Definition Of Positivity Research Articles

Differential expression of epidermal growth factor receptor in various pathological types of salivary gland cancers

ObjectiveWhile several studies reported epidermal growth factor receptor (EGFR) expression in salivary gland cancer (SGC), results varied due to a lack of unified definition of EGFR positivity. In this study, we assessed the EGFR expression level using both EGFR positive score and cumulative EGFR score in the patients with SGC. MethodsBetween January 2010 and April 2021, 102 patients with SGC who underwent surgical resection were reviewed retrospectively by immunohistochemistry. The membrane staining intensity was scored as follows: no staining (0), weak staining (1+), intermediate staining (2+), and strong staining (3+). The cumulative EGFR score was determined on a continuous scale of 0–300 using the formula:1 × (1+: percentage of weakly stained cells) + 2 × (2+: percentage of moderately stained cells) + 3 × (3+: percentage of strongly stained cells). ResultsEGFR expression in SGC varied widely even among the same as well as different histopathological types. The average EGFR positive scores were 46.0 %, 55.7 %, 51.6 %, 1.0 %, 26.8 %, 50 %, and 76.8 % for mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), acinic cell carcinoma (AcCC), adenocarcinoma NOS (ACNOS), carcinoma ex pleomorphic adenoma (CAexPA), and squamous cell carcinoma (SqCC), respectively. The average cumulative EGFR scores were 82, 91, 80, 1, 52, 93, and 185 for MEC, SDC, AdCC, AcCC, ACNOS, CAexPA, and SqCC, respectively. ConclusionsEGFR positive scores and cumulative EGFR scores in SGCs varied among the various histological types, and even in the same histological type. These scores may predict the clinical outcome of SGC treated with EGFR-targeting therapies, such as head and neck photoimmunotherapy, and need to be evaluated in future studies.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Invited Commentary: The Winding Road to Identifying the Annual Rate of Tuberculosis Infection.

Many persons with immunological tests indicating Mycobacterium tuberculosis infection, such as tuberculin skin tests or interferon-γ release assays, are at risk of progression to tuberculosis disease. Persons whose tests revert to negative may no longer be at such risk. Therefore, identifying the rate of test reversion, potentially indicating cure of M. tuberculosis infection, is an important area of investigation. In their accompanying article (Am J Epidemiol. 2023;192(12):1937-1943), Schwalb et al. extract data on test reversion from prechemotherapy literature and construct a model to predict the rate of reversion, and thus the likely cure of infection. Unfortunately, the incompleteness of the historical data and the use of imprecise definitions of test positivity and reversion lead to substantial misclassification and limit the usefulness of the model. Better definitions and improved tests will be needed in order to develop a clear picture of this aspect of the natural history of tuberculosis.

Incidence of Antiphospholipid Syndrome: Is Estimation Currently Possible?

Antiphospholipid syndrome is a systemic autoimmune disorder characterized by vascular thrombosis and/or obstetric events in association with persistently elevated antiphospholipid antibodies. Antiphospholipid syndrome is typically considered a rare disease, but the true incidence is uncertain owing to the diverse antiphospholipid antibody-related clinical manifestations, inconsistent definitions of antiphospholipid antibody positivity, under-recognition of the disease, and limited population-based studies. Published estimates of the incidence of antiphospholipid syndrome range from approximately 2 to 80 per 100 000 person-years. A targeted literature review and applied methodology were performed to derive a best available estimate. Significant limitations of the published literature were observed, some of which have been previously reported. The incidence of antiphospholipid syndrome in the United States was estimated to be approximately 7.1 to 13.7 per 100 000 person-years in the general population. Although this estimate is likely more accurate than previously reported estimates, large, contemporary, population-based studies that reasonably adhere to the antiphospholipid syndrome classification criteria are needed to further refine estimates of the incidence of antiphospholipid syndrome.

Refining the Definition of Stage 1 Type 1 Diabetes: An Ontology-Driven Analysis of the Heterogeneity of Multiple Islet Autoimmunity.

