January 1, 2021
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.
Blood
Age-Related Diseases of Inflammation in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia
Weeks LD, Marinac CR, Redd RA, Abel GA, Lin AE, Agrawal M, Stone RM, Schrag D
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are myeloid malignancies characterized by clonal expansion of hematopoietic cells, dyspoiesis of one or more lineages, and ineffective hematopoiesis. Years prior to displaying clinical or pathologic manifestations of MDS or CMML, patients may have clonal hematopoiesis of indeterminate potential (CHIP), an age-related non-malignant clonal expansion of hematopoietic cells with myeloid malignancy-associated somatic driver mutations. Increasing evidence associates clonal hematopoiesis with systemic inflammation and polymorphic clinical manifestations including cardiovascular diseases. Similarly, cardiovascular and inflammatory diseases have been observed in MDS and CMML, and chronic inflammatory stimuli have been implicated in the pathogenesis of myeloid neoplasia.
Blood
Cutler C, DeFilipp Z
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for 1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
Cancer Cell
Konishi Y, Sklavenitis-Pistofidis R, Yue H, Ferrari F, Redd RA, Lightbody ED, Russo M, Perry J, Horowitz E, Justis AV, Shayegh NA, Savell A, Prescott J, Varmeh S, Nowak RP, Marinac CR, Trippa L, Fischer ES, Ghobrial IM
Patients with hematologic malignancies, including multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), experience worse outcomes in response to SARS-CoV-2 infection and exhibit suboptimal responses to vaccination due to humoral and cellular immunity defects and immunosuppressive therapy. Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and is always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), two precursor conditions that affect approximately 3%–5% of the population over 50 years of age, with African Americans carrying three times the risk. More than 10 million individuals in the United States are estimated to have MGUS, and we have previously shown that MGUS and SMM exhibit immune dysregulation. Therefore, we reason that patients with precursor plasma cell dyscrasias may also be at risk for SARS-CoV-2 infection and suboptimal response to vaccination.
Cell
David M. Livingston (1941-2021)
Bazarbachi AH, Samur AA, Hunter Z, Shammas M, Fulciniti M, Anderson KC, Parmigiani G, Treon SP, Munshi NC, Samur MK
David M. Livingston died suddenly on October 17, 2021 at the age of 80. He was a scientist’s scientist who contributed mightily to two, not one, textbook discoveries—the first being that the retinoblastoma gene product was a cell-cycle regulatory element that linked growth factor availability to S-phase entry and the second being that the BRCA1 gene product played an essential role in DNA repair and homologous combination. His cloning and characterization of p300 and p400 would have also been career-defining for many scientists. David was a highly valued advisor to cancer centers, philanthropic organizations, pharmaceutical companies, and biotechnology investors because of his encyclopedic knowledge of science and medicine, his penetrating intelligence, and his wisdom grounded in the belief that our fundamental responsibility in science is to eventually help patients. The fact that he was funny and charming didn’t hurt. Finally, he was a tireless, generous advocate and mentor to young scientists, including those who were lucky enough to train in his laboratory and also countless scientists who were unaware of the sacrifices he made to improve their lots in science.
Cell
Microenvironment Drives Cell State, Plasticity, and Drug Response in Pancreatic Cancer
Raghavan S, Winter PS, Navia AW, Williams HL, Lowder KE, Galvez-Reyes J, Kalekar RL, Mulugeta N, Kapner KS, Raghavan MS, Borah AA, Liu N, Väyrynen SA, Costa AD, Ng RWS, Wang J, Hill EK, Ragon DY, Brais LK, Spurr LF, Li YY, Cherniack AD, Booker MA, Cohen EF, Tolstorukov MY, Wakiro I, Rotem A, Johnson BE, McFarland JM, Sicinska ET, Sullivan RJ, Shapiro GI, Clancy TE, Perez K, Rubinson DA, Ng K, Cleary JM, Nowak JA, Wolpin BM, Hahn WC, Aguirre AJ, Shalek AK
Prognostically relevant RNA expression states exist in pancreatic ductal denocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in-vivo and ex-vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.
