Welcome to Dana-Farber's Research News
June 15, 2023
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at: Michael_buller@dfci.harvard.edu.
Blood
Khalsa JK, Cha J, Naeem A, Murali I, Kuang Y, Vasquez KA, Li L, Tyekucheva S, Fernandes SM, Kandathilparambil Sasi B, Wang Z, Machado JH, Bai HP, Alasfour M, Danysh BP, Slowik K,
Jacobs RA, Davids MS, Paweletz CP, Leshchiner I, Getz G, Brown JR
Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported but remain poorly understood. Here we analyze longitudinal tumor samples from eleven patients with disease progression on venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at their post-treatment timepoint. We found the previously described acquired BCL2-G101V mutation in only 4/11 patients with 2 patients showing very low variant allele fraction (VAF; 0.03-4.68%). Whole exome sequencing (WES) revealed acquired loss(8p) in 4/11 patients of which 2 patients also have gain (1q21.2-21.3) in the same cells, affecting the MCL-1 gene. In vitro experiments showed that CLL cells from the four patients with loss(8p) were more resistant to venetoclax than those without it, while the cells from two patients also carrying gain (1q21.2-21.3) showed increased sensitivity to MCL-1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to combination MCL-1 inhibitor with venetoclax. Differential gene expression analysis comparing bulk RNAseq data from pre-treatment and progression time points of all patients showed upregulation of proliferation, BCR and NFKB gene sets including MAPK genes. Cells from progression timepoints demonstrated upregulation of surface immunoglobulin M (sIgM) and higher pERK levels compared to the pre-timepoint, suggesting an upregulation of BCR signaling that activates the MAPK pathway. Overall, our data suggest several mechanisms of acquired resistance to venetoclax in CLL that could pave the way for rationally designed combination treatments for venetoclax resistant CLL patients.
Blood
Shipp MA, Armand P
Previous analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (~2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. End points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) by investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). Median DOR was not reached; no patients who achieved complete response had progressed at the data cutoff. Median PFS was 4.3 months; 4-year PFS rate was 33.0%. Median OS was 22.3 months; 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3 or 4 treatment-related AEs occurred in 22.6% of patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.
Cancer Discovery
Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T Cell-Secreted Cytokines
Ito Y, Pan D, Zhang W, Zhang X, Juan TY, Pyrdol JW, Kyrysyuk O, Doench JG, Liu XS,
Wucherpfennig KW
Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I)-bound peptides, but this selection pressure favors outgrowth of MHC-I-deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I-deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I-deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified proapoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I-deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFN?-and TNF?-producing T cells. Tumors with a substantial population of MHC-I-deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacologic approaches.
SIGNIFICANCE: Tumor heterogeneity is a major barrier to immunotherapy. We show that MHC-I-deficient tumor cells are forced into apoptosis by T cell-derived cytokines when TNF signaling and autophagy pathways are targeted. This approach enables T cell-mediated elimination of tumors with a substantial population of resistant, MHC-I-deficient tumor cells. This article is highlighted in the In This Issue feature, p. 1027.
Gastroenterology
Kumar S, Zhao J, Talluri S, Buon L, Mu S, Potluri B, Liao C, Shi J, Chakraborty C, Gonzalez GB,
Tai YT, Patel J, Pal J, Mashimo H, Samur MK, Munshi NC, Shammas MA
BACKGROUND AND AIMS: Purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors.
METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in six cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells, and impact on genome stability and growth monitored in vitro and in vivo. Impact on DNA/chromosomal instability was monitored using multiple approaches including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing (WGS) and/or multicolor fluorescence in situ hybridization.
RESULTS: Expression of four deoxyribonucleases correlated with genomic instability in six human cancers. Functional screens of these genes identified APE1 as top candidate for further evaluation. APE1-suppression in EAC, breast, lung and prostate cancer cell lines caused: 1) Cell cycle arrest; 2) Impaired growth and increased cytotoxicity of cisplatin in all cell lines/types and in mouse model of EAC; 3) inhibition of homologous recombination (HR) and spontaneous and chemotherapy-induced genomic instability. APE1-overexpression in normal cells caused a massive chromosomal instability leading to their oncogenic transformation. Evaluation of these cells by WGS demonstrated the acquisition of changes throughout genome and identified HR as the top mutational process.
CONCLUSIONS: Elevated APE1 dysregulates HR and cell cycle contributing to genomic instability, tumorigenesis and chemoresistance, and its inhibitors have potential to target these processes in EAC and possibly other cancers.