To estimate the risk of progression to stage 3 type 1 diabetes based on varying definitions of multiple islet autoantibody positivity (mIA). Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. Of 865 (5%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85-92%]) to the least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18% [5-40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P < 0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes. The 15-year risk of progression to type 1 diabetes risk varies markedly from 18 to 88% based on the stringency of mIA definition. While initial categorization identifies highest-risk individuals, short-term follow-up over 2 years may help stratify evolving risk, especially for those with less stringent definitions of mIA.

The clinical value of progesterone receptor expression in luminal breast cancer: A study of a large cohort with long-term follow-up.

The routine assessment of progesterone receptor (PR) expression in breast cancer (BC) remains controversial. This study aimed to evaluate the role of PR expression in luminal BC, with emphasis on the definition of positivity and its prognostic significance as compared to Ki67 expression. A large cohort (n=1924) of estrogen receptor (ER)-positive/HER2-negative BC was included. PR was immunohistochemically (IHC) stained on full face sections and core needle biopsies (CNB) where the optimal scoring cutoff was evaluated. In addition, the association of PR with other clinicopathological factors, cellular proliferation, disease outcome, and response to adjuvant therapy were analyzed. Although several cutoffs showed prognostic significance, the optimal cutoff to categorize PR expression into two clinically distinct prognostic groups on CNB was 10%. PR negativity showed a significant association with features of aggressive tumor behavior and poor outcome. Multivariate analyses indicated that the association between PR negativity and poor outcome was independent of tumor grade, size, node stage, and Ki67. PR negativity showed independent association with shorter survival in patients who received endocrine therapy whereas Ki67did not. PR IHC expression provides independent prognostic value superior to Ki67. Routine assessment of PR expression in BC using 10% cutoff in the clinical setting is recommended. In this study, we have established an optimal approach to determine the prognostic value of progesterone receptor expression in estrogen receptor-positive breast cancer patients. To do this, the levels of progesterone receptor were measured in a large cohort of estrogen receptor-positive breast cancer patients. We have refined the definition of progesterone receptor positivity in estrogen receptor-positive breast cancer. We show that progesterone receptor expression adds prognostic and predictive value of endocrine therapy in estrogen receptor-positive breast cancer patients, and our results show that the absence of progesterone receptor is associated with poorer outcomes independent of tumor grade, size, node stage, and Ki67 expression.

Cut-offs for thyroid peroxidase and thyroglobulin antibodies in early pregnancy.

Thyroid disease in women of reproductive age is mainly of autoimmune origin, and thyroid peroxidase antibodies (TPO-Ab) as well as thyroglobulin antibodies (Tg-Ab) are key markers. Adding to this, much focus in pregnancy is on euthyroid women who are thyroid antibody positive. Evidence to substantiate the cut-offs for the definition of thyroid autoantibody positivity in early pregnant women is warranted. Stored serum samples from 14,030 Danish pregnant women were used for the measurement of TPO-Ab, Tg-Ab, TSH, and free thyroxine (ADVIA Centaur XPT, Siemens Healthineers). Among all women, a reference cohort of 10,905 individuals was identified for the establishment of antibody cut-offs. Percentile cut-offs for TPO-Ab and Tg-Ab were determined using regression on order statistics (the reference cohort). The established cut-offs were then applied (the full cohort), and frequencies of early pregnancy as well as later diagnosis of hypothyroidism were evaluated. The highest established cut-offs (95th, 97.5th, and 99th percentiles) were 59, 68, and 81 U/mL for TPO-Ab and 33, 41, and 52 U/mL for Tg-Ab. When the cut-offs were applied in the full cohort, 11.0, 10.2, and 9.7% were TPO-Ab positive, whereas 13.3, 12.3, and 11.2% were Tg-Ab positive. Antibody-positive women (TPO-Ab and/or Tg-Ab) had higher median TSH and were more likely to have hypothyroidism in early pregnancy and to be diagnosed with hypothyroidism during follow-up. This large study established and evaluated pregnancy-specific cut-offs for TPO-Ab and Tg-Ab. The findings are important regarding the classification of exposure in pregnancy and assessment of thyroid autoimmunity per se.

