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Dana-Farber Research Publication 8.1.2022

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August 1, 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:

Cancer Discovery

MOZ and Menin-MLL Complexes Are Complementary Regulators of Chromatin Association and Transcriptional Output in Gastrointestinal Stromal Tumor

Hemming ML, Benson MR, Loycano MA, Anderson JA, Andersen JL, Taddei ML, Krivtsov AV, Aubrey BJ, Cutler JA, Hatton C, Sicinska E, Armstrong SA

Gastrointestinal stromal tumor (GIST) is commonly characterized by activating mutations in the receptor tyrosine kinase KIT. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are urgently needed. As GIST lacks oncogene amplification and relies upon an established network of transcription factors, we hypothesized that unique chromatin-modifying enzymes are essential in orchestrating the GIST epigenome. We identified through genome-scale CRISPR screening that MOZ and Menin-MLL chromatin regulatory complexes are cooperative and unique dependencies in GIST. These complexes were enriched at GIST-relevant genes and regulated their transcription. Inhibition of MOZ and Menin-MLL complexes decreased GIST cell proliferation by disrupting interactions with transcriptional/chromatin regulators, such as DOT1L. MOZ and Menin inhibition caused significant reductions in tumor burden in vivo, with superior effects observed with combined Menin and KIT inhibition. These results define unique Ôªøchromatin regulatory dependencies in GIST and identify potential therapeutic strategies for clinical application.
SIGNIFICANCE: Although many malignancies rely on oncogene amplification, GIST instead depends upon epigenetic regulation of KIT and other essential genes. Utilizing genome-scale CRISPR dependency screens, we identified complementary chromatin-modifying complexes essential to GIST and characterize the consequences of their disruption, elucidating a novel therapeutic approach to this disease. This article is highlighted in the In This Issue feature, p. 1599.

Cancer Discovery

Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Jänne PA

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.
SIGNIFICANCE: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Cancer Discovery

Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts

Ellegast JM, Alexe G, Hamze A, Lin S, Uckelmann HJ, Rauch PJ, Pimkin M, Ross LS, Dharia NV, Robichaud AL, Conway AS, Khalid D, Perry JA, Benajiba L, Pikman Y, Orkin SH, Stegmaier K

Leukemic blasts are immune cells gone awry. We hypothesized that dysregulation of inflammatory pathways contributes to the maintenance of their leukemic state and can be exploited as cell-intrinsic, self-directed immunotherapy. To this end, we applied genome-wide screens to discover genetic vulnerabilities in acute myeloid leukemia (AML) cells implicated in inflammatory pathways. We identified the immune modulator IRF2BP2 as a selective AML dependency. We validated AML cell dependency on IRF2BP2 with genetic and protein degradation approaches in vitro and genetically in vivo. Chromatin and global gene-expression studies demonstrated that IRF2BP2 represses IL1?/TNF? signaling via NF?B, and IRF2BP2 perturbation results in an acute inflammatory state leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for regulated cell death, and establish IRF2BP2-mediated transcriptional repression as a mechanism for blast survival.
SIGNIFICANCE: This study exploits inflammatory programs inherent to AML blasts to identify genetic vulnerabilities in this disease. In doing so, we determined that AML cells are dependent on the transcriptional repressive activity of IRF2BP2 for their survival, revealing cell-intrinsic inflammation as a mechanism priming leukemic blasts for regulated cell death. See related commentary by Puissant and Medyouf, p. 1617. This article is highlighted in the In This Issue feature, p. 1599.


Cancer Vaccines: Building a Bridge Over Troubled Waters

Sellars MC, Wu CJ, Fritsch EF

Cancer vaccines aim to direct the immune system to eradicate cancer cells. Here we review the essential immunologic concepts underpinning natural immunity and highlight the multiple unique challenges faced by vaccines targeting cancer. Recent technological advances in mass spectrometry, neoantigen prediction, genetically and pharmacologically engineered mouse models, and single-cell omics have revealed new biology, which can help to bridge this divide. We particularly focus on translationally relevant aspects, such as antigen selection and delivery and the monitoring of human post-vaccination responses, and encourage more aggressive exploration of novel approaches.