Journal of Clinical Oncology
Matulonis UA
PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor ? (FR?). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC.
METHODS: SORAYA enrolled FR?-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point.
RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively.
CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FR?-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.
Journal of Clinical Oncology
Laws A, Punglia RS
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.
Journal of Clinical Oncology
Weil BR, Weldon CB, Mullen EA, Madenci AL
PURPOSE: To evaluate long-term morbidity and mortality among unilateral, nonsyndromic Wilms tumor (WT) survivors according to conventional treatment regimens.
METHODS: Cumulative incidence of late mortality (? 5 years from diagnosis) and chronic health conditions (CHCs) were evaluated in WT survivors from the Childhood Cancer Survivor Study. Outcomes were evaluated by treatment, including nephrectomy combined with vincristine and actinomycin D (VA), VA + doxorubicin + abdominal radiotherapy (VAD + ART), VAD + ART + whole lung radiotherapy, or receipt of ? 4 chemotherapy agents.
RESULTS: Among 2,008 unilateral WT survivors, 142 deaths occurred (standardized mortality ratio, 2.9, 95% CI, 2.5 to 3.5; 35-year cumulative incidence of death, 7.8%, 95% CI, 6.3 to 9.2). The 35-year cumulative incidence of any grade 3-5 CHC was 34.1% (95% CI, 30.7 to 37.5; rate ratio [RR] compared with siblings 3.0, 95% CI, 2.6 to 3.5). Survivors treated with VA alone had comparable risk for all-cause late mortality relative to the general population (standardized mortality ratio, 1.0; 95% CI, 0.5 to 1.7) and modestly increased risk for grade 3-5 CHCs compared with siblings (RR, 1.5; 95% CI, 1.1 to 2.0), but remained at increased risk for intestinal obstruction (RR, 9.4; 95% CI, 3.9 to 22.2) and kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6). Magnitudes of risk for grade 3-5 CHCs, including intestinal obstruction, kidney failure, premature ovarian insufficiency, and heart failure, increased by treatment group intensity.
CONCLUSION: With approximately 40% of patients with newly diagnosed WT currently treated with VA alone, the burden of late mortality/morbidity in future decades is projected to be lower than that for survivors from earlier eras. Nevertheless, the risk of late effects such as intestinal obstruction and kidney failure was elevated across all treatment groups, and there was a dose-dependent increase in risk for all grade 3-5 CHCs by treatment group intensity.
Journal of Clinical Oncology
Warren KE
PURPOSE: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect.
PATIENTS AND METHODS: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m2/dose), or regimen B, high-dose (115 mg/m2/dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen.
RESULTS: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14).
CONCLUSION: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m2/dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.
Journal of Clinical Oncology
D'Amico AV
PURPOSE: Both the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated.
METHODS: Using a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy.
RESULTS: After a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ?0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL.
CONCLUSION: Among patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.
Journal of Clinical Oncology
Enzinger AC, Keating NL, Cutler DM, Clark CR, Florez N, Landrum MB, Wright AA
PURPOSE: To characterize racial and ethnic disparities and trends in opioid access and urine drug screening (UDS) among patients dying of cancer, and to explore potential mechanisms.
METHODS: Among 318,549 non-Hispanic White (White), Black, and Hispanic Medicare decedents older than 65 years with poor-prognosis cancers, we examined 2007-2019 trends in opioid prescription fills and potency (morphine milligram equivalents [MMEs] per day [MMEDs]) near the end of life (EOL), defined as 30 days before death or hospice enrollment. We estimated the effects of race and ethnicity on opioid access, controlling for demographic and clinical factors. Models were further adjusted for socioeconomic factors including dual-eligibility status, community-level deprivation, and rurality. We similarly explored disparities in UDS.
RESULTS: Between 2007 and 2019, White, Black, and Hispanic decedents experienced steady declines in EOL opioid access and rapid expansion of UDS. Compared with White patients, Black and Hispanic patients were less likely to receive any opioid (Black, -4.3 percentage points, 95% CI, -4.8 to -3.6; Hispanic, -3.6 percentage points, 95% CI, -4.4 to -2.9) and long-acting opioids (Black, -3.1 percentage points, 95% CI, -3.6 to -2.8; Hispanic, -2.2 percentage points, 95% CI, -2.7 to -1.7). They also received lower daily doses (Black, -10.5 MMED, 95% CI, -12.8 to -8.2; Hispanic, -9.1 MMED, 95% CI, -12.1 to -6.1) and lower total doses (Black, -210 MMEs, 95% CI, -293 to -207; Hispanic, -179 MMEs, 95% CI, -217 to -142); Black patients were also more likely to undergo UDS (0.5 percentage points; 95% CI, 0.3 to 0.8). Disparities in EOL opioid access and UDS disproportionately affected Black men. Adjustment for socioeconomic factors did not attenuate the EOL opioid access disparities.