Clinical implication of low estrogen receptor (ER-low) expression in breast cancer.

Breast cancer is a heterogeneous disease, and the estrogen receptor (ER) remains the most important biomarker in breast oncology. Most guidelines set a positive expression threshold of 1% staining in immunohistochemistry (IHC) to define ER positivity. However, different expression levels may be associated with diverse degrees of sensitivity to endocrine therapy as ER expression may impact breast cancer molecular biology as a continuous variable. ER-lo tumors, defined as those with 1-10% ER expression, represent a relatively small subgroup of breast cancer patients, with an estimated prevalence of 2-7%. These tumors are similar to ERneg disease in their molecular landscape, clinicopathological characteristics, prognosis, and response to therapy. Nevertheless, a proportion may retain some degree of ER signaling dependency, and the possibility of responding to some degree to endocrine therapy cannot be completely ruled out. This review article discusses the most important considerations regarding the definition of ER positivity, pathology assessment, prognosis, and therapeutic implication of ERlo breast cancer from the medical oncology perspective.

Best Practices in CD30 Immunohistochemistry Testing, Interpretation, and Reporting: An Expert Panel Consensus.

Although CD30 testing is an established tool in the diagnostic workup of lymphomas, it is also emerging as a predictive biomarker that informs treatment. The current definition of CD30 positivity by immunohistochemistry is descriptive and based on reactivity in lymphomas that are defined by their universal strong expression of CD30, rather than any established threshold. Challenges include inconsistencies with preanalytic variables, tissue processing, pathologist readout, and with the pathologist and oncologist interpretation of reported results. To develop and propose general best practice recommendations for reporting CD30 expression by immunohistochemistry in lymphoma biopsies to harmonize practices across institutions and facilitate assessment of its significance in clinical decision-making. Following literature review and group discussion, the panel of 14 academic hematopathologists and 2 clinical/academic hematologists/oncologists divided into 3 working groups. Each working group was tasked with assessing CD30 testing by immunohistochemistry, CD30 expression readout, or CD30 expression interpretation. Panel recommendations were reviewed and discussed. An online survey was conducted to confirm the consensus recommendations. CD30 immunohistochemistry is required for all patients in whom classic Hodgkin lymphoma and any lymphoma within the spectrum of peripheral T-cell lymphoma are differential diagnostic considerations. The panel reinforced and summarized that immunohistochemistry is the preferred methodology and any degree of CD30 expression should be reported. For diagnostic purposes, the interpretation of CD30 expression should follow published guidelines. To inform therapeutic decisions, report estimated percent positive expression in tumor cells (or total cells where applicable) and record descriptively if nontumor cells are positive.

Immune-Checkpoint Inhibition in the Treatment of Gastro-Esophageal Cancer: A Closer Look at the Emerging Evidence.

To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently withdrawn. Notably, the use of ICIs for first-line therapy of GEC is rapidly evolving, which currently includes high PD-L1 expressing tumors, irrespective of HER2 status, and in the adjuvant setting after neoadjuvant chemoradiotherapy in select patients. In this article, we review the results of studies that have evaluated the utility of ICI in the third-line, second-line, first-line, and peri-operative treatment settings of GECs. Considerations should be made before making any cross-trial comparisons since these trials vary in chemotherapy backbone, anatomical and histological eligibility, biomarker assessment, PD-L1 diagnostic antibodies, and definition of PD-L1 positivity. Regardless, the totality of the data suggest that first-line ICI use may most benefit GEC patients with high PD-L1 combined positivity score (CPS) ≥5 or ≥10, irrespective of histology or anatomy. Moreover, although PD-L1 by CPS has a good negative predictive value for significant benefit from ICIs, it has a low positive predictive value. Therefore, there is a pressing need to identify better biomarkers to predict benefit from ICIs among these patients.