Journal of Clinical Oncology
Burstein HJ
PURPOSE: To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.
METHODS: An Expert Panel conducted a systematic review to identify new, potentially practice-changing data.
RESULTS: Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations.
RECOMMENDATIONS: Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-na?Øve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting. Additional information can be found at www.asco.org/breast-cancer-guidelines.
Journal of Clinical Oncology
Reply to W. E. Rosa et al and T. N. Townsend et al.
Enzinger AC, Keating NL, Cutler DM, Landrum MB, Wright AA
In response to our article, Dr Rosa et al provide a sobering reminder of the vast global inequities in opioid access. Less than 0.04% of the global prescription opioid supply is distributed to low-income countries, and more than 70% of patients with cancer live in countries where opioid analgesics are almost entirely unavailable.4 These disturbing figures underpin unimaginable suffering for millions of patients in low- and middle-income countries. We share the authors' concerns that well-intended but short-sighted opioid policies could hamper efforts to provide quality palliative care globally.
Journal of Clinical Oncology
Krop IE, Winer EP
PURPOSE: We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1).
METHODS: The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.
RESULTS: The median follow-up was 57.1 months (interquartile range 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ‚â• 3 (55.4% v 51.8%) and serious adverse events (23.3% v 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).
CONCLUSION: The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.
JAMA Oncology
La J, Branch-Elliman W, Huhmann LB, Parmigiani G, Tuck DP, Brophy MT, Do NV, Munshi NC, Fillmore NR
IMPORTANCE: Patients with cancer are at increased risk for severe COVID-19, but it is unknown whether SARS-CoV-2 vaccination is effective for them.
OBJECTIVE: To determine the association between SARS-CoV-2 vaccination and SARS-CoV-2 infections among a population of Veterans Affairs (VA) patients with cancer.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective, multicenter, nationwide cohort study of SARS-CoV-2 vaccination and infection among patients in the VA health care system from December 15, 2020, to May 4, 2021. All adults with solid tumors or hematologic cancer who received systemic cancer-directed therapy from August 15, 2010, to May 4, 2021, and were alive and without a documented SARS-CoV-2 positive result as of December 15, 2020, were eligible for inclusion. Each day between December 15, 2020, and May 4, 2021, newly vaccinated patients were matched 1:1 with unvaccinated or not yet vaccinated controls based on age, race and ethnicity, VA facility, rurality of home address, cancer type, and treatment type/timing.
EXPOSURES: Receipt of a SARS-CoV-2 vaccine.
MAIN OUTCOMES AND MEASURES: The primary outcome was documented SARS-CoV-2 infection. A proxy for vaccine effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared with unvaccinated controls.
RESULTS: A total of 184‚485 patients met eligibility criteria, and 113‚796 were vaccinated. Of these, 29‚152 vaccinated patients (median [IQR] age, 74.1 [70.2-79.3] years; 95% were men; 71% were non-Hispanic White individuals) were matched 1:1 to unvaccinated or not yet vaccinated controls. As of a median 47 days of follow-up, 436 SARS-CoV-2 infections were detected in the matched cohort (161 infections in vaccinated patients vs 275 in unvaccinated patients). There were 17 COVID-19-related deaths in the vaccinated group vs 27 COVID-19-related deaths in the unvaccinated group. Overall vaccine effectiveness in the matched cohort was 58% (95% CI, 39% to 72%) starting 14 days after the second dose. Patients who received chemotherapy within 3 months prior to the first vaccination dose were estimated to have a vaccine effectiveness of 57% (95% CI, -23% to 90%) starting 14 days after the second dose vs 76% (95% CI, 50% to 91%) for those receiving endocrine therapy and 85% (95% CI, 29% to 100%) for those who had not received systemic therapy for at least 6 months prior.
