Welcome to Dana-Farber's Research News
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: Michael_buller@dfci.harvard.edu.
Blood
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
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
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
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
Tesch ME, Collins LC, Wong JS, Dominici L, Come SE, Partridge AH
Blood Advances
Little JS, Aleissa MM, Beluch K, Gonzalez-Bocco IH, Marty FM, Manne-Goehler J, Koo S, Hammond SP, Jacobson CA
Blood Cancer Journal
Chen H, Yu T, Lin L, Wen K, Munshi N, Anderson KC, Tai YT
BMC Medical Informatics and Decision Making
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
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
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
Demetri GD, Baldini EH, George S, Raut CP, Schaefer IM, Fletcher CDM, Wagner AJ
Cancers
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
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
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
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
Lu W, Giobbie-Hurder A, Tanasijevic A, Kassis SB, Yang EM, Bierer BE, Ligibel JA
Current Oncology
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
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
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
Odejide OO, Fisher L, Vega B, Rodrigues G, Buchanan S, Fasciano KM, Lakin JR, Lefebvre A, Wall CB, Mack JW
Oncologist
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
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
Lu D, Valdimarsdóttir UA, Koenen KC, Recklitis CJ