Changes in the detection of human epidermal growth factor receptor 2 gene (Her-2) status for Her-2 fluorescent in situ hybridization testing

Changes in the detection of human epidermal growth factor receptor 2 gene (Her-2) status for Her-2 fluorescent in situ hybridization testing

Asynchronous Mean Stabilization of Positive Jump Systems With Piecewise-Homogeneous Markov Chain

In this brief, the mean stabilization of positive Markov jump systems (PMJSs) with piecewise-homogeneous Markov chain with two switching signals simultaneously is considered. Different from the existing results, asynchronous state feedback controllers are considered to achieve the control objective. Based on the hidden Markov model, the closed-loop systems are modeled as hidden Markov jump systems (HMJSs) with piecewise-homogeneous Markov chain. The definitions of positivity and mean stabilization are introduced for the considered system. Some sufficient conditions are derived to ensure that the HMJSs with piecewise-homogeneous Markov chain are positive and mean stable when the Markov chain follows a conditional probability distribution and Bernoulli distribution, respectively. Simulation results are described to demonstrate the effectiveness of our approach.

Muffintops, Fat Rolls, and Self Love: Using Fat Young Adult Texts to Promote Body Positivity

With the findings of Wood-Barcalow, Tylka, and Augustus-Horwath (2009) as a framework, this essay offers an analysis of two texts portraying fat protagonists: The Summer of Jordi Perez and the Best Burger in L.A. by Amy Spalding and To Be Honest by Maggie Ann Martin. I examine the authors’ depictions of fat characters to determine if the characters align with Wood-Barcalow, Tylka, and Augustus-Horwath’s (2009) definition of body positivity. Using critical content analysis (Short, 2017), I consider how relationships, environment, and self-concept support and work against body positive attitudes. This essay also includes suggestions for how educators can use these texts and others to promote transformative discourse (Mirra, 2018) in their classrooms.

A Phase II Study of Brentuximab Vedotin for Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas Other Than Anaplastic Large Cell Lymphoma

IntroductionBrentuximab vedotin is an antibody-drug conjugate targeting CD30 that is a transmembrane glycoprotein of the tumor necrosis factor receptor superfamily. CD30 is involved in signal transduction via the activation of the NF-κB pathway and mitogen-activated protein kinases. CD30 is a non-lineage-specific activation marker expressed by B and T cells. Thus, a subset of T-cell lymphomas such as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) as well as B-cell lymphomas such as EB virus positive diffuse large B-cell lymphoma (DLBCL) may also express CD30. Therefore, brentuximab vedotin may have therapeutic activities against CD30-positive non-Hodgkin lymphoma (NHL) like the previously reported promising outcome of Hodgkin and anaplastic large cell lymphoma (ALCL). In this study, we explored the efficacy of brentuximab vedotin as a salvage treatment in CD30-positive NHL other than ALCL. Considering previous studies did not apply the exact definition of CD30 positivity, we enrolled patients only with more than 30% of tumor cells expressing CD30.MethodsThis is a multi-center, phase II study of brentuximab vedotin for relapsed or refractory CD30-positive NHL. All subtypes of NHL could be enrolled into this study except ALCL. The definition of CD30 positivity was CD30 expression in more than 30% of tumor cells by the immunohistochemistry. Brentuximab vedotin was intravenously administered at the dosage of 1.8mg/kg every 3 weeks. Treatment was repeated until documented disease progression or unacceptable toxicity (maximum of 16 cycles). Prior to the enrollment, patients should have relapsed or refractory NHL and measureable disease that was FDG-PET positive. The primary objective was to assess the overall rate of disease control that was defined as the achievement of complete response (CR), partial response (PR) and stable disease (SD). Response evaluation was done after the 2nd, 4th, 8th, 12th and 16th cycles according to the 2007 Cheson criteria. The planned number of patients was 33, and the target rate of overall disease control was 40% (α=0.05, β=0.20). In the first stage, the rate should be more than 22% (4/18), and the study was registered at ClinicalTrials.gov (NCT02280785).Results33 patients (median age: 56, range: 27 - 73) were enrolled between March 2015 and January 2017. The subtypes were B-cell lymphomas (n=14) and T-cell lymphomas (n=19). B-cell lymphomas consisted of diffuse large B-cell lymphoma (DLBCL, n=11), and primary mediastinal B-cell lymphoma (PMBCL, n=3). T-cell lymphomas included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS, n=8), extranodal NK/T-cell lymphoma (n=7, ENKTL), angioimmunoblastic T-cell lymphoma (AITL, n=2) and Mycosis fungoides (MF, n=2). All patients were heavily pre-treated after relapse or progression, thus, the median number of prior therapies was three (2 - 10). Seven patients relapsed even after autologous stem cell transplantation. At the time of enrollment, 23 patients were refractory to previous salvage treatments and 10 patients had relapsed disease. 79% of patients (26/33) had stage III/IV and the median percentage of CD30 expression was 50% (range: 30-100%). Based on the best response, five and seven patients achieved CR and PR, respectively, thus, the overall response rate was 36% (12/33). As four patients showed SD, the overall rate of disease control was 48% (16/33). Among five patients with CR, four patients completed the 16 cycles of treatment whereas only one patient progressed after 6th cycle. The overall rate of disease control was different according to subtypes: DLBCL (1CR, 3PR, 2SD; 6/11, 55%), PTCL-NOS (2CR, 1PR, 2SD, 5/8, 63%), ENKTL (1CR, 1PR, 2/7, 29%), PMBCL (1CR, 1/3, 33%), MF (2PR, 2/2, 100%) and AITL (0/0, 0%). The extent of CD30 expression was not significantly between responders and non-responders, thus, there was no significant correlation. The hematologic toxicity profile was manageable, thus, most hematologic toxicities were grade 1 or 2 except two cases of grade 3 febrile neutropenia.ConclusionsOur study demonstrated that brentuximab vedotin could have a significant antitumor activity with acceptable safety profiles in heavily pretreated patients with relapsed or refractory CD30-poitive NHL other than ALCL. Given the significant single agent activity, brentuximab vedotin could be used in combination with chemotherapeutic agents as a salvage treatment. DisclosuresKim:J&J: Research Funding; Takeda: Research Funding; Roche: Research Funding; Mundipharma: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding.