Tissue-Resident Memory and Circulating T Cells are Early Responders to Pre-Surgical Cancer Immunotherapy

Luoma AM, Suo S, Gunasti L, Porter CBM, Chen YH, Criscitiello S, Ricker CA, Dionne D, Rozenblatt-Rosen O, Uppaluri R, Haddad RI, Ashenberg O, Regev A, Van Allen EM, Schoenfeld JD, Wucherpfennig KW

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.


DETECT: Development of Technologies for Early HCC Detection

Tayob N

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in patients with cirrhosis and the third most common cause of cancer-related deaths worldwide. Though considered to be a highly fatal cancer, with a 5-year survival rate of less than 15%, curative treatments (surgical resection, liver transplantation, ablation) are available for patients diagnosed at an early stage. U.S. professional society guidelines recommend HCC surveillance in patients with cirrhosis of any etiology with biannual ultrasound ± serum alpha-fetoprotein (AFP), which is associated with survival benefits and receipt of curative treatment. However, ultrasound ± AFP can be associated with physical harms, that is, the need for multiple contrast-enhanced cross-sectional imaging studies and biopsies driven by false-positive tests or indeterminate lesions. Moreover, several new challenges in HCC surveillance are emerging. Contemporary Western cirrhosis cohorts consist of a higher proportion of patients with hepatitis C virus (HCV) after sustained virologic response and nonalcoholic fatty liver disease (NAFLD) with a lower annual risk of HCC (1%–3%), compared with older cohorts with viremic HCV (3%–8%). However, given the high prevalence of NAFLD in the U.S., the population at risk is growing. Given cost and capacity concerns, screening all patients with NAFLD is not feasible. Similar challenges exist for patients with HCV-related cirrhosis who have been cured. In addition, ultrasound has several limitations, including operator dependence, limited visualization in selected patients (particularly in the setting of abdominal adiposity and hepatic steatosis), and low sensitivity for early HCC (?45%). Furthermore, given logistical barriers, imaging-based surveillance continues to be underutilized in clinical practice, with utilization rates of only 24%. Therefore, the current “one-size-fits-all” model of ultrasound-based surveillance should be challenged and the discovery of new approaches and biomarkers are warranted.

Journal of Clinical Oncology

Adjuvant Versus Early Salvage Radiation Therapy After Radical Prostatectomy for pN1 Prostate Cancer and the Risk of Death

D'Amico AV

PURPOSE: An association with a reduction in the risk of all-cause mortality (ACM) and the use of adjuvant as compared with early postradical prostatectomy salvage radiation therapy (sRT) in men with pN1 prostate cancer (PC) has been observed. Yet, whether this finding applies irrespective of the number of positive lymph nodes (LNs) after adjusting for the time-dependent use and duration of androgen deprivation therapy is unknown and is addressed in the current study.
METHODS: Univariable and multivariable Cox regression was used to evaluate whether the ACM risk ratio for time-dependent use of adjuvant versus early sRT per unit increase in positive pelvic LNs was significantly reduced. Adjusted ACM estimates were calculated among men who received adjuvant, early salvage, or no RT stratified by one to three or four or more positive pelvic LNs.
RESULTS: After a median follow-up of 7.02 years, 986 (5.50%) men died, with 223 (22.62%) of PC. Adjuvant compared with early sRT was associated with a significantly lower ACM risk per unit increase in positive pelvic LNs (adjusted hazard ratio: 0.92; 95% CI, 0.85 to 0.99; P = .03). A significant difference in the 7-year adjusted ACM estimates favoring aRT versus early sRT was observed in men with four or more positive LNs (7.74% v 23.36%) in that the 95% CI for the 15.62% difference (5.90 to 25.35) excluded 0.00, but this was not true for men with 1-3 positive LNs (14.27% v 13.89%; 95% CI for the 0.38% difference [-7.02 to 7.79]).
CONCLUSION: Adjuvant compared with early sRT in men with pN1 PC was associated with a decreased ACM risk, and this reduction increased with each additional positive pelvic LN.

