Publications

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Selected Publications

Maximilian Diehn, MD, PhD
Associate Professor of Radiation Oncology (Radiation Therapy)

Publications

  • Integrating genomic features for non-invasive early lung cancer detection NATURE Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y., Nesselbush, M. C., Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020

    View details for DOI 10.1038/s41586-020-2140-0

    View details for Web of Science ID 000521531000011

  • Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. Cell Nabet, B. Y., Esfahani, M. S., Moding, E. J., Hamilton, E. G., Chabon, J. J., Rizvi, H. n., Steen, C. B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Almanza, D. n., Stehr, H. n., Gojenola, L. n., Bonilla, R. F., Jin, M. C., Jeon, Y. J., Tseng, D. n., Liu, C. n., Merghoub, T. n., Neal, J. W., Wakelee, H. A., Padda, S. K., Ramchandran, K. J., Das, M. n., Plodkowski, A. J., Yoo, C. n., Chen, E. L., Ko, R. B., Newman, A. M., Hellmann, M. D., Alizadeh, A. A., Diehn, M. n. 2020

    Abstract

    Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.

    View details for DOI 10.1016/j.cell.2020.09.001

    View details for PubMedID 33007267

  • Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer Nature Cancer Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Yoo, C. H., He, J., Qiao, Y., Xu, T., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1

    View details for DOI 10.1038/s43018-019-0011-0

  • KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

    Abstract

    Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

    View details for DOI 10.1158/2159-8290.CD-20-0282

    View details for PubMedID 33071215

  • Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA CANCER DISCOVERY Dudley, J. C., Schroers-Martin, J., Lazzareschi, D., Shi, W., Chen, S. B., Esfahani, M. S., Trivedi, D., Chabon, J. J., Chaudhuri, A. A., Stehr, H., Liu, C., Lim, H., Costa, H. A., Nabet, B. Y., Sin, M. Y., Liao, J. C., Alizadeh, A. A., Diehn, M. 2019; 9 (4): 500–509

    View details for DOI 10.1158/2159-8290.CD-18-0825

    View details for Web of Science ID 000462990400024

  • Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

    Abstract

    Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

    View details for PubMedID 28899864

  • Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer discovery Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2016

    Abstract

    Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

    View details for PubMedID 27663899

  • Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7

    Abstract

    Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

    View details for DOI 10.1038/ncomms11815

    View details for PubMedID 27283993

  • An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage NATURE MEDICINE Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 552-558

    Abstract

    Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

    View details for DOI 10.1038/nm.3519

    View details for Web of Science ID 000335710700028

  • Deep Learning Based Identification and Segmentation of Lung Tumors on Computed Tomography Images. International journal of radiation oncology, biology, physics Kashyap, M., Panjwani, N., Hasan, M. A., Huang, C., Bush, K., Dong, P., Zaky, S. S., Chin, A. L., Vitzthum, L., Loo, B. W., Diehn, M., Xing, L., Gensheimer, M. F. 2021; 111 (3S): e92-e93

    Abstract

    PURPOSE/OBJECTIVE(S): Rapid and accurate estimation of tumor burden in biomedical images is essential for precisely monitoring cancer progression and assessing therapeutic response. The ability to detect and segment tumors using an automated approach is a key part of this task. Despite recent advances from deep learning, lung tumor delineation remains challenging, particularly when the tumor bounding box is not provided to the model. We hypothesized that clinical radiation oncology contours could supply a large enough dataset of 3D tumor segmentations to enable more accurate models. We developed and validated a deep learning-based model to identify and segment primary and metastatic lung tumors on computed tomography (CT) images.MATERIALS/METHODS: We curated a dataset consisting of CT images and clinical segmentations of 1,916 lung tumors in 1,504 patients who received radiation treatment for one or more primary or metastatic lung tumors. Segmentation quality was independently verified by a radiation oncologist using a custom web application. This dataset was used to train two 3D U-Net convolutional neural networks with varying model properties: one using high-resolution and small input volumes, and one using low-resolution and large input volumes. Models were ensembled together during validation. Performance was evaluated using an external held-out test set of CT images and segmentations from 59 patients with a single primary or metastatic lung tumor, treated at a separate clinical site. This test set consisted of 50 primary lung cancers and 9 metastases. To benchmark model performance against physicians, the test set was also contoured by two additional radiation oncologists.RESULTS: Median tumor volume in the external test set was 80.48 cubic centimeters (interquartile range [IQR]: 14.40 to 177.65). The segmentations generated by the ensembled model produced a mean Dice coefficient of 0.62 (IQR: 0.47 to 0.85) on the test set. The sensitivity for detecting a tumor, as defined by correctly predicting at least one voxel within a ground truth tumor, was 93.2%, and the Dice coefficient for the scans with correctly identified lesions was 0.67 (IQR: 0.53 to 0.85). In comparison, the mean interobserver Dice coefficient for the three physicians on the test set was 0.76 (IQR: 0.70 to 0.84). We observed strong correlation between physician-determined tumor size and model-predicted tumor size (Pearson correlation, r = 0.69, P < 0.0001).CONCLUSION: An end-to-end deep learning-based model was able to identify and segment lung tumors in a completely automated fashion, with near-expert level performance. Such models could soon be useful for clinical contouring and automatic quantification of tumor burden.