Regional forecasting of COVID-19 caseload by non-parametric regression: a VAR epidemiological model.

ObjectivesThe COVID-19 pandemic (caused by SARS-CoV-2) has introduced significant challenges for accurate prediction of population morbidity and mortality by traditional variable-based methods of estimation. Challenges to modelling include inadequate viral physiology comprehension and fluctuating definitions of positivity between national-to-international data. This paper proposes that accurate forecasting of COVID-19 caseload may be best preformed non-parametrically, by vector autoregression (VAR) of verifiable data regionally.MethodsA non-linear VAR model across 7 major demographically representative New York City (NYC) metropolitan region counties was constructed using verifiable daily COVID-19 caseload data March 12–July 23, 2020. Through association of observed case trends with a series of (county-specific) data-driven dynamic interdependencies (lagged values), a systematically non-assumptive approximation of VAR representation for COVID-19 patterns to-date and prospective upcoming trends was produced.ResultsModified VAR regression of NYC area COVID-19 caseload trends proves highly significant modelling capacity of observed patterns in longitudinal disease incidence (county R2 range: 0.9221–0.9751, all p < 0.001). Predictively, VAR regression of daily caseload results at a county-wide level demonstrates considerable short-term forecasting fidelity (p < 0.001 at one-step ahead) with concurrent capacity for longer-term (tested 11-week period) inferences of consistent, reasonable upcoming patterns from latest (model data update) disease epidemiology.ConclusionsIn contrast to macroscopic variable-assumption projections, regionally-founded VAR modelling may substantially improve projection of short-term community disease burden, reduce potential for biostatistical error, as well as better model epidemiological effects resultant from intervention. Predictive VAR extrapolation of existing public health data at an interdependent regional scale may improve accuracy of current pandemic burden prognoses.

Correlation of genomic alterations and PD-L1 expression in thymoma.

