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Dana-Farber Research Publication 9.15.2022

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September 15, 2022

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at:


Increased COVID-19 Breakthrough Infection Risk in Patients with Plasma Cell Disorders

La J, Wu JT, Branch-Elliman W, Huhmann L, Han SS, Brophy M, Do NV, Lin AY, Fillmore NR, Munshi NC

Patients with multiple myeloma (MM) are at increased risk of infection and severe outcomes from COVID-19 infection, partly owing to inadequate protection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Their susceptibility stems from both immune-suppressive treatments used for MM and underlying immune-deficiency from the disease itself. However, it is unknown how much risk is shared by patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor state to MM that does not require immune-suppressive treatment but may be associated with immune-deficiency. Here, we measured the risk of breakthrough infections among vaccinated patients with MM or MGUS relative to the patients without MM or MGUS in the national Veterans Affairs (VA) health care system and described the association of MM-specific treatments with breakthrough risk.

Cancer Cell

Personalized Neoantigen Vaccine NEO-PV-01 with Chemotherapy and Anti-PD-1 as First-Line Treatment for Non-Squamous Non-Small Cell Lung Cancer

Awad MM

Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination. Epitope spread to non-vaccinating neoantigens, including responses to KRAS G12C and G12V mutations, were detected post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination revealed effector and cytotoxic phenotypes with increased CD4+ T cell infiltration in the post-vaccine tumor biopsy. Collectively, these data support the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.

Journal of Clinical Oncology

Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?

Yurgelun MB

Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration-approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.

Journal of Clinical Oncology

Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

Bardia A, Tolaney SM

PURPOSE: Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer.

METHODS: In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. RESULTS: Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%).

CONCLUSION: SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

JAMA Oncology

World Health Organization 2021 Classification of Central Nervous System Tumors and Implications for Therapy for Adult-Type Gliomas: A Review

Berger TR, Wen PY, Lang-Orsini M, Chukwueke UN

IMPORTANCE: Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians' ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care.

OBSERVATIONS: In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas.

CONCLUSIONS AND RELEVANCE: The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.

Nature Communications

Regulation of Neuroendocrine Plasticity by the RNA-Binding Protein ZFP36L1

Chen HY, Durmaz YT, Li Y, Sabet AH, Vajdi A, Denize T, Walton E, Laimon YN, Doench JG, Mahadevan NR, Losman JA, Barbie DA, Tolstorukov MY, Signoretti S, Oser MG

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine "inflammatory" phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

ACS Chemical Biology

Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Verano AL, Donovan KA, Mageed N, Yue H, Nowak RP, Fischer ES

Annals of Surgical Oncology

ASO Visual Abstract: Clinicopathologic Features, Treatment Patterns, and Disease Outcomes in a Modern, Prospective Cohort of Young Women Diagnosed with Ductal Carcinoma In Situ

Tesch ME, Collins LC, Wong JS, Dominici L, Come SE, Partridge AH

Blood Advances

Low Incidence of Invasive Fungal Disease Following CD19 Chimeric Antigen Receptor T-Cell Therapy for Non-Hodgkin Lymphoma

Little JS, Aleissa MM, Beluch K, Gonzalez-Bocco IH, Marty FM, Manne-Goehler J, Koo S, Hammond SP, Jacobson CA

Blood Cancer Journal

y-Secretase Inhibitors Augment Efficacy of BCMA-Targeting Bispecific Antibodies Against Multiple Myeloma Cells Without Impairing T-Cell Activation and Differentiation

Chen H, Yu T, Lin L, Wen K, Munshi N, Anderson KC, Tai YT

BMC Medical Informatics and Decision Making

Concordance Between Influential Adverse Treatment Outcomes and Localized Prostate Cancer Treatment Decisions

Pozzar RA, Xiong N, Hong F, Chang P, Halpenny B/strong>

Cancer Immunology, Immunotherapy

Phase II Trial of CV301 Vaccine Combined with Atezolizumab in Advanced Urothelial Carcinoma

Sonpavde GP, McGregor BA, Wei XX, Kilbridge KL, Lee RJ

Cancer Research

Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers

Patterson-Fortin J, Bose A, Tsai WC, Grochala CJ, Nguyen H, Zhou J, Parmar K, Lazaro JB, Liu JF, McQueen K, Shapiro GI, Kozono D, D'Andrea AD

Cancer Research

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response

Berchuck JE, Adib E, Abou Alaiwi S, Baca SC, Bell C, McClure HM, El Zarif T, Davidsohn MP, Lakshminarayanan G, Kelleher KM, Seo JH, Pomerantz MM, Freedman ML

Cancer Treatment Reviews

Retrospective Observational Studies in Ultra-Rare Sarcomas: A Consensus Paper from the Connective Tissue Oncology Society (CTOS) Community of Experts on the Minimum Requirements for the Evaluation of Activity of Systemic Treatments

Demetri GD, Baldini EH, George S, Raut CP, Schaefer IM, Fletcher CDM, Wagner AJ


Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Tarantino P, Tolaney SM

Cell Chemical Biology

Repurposing the Repurposed: Thalidomide Analogs as Immune Stimulants to Overcome T Cell Exhaustion