CONCLUSION: There are substantial and persistent racial and ethnic inequities in opioid access among older patients dying of cancer, which are not mediated by socioeconomic variables.
Journal of the National Cancer Institute
The "Scope" of Colorectal Cancer Screening in Lynch Syndrome: Is There an Optimal Interval?
Biller LH, Ng K
Lynch syndrome (LS) is one of the most common hereditary colorectal cancer (CRC) predisposition syndromes and is present in 1 out of 279 individuals in the general population and in approximately 3% of unselected cases of CRC. LS is caused by the autosomal dominant inheritance of a pathologic variant in 1 of 4 mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) or deletions in the EPCAM gene (which lead to epigenetic silencing of MSH2). LS carriers are at increased risk of CRC as well as endometrial, ovarian, stomach, small intestine, pancreaticobiliary, urinary tract, and skin cancers, among an increasingly long list of other rarer cancer types. It is now well established that rather than being a singular entity, each individual LS gene phenotype is different with respect to cancer type and risk. MLH1 and MSH2 are highly penetrant, with a cumulative incidence of CRC by age 75 years in MLH1 of 48.3% women and 57.1% men and in MSH2 of 46.6% women and 51.4% men. Cumulative incidence of CRC for MSH6 carriers is less than that for MLH1 and MSH2, at 20.3% and 18.2% for women and men, respectively. PMS2 is the most prevalent LS gene but the least penetrant, with a cumulative CRC incidence of 10.4% in both sexes by age 75 years, and one large study suggested that PMS2 carriers are at increased risk of only CRC and endometrial cancer but not other LS-associated cancers. Across all genes, colonoscopy screening reduces the risk of CRC and improves overall survival among LS carriers and remains the mainstay of current risk reduction recommendations. What remain less clear are the optimal age at which to start screening and the best interval between colonoscopy screenings for LS carriers, such that many international professional society guidelines vary with respect to these recommendations.
Lancet Oncology
Choueiri TK, McDermott DF, Michaelson MD
BACKGROUND: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2? inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy.
METHODS: This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing.
FINDINGS: Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure).
INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor.
FUNDING: Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute.
Lancet Oncology
Dieffenbach BV, Diller LR, Weil BR, Weldon CB
BACKGROUND: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions.
METHODS: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions.
FINDINGS: Between Jan 1, 1970, and Dec 31, 1999, 25?656 survivors were diagnosed (13?721 male, 11?935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28?202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system.
INTERPRETATION: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible.
FUNDING: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.
Nature
PI3K? Controls Immune Evasion in PTEN-Deficient Breast Tumours
Bergholz JS, Wang Q, Wang Q, Ramseier M, Prakadan S, Wang W, Fang R, Kabraji S, Gray GK,
Abell-Hart K, Xie S, Guo X, Gu H, Von T, Jiang T, Tang S, Freeman GJ, Kim HJ, Shalek AK,
Roberts TM, Zhao JJ
Loss of the PTEN tumour suppressor is one of the most common oncogenic drivers across all cancer types1. PTEN is the major negative regulator of PI3K signalling. The PI3K? isoform has been shown to play an important role in PTEN-deficient tumours, but the mechanisms underlying the importance of PI3K? activity remain elusive. Here, using a syngeneic genetically engineered mouse model of invasive breast cancer driven by ablation of both Pten and Trp53 (which encodes p53), we show that genetic inactivation of PI3K? led to a robust anti-tumour immune response that abrogated tumour growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3K? inactivation in the PTEN-null setting led to reduced STAT3 signalling and increased the expression of immune stimulatory molecules, thereby promoting anti-tumour immune responses. Pharmacological PI3K? inhibition also elicited anti-tumour immunity and synergized with immunotherapy to inhibit tumour growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumours upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3K? controls immune escape in PTEN-null tumours, providing a rationale for combining PI3K? inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.
