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BackgroundThe prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies.ObjectivesThis study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies.DesignThis real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014-2018).MethodsTMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1-49%), and negative (

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30-5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15-4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS.

IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients.MethodsWe collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression.ResultsIn multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio [HR], 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch.ConclusionIn this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts. ClinicalTrials.gov Identifier: NCT02478931.

IntroductionOncology media websites such as Oncology Live (OncLive) and Targeted Oncology (TargetedOnc) play an important role in the dissemination of oncology news to patients and clinicians; however, the quality of the content on these websites has not been assessed. Our study aimed to analyze content from these websites and assess financial conflicts of interest (FCOI) amongst speakers interviewed on these websites.MethodsArticles published on OncLive and TargetedOnc during October 2021, were prospectively captured and analyzed. The primary outcome of our study was the quality of oncology news reporting in OncLive and TargetedOnc. We assessed the FCOI amongst speakers using data from Open Payments.ResultsWe examined 196 articles (OncLive 108, TargetedOnc 88). Limitations of cited research were reported in 7% (7/105) of OncLive and zero TargetedOnc articles. Benefit and risks in absolute numbers were reported in 28% (28/99) of OncLive and 16% (7/45) of TargetedOnc articles. Independent experts were quoted in 47% (51/108) and 51% (44/86) of the OncLive and TargetedOnc articles, respectively (Table 3). Pharmaceutical executives were quoted in 18% (20/108) and 11% (10/88) of OncLive and TargetedOnc articles, respectively. No FCOI disclosures were listed or reported for any articles. The mean general payment received from industry by United States physicians was $63,861 in 2019 and $39,639 in 2020.ConclusionOur study demonstrates low quality and potentially biased reporting of oncology news on OncLive and TargetedOnc. Careful safeguards, oversight and reporting of relevant FCOI are needed to maintain the quality and transparency of content being provided.

Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38-0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30-0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42-0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.

Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38-0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30-0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42-0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.

BackgroundIn the US, medical costs for cancer patients have grown from $27 billion in 1990 to $174 billion in 2020. The increased financial strain that cancer patients and survivors endure is referred to as financial toxicity.ObjectiveTo quantify the relationship between indicators of financial toxicity and health utilization and quality of life in patients ever diagnosed with cancer.MethodsAdult cancer patients and survivors in 2017 were identified using the Medical Expenditure Panel Survey. Multiple logistic regression models were used to quantify the relationship between three financial toxicity exposures (concern for keeping an income, paying large medical bills, and going into debt or borrowing money) and two discrete outcomes of being able to purchase prescriptions and often worrying that cancer would worsen or come back.ResultsThis study assessed 609 respondents. After survey weighting was applied, that represented 16,215,673 individuals. Patients who reported concern for keeping an income were at 2.91 (95% Confidence Interval [CI], 1.16 to 7.31) and 2.97 (95% CI, 2.01 to 2.67) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not. Patients who reported worry about paying large medical bills were at 4.46 (95% CI, 2.15 to 9.24) and 2.80 (95% CI, 1.98 to 3.96) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not. Patients who reported borrowing money or going into debt were at 3.04 (95% CI, 1.19 to 7.76) and 2.42 (95% CI, 1.54 to 3.18) times increased odds to report avoiding purchase of prescriptions and worry of cancer status, respectively, versus those who did not.ConclusionsFinancial toxicity is associated with decreased prescription utilization and quality of life in the form of excessive worry among cancer patients including cancer survivors.

BackgroundAs the landscape of haematological malignancies dramatically changes due to diagnostic and therapeutic advances, it is important to evaluate trends in clinical trial designs. The objective of our study was to describe the design of clinical trials for five common haematological malignancies with respect to randomisation and end-points. We also aimed to assess trends over time and examine the relationships of funding source and country of origin to proportions of randomisation and utilisation of clinical end-points.MethodsThis systematic review identified haematological malignancy clinical trials starting in 2015-2020 registered at ClinicalTrials.gov as of 20th February 2021. Trial-related variables including randomisation status, type of primary end-point, and both projected and actual enrolment numbers were captured. Clinical end-points were defined as overall survival and quality of life, while surrogate end-points included all other end-points.ResultsOf 2609 relevant trials included in this analysis, only one-fifth were randomised (538, 21%), with a significant decrease in the proportion of randomised clinical trials from 26% of trials in 2015 to 19% in 2020 (p

BackgroundTumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established.MethodsWe curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies.ResultsThe mean (95% CI) TMB difference between samples was 0.583 [- 0.900-2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00-98.31] versus 14.14 [range, 0.00-100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals.ConclusionsOverall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB.Trial registrationNCT02478931 , registered June 23, 2015.

