Dana-Farber Cancer Institute News - December 1, 2022

Blood

Clonal Hematopoiesis of Indeterminate Potential and Risk of Death From COVID-19

Miller PG, Fell GG, Foy BH, Scherer AK, Gibson CJ, Sperling AS, Nakao T, Uddin MM, Warren H,
Bry L, Pozdnyakova O, Frigault MJ, Neuberg D, Higgins JM, Mansour MK, Natarajan P, Kim AS, Kitzman JO, Ebert BL

Clonal hematopoiesis is an age-related phenomenon in which a clonal population of blood cells emerges and is often detected by the presence of a mutation present in a peripheral blood sample. Clonal hematopoiesis of indeterminate potential (CHIP) is a subtype of clonal hematopoiesis found in individuals without a hematologic malignancy in which a somatic pathogenic mutation in a gene mutated in myeloid neoplasia is present in at least 2% of the sequenced blood DNA (termed variant allele fraction [VAF]). CHIP is associated with increased mortality and risk of adverse outcomes including cardiovascular and pulmonary disease (eg, chronic obstructive pulmonary disease). These associations, which are largely driven by CHIP clones with a VAF of greater than 0.1, are thought to arise from augmentation of inflammasome-mediated interleukin-1β (IL-1β) and IL-6 production by mutant macrophages.

Blood

Ipilimumab Plus Decitabine for Patients with MDS or AML in Post-Transplant or Transplant Naïve Settings

Garcia JS, Flamand Y, Penter L, Cullen N, Arihara Y, Pfaff KL, Wolff JO, Brunner AM, Galinsky I,
Antin JH, Cutler CS, Ho VT, Luskin MR, Wadleigh M, Winer ES, Savell A, Leonard R, Robertson T, Davids MS, Rodig SJ, Ritz J, Wu CJ, DeAngelo DJ, Neuberg D, Stone RM, Soiffer RJ

CTLA-4 blockade has generated long-lasting remissions for subsets of cancer patients where traditional chemotherapies have failed. We have previously demonstrated clinical activity with ipilimumab (IPI) monotherapy at a 10mg/kg dose in the treatment of postHSCT relapse (including leukemia cutis) without excessive graft-versus-host disease (GVHD) induction rate. Epigenetic modifiers enhance expression of CTLA-4, CD80 and tumor antigen expression on leukemia cells and can induce cytotoxic CD8+ T-cell activation. We set out to determine if combining decitabine (DEC) with IPI could augment responses without causing unacceptable immune toxicity. Here, we report the results of a multicenter phase 1 trial with combination IPI+DEC in patients with relapsed, refractory (R/R) or secondary myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) in both the post-HSCT and transplant-naïve settings (NCT02890329; CTEP10026).

Cell

Architecture of the Outbred Brown Fat Proteome Defines Regulators of Metabolic Physiology

Xiao H, Bozi LHM, Sun Y, Riley CL, Li J, Zhang T, Mills EL, Emont MP, Reddy A, Garrity R, Vitas LP, Laznik-Bogoslavski D, Ordonez M, Liu X, Chen X, Wang Y, Liu W, Tran N, Liu Y, Zhang Y, White AP, He Y, Paulo JA, Jedrychowski MP, Banks AS, Tseng YH, Tsai LT, Rosen ED, Huttlin EL,
Spiegelman BM, Gygi SP, Chouchani ET

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

Gastroenterology

A Growing Hope for Earlier Detection of Pancreatic Cancer

Rosenthal M, Schawkat K, Wolpin B

Mukherjee et al have delivered a highly interesting study showing that subtle radiologic features of the pancreas are different in people who will develop pancreatic cancer in the next 3 to 36 months than in those who will not. This finding adds to the growing body of evidence that local and systemic effects of pancreatic cancer may precede the development of a clinically detectable pancreatic mass and could form the basis of novel approaches to pancreatic cancer screening.

Journal of Clinical Oncology

Exploring the Next Frontier in Non-Small-Cell Lung Cancer with High MET and Mutated Epidermal Growth Factor Receptor

Sattler M

The receptor tyrosine kinase MET is widely expressed in normal tissue and is typically activated by its ligand hepatocyte growth factor. Some solid tumors and particularly non–small-cell lung cancer (NSCLC) cells are frequently associated with elevated levels of MET or hepatocyte growth factor. A variety of mutations in MET are known to occur in lung cancers at a low frequency in the tyrosine kinase domain, exon 14 skipping mutations, and others. Treatment of patients with mutational activation of MET extends survival in NSCLC harboring MET exon 14 skipping alterations. Capmatinib and tepotinib are US Food and Drug Administration–approved MET-specific inhibitors available for the treatment of patients with active MET, in particular the exon 14 skipping mutation (see for review Mathieu et al), but in general, they would not be expected to be active in cancers with high MET protein expression.

Journal of Clinical Oncology

Inequities in Alliance Acute Leukemia Clinical Trial and Biobank Participation: Defining Targets for Intervention

Hantel A, Stone RM, Lathan CS, DeAngelo DJ, Abel GA

PURPOSE: Representativeness in acute leukemia clinical research is essential for achieving health equity. The National Cancer Institute's mandate for Comprehensive Cancer Centers (CCCs) to define and assume responsibility for cancer control and treatment across a geographic catchment area provides an enforceable mechanism to target and potentially remediate participatory inequities.