Nature Communications
Zhang Y, Xiang G, Jiang AY, Lynch A, Zeng Z, Wang C, Zhang W, Fan J, Kang J, Gu SS, Wan C,
Zhang B, Liu XS, Brown M, Meyer CA
Recent advances in single-cell RNA sequencing have shown heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can indicate common cell types and states in the tumor microenvironment (TME). We develop a data driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labelling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are biologically interpretable as cell types, cell states, and signaling activities. By projecting onto the MetaTiME space, we provide a tool to annotate cell states and signature continuums for TME scRNA-seq data. Leveraging epigenetics data, MetaTiME reveals critical transcriptional regulators for the cell states. Overall, MetaTiME learns data-driven meta-components that depict cellular states and gene regulators for tumor immunity and cancer immunotherapy.
Nature Genetics
Ravi A, Arniella MB, Holton M, Freeman SS, Naranbhai V, Stewart C, Leshchiner I, Akiyama Y,
Sakhi M, Kamesan V, Ricciuti B, Digumarthy SR, Mino-Kenudson M, Jänne PA, Awad MM, Shaw AT, Hacohen N, Getz G, Gainor JF
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
Nature Genetics
Cortés-Ciriano I, Lee JJ, Jain D, Jung YL, Zhang CZ, Pellman DS, Park PJ
Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658?tumors from 38?cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
Nature Medicine
A Deep Learning Algorithm to Predict Risk of Pancreatic Cancer from Disease Trajectories
Yuan B, Zheng C, Yuan C, Kim J, Umeton R, Antell G, Chowdhury A, Franz A, Brais L, Andrews E, Marks DS, Regev A, Ayandeh S, Brophy MT, Do NV, Kraft P, Wolpin BM, Rosenthal MH, Fillmore NR, Sander C
Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36?months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve?=?0.88 and decreases to AUROC (3m)?=?0.83 when disease events within 3?months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50?years. Cross-application of the Danish model to US-VA data had lower performance (AUROC?=?0.71), and retraining was needed to improve performance (AUROC?=?0.78, AUROC (3m)?=?0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer.
New England Journal of Medicine
Cabozantinib Plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma
Choueiri TK
BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown.
METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization.
RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P?=?0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing.
CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).
New England Journal of Medicine
Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer
Partridge AH, Niman SM, Gelber RD
BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking.
METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial.
RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort.
CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).
New England Journal of Medicine
Zanubrutinib in Chronic Lymphocytic Leukemia. Reply.
Brown JR
In the ALPINE trial involving patients with relapsed or refractory chronic lymphocytic leukemia (CLL), Brown and colleagues (Jan. 26 issue) report that the Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib was superior to ibrutinib with respect to the overall response, progression-free survival, and adverse-events profile. These results mirror those of the ELEVATE-RR trial, which showed a better safety profile with acalabrutinib than with ibrutinib, although the patients had a similar overall response and progression-free survival.
Advances in Radiation Oncology
Abunimer AM, Lee HY, Dee EC, Yaguang P, Shin KY, Chen YH, Huynh MA, Spektor A, Guenette JP, Balboni T
AJR American Journal of Roentgenology
Beyond the AJR: CT Radiomic Features of the Pancreas Predict Development of Pancreatic Cancer
Rosenthal MH, Schawkat K
American Society of Clinical Oncology Educational Book
Patient Advocates and Researchers as Partners in Cancer Research: A Winning Combination
Garrett WS
Blood Advances
FLT3-ITD Does not Predict Inferior Prognosis in Acute Myeloid Leukemia Patients Age ?60 Years