Slabicki M, Sperling AS

Cell Chemical Biology

Temporal Resolution of Gene Derepression and Proteome Changes Upon PROTAC-Mediated Degradation of BCL11A Protein in Erythroid Cells

Mehta S, Buyanbat A, Kai Y, Goldman SR, Zhang K, Fujiwara Y, Donovan KA, Zhu Q, Yang H, Fischer ES, Adelman K, Orkin SH

Cell Reports Methods

Direct Capture of Neutralized RBD Enables Rapid Point-of-Care Assessment of SARS-CoV-2 Neutralizing Antibody Titer

Jee H, Koehler AN, London WB, Lee PY, Bhatia SN, Li H

Chemical Communications

(15)N-Detected TROSY NMR Experiments to Study Large Disordered Proteins in High-Field Magnets

Dubey A, Viennet T, Chhabra S, Seo HC, Arthanari H

Clinical Infectious Diseases

Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccines in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Immunogenicity and Reactogenicity

Sherman AC, Desjardins M, Cheng CA, Bausk B, Izaguirre N, Zhou G, Krauss J, Tolan N, Walt DR, Soiffer R, Ho VT, Issa NC, Baden LR

Contemporary Clinical Trials

Acupuncture for Hot Flashes in Hormone Receptor-Positive Breast Cancer, a Coordinated Multinational Study: Rationale and Design of the Study Protocol

Lu W, Giobbie-Hurder A, Tanasijevic A, Kassis SB, Yang EM, Bierer BE, Ligibel JA

Current Oncology

Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments

Trapani D, Tesch ME, Hassett MJ, Kesselheim AS

Digestive Diseases and Sciences

Standard Adult Gastric Emptying Scintigraphy Criteria Is Applicable for Partial Meal Ingestion

Shah H, Prado DEA, Dong JW, Chow DZ, Kuo B, Voss SD, Jacene HA, Robertson MS, Ng TSC

European Urology Focus

Moving Precision Oncology for Advanced Prostate Cancer from Theory to Practice

Beltran H

Genetic Medicine

A Validation of Models for Prediction of Pathogenic Variants in Mismatch Repair Genes

Shyr C, Huang T, Trippa L, Syngal S, Ukaegbu C, Uno H, Braun D, Parmigiani G

Genome Biology

Identifying and Correcting Repeat-Calling Errors in Nanopore Sequencing of Telomeres

Tan KT, Slevin MK, Meyerson M, Li H

Journal of Computer Assisted Tomography

Interstitial Lung Abnormalities in Patients with Locally Advanced Esophageal Cancer: Prevalence, Risk Factors, and Clinical Implications

Tseng SC, Hino T, Hatabu H, Park H, Nishino M, Mamon H

Journal of Pain and Symptom Management

Specialty-Aligned Palliative Care: Responding to the Needs of a Tertiary Care Health System

Gelfand SL, Lakin JR, Sciacca KR, Rivkin ER, Eves JC, Anderson S, Mandel EI, Desai AS, Jain N, Landzberg MJ, Lever NM, Schaefer KG, Leiter RE, Tulsky JA

JAMA Psychiatry

Potential Limitations for the Culturally Tailored Version of Internet-Delivered Cognitive Behavioral Therapy for Insomnia in Black Women-Reply

Zhou ES

JCI Insight

VRK1 as a Synthetic Lethal Target in VRK2-Methylated Cancers of the Nervous System

So J, Mabe NW, Englinger B, Chow KH, Moyer SM, Yerrum S, Trissal MC, Graca Marques J, Kwon JJ, Shim BH, Pal S, Panditharatna E, Quinn TW, Schaefer DA, Jeong D, Mayhew DL, Beroukhim R, Ligon KL, Stegmaier K, Filbin MG, Hahn WC

JCO Oncology Practice

Patient, Family, and Clinician Perspectives on Location of Death for Adolescents and Young Adults with Cancer

Odejide OO, Fisher L, Vega B, Rodrigues G, Buchanan S, Fasciano KM, Lakin JR, Lefebvre A, Wall CB, Mack JW


Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas

Thouvenin J, Hirsch L, Viswanathan SR, Bakouny Z, Choueiri TK

Open Forum Infectious Diseases

Immunogenicity of a Three-Dose Primary Series of mRNA COVID-19 Vaccines in Patients with Lymphoid Malignancies

Sherman AC, Crombie JL, Cheng C, Desjardins M, Zhou G, Ometoruwa O, Rooks R, Senussi Y, McDonough M, Guerrero LI, Kupelian J, Doss-Gollin S, Smolen KK, van Haren SD, Armand P, Levy O, Walt DR, Baden LR, Issa NC

Supportive Care in Cancer

Coping Strategies and Anxiety in Young Breast Cancer Survivors

Poorvu PD, Gelber SI, Peppercorn J, Come SE, Partridge AH, Rosenberg SM

Translational Psychiatry

Genome-Wide Association Study of Posttraumatic Stress Disorder Among Childhood Cancer Survivors: Results from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort

Lu D, Valdimarsdóttir UA, Koenen KC, Recklitis CJ