, Normilus S, Solomon S, Montegaard J, Kim AI, Merryman RW, Armand P, Fisher DC, Brown JR, Davids MS
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Blood Advances
Supportive Care Interventions in Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Schaefer DA, Guo M, Keane EP, Song MT, Larizza IS, Adri FN, Saadeh N, Boardman AC, Acharya NB, Waldman LP, Monahan JA, Ramirez-Gomero AF, González-Colmenero FD, Watson J, Cronin AE, Celano CM, Stoto MA, Gudenkauf LM, Amonoo HL
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Cell Reports
Recurrent ZC3H18 Mutations Stabilize Oncogenic Endogenous Retroviral RNA
Tanu T, Cox AM, Karlow JA, Sharma P, Sun K, Babu S, Roelofs MK, Jeon E, Chen J, Wu C, Brown J, Liu D, Burns KH, Insco ML
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Genome Medicine
ESR1 Mutations and CDK4/6 Inhibitor Choice Shape Clonal Selection and Adaptive Cell States During Acquired Resistance
Guarducci C, Abravanel D, Russo D, Prasad K, Fu J, Nagy Z, Rao V, Nardone A, Kuang Y, Feit A, Ma W, Feit GC, Hermida-Prado F, Heraud C, Munoz Gomez M, Garcia Cortes DE, Kurnia P, Gomez Tejeda Zanudo J, Li R, Qiu X, Cristea S, Feiglin A, Cheng YC, Lin NU, Tolaney SM, Sicinski P, Polyak K, Paweletz C, Long H, Stewart C, Michor F, Getz G, Brown M, Jeselsohn R
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Haematologica
Dual CDK2 and CDK4/6 Inhibition Suppresses Rb/E2F Signaling and Enhances Anti-Leukemic Activity in Acute Myeloid Leukemia
Weisberg E, Chowdhury B, Garg S, Akatsu T, Ni W, Gokhale PC, Eschle BK, Sattler M, DeCaprio JA, Nöltner L, Garcia J, Marinchev K, Galinsky I, Stone RM, Griffin JD
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Journal of the National Comprehensive Cancer Network
A Virtual Reality Psychosocial Intervention for Patients Undergoing Bone Marrow Transplantation (BMT-VR): Pilot Randomized Clinical Trial
Amonoo HL, Newcomb R, Psenka R, Samarakoon U, Greer JA, Nelson AM, Barata A, Farnam EJ, Pepper J, Caruso E, Larizza IS, Keane EP, Rabideau DJ, Horick N, DeFilipp Z, Chen YB, Temel JS, El-Jawahri A
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Neuro-Oncology
Selective Histone Deacetylase Inhibition as a Therapeutically Relevant Strategy in H3K27M-Glioma
Groves A, Kirkland OO, Cascio CL, Wang X, Heaslip C, Marques JG, Song C, Poetschke R, Wang T, Liu Q, Trissal M, Labelle J, Cruzeiro GAV, Jones KL, Cameron AB, Clark LM, Leeper B, Nguyen QD, Filbin MG, Qi J
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STAR Protocols
Classifying Germline and Somatic Structural Variants in Tumor-Only Contexts Using GaTSV
Chukwu W, Lee S, Crane A, Zhang S, Wala J, Dakhama O, Raskind G, Sun J, Beroukhim R, Dubois F, Dalin S
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Translational Oncology
Combined Inhibition of CDK4/6 and PI3K Pathways Exhibit Highly Synergistic Activity and Translational Potential in Ewing Sarcoma
Gloege HF, De Los Santos MAIC, Chakraborty A, Chadha M, Aguilar-Quintero A, Heaslip CO, Finstuen-Magro S, McDannell B, Tanhaemami M, Meyer S, Klega K, Shulman DS, DuBois SG, Blandin AF, Crompton BD
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