Thymic epithelial tumors (TETs) include several anterior mediastinal malignant tumours: thymomas, thymic carcinomas and thymic neuroendocrine cancers. There is significant variety in the biologic features and clinical course of TETs and many attempts have been made to identify target genes for successful therapy of TETs. Next generation sequencing (NGS) represents a huge advancement in diagnostics and these new molecular technologies revealed that thymic neoplasms have the lowest tumor mutation burden among all adult malignant tumours with a different pattern of molecular aberrations in thymomas and thymic carcinomas. As for the PD-L1 expression in tumor cells in thymoma and thymic carcinoma, it varies a lot in published studies, with findings of PD-L1 expression from 23% to 92% in thymoma and 36% to 100% in thymic carcinoma. When correlated PD-L1 expression with disease stage some controversial results were obtained, with no association with tumor stage in most studies. This is, at least in part, explained by the fact that several diverse PD-L1 immunohistochemical tests were used in each trial, with four different antibodies (SP142, SP263, 22C3, and 28-8), different definition of PD-L1 positivity and cutoff values throughout the studies as well. There is a huge interest in using genomic features to produce predictive genomic-based immunotherapy biomarkers, particularly since recent data suggest that certain tumor-specific genomic alterations, either individually or in combination, appear to influence immune checkpoint activity and better responses as the outcome, so as such in some cancer types they may complement existing biomarkers to improve the selection criteria for immunotherapy.

Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

BackgroundMET amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in MET amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or MET amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup.MethodsA total of 373 unselected patients with NSCLC were consecutively tested for MET gene copy number (GCN) by FISH. Mean GCN, MET/CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data.ResultsBased on the variability of obtained data a top-level category of MET amplification was newly defined (>90th percentile of average GCN; ≥10 MET gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected (KRAS mutation or MET exon 14 skipping mutation). In this top-level group, there were no EGFR mutations or ALK or ROS1 alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 vs. 23.6 months). Worse prognosis did not depend on initial stage or treatment.ConclusionsThe newly defined top-level category of MET amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of MET gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.

Discordance of HER2 expression in distant metastatic tumors (MTs) versus primary tumors (PTs) in urothelial carcinoma (UC).

550 Background: Available HER2 targeted agents have limited benefit for UC, but exceptional tumor responses are occasionally seen. HER2 expression has been tested as a biomarker of response to these drugs. Trial eligibility is often based on HER2 expression in PTs. Previous studies found moderate to high concordance of HER2 expression in PTs and synchronous regional nodes at cystectomy, but the concordance rate with distant MTs is poorly defined and further complicated by shifting definitions of HER2 positivity. Methods: Immunohistochemical (IHC) staining for HER2 (Ventana Pathway clone 4B5) was performed on PTs and matched MTs in 79 patients with UC. IHC staining was scored (0-3+) using intensity and % positive tumor cells using 2018 ASCO/CAP guidelines for breast cancer. Fisher’s Exact Test assessed association of PT and MT HER2 scores, and Cohen’s kappa statistic (κ) assessed agreement in HER2 3+ between groups. MTs were defined as synchronous if biopsied &lt;60 days after the PT biopsy. Results: There were 67 metachronous and 12 synchronous paired biopsies; median time between metachronous biopsies was 418 days. MT biopsy sites included lymph node (30%), bone (22%), lung (18%), pelvic/peritoneal soft tissue (11%), liver (8%), brain (4%), other (6%). HER2 2+ and 3+ expression was seen in 30.4% and 12.7% of PTs and 12.7% and 7.6% of MTs, respectively. Of HER2 3+ PTs (n=10), HER2 expression in paired MTs was 0 (n=3), 1+ (n = 3), 2+ (n = 2), and 3+ (n = 2). Of HER2 3+ MTs (n=6), HER2 expression in paired PTs was 0 (n=1), 2+ (n=3), and 3+ (n=2). An association was observed between PT and MT HER2 scores (p=0.004), however there was low agreement of HER2 3+ rates between PT and MT lesions (κ = 0.17, p=0.113). Discordance was noted in both synchronous and metachronous biopsies. Conclusions: Based on the current HER2 3+ definition, HER2 overexpression is spatially and temporally discordant in UC between PTs and distant MTs. These findings suggest that both PTs and MTs should be tested for HER2 expression in future clinical trials assessing the efficacy of HER2 targeted agents in UC. The high discordance may explain previously negative therapeutic studies.