CONCLUSIONS AND RELEVANCE: In this cohort study, COVID-19 vaccination was associated with lower SARS-CoV-2 infection rates in patients with cancer. Some immunosuppressed subgroups may remain at early risk for COVID-19 despite vaccination, and consideration should be given to additional risk reduction strategies, such as serologic testing for vaccine response and a third vaccine dose to optimize outcomes.
JAMA Oncology
McCleary NJ, Wolpin BM, Schrag D, Wang J
IMPORTANCE: Patients 80 years and older with pancreatic ductal adenocarcinoma (PDAC) have not consistently received treatments that have established benefits in younger older adults (aged 60-79 years), yet patients 80 years and older are increasingly being offered surgery. Whether adjuvant chemotherapy (AC) provides additional benefit among patients 80 years and older with PDAC following surgery is not well understood.
OBJECTIVE: To describe patterns of AC use in patients 80 years and older following surgical resection of PDAC and to compare overall survival between patients who received AC and those who did not.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study among patients 80 years or older diagnosed with PDAC (stage I-III) between 2004 to 2016 who underwent a pancreaticoduodenectomy at hospitals across the US reporting to the National Cancer Database.
EXPOSURES: AC vs no AC 90 days following diagnosis of PDAC.
MAIN OUTCOMES AND MEASURES: The proportion of patients who received AC was assessed over the study period. Overall survival was compared between patients who received AC and those who did not using Kaplan-Meier estimates and multivariable Cox proportional hazards regression. A landmark analysis was performed to address immortal time bias. A propensity score analysis was performed to address indication bias. Subgroup analyses were conducted in node-negative, margin-negative, clinically complex, node-positive, and margin-positive cohorts.
RESULTS: Between 2004 and 2016, 2569 patients 80 years and older (median [IQR] age, 82 [81-84] years; 1427 were women [55.5%]) underwent surgery for PDAC. Of these patients, 1217 (47.4%) received AC. Findings showed an 18.6% (95% CI, 8.0%-29.0%; P = .001) absolute increase in the use of AC among older adults who underwent a pancreaticoduodenectomy comparing rates in 2004 vs 2016. Receipt of AC was associated with a longer median survival (17.2 months; 95% CI, 16.1-19.0) compared with those who did not receive AC (12.7 months; 95% CI, 11.8-13.6). This association was consistent in propensity and subgroup analyses. In multivariable analysis, receipt of AC (hazard ratio [HR], 0.72; 95% CI, 0.65-0.79; P < .001), female sex (HR, 0.88; 95% CI, 0.80-0.96; P < .001), and surgery in the more recent time period (2011) (HR, 0.90; 95% CI, 0.82-0.99; P = .02) were associated with a decreased hazard of death. An increased hazard of death was associated with higher pathologic stage (stage II: HR, 1.68; 95% CI, 1.43-1.97; P < .001; stage III: HR, 2.39; 95% CI, 1.88-3.04; P < .001), positive surgical margins (HR, 1.49; 95% CI, 1.34-1.65; P < .001), length of stay greater than median (10 days) (HR, 1.17; 95% CI, 1.07-1.28; P < .001), and receipt of oncologic care at a nonacademic facilities (Community Cancer Program: HR, 1.20; 95% CI, 1.07-1.35; P < .001; Integrated Network Cancer Program: HR, 1.25; 95% CI, 1.07-1.46; P < .001).
CONCLUSIONS AND RELEVANCE: In this cohort study, the use of AC among patients who underwent resection for PDAC increased over the study period, yet it still was administered to fewer than 50% of patients. Receipt of AC was associated with a longer median survival.
Lancet Oncology
Jacobson CA
BACKGROUND: Most patients with advanced-stage indolent non-Hodgkin lymphoma have multiple relapses. We assessed axicabtagene ciloleucel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory indolent non-Hodgkin lymphoma.