Fell GG, Chen EC, Tsai HK, Wadleigh M, Winer ES, Garcia JS, Luskin MR, Stahl M, Neuberg DS, DeAngelo DJ, Lindsley RC, Stone RM
Blood Advances
Abel GA
Blood Advances
Naeem A, Cha J, Martindale S, Zhou Y, Ren Y, Tyekucheva S, Kim AS, Fernandes SM, Saksena G, Danysh BP, Slowik K, Jacobs RA, Davids MS, Lederer JA, Leshchiner I, Getz G, Brown JR
BMC Medical Ethics
Clinical Ethics Consultation Documentation in the Era of Open Notes
Childers C, Marron J, Meyer EC, Abel GA
British Journal of Haematology
Jing CB, Prutsch N, He S, Zimmerman MW, Look AT
Breast Cancer Research and Treatment
Odai-Afotey A, Lederman RI, Gagnon H, Gundersen DA, Revette AC, Keating NL, Freedman RA
Breast Cancer Research and Treatment
Bychkovsky BL, Garber JE, Scheib R, Rana HQ
Cancer Prevention Research
Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ
Garber JE, Husband A, Pastorello R, Mittendorf EA
Clinical Cancer Research
Wang QL, Ma C, Yuan C, Wolpin BM, Zhang Y, Meyerhardt JA, Ng K
European Radiology
Tran NA, Palotai M, Hanna GJ, Schoenfeld JD, Bay CP, Rettig EM, Juliano AF, Kelly HR,
Morales Pinzon A, Kann BH, Huang RY, Haddad RI, Guttmann CRG, Guenette JP
Expert Review of Anticancer Therapy
Emerging Predictive Biomarkers in the Management of Bone and Soft Tissue Sarcomas
Haddox CL
Genome Research
Efficient and Accurate KIR and HLA Genotyping with Massively Parallel Sequencing Data
Song L, Bai G, Liu XS, Li H
International Journal of Cancer
Dysfunctions of Innate and Adaptive Immune Tumor Microenvironment in Waldenström Macroglobulinemia
Hunter ZR, Hideshima T, Flores L, Treon SP, Dorfman DM, Anderson KC, Jakubikova J
JAMA Internal Medicine
Private Equity Acquisition of Oncology Clinics in the US From 2003 to 2022
Tyan K, Lam MB, Milligan M
JCO Precision Oncology
Brett JO, Dubash TD, Johnson GN, Niemierko A, Lloyd MR, Kambadakone A, Spring LM, Micalizzi DS, Onozato ML, Che D, Nayar U, Iafrate AJ, Ryan LY, Juric D, Moy B, Ellisen LW, Maheswaran S, Wagle N, Haber DA, Bardia A, Wander SA
Journal of Clinical Investigation
Weichert-Leahey N, Shi H, Tao T, Zimmerman MW, Reyon D, Joung JK, Young RA, Look AT
Journal of Computer Assisted Tomography
Miskin N, Qin L, Silverman SG, Shinagare AB
Journal of Immunotherapy
Buchbinder EI, Pfaff KL, Turner MM, Manos M, Ouyang O, Ott PA, Giobbie-Hurder A, Rodig SJ,
Hodi FS
Journal of the National Cancer Institute Monographs
Translational and Transdisciplinary Research in Energy Balance and Cancer: Past is Prologue
Ligibel J
Journal of Pain and Symptom Management
"It's Hard Not to Have Regrets:" Qualitative Analysis of Decisional Regret in Bereaved Parents
Feifer D, Broden EG, Baker JN, Wolfe J, Snaman J
Journal of Palliative Medicine
Block SD
Journal of Thoracic Oncology
Awad MM
Laboratory Investigation
Profiling of Natural Killer Interactions with Cancer Cells Using Mass Cytometry
Hallisey M, Dennis J, Gabriel EP, Masciarelli A, Chen J, Abrecht C, Brainard M, Marcotte WM, Dong H, Hathaway E, Tarannum M, Vergara JA, Schork AN, Tyan K, Tarantino G, Liu D, Romee R, Rahma OE, Severgnini M, Hodi FS, Baginska J
Nature Reviews Cancer
Dynamics and Specificities of T Cells in Cancer Immunotherapy
Oliveira G, Wu CJ
Nature Reviews Clinical Oncology
Determinants of Response and Resistance to T Cell-Engaging Therapies in Multiple Myeloma
Midha S, Anderson KC
Neuro-Oncology
Lamba N, Catalano PJ, Elhalawani H, Haas-Kogan DA, Wen PY, Wagle N, Lin NU, Aizer AA,
Tanguturi S
Oncologist
Perez K, Cleary JM, Horick N, Weekes C, Abrams T, Blaszkowsky L, Enzinger P, Giannakis M,
Goyal L, Meyerhardt JA, Rubinson D, Yurgelun MB, Goessling W, Giantonio BJ, Brais L, Germon V, Stonely D, Raghavan S, Aguirre AJ, Wolpin BM
Pharmacoepidemiology and Drug Safety
La J, DuMontier C, Dharne M, Corrigan J, Gaziano JM, Do NV, Brophy MT, Driver JA, Munshi NC, Fillmore NR
Seminars in Nuclear Medicine
Interim FDG-PET/CT for Response Assessment of Lymphoma
Zeman MN, Merryman RW, Jacene HA
Seminars in Oncology Nursing
Pozzar RA, Hammer MJ
STAR Protocols
Protocol to Establish a Genetically Engineered Mouse Model of IDH1-Mutant Astrocytoma
Shi DD, Lee JH, Wang AC, Khanal J, Gao W, Kaelin WG Jr
Transplantation and Cellular Therapy
Delirium and Healthcare Utilization in Patients Undergoing Hematopoietic Stem Cell Transplantation