Journal of Clinical Oncology

Long-Term Benefits of Tagraxofusp for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm

Lane AA

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy. We report long-term results, including data from the continued access phase, of the largest prospective BPDCN trial evaluating the CD123-targeted therapy tagraxofusp (TAG) in adults with treatment-naive and relapsed/refractory BPDCN. The primary outcome was complete response (CR) + clinical CR (CRc: CR with residual skin abnormality not indicative of active disease). Eighty-four (65 treatment-naive and 19 relapsed/refractory) of 89 patients received TAG 12 μg/kg once daily; the median follow-up was 34.0 months. For treatment-naive patients, the overall response rate was 75%; 57% achieved CR + CRc. The median time to remission was 39 (range, 14-131) days, and the median CR + CRc duration was 24.9 (95% CI, 3.8 to not reached) months. Nineteen patients (51%) with CR + CRc were bridged to stem-cell transplant, with a median CR + CRc duration of 22.2 (range, 1.5-57.4) months. Most common adverse events were increased alanine (64%) or aspartate (60%) aminotransferase and hypoalbuminemia (51%); most occurred in cycle 1 and were transient. Capillary leak syndrome occurred in 21% of patients (grade 3: 7%). In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant. TAG was generally well-tolerated with a predictable and manageable safety profile.

Journal of Clinical Oncology

Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial

Liu JF, Matulonis UA

PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.
PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs).
RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.
CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.

Journal of Clinical Oncology

Reply to L. Marandino et al

Sweeney CJ

We thank Marandino et al and agree that cognitive function is important and complex in men with metastatic, hormone-sensitive prostate cancer. Cognitive decline increases with age, as does the incidence of metastatic prostate cancer, and has been associated with a diagnosis of cancer, androgen deprivation therapy, early generation antiandrogens, novel androgen signaling inhibitors, and chemotherapy. ENZAMET provides unique information about self-ratings of cognitive function and other aspects of health-related quality of life (HRQoL) in men receiving these treatments for metastatic, hormone-sensitive prostate cancer.


Spirituality in Serious Illness and Health

Balboni TA, VanderWeele TJ, Doan-Soares SD, Long KNG, Bain PA, Koh HK

Importance: Despite growing evidence, the role of spirituality in serious illness and health has not been systematically assessed.
Objective: To review evidence concerning spirituality in serious illness and health and to identify implications for patient care and health outcomes.
Evidence review: Searches of PubMed, PsycINFO, and Web of Science identified articles with evidence addressing spirituality in serious illness or health, published January 2000 to April 2022. Independent reviewers screened, summarized, and graded articles that met eligibility criteria. Eligible serious illness studies included 100 or more participants; were prospective cohort studies, cross-sectional descriptive studies, meta-analyses, or randomized clinical trials; and included validated spirituality measures. Eligible health outcome studies prospectively examined associations with spirituality as cohort studies, case-control studies, or meta-analyses with samples of at least 1000 or were randomized trials with samples of at least 100 and used validated spirituality measures. Applying Cochrane criteria, studies were graded as having low, moderate, serious, or critical risk of bias, and studies with serious and critical risk of bias were excluded. Multidisciplinary Delphi panels consisting of clinicians, public health personnel, researchers, health systems leaders, and medical ethicists qualitatively synthesized and assessed the evidence and offered implications for health care. Evidence-synthesis statements and implications were derived from panelists' qualitative input; panelists rated the former on a 9-point scale (from "inconclusive" to "strongest evidence") and ranked the latter by order of priority.
Findings: Of 8946 articles identified, 371 articles met inclusion criteria for serious illness; of these, 76.9% had low to moderate risk of bias. The Delphi panel review yielded 8 evidence statements supported by evidence categorized as strong and proposed 3 top-ranked implications of this evidence for serious illness: (1) incorporate spiritual care into care for patients with serious illness; (2) incorporate spiritual care education into training of interdisciplinary teams caring for persons with serious illness; and (3) include specialty practitioners of spiritual care in care of patients with serious illness. Of 6485 health outcomes articles, 215 met inclusion criteria; of these, 66.0% had low to moderate risk of bias. The Delphi panel review yielded 8 evidence statements supported by evidence categorized as strong and proposed 3 top-ranked implications of this evidence for health outcomes: (1) incorporate patient-centered and evidence-based approaches regarding associations of spiritual community with improved patient and population health outcomes; (2) increase awareness among health professionals of evidence for protective health associations of spiritual community; and (3) recognize spirituality as a social factor associated with health in research, community assessments, and program implementation.
Conclusions and relevance: This systematic review, analysis, and process, based on highest-quality evidence available and expert consensus, provided suggested implications for addressing spirituality in serious illness and health outcomes as part of person-centered, value-sensitive care.