METHODS: We examined enrollee characteristics across 15 Cancer and Leukemia Group B/Alliance cooperative group adult acute leukemia clinical trials (N = 3,734) from 1998 to 2013, including participation in optional companion biobanks. We determined enrollment odds by race-ethnicity for all participants adjusted for national incidence, and for those enrolled at CCCs adjusted for catchment area incidence. We modeled biobank participation by sociodemographics using logistic regression.

RESULTS: Non-Hispanic (NH)-White patients were more likely to be enrolled than NH-Black, NH-Asian, or Hispanic patients (odds ratio [OR], 0.75, 0.48, and 0.44, respectively; all P < .001), but less likely than NH-Native American patients (OR, 1.91; P < .001), adjusted for national incidence. Enrollment odds were lower for NH-Black, NH-Asian, and Hispanic patients at CCCs adjusted for catchment area incidence (OR, 0.57, 0.26, and 0.32, respectively; P < .001); differences were driven by overenrollment of NH-White patients from outside self-defined catchment areas (18.1% v 12.3%; œá2 P = .01) and by CCCs with less absolute enrollee diversity (rank sum P = .03). Among all enrollees, NH-White race-ethnicity and lower neighborhood deprivation correlated with biobank participation (OR, 1.81 and 1.45, respectively; P = .01 and .03). For CCC enrollees, the correlation of race-ethnicity with biobank participation was attenuated by a measure accounting for their site's degree of enrollment disparity but not neighborhood deprivation.

CONCLUSION: Acute leukemia clinical research disparities are substantial and driven by structural trial enrollment barriers at CCCs. Real-time CCC access and enrollment monitoring is needed to better align research participation with local populations.

JAMA Oncology

Association of Hormone Receptors with Clinical Outcomes in Patients with ERBB2-Low Breast Cancer-Reply

Tarantino P, Tayob N, Tolaney SM

In Reply: We appreciate the comments from Cappelletti and colleagues regarding our cohort study on the prognostic and biologic role of ERBB2-low expression in breast cancer.¹ The authors raise some valuable points of discussion regarding our work.

JAMA Oncology

Interplay of Immunosuppression and Immunotherapy Among Patients with Cancer and COVID-19

Bakouny Z, Labaki C, Schmidt AL, Choueiri TK

IMPORTANCE: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.

OBJECTIVE: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.

DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included 12‚ÄØ046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.

EXPOSURES: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).

MAIN OUTCOMES AND MEASURES: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.

RESULTS: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).

CONCLUSIONS AND RELEVANCE: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04354701.

Lancet Oncology

Fluorouracil and Dose-Dense Adjuvant Chemotherapy in Breast Cancer: Lessons Learned from the 20-Year-Old GIM2 trial

Morganti S, Tolaney SM

In 1976, approximately 50 years ago, the first randomised study leading to approval of adjuvant chemotherapy for breast cancer was reported. Chemotherapy remains a pillar of breast cancer treatment; however, in the past 50 years, we have learned that breast cancer is a heterogeneous disease and treatment should be tailored accordingly. We moved from a one-size-fits-all approach to a more personalised one, in which treatment decisions hinge upon the estimated risk of recurrence based not just on clinicopathological risk, but sometimes also on genomic information.

Nature Medicine

Unresolved Questions in the Second-Line Use of CAR-T Cells for Diffuse Large B Cell Lymphoma

Cliff ERS, Merryman RW, Armand P, Jacobson CA

Following the positive results of the ZUMA-7 and TRANSFORM trials , and the US Food and Drug Administration (FDA) approvals of axicabtagene ciloleucel and lisocabtagene maraleucel as second-line therapies for diffuse large B cell lymphoma (DLBCL), CD19-directed chimeric antigen receptor (CAR) T cell therapy is likely to become the standard of care for patients with primary-refractory or early-relapsed DLBCL in which initial remission lasted <12 months. Both axicabtagene ciloleucel and, based on interim results, lisocabtagene maraleucel showed improved event-free survival compared with salvage chemoimmunotherapy followed by autologous stem-cell transplant (ASCT). As yet, no overall survival benefit has emerged, although it may over time. These trials herald a paradigm shift for patients with high-risk relapsed or refractory DLBCL, who are in need of improved therapies. However, they raise important unanswered questions about the role of bridging therapy; the optimal treatment of patients with chemotherapy-sensitive disease; and the substantial costs of CAR-T therapy.

Proceedings of the National Academy of Sciences of the U.S.A.

Recent Common Human Coronavirus Infection Protects Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Veterans Affairs Cohort Study

Fillmore NR, Szalat RE, La J, Branch-Elliman W, Monach PA, Nguyen V, Samur MK, Brophy MT,
Do NV, Munshi NC

Solomon et al. identified an association between exposure to young children and lower risk of severe Coronavirus disease 2019 (COVID-19) in adults. The authors theorize that this protection may be due to higher rates of coronavirus immunity conferred by recent exposure to and subsequent infection with other human coronaviruses (HCoVs). Cross-protection is also supported by laboratory studies. Although laboratory and epidemiologic studies are suggestive, the clinical impact of HCoV infection on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility is not fully elucidated. Thus, the aim of this study was to measure the association between recent HCoV infection with common strains (HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1) and future risk of SARS-CoV-2 prior to widespread vaccination and immunity.

Advanced Healthcare Materials

New Strategy for Promoting Vascularization in Tumor Spheroids in a Microfluidic Assay

Wan Z, Shelton SE, Barbie DA

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