Amonoo HL, Markovitz NH, Johnson PC, Kwok A, Dale C, Deary EC, Daskalakis E, Choe JJ, Yamin N, Gothoskar M, Cronin KG, Fernandez-Robles C, Pirl WF, Chen YB, Cutler C, Lindvall C, El-Jawahri A
Transplantation and Cellular Therapy
Sherman AC, Cheng CA, Swank Z, Zhou G, Li X, Issa NC, Walt DR, Baden LR, Soiffer RJ
Blood
Intercepting the B-T Cell Tête-à-Tête
Castillo JJ
In this issue of Blood, Sacco and colleagues provide insights into the overbearing influence of the domineering T regulatory (Treg) cells that interact with malignant B cells, via the CD40/CD40-ligand axis, to facilitate evasion of the immune system in Waldenström macroglobulinemia (WM). The treatment of this immunoglobulin M–secreting B-cell lymphoplasmacytic lymphoma has witnessed remarkable progress in recent years.
Blood
Ubiquitin Receptor PSMD4/Rpn10 is a Novel Therapeutic Target in Multiple Myeloma
Du T, Song Y, Ray A, Wan X, Yao Y, Samur MK, Shen C, Penailillo J, Sewastianik T, Tai YT, Fulciniti M, Munshi NC, Wu H, Carrasco RD, Chauhan D, Anderson KC
PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the 26S proteasome. Because proteasome inhibition is a common therapeutic strategy in multiple myeloma (MM), we investigated Rpn10 and found that it is highly expressed in MM cells compared with normal plasma cells. Rpn10 levels inversely correlated with overall survival in patients with MM. Inducible knockout or knockdown of Rpn10 decreased MM cell viability both in vitro and in vivo by triggering the accumulation of polyubiquitinated proteins, cell cycle arrest, and apoptosis associated with the activation of caspases and unfolded protein response-related pathways. Proteomic analysis revealed that inhibiting Rpn10 increased autophagy, antigen presentation, and the activation of CD4+ T and natural killer cells. We developed an in vitro AlphaScreen binding assay for high-throughput screening and identified a novel Rpn10 inhibitor, SB699551 (SB). Treating MM cell lines, leukemic cell lines, and primary cells from patients with MM with SB decreased cell viability without affecting the viability of normal peripheral blood mononuclear cells. SB inhibited the proliferation of MM cells even in the presence of the tumor-promoting bone marrow milieu and overcame proteasome inhibitor (PI) resistance without blocking the 20S proteasome catalytic function or the 19S deubiquitinating activity. Rpn10 blockade by SB triggered MM cell death via similar pathways as the genetic strategy. In MM xenograft models, SB was well tolerated, inhibited tumor growth, and prolonged survival. Our data suggest that inhibiting Rpn10 will enhance cytotoxicity and overcome PI resistance in MM, providing the basis for further optimization studies of Rpn10 inhibitors for clinical application.
Gastroenterology
TGF? Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy
Qiang L, Hoffman MT, Ali LR, Castillo JI, Kageler L, Temesgen A, Lenehan P, Wang SJ, Bello E, Cardot-Ruffino V, Uribe GA, Yang A, Dougan M, Aguirre AJ, Raghavan S, Dougan SK
BACKGROUND AND AIMS: TGF? plays pleiotropic roles in pancreatic cancer including promoting metastasis, attenuating CD8 T cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGF? inhibition has shown limited efficacy against pancreatic cancer in mice or humans.
METHODS: We evaluated the TGF? blocking antibody NIS793 in combination with either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX chemotherapy in orthotopic pancreatic cancer models. Single-cell RNA-seq and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment.
RESULTS: Blockade of TGF? with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, as response to TGF? blockade was preserved in CD8-depleted or RAG2-/- mice. TGF? blockade decreased total ?SMA+ fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA-seq on tumor cells sorted ex vivo revealed that tumor cells treated with TGF? blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGF? blockade increased chemotherapy-induced cell death in vivo.
CONCLUSIONS: TGF? regulates pancreatic cancer cell plasticity between classical and basal cell states. TGF? blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with either FOLFIRINOX or gemcitabine/n(ab)paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.