    View details for DOI 10.1016/j.ijrobp.2021.07.476

    View details for PubMedID 34702000

  • Impact of Facility Treatment Volume on Stereotactic Ablative Radiotherapy (SABR) Outcomes in Early-Stage Non-Small Cell Lung Cancer (NSCLC). International journal of radiation oncology, biology, physics Marar, M., Bryant, A. K., Nalawade, V., Das, M., Jr, B. W., Diehn, M., Chin, A. L., Murphy, J. D., Vitzthum, L. 2021; 111 (3S): e447

    Abstract

    PURPOSE/OBJECTIVE(S): Prior research suggests that radiation oncologist provider experience may influence outcomes for radiation treatment modalities requiring greater technical expertise for given disease sites. We investigated whether institution treatment volume (TV) for SABR technique impacted survival outcomes for patients with NSCLC.MATERIALS/METHODS: We conducted a retrospective cohort study using the Veteran's Affairs Informatics and Computing Infrastructure (VINCI) database to identify patients who underwent treatment for NSCLC between 2012 and 2017 at Veteran's Health Administration Medical Centers (VHAMCs). Patients were included in the cohort if they had tumor (T) stage 1 or 2 disease, node negative (N0) disease, and underwent SABR radiation treatment based on associated Current Procedural Terminology codes. We conducted univariate and multivariate analyses for overall survival (OS) and cause-specific survival (CSS) using Cox regression models accounting for age, sex, race, histology, T stage, tobacco history, ECOG status, and VHAMC facility TV. TV was calculated as the total number of SABR treatments performed per facility over the study period and was categorized into high and low volume groups based on a median TV cutoff.RESULTS: The observational cohort included N = 433 patients with early-stage NSCLC who underwent treatment with SABR across 25 VHAMC facilities. Most patients (83.1%) had T stage 1 disease, and nearly equal proportions had SCC (31.2%) and adenocarcinoma (32.5%) histologies, with the remaining having clinical diagnoses of NSCLC. Median facility TV was 29 SABR treatments (interquartile range 19-33). Median follow up was 657 days. Estimated 2-year overall and cause-specific survival rates were 78.4% (95% CI: 73.9% - 82.1%) and 87.0% (95% CI: 83.2% - 90.0%), respectively. On univariate analysis, high versus low facility TV was not significantly associated with OS (hazard ratio (HR) 1.08, 95% CI: 0.74-1.58) or CSS (HR 1.06, 95% CI: 0.65 - 1.73). Similarly, facility volume was not associated with OS or CSS on multivariate analysis. In a sensitivity analysis, facility volume was not associated with survival outcomes when treated as a continuous variable. Covariates associated with decreased OS included male sex (HR 4.5, P < 0.05), age over 65 (HR 1.77, P < 0.05), ECOG status 2 or greater (HR 1.94, P < 0.05), SCC histology (HR 1.66, P < 0.05), and T stage 2 disease (HR 1.68, P < 0.05).CONCLUSION: In this observational cohort of patients treated at VHAMCs, facility TV was not associated with survival outcomes for early-stage NSCLC radiation treatment using SABR technique. Research is ongoing to account for factors including baseline pulmonary function, comorbidities, and variations in institutional treatment patterns such as propensity for treatment with surgery versus radiation.

    View details for DOI 10.1016/j.ijrobp.2021.07.1262

    View details for PubMedID 34701476

  • A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR). International journal of radiation oncology, biology, physics Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. 2021; 111 (3S): S89-S90

    Abstract

    PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

    View details for DOI 10.1016/j.ijrobp.2021.07.212

    View details for PubMedID 34700657

  • Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. 2021; 111 (3S): e435

    Abstract

    PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

    View details for DOI 10.1016/j.ijrobp.2021.07.1235

    View details for PubMedID 34701446

  • Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H., (Fred) Wu, Y., Devine, M., Ko, R., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S105

    View details for Web of Science ID 000701779700169

  • Treatment Patterns for Isolated Nodal Recurrences in Non-Small Cell Lung Cancer After Definitive Stereotactic Ablative Radiotherapy No, H., Devine, M., Lau, B., Loo, B., Diehn, M., Chin, A., Vitzthum, L. LIPPINCOTT WILLIAMS & WILKINS. 2021: S109

