David L Rimm

Yale University, New Haven, Connecticut, United States

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Publications (315)2138.73 Total impact

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    ABSTRACT: Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits anti-tumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy.Pre-treatment biopsies from 105 breast cancer patients from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis (AQUA) with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain. Additionally, tumor infiltrating lymphocytes (TILs) were assessed on H&E slides.PD-L1 expression was observed in 30% of patients and it was positively associated with hormone receptor negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathological complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analysis. However, since they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model.PD-L1 expression is prevalent in breast cancer, particularly hormone receptor negative and triple-negative patients, indicating a subset of patients which may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR and high PD-L1 predicts pCR in multivariate analysis. Copyright © 2014, American Association for Cancer Research.
    Cancer immunology research. 12/2014;
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    ABSTRACT: Detection of biomolecules in tissues provides contextual information and the possibility to assess the interaction of different cell types and markers. Routine qualitative assessment of immune- and oligonucleotide-based methods in research and the clinic has been associated with assay variability because of lack of stringent validation and subjective interpretation of results. As a result, the vast majority of in situ assays in clinical usage are nonquantitative and, although useful, often of questionable scientific validity. Here, we revisit the reporters and methods used for single- and multiplexed in situ visualization of protein and RNA. Then we examine methods for the use of quantitative platforms for in situ measurement of protein and mRNA levels. Finally, we discuss the challenges of the transition of these methods to the clinic and their potential role as tools for development of companion diagnostic tests.Laboratory Investigation advance online publication, 15 December 2014; doi:10.1038/labinvest.2014.157.
    12/2014;
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    ABSTRACT: Individualized targeted therapies for cancer patients require accurate and reproducible assessment of biomarkers to be able to plan treatment accordingly. Recent studies have shown highly variable effects of preanalytical variables on gene expression profiling and protein levels of different tissue types. Several publications have described protein degradation of tissue samples as a direct result of delay of formalin fixation of the tissue. Phosphorylated proteins are more labile and epitope degradation can happen within 30 min of cold ischemic time. To address this issue, we evaluated the change in antigenicity of a series of phosphoproteins in paraffin-embedded samples from breast tumors as a function of time to formalin fixation. A tissue microarray consisting of 93 breast cancer specimens with documented time-to-fixation was used to evaluate changes in antigenicity of 12 phosphoepitopes frequently used in research settings as a function of cold ischemic time. Analysis was performed in a quantitative manner using the AQUA technology for quantitative immunofluorescence. For each marker, least squares univariate linear regression was performed and confidence intervals were computed using bootstrapping. The majority of the epitopes tested revealed changes in expression levels with increasing time to formalin fixation. Some phosphorylated proteins, such as phospho-HSP27 and phospho-S6 RP, involved in post-translational modification and stress response pathways increased in expression or phosphorylation levels. Others (like phospho-AKT, phosphor-ERK1/2, phospho-Tyrosine, phospho-MET, and others) are quite labile and loss of antigenicity can be reported within 1-2 h of cold ischemic time. Therefore specimen collection should be closely monitored and subjected to quality control measures to ensure accurate measurement of these epitopes. However, a few phosphoepitopes (like phospho-JAK2 and phospho-ER) are sufficiently robust for routine usage in companion diagnostic testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.139.
    Laboratory Investigation 11/2014; · 3.83 Impact Factor
  • International journal of radiation oncology, biology, physics 11/2014; 90(5). · 4.59 Impact Factor
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    ABSTRACT: Purpose: Approximately 40% of metastatic melanoma patients develop brain metastases. Our purpose was to identify genes aberrantly expressed in melanoma that might be associated with propensity for brain homing. Experimental Design: We studied gene expression profiles in a cell line model of brain metastasis (cerebrotropic A375Br cells versus parental A375P cells) and compared them to profiles of patients who developed early brain metastases and who did not. A tissue microarray containing 169 metastatic melanoma cases with variable time to brain metastasis was constructed to further study marker expression by quantitative immunofluorescence. An in vitro model of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. Results:PLEKHA5 was differentially expressed in both the A375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasis free survival. PLEKHA5 over-expression was not associated with other metastatic sites. Knock-down of PLEKHA5 decreases viability of A375Br cells, inhibits BBB transmigration and invasion in vitro. Similar results were found with YUMUL cells, cultured from a patient with overwhelming brain metastases. PLEKHA5 knock-down did not affect the viability of A375P cells. Conclusions: PLEKHA5 expression in melanoma tumors was associated with early development of brain metastases. Inhibition of PLEKHA5 might decrease passage across the BBB and decrease proliferation and survival of melanoma cells both in the brain and in extra-cerebral sites.
    Clinical Cancer Research 10/2014; · 8.19 Impact Factor
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    ABSTRACT: Purpose: Although tumor infiltrating lymphocytes have been associated with response to neoadjuvant therapy, measurement is typically subjective, semi-quantitative and does not differentiate between subpopulations. Here we describe a quantitative objective method for analyzing lymphocyte subpopulations and assess their predictive value. Methods: We develop a quantitative immunofluorescence (QIF) assay to measure stromal expression of CD3, CD8, and CD20 on one slide. We validate this assay by comparison to flow cytometry on tonsil and assess predictive value in breast cancer on a neoadjuvant cohort (n = 95). Then each marker is tested for prediction of pathologic complete response (pCR) compared to pathologist estimation of percentage lymphocyte infiltrate. Results: Lymphocyte percentage and CD3, CD8, and CD20 proportions were similar between flow cytometry and QIF on tonsil. Pathologist TIL count predicted pCR (p = 0.043, OR: 4.77[1.05-21.6]) despite fair interobserver reproducibility (kappa= 0.393). Stromal AQUA scores for CD3 (p = 0.023, OR: 2.51[1.13-5.57]), CD8 (p = 0.029, OR: 2.00[1.08-3.72]), and CD20 (p = 0.005, OR: 1.80[1.19-2.72]) predicted pCR in univariate analysis. CD20 AQUA score predicted pCR (p = 0.019, OR: 5.37[1.32-21.8]) independently of age, size, nuclear grade, nodal status, ER, PR, HER2, and Ki-67, whereas CD3, CD8, and pathologist estimation did not. Conclusions: We have developed and validated an objective, quantitative assay measuring tumor infiltrating lymphocytes in breast cancer. While this work provides analytic validity, future larger studies will be required to prove clinical utility.
    Clinical Cancer Research 09/2014; · 8.19 Impact Factor
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    ABSTRACT: Background The morphological evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of (H&E) hematoxylin and eosin-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple negative and HER2-overexpressing breast cancer.Design A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in breast cancer in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E-sections, acknowledging the future potential of molecular/multiplexed approaches.Conclusion The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.