Journal of Clinical Oncology
ASCO Ethical Guidance for the US Oncology Community Where Reproductive Health Care Is Limited by Law
Jimenez RB, Rosenberg AR
The decision in Dobbs v Jackson Women's Health Organization overturned federal protections for abortion rights, making way for states to enact abortion bans with or without exceptions for the health or life of the pregnant patient. Patient care across many areas of medicine including oncology continues to be affected. Although the change in the legal landscape is widely felt, the core ethical considerations for physicians do not change because of restrictions on the practice of medicine. ASCO offers this guidance to assist US oncologists and institutions who must balance limitations with established ethical duties. This paper articulates principles for cancer care and pregnancy, offers a framework for ethical reflection and action for oncologists who care for pregnant patients, and makes recommendations for individual and institutional action to support evidence-based, patient-centered care in the United States where abortion is illegal or access is limited.
Journal of Clinical Oncology
El Zarif T, Adib E, Huang J, Freeman D, Xie W, Choueiri TK, Baden LR
PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer.
METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC).
RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ?200 cells/µL, and 94% (179/190) had HIV viral load
CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.
Journal of Clinical Oncology
Burstein HJ
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. See the Appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).
JAMA Oncology
External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients with Glioblastoma
Rahman R, Trippa L
To the Editor We read with interest the results of the autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) externally controlled nonrandomized trial by Liau et al, which leverages external data to perform a comparative analysis of DCVax-L survival outcomes in newly diagnosed glioblastoma (GBM). A careful choice of the analysis methods is necessary to avoid biases, which can translate into errors in the regulatory process and potential loss of credibility of future trials that integrate external data.
JAMA Oncology
Lin NU
In Reply We appreciate the comments from Mo et al regarding the overall survival (OS) of patients with stable brain metastases (BMs) at baseline in the exploratory subgroup analysis1 of HER2CLIMB. The HER2CLIMB randomized clinical trial2 was not designed to conduct a formal comparison between treatment groups or statistically powered for this subgroup. The estimated hazard ratio (HR) across all patients (n?=?291) with BMs at baseline showed a 40% reduction in the risk of death in the tucatinib-combination group (HR, 0.60 [95% CI, 0.44-0.81]; P?P?=?.16). Additionally, the median OS was 5.2 months longer, and the 1-year and 2-year OS rates were numerically higher in the tucatinib-combination group in patients with stable BMs.
Nature Communications
Deep Learning to Estimate Lung Disease Mortality from Chest Radiographs
Weiss J, Raghu VK, Bontempi D, Christiani DC, Mak RH, Lu MT, Aerts HJWL
Prevention and management of chronic lung diseases (asthma, lung cancer, etc.) are of great importance. While tests are available for reliable diagnosis, accurate identification of those who will develop severe morbidity/mortality is currently limited. Here, we developed a deep learning model, CXR Lung-Risk, to predict the risk of lung disease mortality from a chest x-ray. The model was trained using 147,497 x-ray images of 40,643 individuals and tested in three independent cohorts comprising 15,976 individuals. We found that CXR Lung-Risk showed a graded association with lung disease mortality after adjustment for risk factors, including age, smoking, and radiologic findings (Hazard ratios up to 11.86 [8.64-16.27]; p?
Nature Communications
Potter DS, Du R, Bohl SR, Chow KH, Ligon KL, Bueno R, Letai A
Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.
Nature Communications
Li X, Ng R, Zhang A, Xu S, Gaiha GD, Wang JH
Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.