METHODS: ZUMA-5 is a single-arm, multicentre, phase 2 trial being conducted at 15 medical cancer centres in the USA and two medical cancer centres in France. Patients were eligible if they were aged 18 years or older, with histologically confirmed indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide at 500 mg/m2 per day and fludarabine at 30 mg/m2 per day on days -5, -4, and -3) followed by a single infusion of axicabtagene ciloleucel (2 *106 CAR T cells per kg) on day 0. The primary endpoint was overall response rate (complete response and partial response) assessed by an independent review committee per Lugano classification. The primary activity analysis was done after at least 80 treated patients with follicular lymphoma had been followed up for at least 12 months after the first response assessment at week 4 after infusion. The primary analyses were done in the per-protocol population (ie, eligible patients with follicular lymphoma who had 12 months of follow-up after the first response assessment and eligible patients with marginal zone lymphoma who had at least 4 weeks of follow-up after infusion of axicabtagene ciloleucel). Safety analyses were done in patients who received an infusion of axicabtagene ciloleucel. This study is registered with ClinicalTrials.gov, NCT03105336, and is closed to accrual.
FINDINGS: Between June 20, 2017, and July 16, 2020, 153 patients were enrolled and underwent leukapheresis, and axicabtagene ciloleucel was successfully manufactured for all enrolled patients. As of data cutoff (Sept 14, 2020), 148 patients had received an infusion of axicabtagene ciloleucel (124 [84%] who had follicular lymphoma and 24 [16%] who had marginal zone lymphoma). The median follow-up for the primary analysis was 17¬?5 months (IQR 14¬?1-22¬?6). Among patients who were eligible for the primary analysis (n=104, of whom 84 had follicular lymphoma and 20 had marginal zone lymphoma), 96 (92%; 95% CI 85-97) had an overall response and 77 (74%) had a complete response. The most common grade 3 or worse adverse events were cytopenias (104 [70%] of 148 patients) and infections (26 [18%]). Grade 3 or worse cytokine release syndrome occurred in ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Serious adverse events (any grade) occurred in 74 (50%) patients. Deaths due to adverse events occurred in four (3%) patients, one of which was deemed to be treatment-related (multisystem organ failure).
INTERPRETATION: Axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma.
FUNDING: Kite, a Gilead Company.
Lancet Oncology
HLA-A*03 and Response to Immune Checkpoint Blockade in Cancer: An Epidemiological Biomarker Study
Naranbhai V, Groha S, Braun DA, Labaki C, Shukla SA, Gusev A, Choueiri TK
BACKGROUND: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.
METHODS: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10‚Äâ917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials).
FINDINGS: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1¬?48 per HLA-A*03 allele [95% CI 1¬?20-1¬?82], p=0¬?00022), the validation DFCI Profile cohort (HR 1¬?22 per HLA-A*03 allele, 1¬?05-1¬?42; p=0¬?0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1¬?36 per HLA-A*03 allele, 1¬?01-1¬?85; p=0¬?047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1¬?31, 1¬?01-1¬?71; p=0¬?044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26¬?6%] of 222 HLA-A*03 non-carriers and 13 (17¬?1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1¬?59 per HLA-A*03 allele, 1¬?16-2¬?16; p=0¬?0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12¬?5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63¬?8%] of 254 HLA-A*03 non-carriers and 40 [55¬?6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2¬?01‚10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0¬?76).
INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer.
FUNDING: National Institutes of Health, Merck KGaA, and Pfizer.
Nature Genetics
Decoding Complex Patterns of Oncogene Amplification
Bazarbachi AH, Samur AA, Hunter Z, Shammas M, Fulciniti M, Anderson KC, Parmigiani G, Treon SP, Munshi NC, Samur MK
Oncogene amplification is a major driver of tumorigenesis; yet, the mechanisms generating amplification are only partially understood. New research reports on the identification of a new focal amplification pattern termed ‘seismic amplification’ that is hypothesized to originate from recombination between extrachromosomal DNA circles.