IntroductionChimeric antigen receptor T-cell therapy (CART) has revolutionised treatment of haematological malignancies; however, current reporting uses a modified intention-to-treat analysis (mITT) which over-estimates efficacy. We assessed what proportion of CD19 and B-cell maturation antigen (BCMA) CART trials report the number of patients not receiving CART after being enrolled by performing meta-analysis of the mITT and intention-to-treat (iTT) overall response rate (ORR).MethodsPubMed/MEDLINE, EMBASE and Cochrane databases were searched. All prospective clinical trials of CD19 and BCMA-targeting CART enrolling two or greater patients from 1st January 2013 to 1st November 2020 were included.ResultsA total of 28 BCMA CART and 74 CD19 CART trials were identified. These included 10 BCMA CART (35.7%) and 52 (70.2%) CD19 CART trials reporting total number of patients enrolled and number of patients treated with CART. For this cohort of trials, the mITT ORR for BCMA CART was 78.0% (95% confidence interval (CI) = 67.0-89.0%), and the iTT ORR was 70.0% (95% CI = 59.0-80.0%). For CD19 leukaemia CART, the mITT ORR was 87.2% (95% CI = 83.1-91.2), and the iTT ORR was 74.9 (95% CI = 64.8-85.0). For CD19 lymphoma CART, the mITT ORR was 70.7% (95% CI = 63.9-77.5), and the iTT ORR was 58.7% (95% CI = 49.7-67.7).ConclusionAcross BCMA and CD19 CART trials, there is a difference of up to 8-12% in the ORR between modified and iTT analyses and a paucity of information regarding reasons why patients did not receive the intended study treatment.

ImportanceA thorough understanding of the optimal role and sequence of agents for treatment of multiple myeloma (MM) requires knowledge of the use and rate of postprotocol therapies in randomized clinical trials (RCTs).ObjectivesTo examine the proportion of MM RCTs that reported postprotocol therapies and, among those, the percentage of patients who received no further therapy and how treatments differed between the control and intervention arms.Evidence reviewThe reporting of postprotocol therapies was systematically assessed in published MM RCTs using 3 databases (PubMed, Embase, and Cochrane Registry of Controlled Trials) for MM RCTs from January 1, 2005, to December 30, 2019. All MM RCTs were included, and all other studies, such as editorials, nonrandomized studies, and review articles, were excluded.FindingsA total of 103 RCTs were identified (47 251 patients); of these, 45 (43.7%) reported subsequent treatments in that publication or in any subsequent publication. Trials funded by pharmaceutical companies (26 of 47 [55.3%]) were more likely to report subsequent treatments than cooperative group studies (19 of 56 [33.9%]) (χ21,103 = 4.8; P = .03). Differences were found in the treatments received between the intervention and control arms of RCTs. When data were reported, 5150 of 9351 patients (54.9%) in RCTs of newly diagnosed MM and 2197 of 4501 patients (48.8%) in RCTs of relapsed/refractory MM received any subsequent therapy.Conclusions and relevancePostprotocol therapies in MM RCTs are often not reported and, when they are, many patients receive no further therapy. Reporting guidelines for postprotocol therapies are needed.

To our knowledge, no study has evaluated the quality of control groups in randomised controlled trials of multiple myeloma. We aimed to do a systematic review of randomised controlled trials of multiple myeloma to ascertain the quality of the control groups used. PubMed (MEDLINE), Embase, Cochrane Controlled Register of Trials, and CinicalTrials.gov were searched for articles of randomised controlled trials of multiple myeloma based in the USA that initiated participant enrolment between Jan 1, 2010, and June 30, 2020. A control group regimen was considered to be inferior if a previous randomised controlled trial had shown an improved progression-free survival versus the control group before enrolment. Of 49 identified randomised controlled trials, seven (14%) began enrolling patients into inferior control groups after an existing superior regimen to the control had already been published. Nine (18%) of the 49 trials continued enrolment on substandard control groups after data emerged during the study enrolment period. The median time that newer data emerged regarding inferiority of the control group from the time a trial first enrolled a patient was 13 months (IQR 8-29 months). 12 (75%) of these 16 randomised controlled trials are published, and nine (75%) of the 12 published trials had overlapping investigators with trials that had previously shown the inferiority of the control group being used. Greater scrutiny on the quality of control groups in randomised controlled trials of multiple myeloma is needed.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

BackgroundImmune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB.MethodsComprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient.ResultsThe median progression-free survival (PFS) for PHBR score  6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients.ConclusionsPoor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.

Studies have demonstrated an association between quantity of circulating tumor DNA (ctDNA) and poorer survival. We investigated the relationship between percent ctDNA (%ctDNA), total number of ctDNA alterations, and overall survival (OS) in liquid biopsies. Overall, 418 patients with blood-based next-generation sequencing (54 to 73 genes) were analyzed. Eligible patients included those who had advanced/metastatic solid tumor malignancies and never received immunotherapy treatment, which may alter the survival curve in patients with high mutational burden. Patients with a high (≥ 5%) %ctDNA had significantly shorter OS versus those with intermediate (≥ 0.4% to < 5%) or low (< 0.4%) values (median OS, 7.0 v 14.1 v not reached [NR] months, respectively; P < .0001). Patients with a high (≥ 5) total number of alterations had significantly shorter OS versus those with intermediate (≥ 1.46 to < 5), low (< 1.46), or no alterations (median OS, 4.6 v 11.7 v 21.3 v NR months, respectively; P < .0001). The total number of alterations correlated with %ctDNA (r = 0.85; 95% CI, 0.81 to 0.87; P < .0001). However, only an intermediate to high total number of alterations (≥ 1.46) was an independent predictor of worse OS (hazard ratio, 1.96; 95% CI, 1.30 to 2.96; P = .0014; multivariate analysis). We demonstrate that the total number of alterations and %ctDNA have prognostic value and correlate with one another, but only the total number of alterations was independently associated with survival outcomes. Our findings suggest that the total number of alterations in plasma may be an indicator of more aggressive tumor biology and therefore poorer survival.