    View details for Web of Science ID 000701779700174

  • Local Recurrence Outcomes of Colorectal Cancer Oligometastases Treated With Stereotactic Ablative Radiotherapy. American journal of clinical oncology Benson, K. R., Sandhu, N., Zhang, C., Ko, R., Toesca, D. A., Lee, P. E., Von Eyben, R., Diehn, M., Gensheimer, M., Maxim, P. G., Bush, K., Loo, B. W., Soltys, S. G., Pollom, E. L., Chang, D. T. 2021

    Abstract

    PURPOSE: The aim of this study was to report local failure (LF) outcomes and associated predictors in patients with oligometastatic colorectal cancer (CRC) treated with stereotactic ablative radiotherapy (SABR).MATERIALS AND METHODS: We retrospectively reviewed patients with CRC metastases to the brain, liver, spine, or lung treated with SABR between 2001 and 2016. Time to LF was summarized using cumulative incidence of LF curves with death as a competing risk.RESULTS: The analysis included a total of 130 patients and 256 lesions. Of the metastases treated, 129 (50%) were brain, 50 (20%) liver, 49 (19%) spine, and 28 (11%) lung. Median gross tumor volume was 24 mL for liver metastases, 2 mL for brain metastases, 4 mL for spine metastases, and 1 mL for lung metastases. The overall 1, 2, and 3-year cumulative incidence of LF rates were 21.6% (16.5, 27.1), 28.2% (22.3, 34.4), and 31.5% (25.2, 38.0), respectively. LF was highest among the liver metastases (1 y: 26.0%, 2 y: 38.5%), followed by spine (1 y: 25.1%, 2 y: 31.1%), brain (1 y: 20%, 2 y: 25.2%), and lung (1 y: 13.7%, 2 y: insufficient data). Metastases from right-sided primary CRC were significantly more likely to have LF (P=0.0146, HR=2.23). Biologically effective dose>70 Gy, defined using a standard linear quadratic model using alpha/beta ratio of 10 on the individual lesion level, and pre-SABR chemotherapy were also significant predictors of LF (P= 0.0009 and 0.018, respectively).CONCLUSIONS: CRC metastases treated with SABR had significantly higher rates of LF if they originated from right-sided primary CRC, compared with left-sided. Liver metastases had the highest rates of LF compared with other metastatic sites. Thus, CRC liver metastases and metastases from right-sided CRC may benefit from more aggressive radiotherapy.

    View details for DOI 10.1097/COC.0000000000000864

    View details for PubMedID 34534143

  • Radiological tumour classification across imaging modality and histology NATURE MACHINE INTELLIGENCE Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schonlieb, C., Price, S., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021

    View details for DOI 10.1038/s42256-021-00377-0

    View details for Web of Science ID 000685037800005

  • A comprehensive circulating tumor DNA assay for detection of translocation and copy number changes in pediatric sarcomas. Molecular cancer therapeutics Shah, A. T., Azad, T. D., Breese, M. R., Chabon, J. J., Hamilton, E. G., Straessler, K., Kurtz, D. M., Leung, S. G., Spillinger, A., Liu, H., Behroozfard, I. H., Wittber, F. M., Hazard, F. K., Cho, S., Daldrup-Link, H. E., Vo, K. T., Rangaswami, A., Pribnow, A., Spunt, S. L., Lacayo, N. J., Diehn, M., Alizadeh, A. A., Sweet-Cordero, E. A. 2021

    Abstract

    Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients. Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

    View details for DOI 10.1158/1535-7163.MCT-20-0987

    View details for PubMedID 34353895

  • Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nature biotechnology Kurtz, D. M., Soo, J., Co Ting Keh, L., Alig, S., Chabon, J. J., Sworder, B. J., Schultz, A., Jin, M. C., Scherer, F., Garofalo, A., Macaulay, C. W., Hamilton, E. G., Chen, B., Olsen, M., Schroers-Martin, J. G., Craig, A. F., Moding, E. J., Esfahani, M. S., Liu, C. L., Duhrsen, U., Huttmann, A., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2021

    Abstract

    Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

    View details for DOI 10.1038/s41587-021-00981-w

    View details for PubMedID 34294911

  • Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Rolfo, C., Mack, P., Scagliotti, G. V., Aggarwal, C., Arcila, M. E., Barlesi, F., Bivona, T., Diehn, M., Dive, C., Dziadziuszko, R., Leighl, N., Malapelle, U., Mok, T., Peled, N., Raez, L. E., Sequist, L., Sholl, L., Swanton, C., Abbosh, C., Tan, D., Wakelee, H., Wistuba, I., Bunn, R., Freeman-Daily, J., Wynes, M., Belani, C., Mitsudomi, T., Gandara, D. 2021

    View details for DOI 10.1016/j.jtho.2021.06.017

    View details for PubMedID 34246791

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