Nature Genetics
Ito T, Young MJ, Li R, Jain S, Wernitznig A, Krill-Burger JM, Lemke CT, Monducci D, Rodriguez DJ, Chang L, Dutta S, Pal D, Paolella BR, Rothberg MV, Root DE, Johannessen CM, Getz G, Vazquez F, Doench JG, Zamanighomi M, Sellers WR
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer.
Nature Medicine
DeAngelo DJ
Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 * 10-9), with an ORR of 75% (95% confidence interval 57-89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of 50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade 3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.
Nature Medicine
Safety and Efficacy of Avapritinib in Advanced Systemic Mastocytosis: The Phase 1 EXPLORER Trial
DeAngelo DJ
Advanced systemic mastocytosis (AdvSM) is a rare hematologic neoplasm driven by the KIT D816V mutation and associated with poor survival. This phase 1 study ( NCT02561988 ) evaluated avapritinib (BLU-285), a selective KIT D816V inhibitor, in patients with AdvSM. The primary endpoints were the maximum tolerated dose, recommended phase 2 dose and safety of avapritinib. Secondary endpoints included overall response rate and changes in measures of mast cell burden. Avapritinib was evaluated at doses of 30-400‚Äâmg once daily in 86 patients, 69 with centrally confirmed AdvSM. Maximum tolerated dose was not reached, and 200mg and 300mg daily were studied in dose-expansion cohorts. The most frequent adverse events observed were periorbital edema (69%), anemia (55%), diarrhea (45%), thrombocytopenia (44%) and nausea (44%). Intracranial bleeding occurred in 13% overall, but in only 1% of patients without severe thrombocytopenia (platelets <50*109/l). In 53 response-evaluable patients, the overall response rate was 75%. The complete remission rate was 36%. Avapritinib elicited 50% reductions in marrow mast cells and serum tryptase in 92% and 99% of patients, respectively. Avapritinib induced deep and durable responses, including molecular remission of KIT D816V in patients with AdvSM, and was well tolerated at the recommended phase 2 dose of 200mg daily.
AIDS
Multimorbidity Networks Associated with Frailty Among Middle-Aged and Older People with HIV
Lorenz DR, Mukerji SS, Misra V, Uno H, Gabuzda D
American Journal of Human Genetics
H3K27ac HiChIP in Prostate Cell Lines Identifies Risk Genes for Prostate Cancer Susceptibility
Seo JH, Spisak S, Baca SC, Gusev A, Freedman ML
Annals of Surgical Oncology
Weiss A, Partridge AH
Annals of Surgical Oncology
Quintana LM, Nimbkar SN, King TA, Schnitt SJ
Annals of Surgical Oncology
Kantor O, Wang ML, Freedman RA, King TA, Mittendorf EA
Annals of Surgical Oncology
Kantor O, Means J, Grossmith S, Dey T, Bellon JR, Mittendorf EA, King TA
Blood Advances
Investigational Curative Gene Therapy Approaches to Sickle Cell Disease
Williams DA, Esrick E
Blood Advances
Davids MS
Blood Advances
Kuczmarski TM, Jaung T, Mancuso CE, Abel GA, Odejide OO
Bone Marrow Transplantation
Richardson PG
British Journal of Cancer
Konstantinopoulos PA, Cheng SC, Supko JG, Polak M, Bowes B, Sawyer H, Basada P, Hayes M, Curtis J, Horowitz N, Wright AA, Campos SM, Ivanova EV, Paweletz CP, Palakurthi S, Liu JF, D'Andrea AD, Gokhale PC, Chowdhury D, Matulonis UA, Shapiro GI
Cancer
Bychkovsky BL, Garber JE, Rana HQ
Cancer Causes and Control
Papatheodorou SI, Nohria A, Asnani A, Partridge AH
Cancer Epidemiology, Biomarkers, and Prevention
Regular Aspirin Use and Mortality in Multiple Myeloma Patients
Marinac CR, Lee DH, Rebbeck TR, Rosner B, Ghobrial IM, Birmann BM
Cancer Immunology Research
Monitoring PD-1 Phosphorylation to Evaluate PD-1 Signaling during Antitumor Immune Responses
Bu X, Juneja VR, Reynolds CG, Mahoney KM, Bu MT, McGuire KA, Maleri S, Hua P, Zhu B, Klein SR, Greenfield EA, Armand P, Ritz J, Sharpe AH, Freeman GJ
Cancer Research
Are CRISPR Screens Providing the Next Generation of Therapeutic Targets?