    Annals of Oncology 09/2014; · 6.58 Impact Factor
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    ABSTRACT: Background:Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial.Methods:Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130).Results:Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28-3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073).Conclusions:High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.British Journal of Cancer advance online publication, 12 August 2014; doi:10.1038/bjc.2014.442 www.bjcancer.com.
    British Journal of Cancer 08/2014; · 4.82 Impact Factor
  • Breast Cancer Research and Treatment 08/2014; 147(2). · 4.47 Impact Factor
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    ABSTRACT: Background:Key challenges of biopsy-based determination of prostate cancer aggressiveness include tumour heterogeneity, biopsy-sampling error, and variations in biopsy interpretation. The resulting uncertainty in risk assessment leads to significant overtreatment, with associated costs and morbidity. We developed a performance-based strategy to identify protein biomarkers predictive of prostate cancer aggressiveness and lethality regardless of biopsy-sampling variation.Methods:Prostatectomy samples from a large patient cohort with long follow-up were blindly assessed by expert pathologists who identified the tissue regions with the highest and lowest Gleason grade from each patient. To simulate biopsy-sampling error, a core from a high- and a low-Gleason area from each patient sample was used to generate a 'high' and a 'low' tumour microarray, respectively.Results:Using a quantitative proteomics approach, we identified from 160 candidates 12 biomarkers that predicted prostate cancer aggressiveness (surgical Gleason and TNM stage) and lethal outcome robustly in both high- and low-Gleason areas. Conversely, a previously reported lethal outcome-predictive marker signature for prostatectomy tissue was unable to perform under circumstances of maximal sampling error.Conclusions:Our results have important implications for cancer biomarker discovery in general and development of a sampling error-resistant clinical biopsy test for prediction of prostate cancer aggressiveness.British Journal of Cancer advance online publication, 17 July 2014; doi:10.1038/bjc.2014.396 www.bjcancer.com.
    British Journal of Cancer 07/2014; · 4.82 Impact Factor
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    ABSTRACT: Though the role of Estrogen Receptor (ER)α in breast cancer has been studied extensively, there is little consensus about the role of alternative ER isoform ERβ in breast cancer biology. ERβ has significant sequence homology to ERα but is located on a different chromosome and maintains both overlapping and unique functional attributes. Five variants exist, resulting from alternative splicing of the C-terminal region of ERβ. The relevance of ERβ variants in breast cancer outcomes and response to therapy is difficult to assess because of conflicting reports in the literature, likely due to variable methods used to assess ERβ in patient tumors. Here, we quantitatively assess expression of ERβ splice variants on over 2,000 breast cancer patient samples. Antibodies against ERβ variants were validated for staining specificity in cell lines by siRNA knockdown of ESR2 and staining reproducibility on formalin-fixed paraffin-embedded tissue by quantitative immunofluorescence (QIF) using AQUA technology. We found antibodies against splice variants ERβ1 and ERβ5, but not ERβ2/cx, which were sensitive, specific, and reproducible. QIF staining of validated antibodies showed both ERβ1 and ERβ5 QIF scores, which have a normal (bell shaped) distribution on most cohorts assessed, and their expression is significantly associated with each other. Extensive survival analyses show that ERβ1 is not a prognostic or predictive biomarker for breast cancer. ERβ5 appears to be a context-dependent marker of worse outcome in HER2-positive and triple-negative patients, suggesting an unknown biological function in the absence of ERα.
    Breast Cancer Research and Treatment 07/2014; · 4.47 Impact Factor
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    ABSTRACT: E2303 evaluated cetuximab, paclitaxel and carboplatin used as induction therapy and concomitant with radiation therapy in patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) determining pathologic complete response, event-free survival, and toxicity.
    Annals of Oncology 07/2014; · 6.58 Impact Factor
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    ABSTRACT: We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.
    PLoS ONE 06/2014; 9(6):e99131. · 3.53 Impact Factor
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    ABSTRACT: Sorafenib is an inhibitor of VEGFR, PDGFR, and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel +/- sorafenib (CP vs. Pre-treatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed. Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes. Statistical analysis was performed using Fisher's exact test, logistic regression, and Cox's proportional-hazards models. Progression free survival and overall survival were estimated using Kaplan-Meier methods. BRAF and NRAS mutations were found at frequencies consistent with other metastatic melanoma cohorts. BRAF-mutant melanoma was associated with worse performance status, increased number of disease sites, and younger age at diagnosis; NRAS-mutant melanoma was associated with better performance status, fewer sites of disease, and female gender. BRAF and NRAS mutations were not significantly predictive of response or survival when treated with CPS vs. CP. However, patients with NRAS-mutant melanoma trended towards a worse response and PFS on CP than those with BRAF-mutant or WT/WT melanoma, an association that was reversed for this group on the CPS arm. This study of somatic mutations in melanoma is the last prospectively collected phase III clinical trial population prior to the era of BRAF targeted therapy. A trend towards improved clinical response in patients with NRAS-mutant melanoma treated with CPS was observed, possibly due to sorafenib's effect on CRAF.
    Clinical Cancer Research 06/2014; 20(12):3328-3337. · 8.19 Impact Factor
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    ABSTRACT: Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy.
    BMC Cancer 05/2014; 14(1):326. · 3.32 Impact Factor
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    ABSTRACT: Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis. Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis. There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS. The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.
    PLoS ONE 04/2014; 9(4):e94273. · 3.53 Impact Factor
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    ABSTRACT: We sought to evaluate correlation between tissue biomarker expression and clinical outcome in E2303 trial. Sixty-three eligible patients with operable stage III/IV HNSCC participated in ECOG 2303, phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin followed by chemoradiation with same regimen. A tissue microarray (TMA) was constructed and epidermal growth factor receptor (EGFR), ERK1/2, Met, Akt, STAT3, beta-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-kappa b, p53, PI3Kp85, PI3Kp110a, PTEN, ΝRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) were estimated by Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and test for significance. Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor ERK1/2 levels were significantly associated with PFS (HR (low/high)=3.29, p=0.026) and OS (HR (low/high)=4.34, p=0.008). On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (p=0.024) and PFS (p=0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis. These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results.
    Clinical Cancer Research 04/2014; · 8.19 Impact Factor
  • David L Rimm
    Nature Methods 03/2014; 11(4):381-3. · 23.57 Impact Factor
  • Cancer Research 03/2014; 73(24 Supplement):P1-08-09-P1-08-09. · 9.28 Impact Factor