Lancet Oncology

Nivolumab Plus Cabozantinib Versus Sunitinib in First-Line Treatment for Advanced Renal Cell Carcinoma (CheckMate 9ER): Long-Term Follow-Up Results from an Open-Label, Randomised, Phase 3 Trial

Choueiri TK

BACKGROUND: In the primary analysis of CheckMate 9ER, nivolumab plus cabozantinib showed superior progression-free survival, overall survival, and objective response over sunitinib in patients with previously untreated advanced renal cell carcinoma (median follow-up of 18¬?1 months). Here, we report extended follow-up of overall survival and updated efficacy and safety.
METHODS: This open-label, randomised, phase 3 trial was done in 125 hospitals and cancer centres across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumour tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomisation, stratified by IMDC risk status, tumour PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug. This ongoing study, closed to recruitment, is registered with, NCT03141177.
FINDINGS: Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32¬?9 months [IQR 30¬?4-35¬?9]), median overall survival was 37¬?7 months (95% CI 35¬?5-not estimable) in the nivolumab plus cabozantinib group and 34¬?3 months (29¬?0-not estimable) in the sunitinib group (hazard ratio [HR] 0¬?70 [95% CI 0¬?55-0¬?90], p=0¬?0043) and updated median progression-free survival was 16¬?6 months (12¬?8-19¬?8) versus 8¬?3 months (7¬?0-9¬?7; HR 0¬?56 [95% CI 0¬?46-0¬?68], p<0¬?0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysaesthesia (25 [8%] vs 26 [8%]), and diarrhoea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden
INTERPRETATION: With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma.
FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.


Structure-Function Analysis of the SHOC2-MRAS-PP1C Holophosphatase Complex

Kwon JJ, Hajian B, Bian Y, Amor AJ, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Perry CK, Burgin A, Lemke CT, Hahn WC, Aguirre AJ

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development.

New England Journal of Medicine

Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation

Jänne PA, Heist RS

BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study.
METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy and anti-programmed death 1 or programmed death ligand 1 therapy. The primary end point was objective response assessed by blinded independent central review. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.
RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8), and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As of January 15, 2022 (median follow-up, 15.6 months), the median overall survival was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug discontinuation in 6.9% of patients.
CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; number, NCT03785249.).

New England Journal of Medicine

Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

Richardson PG, Jacobus SJ, Weller EA, Raje NS, Yee AJ, Fulciniti M, Hebert K, Samur MK, Masone K, Maglio ME, Zeytoonjian AA, Nadeem O, Schlossman RL, Laubach JP, Paba-Prada C, Ghobrial IM, Anderson KC, Munshi NC

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.
METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.
RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P=0.55); 42.0% and 46.8%, respectively, had a complete response or better (P=0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).
CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION number, NCT01208662.).

American Journal of Hematology

EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified: 2022 Update on Diagnosis, Risk-Stratification, and Management

Castillo JJ

Analytic Chemistry

On-Chip Preconcentration Microchip Capillary Electrophoresis Based CE-PRM-LIVE for High-Throughput Selectivity Profiling of Deubiquitinase Inhibitors

Zhu H, Chan WC, Ficarro SB, Tavares I, Bratt AS, Buhrlage SJ, Marto JA

Annals of Palliative Medicine

Longitudinal Symptoms and Temporal Trends in Palliative Care, Palliative Radiotherapy, and Anti-Cancer Treatment Near End of Life Among Patients with Metastatic Cancer

Shin KY, Hong PJ, Hertan LM, Krishnan MS, Huynh MA, Spektor A, Balboni TA

Annals of Surgery

Surgical Treatment After Neoadjuvant Systemic Therapy in Young Women with Breast Cancer: Results from a Prospective Cohort Study

Dominici L, Rosenberg SM, Zheng Y, Pak LM, Poorvu PD, Tamimi R, Come SE, Peppercorn J, Gaither R, King TA, Partridge AH

Annals of Surgical Oncology

Utilization of National Cancer Institute-Designated Cancer Centers by Medicare Beneficiaries with Cancer

Erfani P, Ojo A, John Orav E, Lam MB

Annals of Surgical Oncology

ASO Visual Abstract: Sentinel Lymph Node Biopsy Alone is Adequate for Chemotherapy Decisions in Postmenopausal Early-Stage, Hormone-Receptor-Positive, HER2-Negative Breast Cancer with 1-3 Positive Sentinel Lymph Nodes