Vazquez F, Sellers WR
Cancers
Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma
Cho SF, Anderson KC, Tai YT
Clinical Cancer Research
Detecting Neuroendocrine Prostate Cancer Through Tissue-Informed Cell-Free DNA Methylation Analysis
Berchuck JE, McClure HM, Tsai HK, Vitale Nuzzo P, Kelleher KM, He M, Steinharter JA, Zacharia S, Seo JH, Hirsch MS, Taplin ME, Choueiri TK, Pomerantz MM, Beltran H, Freedman ML
Clinical Cancer Research
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Clinical Oncology | The Royal College of Radiologists
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European Journal of Medical Genetics
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Future Oncology
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Gynecologic Oncology
MicroRNA Profiling in a Case-Control Study of African American Women with Uterine Serous Carcinoma
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Gynecologic Oncology
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Haematologica
Allogeneic Hematopoietic Cell Transplantation Outcomes in Patients with Richter's Transformation
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Hematology, The American Society of Hematology Education Program
Acute Lymphoblastic Leukemia in Older Adults: Curtain Call for Conventional Chemotherapy?
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International Journal of Radiation Oncology, Biology, Physics
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Investigational New Drugs
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Journal of Acquired Immune Deficiency Syndrome
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Journal of Adolescent and Young Adult Oncology
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Journal of Experimental Medicine
Dnmt3a-Mutated Clonal Hematopoiesis Promotes Osteoporosis
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Journal of Neuroimaging
Mishra S, Bergmark RW, Jo VY, Miyawaki EK, Schoenfeld JD, Uppaluri R, Guenette JP
Journal of Pain and Symptom Management
Knoerl R, Emanuele M, Woods H, Buchbinder E, Frazier L, LaCasce A, Luskin MR, Phillips CS, Ligibel JA
Journal of Pediatric Hematology/Oncology
Meyer EJ, Umaretiya P, Vrooman LM
Leukemia Lymphoma
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Leukemia Lymphoma
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Leukemia Lymphoma
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Leukemia
Raje N, Laubach JP, Bianchi G, Richardson PG
Lung Cancer
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Molecular Cancer Research
Rosenthal J, Nyman J, Hari SN, Van Allen EM, Umeton R
NAR Genomics and Bioinformatics
Characterizing Batch Effects and Binding Site-Specific Variability in ChIP-seq Data
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Nature Reviews Cancer
Glial and Myeloid Heterogeneity in the Brain Tumour Microenvironment
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Neoplasia
STAT3 as a Mediator of Oncogenic Cellular Metabolism: Pathogenic and Therapeutic Implications
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Neuro-Oncology
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Neuro-Oncology
Telomerase as a Therapeutic Target in Glioblastoma
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Oncologist
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Pediatric Blood and Cancer
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Pediatric Blood and Cancer
Howard TP, Boyle PJ, Marcus KJ, Haas-Kogan DA, Liu KX
Pediatric Blood and Cance
Pediatric Palliative Care has a Place Everywhere
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Pediatric Blood and Cancer
Thinking Ahead: Parents' Worries About Late Effects of Childhood Cancer Treatment
Greenzang KA, Kelly CA, Al-Sayegh H, Mack JW
Prostate Cancer and Prostatic Diseases
Outcomes of Older Men Receiving Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer
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Stem Cell Research and Therapy
Cytokine-Induced Memory-Like Natural Killer Cells for Cancer Immunotherapy
Tarannum M, Romee R
Transplantation and Cellular Therapy
Stahl M
Trends in Cell Biology
REV7 Directs DNA Repair Pathway Choice
Clairmont CS, D'Andrea AD