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (

BackgroundHigh tumor mutational burden (TMB) predicts checkpoint blockade responsiveness, although the association with outcomes may be nuanced in certain tissue contexts. The correlation between TMB and cytotoxic chemotherapy sensitivity is unknown. This study evaluated the relationship between TMB and outcome in patients with solid tumors receiving cytotoxic chemotherapy.MethodsUniversity of California San Diego patients who received cytotoxic chemotherapy within one year after biopsy for TMB evaluation were included in a retrospective analysis. Physician notes and imaging reports in the electronic medical record were reviewed to determine clinical benefit and progression-free survival (PFS).ResultsAmong 1526 patients with TMB availability, there were 294 eligible patients who received chemotherapy. There were no significant differences in TMB between those with stable disease ≥6 months/partial response/complete response versus others (t-test, p = .22). There were no significant differences in PFS for patients with TMB

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p

BACKGROUND:Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. The BRAF inhibitor vemurafenib is approved by the U.S. Food and Drug Administration (FDA) for patients with ECD harboring a BRAF V600E mutation. Successful treatment has also been reported with MEK-targeted therapies, likely because of the fact that BRAF mutant-negative patients harbor MEK pathway alterations. In our Rare Tumor Clinic, we noted that these patients have frequent drug-related toxicity, consistent with previous reports indicating the need to markedly lower doses of interferon-alpha when that agent is used in these patients. PATIENTS AND METHODS:We performed a review of ten patients with ECD seen at the Rare Tumor Clinic at University of California San Diego receiving 16 regimens of targeted BRAF, MEK, or combined therapies. RESULTS:The median age of the ten patients with ECD was 53 years (range, 29-77); seven were men. The median dose percentage (percent of FDA-approved dose) tolerated was 25% (range, 25%-50%). The most common clinically significant adverse effects resulting in dose adjustments of targeted therapies were rash, arthralgias, and uveitis. Renal toxicity and congestive heart failure were seen in one patient each. In spite of these issues, eight of ten patients (80%) achieved a partial remission on therapy. DISCUSSION:Patients with ECD appear to require substantially reduced doses of BRAF and MEK inhibitors but are responsive to these lower doses.

Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the "cancer-immunity cycle" in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P

Evolve-and-resequence (E+R) experiments leverage next-generation sequencing technology to track the allele frequency dynamics of populations as they evolve. While previous work has shown that adaptive alleles can be detected by comparing frequency trajectories from many replicate populations, this power comes at the expense of high-coverage (>100x) sequencing of many pooled samples, which can be cost-prohibitive. Here, we show that accurate estimates of allele frequencies can be achieved with very shallow sequencing depths (

PurposeTo date, evidence for tissue epidermal growth factor receptor (EGFR) overexpression as a biomarker for anti-EGFR therapies has been weak. We investigated the genomic landscape of EGFR amplification in blood-derived cell-free tumor DNA (cfDNA) across diverse cancers and the role of anti-EGFR therapies in achieving response.MethodsWe assessed EGFR amplification status among 28,584 patients with malignancies evaluated by clinical-grade next-generation sequencing (NGS) of blood-derived cfDNA (54- to 73-gene panel). Furthermore, we curated the clinical characteristics of 1,434 patients at the University of California San Diego who had cfDNA testing by this NGS test.ResultsOverall, EGFR amplification was detected in cfDNA from 8.5% of patients (2,423 of 28,584), most commonly in colorectal (16.3% [458 of 2,807]), non-small-cell lung (9.0% [1,096 of 12,197]), and genitourinary cancers (8.1% [170 of 2,104]). Most patients had genomic coalterations (96.9% [95 of 98]), frequently involving genes affecting other tyrosine kinases (72.4% [71 of 98]), mitogen-activated protein kinase cascades (56.1% [55 of 98]), cell-cycle-associated signals (52.0% [51 of 98]), and the phosphoinositide 3-kinase pathway (35.7% [35 of 98]). EGFR amplification emerged in serial cfDNA after various anticancer therapies (n = 6), including checkpoint inhibitors (n = 4), suggesting a possible role for these amplifications in acquired resistance. Nine evaluable patients with EGFR amplification were treated with anti-EGFR-based regimens; five (55.6%) achieved partial responses, including three patients whose tissue NGS lacked EGFR amplification.ConclusionEGFR amplification was detected in cfDNA among 8.5% of 28,584 diverse cancers. Most patients had coexisting alterations. Responses were observed in five of nine patients who received EGFR inhibitors. Incorporating EGFR inhibitors into the treatment regimens of patients harboring EGFR amplification in cfDNA merits additional study.