Molecular landscape and prognostic value of HER2 low-expression on metastatic colorectal cancer.

229 Background: HER2 dual blockade showed the promise in clinical trials in patients (pts) with HER2-positive (HER2-Pos) metastatic colorectal cancer (mCRC). A phase I/II study of a novel anti-HER2 antibody-drug conjugate (HER2-ADC) showed promising activities across different cancer subtypes including HER2-Pos mCRC, and also showed a hint of activity for low-expressing (HER2-L) mCRC, regardless of RAS mutation. However, molecular landscape and prognostic value of HER2-L on mCRC are unclear. Methods: The eligibility included pts with mCRC who had undergone surgical resection of primary tumor. Using the specimen, HER2 expression was evaluated by immunohistochemistry (IHC) and FISH. Definition of HER2 positivity was as follows; HER2-Pos as IHC 3+ or IHC 2+/FISH positive: HER2-L as IHC 2+/FISH negative or IHC 1+: Negative (HER2-Neg) as IHC 0+. NGS tests were also done. Results: Between 2005 and 2015, a total of 370 pts were analyzed; 60% were male, with a median age of 64 y/o. Fifteen pts (4%) with HER2-Pos, 21 (6%) with HER2-L, and 334 (90%) with HER2-Neg were identified. Proportion of left-sided primary tumor was similar among groups ranging from 72% to 78%. No difference was observed in terms of major clinicopathological characteristics. The proportion of co-altered RAS mutations in HER2-L was significantly higher than HER2-Pos ( p = 0.037) and similar to HER2-Neg (27% in HER2-Pos vs. 62% in HER2-L vs. 56% in HER2-Neg). As of median follow-up of 24.8 months, median overall survival (mOS) in HER2-L was significantly better than that in HER2- Pos ( p = 0.029, 18.2 months in HER2-Pos vs. 33.3 in HER2-L vs. 27.9 in HER2-Neg). In 58 pts harboring RAS wild-type who received an anti-EGFR monoclonal antibody therapy, median progression-free survival (mPFS) in HER2-L tended to be better than that in HER2- Pos, with 2.2 months in HER2-Pos, 7.8 in HER2-L, and 5.5 in HER2-Neg ( p = 0.099). Conclusions: Since HER2-L mCRC had the high prevalence of co-altered RAS mutations but showed a better prognosis and might benefit more from an anti-EGFR therapy than HES2-Pos, the HER2-L mCRC seems to have a different biological behavior from HER2-Pos in terms of molecular landscape and prognostic value on mCRC.

The Clinicopathological Significance of Basal Markers in Early-Stage Invasive Carcinoma of No Special Type of the Breast.

Basal markers [cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR)] are used in identifying the basal-like breast carcinoma subtype, which is associated with a poor prognosis. However, the clinicopathological significance in early-stage invasive carcinoma of no special type (IC, NST) has not been well established. In a five-year period, 133 female patients with early-stage IC, NST with a median follow-up time of 89 months were included. The immunohistochemistry-based molecular subtypes were identified according to ASCO/CAP guidelines in 2013. The cutoff values for basal positivity were determined as 10% for each marker. Basal positivity was recorded in 83.3% (5/6) of triple-negative breast cancers, 50% (2/4) of HER2-enriched, 18.6% (13/70) of luminal B, and 8.3% of luminal A (4/48) subtype. CK5/6 and EGFR positivity were significantly associated with ER negativity (p < 0.001). EGFR positive cases were significantly associated with PR negativity and HER2 positivity compared to negative cases. However, basal positivity was not associated with the patient outcome (p = 0.006 and p = 0.004, respectively). Basal positive IC, NSTs were associated with hormone receptor negativity and HER2 overexpression; these patients would therefore be less likely to respond to hormonotherapy and more likely to benefit from anti-HER2 treatment as well as dual-kinase inhibitors. The lack of standardization of the definition of basal marker positivity may contribute to the conflicting results of prognostic studies. Hence, further studies focusing on developing a standard protocol for determining basal marker positivity are needed not only for IC, NST but also for other histological types of breast cancer.