Kantor O, Weiss A, Burstein HJ, Mittendorf EA, King TA

Bioorganic and Medicinal Chemistry Letters

Quinazolinones as Allosteric Fourth-Generation EGFR Inhibitors for the Treatment of NSCLC

Gero TW, Heppner DE, Beyett TS, To C, Azevedo SC, Jang J, Bunnell T, Feru F, Li Z, Shin BH, Soroko KM, Gokhale PC, Gray NS, Jänne PA, Eck MJ, Scott DA

Blood Advances

Low Incidence of Invasive Fungal Disease Following CD19 Chimeric Antigen Receptor T-Cell (CAR-T) 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

BMJ Open Quality

Development of a Taxonomy for Characterising Medical Oncology-Related Patient Safety and Quality Incidents: A Novel Approach

Jacobson JO, Zerillo JA, Mulvey T, Stuver SO, Revette AC

British Journal of Haematology

Daratumumab with Ifosfamide, Carboplatin and Etoposide for the Treatment of Relapsed Plasmablastic Lymphoma

Castillo JJ

British Journal of Haematology

Lenalidomide, Bortezomib and Dexamethasone Induction Therapy for the Treatment of Newly Diagnosed Multiple Myeloma: A Practical Review

Richardson PG


First Pointwise Encoding Time Reduction with Radial Acquisition (PETRA) Implementation for Catheter Detection in Interstitial High-Dose-Rate (HDR) Brachytherapy

Kaza E, Lee CY, King MT, Dyer MA, Cormack RA, Buzurovic I

Breast Cancer Research and Treatment

The Feasibility of Using an Autologous GM-CSF-Secreting Breast Cancer Vaccine to Induce Immunity in Patients with Stage II-III and Metastatic Breast Cancers

Erick TK, Daley H, Campbell M, Colson Y, Mihm M, Zakka LR, Barry W, Winer EP, Dranoff G, Overmoyer B

CA: Cancer Journal for Clinicians

Genetic Testing in Prostate Cancer Management: Considerations Informing Primary Care

Berchuck JE, Taplin ME


Attention to Diet, Exercise, and Weight in Oncology Care: Results of an American Society of Clinical Oncology National Patient Survey

Ligibel JA, Dieli-Conwright C 


Body Weight Changes and Associated Predictors in a Prospective Cohort of Young Breast Cancer Survivors

Sella T, Zheng Y, Tan-Wasielewski Z, Poorvu PD, Tayob N, Gelber SI, Come SE, Peppercorn JM, Partridge AH, Ligibel JA


In Pursuit of Equity in Cancer Care: Moving Beyond the Affordable Care Act

Lam MB

Cancer Immunology Research

Comprehensive Characterizations of Immune Receptor Repertoire in Tumors and Cancer Immunotherapy Studies

Song L, Ouyang Z, Cohen D, Cao Y, Altreuter J, Bai G, Hu X, Livak KJ, Li H, Tang M, Liu XS

Cancer Nursing

Stability of Symptom Clusters in Patients with Gynecologic Cancer Receiving Chemotherapy

Pozzar RA, Hammer MJ

Cancer Research

Pyruvate Kinase M1 Suppresses Development and Progression of Prostate Adenocarcinoma

Davidson SM, Schmidt DR, Bellinger G, Carracedo A, Pandolfi PP, Courtney KD, DePinho RA, Horner JW, Cantley LC, Loda M, Vander Heiden MG

Cancer Research

FOXR2 is an Epigenetically Regulated Pan-Cancer Oncogene that Activates ETS Transcriptional Circuits

Tsai JW, Cejas P, Wu DW, Zhou N, Syamala S, Dubois FPB, Crane A, Pelton K, Vogelzang J, Sousa C, Condurat AL, Dixon-Clarke SE, Zhou KN, Lu SD, Gonzalez EM, Chacon MS, Digiacomo JJ, Kumbhani R, Novikov D, Hunter J, McFarland JM, Getz G, Aguet F, Ligon KL, Hovestadt V, Long H, Bandopadhayay P

Clinical Cancer Research

Linking Genotype to Phenotype: Bench to Bedside

George S, Bertagnolli MM

Clinical Drug Investigation

Temporal Trends in Grade 3/4 Adverse Events and Associated Costs of Nivolumab Plus Cabozantinib Versus Sunitinib for Previously Untreated Advanced Renal Cell Carcinoma