Biomolecular NMR Assignments
1H, 13C and 15N Backbone and Sidechain Assignment of the Burkholderia Mallei Acyl Carrier Protein
Matosin S, Fischer PD, Droemer MA, Tavares I, Ficarro SB, Arthanari H
Blood Advances
Kean L, Horan J
Blood Advances
Shapiro RM, Kim HT, Ansuinelli M, Guleria I, Cutler CS, Koreth J, Gooptu M, Antin JH, Kelkar AH,
Ritz J, Wu CJ, Soiffer RJ, Ho VT, Nikiforow S, Romee R
Blood Advances
Wobma HM, Kapadia M, Kim HT, Alvarez-Calderon F, Baumeister S, Duncan C, Forrest S, Gorfinkel L, Huang J, Lehmann LE, Li H, Schwartz MA, Koreth J, Ritz J, Kean LS, Whangbo JS
BMC Palliative Care
Rosenberg AR
CA Cancer Journal for Clinicians
Haddox CL, Baldini EH, Jagannathan JP, Hornick JL, Raut CP
Child Abuse and Neglect
Revisiting Medical Neglect Concerns in Children with Life-Threatening Complex Chronic Conditions
Cleveland RW, Deming RS, Helton G, Wilson CR, Ullrich CK
Clinical Cancer Research
The Immunogenomic Landscape of Neuroendocrine Prostate Cancer
Beltran H
Developmental Cell
A Tubule-Sheet Continuum Model for the Mechanism of Nuclear Envelope Assembly
Zhao G, Liu S, Arun S, Pellman D
Future Oncology
Jänne PA
Future Oncology
Sands J
Hematology/Oncology Clinics of North America
Serzan MT, Xu W, Berg SA
Hematology/Oncology Clinics of North America
Novel Agents in Waldenström Macroglobulinemia
Sarosiek S, Castillo JJ
Hematology/Oncology Clinics of North America
Waldenström Macroglobulinemia: A Myriad of Effective Treatment Options, but Still Work to be Done
Castillo JJ, Sarosiek S
International Journal of Radiation Oncology, Biology, Physics
Patenaude R, Yasmin-Karim S, Peng Y, Wucherpfennig KW, Ngwa W, Kheir JN, Polizzotti BD
International Journal of Radiation Oncology, Biology, Physics
Smart AC, Liu KX, Mancias JD, Shiloh RY, Wintner A, Zietman AL, Dyer MA, Russo AL
Investigational New Drugs
A Phase I/II Study of LY3022855 with BRAF/MEK Inhibition in Patients with Melanoma
Buchbinder EI, Giobbie-Hurder A, Haq R, Ott PA
iScience
The Human E3 Ligase RNF185 is a Regulator of the SARS-CoV-2 Envelope Protein
Zou C, Yoon H, Park PMC, Pellman J, Carreiro J, Tsai JM, Li YD, Roy Burman SS, Donovan KA, Gasser J, Sperling AS, Nowak RP, Fischer ES, Ebert BL, S?abicki M
Journal of the American College of Surgeons
Weiss A, Li T, Desai NV, Tung NM, Poorvu PD, Partridge AH, Nakhlis F, Dominici L, Sinclair N,
Spring LM, Faggen M, Constantine M, Krop IE, DeMeo M, Wrabel E, Alberti J, Chikarmane S,
Tayob N, King TA, Tolaney SM, Winer EP, Mittendorf EA, Waks AG
Journal of Thoracic Oncology
Alessi JV, Wang X, Ricciuti B, Li YY, Gupta H, Luo J, Pecci F, Lamberti G, Recondo G, Venkatraman D, Di Federico A, Gandhi MM, Vaz VR, Nishino M, Sholl LM, Cherniack AD, Lindsay J, Sharma B, Turner MM, Pfaff KL, Felt KD, Rodig SJ, Lin X, Meyerson ML, Johnson BE, Christiani DC, Awad MM
JCO Oncology Practice
Trapani D, Jin Q, Block CC, Freedman RA, Lin NU, Tarantino P, Mittendorf EA, King TA, Lester SC, Brock JE, Tayob N, Bunnell CA, Tolaney SM, Burstein HJ
JCO Oncology Practice
Detecting and Managing T-DXd-Related Interstitial Lung Disease: The Five "S" Rules
Tarantino P, Tolaney SM
Leukemia
Rizq O, Tai YT, Anderson KC
NPJ Breast Cancer
Liquid Biopsy for Brain Metastases and Leptomeningeal Disease in Patients with Breast Cancer
Morganti S, Parsons HA, Lin NU, Grinshpun A
Oncologist
Morganti S, Bychkovsky BL, Poorvu PD, Garrido-Castro AC, Block CC, Partridge AH, Tung NM, Lin NU, Garber JE, Tolaney SM, Lynce F
Psycho-Oncology
Chevalier LL, Blackmon JE, Roman A, Chang G, Recklitis CJ
Seminars in Nephrology
Updates in Plasma Cell Dyscrasias and Related Monoclonal Immunoglobulin-Mediated Renal Disease
Midha S, Nadeem O, Selamet U
Trends in Cancer
Clinical and Translational Relevance of Intratumor Heterogeneity
Goyette MA, Lipsyc-Sharf M, Polyak K
Urologic Oncology
Morgans AK, Sonpavde GP