Publication Stats

12k Citations
2,138.73 Total Impact Points

Institutions

  • 1998–2014
    • Yale University
      • • Yale Cancer Center
      • • School of Medicine
      • • Department of Cell Biology
      • • Department of Internal Medicine
      New Haven, Connecticut, United States
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York City, NY, United States
  • 1994–2014
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2013
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2012
    • University of Rochester
      Rochester, New York, United States
  • 2009–2012
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Belfer Institute for Applied Cancer Science
      Boston, MA, United States
    • Georgia Health Sciences University
      • Department of Otolaryngology
      Augusta, GA, United States
    • Albert Einstein College of Medicine
      • Department of Epidemiology & Population Health
      New York City, NY, United States
  • 2011
    • University of Texas MD Anderson Cancer Center
      • Department of Systems Biology
      Houston, Texas, United States
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2010
    • CUNY Graduate Center
      New York City, New York, United States
    • Arizona Research Center
      Phoenix, Arizona, United States
    • Integrated BioBank of Luxembourg
      Letzeburg, Luxembourg, Luxembourg
  • 2007
    • University of California, Santa Barbara
      • Department of Electrical and Computer Engineering
      Santa Barbara, CA, United States
    • Athens State University
      Athens, Alabama, United States
  • 2006–2007
    • National Institutes of Health
      • • Branch of Genetic Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
  • 2002–2003
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 2001
    • University of Oviedo
      Oviedo, Asturias, Spain
  • 1999
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 1997–1999
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 1996–1997
    • Virginia Commonwealth University
      • Department of Pathology
      Richmond, Virginia, United States
  • 1995
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 1988–1991
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 1986–1991
    • Johns Hopkins University
      • Department of Medicine
      Baltimore, Maryland, United States