Choueiri TK, McGregor B

Clinical Lymphoma, Myeloma and Leukemia

SOHO State of the Art Updates and Next Questions: Mini-Hyper-CVD Combinations for Older Adults: Results of Recent Trials and a Glimpse into the Future

Luskin MR

Critical Reviews in Oncology/Hematology

Quantifying Absolute Benefit for Adjuvant Treatment Options in Renal Cell Carcinoma: A Living Interactive Systematic Review and Network Meta-Analysis

Riaz IB, Xu W

Current Oncology Reports

Interventions to Reduce Sedentary Behavior in Cancer Patients and Survivors: A Systematic Review

Kang DW, Yunker AG, Dieli-Conwright CM


Breast Cancer Awareness Among Afghan Refugee Women in Turkey

Faggen M, Warren L, Wong J, Punglia R, Bellon J, Sayan M

European Journal of Cancer

Impact of MET Status on Treatment Outcomes in Papillary Renal Cell Carcinoma: A Pooled Analysis of Historical Data

Albiges L, Choueiri T, Signoretti S

European Journal of Medical Research

A Phase Ib Dose-Escalation Study of Troriluzole (BHV-4157), an Oral Glutamatergic Signaling Modulator, in Combination with Nivolumab in Patients with Advanced Solid Tumors

Silk AW

Genome Biology

DeCAF: A Novel Method to Identify Cell-Type Specific Regulatory Variants and Their Role in Cancer Risk

Kalita CA, Gusev A

International Journal of Cancer

An International Report on Bacterial Communities in Esophageal Squamous Cell Carcinoma

Nomburg J, DeCaprio JA, Meyerson M

Journal of the American Society of Nephrology

Recognizing the Potential Importance of Religion and Spirituality in the Care of Black Americans with Kidney Failure

Gelfand SL

Journal of Clinical Investigation

Reversal of Viral and Epigenetic HLA Class I Repression in Merkel Cell Carcinoma

Lee PC, Klaeger S, Le PM, Cheng J, Ananthapadmanabhan V, Frost TC, Stevens JD, Wong AY, Iorgulescu JB, Tarren AY, Chea VA, Carulli IP, Gartin AK, Sarkizova S, Wright KT, Li LW, Nomburg J, Li S, Huang T, Liu X, Pomerance L, Doherty LM, Apffel AM, Wallace LJ, Rachimi S, Felt KD, Wolff JO, Witten E, Zhang W, Neuberg D, Lane WJ, Thakuria M, Rodig SJ, Clauser KR, Doench JG, Buhrlage SJ, Carr SA, DeCaprio JA, Wu CJ, Keskin DB

Journal of Geriatric Oncology

Age and Comorbidity Association with Survival Outcomes in Metastatic Colorectal Cancer: CALGB 80405 Analysis

McCleary NJ, Zhang S, Ma C, Ng K, Mayer RJ, Meyerhardt JA

Journal of Integrative and Complementary Medicine

Skin Temperature of Acupoints in Health and Disease: A Systematic Review

Yang E, Lu W, Muñoz-Vergara D, Goldfinger E, Kaptchuk TJ, Napadow V, Ahn AC, Wayne PM

Journal of the National Comprehensive Cancer Network

Role of Radiation Therapy in Retroperitoneal Sarcoma

Baldini EH

Journal of Pain and Symptom Management

Identification of Distinct Symptom Profiles in Cancer Patients Using a Pre-Specified Symptom Cluster

Hammer MJ

Journal of Palliative Medicine

Top Ten Tips Palliative Care Clinicians Should Know About Solid Organ Transplantation

Murakami N, Goldberg HJ, Jain N, Landzberg M, Ufere NN, Lakin JR

JCI Insight

Milademetan is a Highly Potent MDM2 Inhibitor in Merkel Cell Carcinoma

Ananthapadmanabhan V, Frost TC, Soroko KM, Knott A, Magliozzi BJ, Gokhale PC, DeCaprio JA

JCO Oncology Practice

Adjuvant Abemaciclib Plus Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Guideline Rapid Recommendation Update Q and A

Freedman RA

JCO Oncology Practice

Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline Summary and Q&A

Ligibel JA

JCO Precision Oncology

Multidimensional Molecular Profiling of Metastatic Triple-Negative Breast Cancer and Immune Checkpoint Inhibitor Benefit

Forman J, Jammihal TR, Kao KZ, Richardson ET 3rd, Keenan T, Cohen O, Manos MP, Brennick RC, Ott PA, Hodi FS, Dillon DA, Attaya V, O'Meara T, Lin NU, Van Allen EM, Rodig S, Winer EP, Mittendorf EA, Wu CJ, Wagle N, Shukla SA, Tolaney SM


Efficacy of Avapritinib Versus Best Available Therapy in the Treatment of Advanced Systemic Mastocytosis

Galinsky IA, DeAngelo DJ

Nature Cancer

Structural Variants Shape Driver Combinations and Outcomes in Pediatric High-Grade Glioma

Dubois FPB, Shapira O, Greenwald NF, Zack T, Wala J, Tsai JW, Crane A, Kumar KH, Vogelzang J, Sousa C, Kang KS, Sinai C, Wang DK, Khadka P, Lewis K, Nguyen L, Malkin H, Ho P, O'Rourke R, Zhang S, Gold R, Deng D, Wright KD, Chi SN, Goumnerova LC, Kieran MW, Ligon KL, Beroukhim R, Bandopadhayay P

Nature Cancer

Transition to a Mesenchymal State in Neuroblastoma Confers Resistance to Anti-GD2 Antibody Via Reduced Expression of ST8SIA1

Mabe NW, Alexe G, Schaefer DA, Robichaud AL, Conway AS, Khalid D, Ross KN, Sheffer M, Mitsiades CS, Stegmaier K

Nature Materials

Mechanical Checkpoint Regulates Monocyte Differentiation in Fibrotic Niches

Vining KH, Marneth AE, Adu-Berchie K, Grolman JM, Tringides CM, Liu Y, Wong WJ, Pozdnyakova O, Severgnini M, Stafford A, Duda GN, Hodi FS, Mullally A, Wucherpfennig KW, Mooney DJ

Nature Reviews Molecular Cell Biology

Mechanisms of Mitochondrial Respiratory Adaptation

Bennett CF, Latorre-Muro P, Puigserver P


Clinical Utility of Targeted Next-Generation Sequencing Assay in IDH-Wildtype Glioblastoma for Therapy Decision-Making

Youssef GC, Iorgulescu JB, Whorral S, Allen M, Rahman R, Chukwueke U, McFaline-Figueroa JR, Nayak L, Lee EQ, Batchelor TT, Arnaout O, Peruzzi PP, Chiocca EA, Reardon DA, Meredith D, Santagata S, Beroukhim R, Bi WL, Ligon KL, Wen PY


Addiction of Merkel Cell Carcinoma to MUC1-C Identifies a Potential New Target for Treatment

Morimoto Y, Fushimi A, Yamashita N, Hagiwara M, Bhattacharya A, Cheng J, Frost TC, Ahmad R, Daimon T, T, Takahashi H, Yamamoto M, Suzuki Y, DeCaprio JA, Kufe D

Oral Oncology

The Mouse Oral Carcinoma (MOC) Model: A 10-Year Retrospective on Model Development and Head and Neck Cancer Investigations

Kono M, Saito S, Egloff AM, Uppaluri R

Pediatric Blood and Cancer

Hyperglycemia During Induction Therapy for Acute Lymphoblastic Leukemia is Temporally Linked to Pegaspargase Administration

Pollock NI, Flamand Y, Zhu J, Millington K, Stevenson K, Silverman LB, Vrooman LM, Cohen LE

Transplantation and Cellular Therapy

Hepatitis B Virus Vaccination after Allogeneic Hematopoietic Cell Transplantation Prevents Post-Transplantation Hepatitis B Virus Reactivation

Hammond SP, Ho VT, Marty FM

Transplantation and Cellular Therapy

It Takes a Village: The Importance of Social Support after Hematopoietic Stem Cell Transplantation, a Qualitative Study

Amonoo HL, Deary EC, Harnedy LE, Daskalakis EP, Goldschen L, Desir MC, Newcomb RA, Wang AC, Boateng K, Nelson AM, Jawahri AE

Trends in Biochemical Sciences

Coordinating Gene Expression During the Cell Cycle

Schade AE, Branigan TB, DeCaprio JA